US20140343277A1 - Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation - Google Patents

Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation Download PDF

Info

Publication number
US20140343277A1
US20140343277A1 US14/314,142 US201414314142A US2014343277A1 US 20140343277 A1 US20140343277 A1 US 20140343277A1 US 201414314142 A US201414314142 A US 201414314142A US 2014343277 A1 US2014343277 A1 US 2014343277A1
Authority
US
United States
Prior art keywords
compound
optionally substituted
lower alkyl
formula
group
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US14/314,142
Inventor
Shinichi Taira
Kunio Oshima
Takashi Oshiyama
Yasuhiro Menjo
Yasuo Koga
Hokuto Yamabe
Sunao Nakayama
Kenji Tsujimae
Toshiyuki Onogawa
Kuninori Tai
Motohiro Itotani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharcaceutical Co., Ltd.
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 Otsuka Pharcaceutical Co., Ltd. filed Critical Otsuka Pharcaceutical Co., Ltd.
Publication of US20140343277A1 publication Critical patent/US20140343277A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a nitrogen-containing compound and a pharmaceutical composition containing the same.
  • Atrial fibrillation (hereinafter referred to as “AF”) is the most frequently observed type of arrhythmia in clinical examinations. Although not a lethal arrhythmia, AF causes cardiogenic cerebral embolism, and is therefore recognized as an arrhythmia that greatly affects vital prognoses and QOL. It is known that the onset of AF increases with age, and that repeated AF strokes lead to chronic (serious) AF (The Journal of American Medical Association, 285, 2370-2375 (2001) and Circulation, 114, 119-123 (2006)).
  • Antiarrhythmic drugs (classes I and III) are most commonly used as pharmacotherapy, but these drugs achieve insufficient therapeutic effects, while causing serious side effects such as a proarrhythmic effect (Am. J. Cardiol., 72, B44-B49 (1993)).
  • the onset of AF is triggered by atrial premature contraction with underlining causes such as intra-atrial conduction delay, shortening and heterogeneity of the atrial refractory period (Nature Reviews DRUG DISCOVERY 4, 899-910 (2005)). It is known that the prolongation of refractory period of atrial muscle can terminate AF (defibrillation) or prevent the occurrence of AF.
  • the action potential duration of the mammalian cardiac muscle is predominantly determined by voltage-dependent K + channels. Inhibition of the K + channel prolongs myocardial action potential duration, which results in prolongation of the refractory period (Nature Reviews DRUG DISCOVERY 5, 1034-49 (2006)).
  • class III antiarrhythmic drugs e.g., Dofetilide
  • K + current K + current encoded by HERG.
  • I Kr rapid delayed rectifier K + current
  • K + current encoded by HERG K + current encoded by HERG.
  • I Kr is present in both the atria and ventricles, such drugs might cause ventricular arrhythmias, such as torsades de pointes (Trends Pharmacol. soc., 22, 240-246 (2001)).
  • K + current (I Kur ), K + current encoded by Kv1.5, has been identified as K + channel that is specifically expressed only in human atria (Cric. Res., 73, 1061-1076 (1993), J. Physiol., 491, 31-50 (1996) and Cric. Res., 80, 572-579 (1997)).
  • Muscarine potassium current (I KACh ) encoded by two genes called GIRK1 and GIRK4 is known as a K + channel specifically expressed inhuman atria (Nature 374, 135-141 (1995)).
  • a pharmacologically acceptable substance that selectively blocks the I Kur current (the Kv1.5 channel) or the I KACh current (GIRK1/4 channel) can act selectively on the atrial muscle and is considered effective to exclude the proarrhythmic effect caused by prolonged action potential duration of the ventricular muscle.
  • the present specification discloses three inventions (three nitrogen-containing compounds each having a different structure).
  • the inventions are respectively expressed as a “First Invention”, “Second Invention”, and “Third Invention”, which are described in detail below.
  • the present inventors conducted extensive research to develop a compound that blocks the I Kur current (Kv1.5 channel) and/or the I KACh current (GIRK1/4 channel) potently and more selectively than other K + channels.
  • a novel diazepine compound represented by General Formula (1) below could be the desired compound.
  • the present invention has been accomplished based on the above findings.
  • the present invention provides diazepine compounds, and pharmaceutical compositions comprising the diazepine compounds as summarized in items 1 to 16 below.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl; R 2 and R 3 may be linked to form lower alkylene;
  • a 1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo;
  • Y 1 and Y 2 are each independently —N ⁇ or —CH ⁇ ;
  • R 5 is group represented by
  • R 6 and R 7 are each independently hydrogen or an organic group; R 6 and R 7 may be linked to form a ring together with the neighboring group —X A —N—X B —; X A and X B are each independently a bond, alkylene, alkenylene, —CO—, —SO 2 —, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C( ⁇ S)—, —SO 2 —, —CO—, —O—, —NH—, —CONH— and —SO 2 NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in X A and X B is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl.
  • Item 2 A diazepine compound or a salt thereof according to Item 1, wherein R 6 and R 7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or heterocyclic group, each of which is optionally substituted, and X A and X B are each independently a bond, lower alkylene, lower alkenylene, —CO—, —SO 2 —, -lower alkylene-SO 2 —, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower al
  • Item 3 A diazepine compound or a salt thereof according to Item 2, wherein R 6 and R 7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, each of which is optionally substituted.
  • Item 4 A diazepine compound or a salt thereof according to Item 3, wherein R 6 and R 7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, naphthyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5
  • Item 6 A diazepine compound or a salt thereof according to Item 5, wherein R 6 and R 7 are each independently (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35), (40a), (40b), (42a), (43a), (44a), and (53):
  • Item 7 A diazepine compound or a salt thereof according to Item 6, wherein R 6 and R 7 are each independently phenyl, pyridyl, pyrazolyl, indolyl, 4,5-dihydrofuro[3,2-c]pyridyl, and 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or two substituents selected from the group consisting of oxo, lower alkyl, lower alkoxy lower alkyl, and lower alkylsulfonylamino.
  • Item 8 A diazepine compound or a salt thereof according to Item 7, which is selected from the group consisting of the following compounds:
  • a diazepine compound according to Item 8 which is selected from the group consisting of the following compounds:
  • Item 10 A diazepine compound or a salt thereof according to Item 1, wherein Y 1 and Y 2 are each —CH ⁇ .
  • Item 11 A pharmaceutical composition comprising a diazepine compound or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 12 A pharmaceutical composition according to Item 11 for preventing and/or treating arrhythmia.
  • Item 13 A diazepine compound or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 14 Use of a diazepine compound or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 15 Use of a diazepine compound or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 16 A method of preventing and/or treating arrhythmia, comprising administering to a patient a diazepine compound or a salt thereof according to Item 1.
  • one or more may be preferably 1 to 6, more preferably 1 to 3.
  • lower alkyl examples include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • alkylene examples include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.
  • lower alkylene examples include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • alkenylene examples include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.
  • lower alkenylene examples include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • cyclo lower alkyl examples include linear or branched cyclo alkyl having 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclohexylmethyl.
  • lower alkoxy examples include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • halogen examples are fluorine, chlorine, bromine, and iodine.
  • lower alkylenedioxy examples include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • lower alkanoyl examples include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • lower alkoxycarbonyl examples include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • aralkyl group examples include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.
  • organic group examples include lower alkyl, cyclo lower alkyl, aryl, and heterocyclic group, each of which is optionally substituted.
  • aryl group examples include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.
  • aroyl group examples include benzoyl and naphthoyl.
  • heterocyclic group examples include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen.
  • heterocyclic groups include the following (a) to (n):
  • azaspiroundecanyl e.g., 3-azaspiro[5.5]undecanyl
  • heterocyclic groups may be substituted with one or more suitable substituents.
  • heterocyclic groups examples include piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, benzothienyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo
  • Substituents of “aryl group which is optionally substituted” represented by R 6 and R 7 are independently one or more substituents selected from the group consisting of:
  • Substituents of “heterocyclic group which is optionally substituted” represented by R 6 and R 7 are independently one or more substituents selected from the group consisting of:
  • R 6 and R 7 are each independently selected from the group consisting of the following substituents (1) to (54):
  • Examples of more preferable substituents represented by R 6 and R 7 include the following substituents (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35a), (40a), (40b), (42a), (43a), (44a), and (53):
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl, and preferably hydrogen, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl), C 1-6 cyclo alkyl (e.g., cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl), or C 1-6 alkoxy C 1-6 alkyl (e.g., 2-methoxyethyl and 2-ethoxyethyl).
  • C 1-6 alkyl e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl
  • C 1-6 cyclo alkyl e.g.
  • Both Y 1 and Y 2 are —C ⁇ .
  • a 1 is lower alkylene, and preferably C 1-6 alkylene such as methylene, ethylene, trimethylene, or tetramethylene.
  • X A and X B are each independently lower alkylene, which is preferably C 1-6 alkylene such as methylene, ethylene, trimethylene, or tetramethylene; a bond; —CO—; or —SO 2 —.
  • R 6 and R 7 are each independently a group selected from (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30b), (31b), (32b), (33b), (35a), (40b), (42a), (43a), (44a), and (53):
  • Examples of X A and X B include a bond, lower alkylene, lower alkenylene, —CO—, —SO 2 —, -lower alkylene-SO 2 —, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-
  • Preferred examples of X A and X B include a bond, lower alkylene, lower alkenylene, —CO—, —SO 2 —, -lower alkylene-SO 2 —, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, and —O-lower alkylene-.
  • Either of the two bonds in X A may be bonded to R 1 or N, and either of the two bonds in X B may be bonded to R 2 or N.
  • the ring formed when R 6 and R 7 are linked together with the neighboring group —X A —N—X B — is a nitrogen-containing heterocyclic group optionally having one or more substituents.
  • the nitrogen-containing heterocyclic group include the above-mentioned heterocyclic groups (a) to (c), (f) to (j), and (m) to (n).
  • substituents of the nitrogen-containing heterocyclic group optionally having one or more substituents include the above-mentioned substituents (h1) to (h20).
  • the diazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification.
  • the diazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , Y 1 and Y 2 are the same as above, and X 1 is a leaving group.
  • reaction of the compound of Formula (2) with the compound of Formula (3) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound and/or catalyst.
  • Examples of the leaving groups represented by X 1 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkane sulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • halogen atoms e.g., chlorine, bromine, iodine, and like atoms
  • lower alkane sulfonyloxy e.g., methanesulfonyloxy
  • halo substituted lower alkane sulfonyloxy e.g., trifluoromethanesulfonyloxy
  • inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
  • a wide variety of known basic compounds can be used as the basic compound.
  • Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]o
  • the catalyst examples include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone) palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone) palladium, copper iodide/bis(triphenylphosphine) palladium dichloride, tris(dibenzylideneacetone) dipalladium, R-tris (dibenzylideneacetone)-dipalladium, S-tris (dibenzylideneacetone) dipalladium, palladium(II) acetate, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), and tetrakis (triphenylphosphine) palladium.
  • palladium compounds such as palladium acetate, bis(tributyltin)/bis(
  • Additives can be used together with the catalyst.
  • the additive include compounds such as R-2,2′-bis diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), and 2,2-bis(diphenylimidazolidinyliden), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.
  • the above reaction may be performed by adding to the reaction system, as required, an alkali metal iodide serving as a reaction accelerator, such as potassium iodide or sodium iodide.
  • an alkali metal iodide serving as a reaction accelerator, such as potassium iodide or sodium iodide.
  • the compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (2).
  • the amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).
  • the catalyst is appropriately used in a typical catalytic amount, preferably 0.0001 to 1 moles, and more preferably 0.001 to 0.5 moles, per mole of the compound (2).
  • the reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • R 1 , R 2 , R 3 , R 4 , Y 1 and Y 2 are the same as above.
  • the reaction converting the compound of Formula (4) to the compound of Formula (1a) can be performed by catalytic reduction of the compound of Formula (4) in a suitable solvent, in the presence of a catalytic hydrogenation reducing agent.
  • the solvent is not limited as long as it does not adversely affect the reduction reaction.
  • solvents include carboxylic acids such as formic acid and acetic acid; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; and lower (e.g., C 1-6 ) alcohols such as methanol, ethanol, and isopropanol.
  • catalytic hydrogenation reducing agents examples include palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • the amount of catalytic hydrogenation reducing agent is typically 0.1 to 40 wt %, and preferably 1 to 20 wt %, based on the compound of Formula (4).
  • the reaction can be typically performed in a hydrogen atmosphere at atmospheric pressure to about 20 atm, and preferably atmospheric pressure to 10 atm; or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
  • the reaction temperature may typically be about ⁇ 30 to about 100° C., and preferably about 0 to about 60° C.
  • R 1 , R 2 , R 3 , R 4 , Y 1 and Y 2 are the same as above; and R 8 is lower alkyl.
  • the reaction converting the compound of Formula (5) to the compound of Formula (6) can be performed in a general inert solvent or without using any solvent, in the presence of an azide compound, a basic compound, and a lower (C 1-6 ) alcohol (R 8 OH).
  • lower alkyl represented by R 8 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and tert-butyl, with tert-butyl being preferred.
  • inert solvents examples include ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • azide compounds examples include sodium azide, lithium azide, and diphenylphosphoryl azide (DPPA).
  • Examples of usable basic compounds include organic bases such as triethylamine; tripropylamine; diisopropylethylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • organic bases such as triethylamine; tripropylamine; diisopropylethylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • the reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • a carboxylic azide is produced from the carboxylic compound of Formula (5) and an azide compound, and the carboxylic azide undergoes subsequent Curtius rearrangement to produce an isocyanate.
  • the isocyanate reacts with a lower (C 1-6 ) alcohol (R 8 OH) to produce a urethane compound of Formula (6).
  • reaction converting the compound of Formula (6) to the compound of Formula (1b) can be performed by solvolysis in a suitable solvent, in the presence of an acid or basic compound.
  • Examples of usable solvents include water; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol
  • ketones such as acetone and methyl eth
  • acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, thioglycolic acid, trifluoroacetic acid, and sulfonic acids such as p-toluenesulfonic acid. These acids may be used singly or in a combination of two or more.
  • Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.
  • the amount of acid or basic compound is typically at least 1 mole, and preferably about 1 to about 10 moles, per mole of the compound of Formula (6).
  • the solvolysis reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 10 minutes to about 80 hours.
  • R 8 is tert-butyl
  • the solvolysis can be easily accomplished using the above-mentioned acids (particularly hydrochloric acid and the like) to produce the compound of Formula (1b).
  • the compound of Formula (5) can be directly converted to the compound of Formula (1b).
  • This reaction can be performed by reacting the compound (5) with an azide compound in a general inert solvent or without using any solvent, in the presence of a basic compound, followed by treating the product with water.
  • an isocyanate is produced from the above-mentioned carboxylic compound of Formula (5) and azide compound, and the isocyanate is hydrolyzed to produce the amine compound of Formula (1b).
  • R 1 , R 2 , R 3 , R 4 , Y 1 and Y 2 are the same as above; and A 1a is lower alkylene with 3 or more carbon atoms.
  • Examples of “lower alkylene with 3 or more carbon atoms” represented by A 1a include alkylene groups with 3 to 6 carbon atoms, such as trimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • the reaction converting the compound of Formula (7) to the compound of Formula (1c) can be performed by reacting the compound (7) with hydrazine in a suitable solvent, or by hydrolysis.
  • hydrazine hydrate may be used as the hydrazine.
  • solvents used in reacting the hydrazine include water; halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate and ethyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; and mixtures thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroe
  • the amount of hydrazine is typically at least about 1 mole, and preferably about 1 to about 5 moles, per mole of the compound of Formula (7).
  • the reaction is performed typically at about 0 to about 120° C., and preferably at about 0 to about 100° C., and is typically completed in about 0.5 to about 5 hours.
  • R 7a is hydrogen or lower alkyl.
  • “lower alkyl” represented by R 7a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • reaction between the compound of Formula (1d) and the compound of Formula (8) is performed, for example, in a suitable solvent or without using any solvent, in the presence of a reducing agent.
  • Examples of usable solvents include water; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; acetonitrile; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol
  • aliphatic acids such as formic acid, and acetic acid
  • ethers such as diethylether
  • reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, lithium aluminium hydride, and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts with hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • aliphatic acids such as formic acid
  • aliphatic acid alkali metal salts such as sodium formate
  • hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, lithium aluminium hydride, and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts with hydride
  • a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours.
  • the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1d).
  • a suitable reaction temperature is typically about ⁇ 80 to about 100° C., and preferably about ⁇ 80 to about 70° C.
  • the reaction is typically completed in about 30 minutes to about 60 hours.
  • the hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1d).
  • lithium aluminium hydride is used as a hydride reducing agent
  • a solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene.
  • an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine
  • a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).
  • the reaction is typically performed at about ⁇ 30 to about 100° C., and preferably at about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
  • a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
  • the reaction is typically completed in about 1 to about 12 hours.
  • the catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1d).
  • the compound of Formula (8) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1d).
  • the compound of Formula (8) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , X A , X B , A 1 , X B , Y 1 and Y 2 are the same as above.
  • reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed by the known “Ullmann condensation” etc.
  • the reaction can be preferably adopted especially when X B is a bond and R 7 is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted.
  • the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of copper compound (e.g., copper oxides, copper halides such as copper iodide), a basic compound (e.g., sodium tert-butoxide, K3PO4 and Cs2CO3), and if necessary a phosphine (e.g., triphenylphosphine, xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).
  • a solvent e.g., toluene,
  • the reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 and Y 2 are the same as above.
  • reaction of the compound of Formula (10) with the compound of Formula (3) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.
  • R 2 , R 3 , R 4 , R 5 , A 1 , X 1 , Y 1 and Y 2 are the same as above; and R 1a is lower alkyl.
  • lower alkyl represented by R 1a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
  • reaction of the compound of Formula (1 g) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • R 1a , R 4 , R 5 , A 1 , X 1 , Y 1 and Y 2 are the same as above.
  • reaction of the compound of Formula (1i) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • R 1 , R 4 , R 5 , A 1 , X 1 , Y 1 and Y 2 are the same as above; and R 2a is lower alkyl.
  • lower alkyl represented by R 2a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
  • reaction of the compound of Formula (1k) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • R 2 , R 3 , R 4 , R 1a , X 1 , Y 1 and Y 2 are the same as above; R 9 is lower alkoxy; and R 10 is lower alkoxycarbonyl.
  • Examples of “lower alkoxy” represented by R 9 include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, and ethoxy.
  • Examples of “lower alkoxycarbonyl” represented by R 10 include (C 1-6 alkoxy) carbonyl groups, such as methoxycarbonyl, ethoxycarbonyl.
  • the compound of Formula (13) is reacted with the carboxylic acid compound of Formula (14) through a general amide bond formation reaction.
  • Conditions for known amide bond formation reactions can be easily employed in this amide formation reaction.
  • reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (14) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (13); (ii) an active ester method, in which Carboxylic Acid (14) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or to an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (13); (iii) a carbodiimide method, in which Carboxylic Acid (14) is subjected to a condensation reaction with Amine (13) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-eth
  • the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound.
  • Any solvents used for conventional mixed acid anhydride methods are usable.
  • Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.
  • organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyld
  • Carboxylic Acid (14), an alkyl halocarboxylate, and Amine (13) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (14) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (13).
  • the reaction is typically performed at about ⁇ 20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.
  • Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound.
  • Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (13) mentioned above as one of the other methods (iv).
  • a suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (13).
  • WSC is used as an activating agent, the addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously.
  • the reaction is typically performed at about ⁇ 20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.
  • a carboxylic acid halide is reacted with Amine (13), mentioned above as one of the other methods (iv)
  • the reaction is performed in the presence of a basic compound in a suitable solvent.
  • a basic compound include a wide variety of known basic compounds, such as those for use in the Schotten-Baumann reaction described above.
  • usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; acetone; and water.
  • the ratio of the carboxylic acid halide to Amine (13) is not limited, and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (13).
  • the reaction is typically performed at about ⁇ 20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 30 hours.
  • the amide bond formation reaction shown in Reaction Formula 11 can also be performed by reacting Carboxylic Acid (14) with Amine (13) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis (2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.
  • a phosphorus compound serving as a condensing agent such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis (2-oxo-3-oxazolidinyl)phosphinic chloride,
  • the reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (13), typically at about ⁇ 20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (14) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (13).
  • the reaction converting the compound of Formula (15) to the compound of Formula (16) can be performed by, for example, [1] reducing the compound of Formula (15) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (15) in a suitable inert solvent using a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof.
  • Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel.
  • the reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (15).
  • the reaction temperature is typically about ⁇ 20 to about 150° C., and preferably about 0 to about 100° C.
  • the hydrogen pressure is typically about 1 to 10 atm.
  • the reaction is typically completed in about 0.5 to about 100 hours.
  • An acid such as hydrochloric acid may be added to the reaction.
  • alkali metal hydroxide such as sodium hydroxide
  • a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride
  • inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof.
  • Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used.
  • the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours.
  • a reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (15).
  • reaction converting the compound of Formula (16) to the compound of Formula (17) is performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14).
  • reaction of the compound of Formula (17) with the compound of Formula (11) is performed under the same reaction conditions as those for the reaction of the compound of Formula (1 g) with the compound of Formula (11) in Reaction Formula 8.
  • R 1 , R 2a , R 4 , R 9 , X 1 , Y 1 and Y 2 are the same as above.
  • reaction of the compound of Formula (19) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • R 1 and/or R 4 is hydrogen in the reaction of the compound of Formula (19) with the compound of Formula (12), the hydrogen atom may be replaced with R 2a .
  • the compound of Formula (18) can also be produced according to the process shown in the following Reaction Formula 13.
  • R 1 , R 2 , R 3 , R 4 , R 9 , Y 1 and Y 2 are the same as above.
  • reaction of the compound of Formula (20) with the compound of Formula (21) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14) shown in Reaction Formula 11 above.
  • R 1 , R 2 , R 3 , R 4 , R 9 , Y 1 and Y 2 are the same as above; and Tf is trifluoromethanesulfonyl (CF 3 SO 2 —).
  • reaction converting the compound of Formula (18) to the compound of Formula (22) can be performed in a suitable solvent in the presence of an acid.
  • solvents examples include water; lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol
  • ethers such as dioxane, tetrahydrofuran, and diethylether
  • halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride
  • polar solvents such as acetonitrile
  • acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.
  • the reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours.
  • the amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (18).
  • the reaction converting the compound of Formula (22) to the compound of Formula (23) is performed by reacting the compound of Formula (22) with trifluoromethanesulfonic anhydride in a suitable solvent, in the presence or absence of a basic compound.
  • solvents examples include ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof.
  • Examples of basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DA
  • the reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • R 1 , R 2 , R 3 , R 4 , Tf, Y 1 and Y 2 are the same as above;
  • M is a metal, for example, Na, K, Ag, Zu, Cu, and the like; and
  • X is a positive number.
  • the reaction converting the compound of Formula (23) to the compound of Formula (4) can be performed by reacting the compound of Formula (23) with a cyano metal in a suitable solvent, in the presence of a catalyst.
  • metal cyanides examples include sodium cyanide, potassium cyanide, silver cyanide, zinc cyanide, and cuprous cyanide.
  • solvents usable in this reaction include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • catalysts include palladium compounds such as tetrakis (triphenylphosphine) palladium (0); dichlorobis (triphenylphosphine) palladium (II); and tris (dibenzylideneacetone) dipalladium (0).
  • a ligand such as 1,1′-bis (diphenylphosphino) ferrocene or zinc dust may be added, as required, in order to promote the reaction.
  • the catalyst can be typically used in an amount of 0.01 to 1 mole, and preferably 0.01 to 0.5 moles, per mole of the compound of Formula (23).
  • the metal cyanide can be typically used in an amount of at least 1 mole, and preferably 1 to 3 moles, per mole of the compound of Formula (23).
  • the reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C.
  • the reaction is typically completed in about 1 hour to about 1 week.
  • reaction converting the compound of Formula (4) to the compound of Formula (10) is performed in a suitable solvent, in the presence of a reducing agent.
  • solvents include aliphatic acids such as formic acid; ethers such as dioxane, tetrahydrofuran, diethylether, and diethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • reducing agents include alkylaluminum hydrides such as diisobutylaluminum hydride; and Raney nickel.
  • the reducing agent is typically used in an amount at least equal to, and preferably from an equal weight to 5 times the weight of the compound of Formula (4).
  • the reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C.
  • the reaction is typically completed in about 0.5 to about 20 hours.
  • R 1 , R 2 , R 3 , R 4 , Tf, Y 1 and Y 2 are the same as above; and R 11 is lower alkyl.
  • lower alkyl represented by R 11 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, and ethyl.
  • reaction converting the compound of Formula (23) and the compound of Formula (24) to the compound of Formula (25) can be performed in a suitable solvent, in the presence of a catalyst.
  • Examples of usable solvents include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • the catalyst are palladium compounds, for example, tetrakis(triphenylphosphine)palladium (0); dichlorobis(triphenylphosphine)palladium (II); and the like.
  • the catalyst is typically used in an amount of about 0.01 to about 1 mole, and preferably about 0.01 to about 0.5 moles, per mole of the compound of Formula (23).
  • a basic compound such as triethylamine, pyridine, may be added, as required.
  • the reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • the reaction converting the compound of Formula (25) to the compound of Formula (26) can be performed by catalytic reduction of the compound of Formula (25) in a suitable solvent in a hydrogen atmosphere.
  • Catalysts suitable for use in catalytic reduction include platinum catalysts, such as platinum plates, spongy platinum, platinum black, colloid platinum, platinum oxide, and platinum wires; palladium catalysts, such as spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, and palladium/barium carbonate; nickel catalysts, such as reduced nickel, nickel oxide, and Raney nickel; cobalt catalysts, such as reduced cobalt and Raney cobalt; and iron catalysts, such as reduced iron.
  • platinum catalysts such as platinum plates, spongy platinum, platinum black, colloid platinum, platinum oxide, and platinum wires
  • palladium catalysts such as spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, and palladium/barium carbonate
  • nickel catalysts such as reduced nickel, nickel oxide, and Raney nickel
  • cobalt catalysts such as reduced
  • the amount of the catalyst used for catalytic reduction is not limited, and may be an amount generally used.
  • the reaction temperature is typically 0 to 120° C., preferably room temperature to about 100° C., and more preferably room temperature to 80° C.
  • the reaction time is typically 30 minutes to 24 hours, preferably 30 minutes to 10 hours, and more preferably 30 minutes to 4 hours.
  • reaction converting the compound of Formula (26) to the compound of Formula (5) can be performed by hydrolysis of the compound (26).
  • This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acid or basic compound.
  • solvents include water; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol
  • ketones such as acetone and methyl ethyl ket
  • acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and like sulfonic acids. These acids may be used singly or in a combination of two or more.
  • Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.
  • the hydrolytic reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C.
  • the reaction is typically completed in about 10 minutes to about 30 hours.
  • R 1 , R 2 , R 3 , R 4 , Tf, Y 1 and Y 2 are the same as above; and A 1b is lower alkylene.
  • Examples of “lower alkylene” represented by A 1b include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • the reaction converting the compound of Formula (23) and the compound of Formula (27) to the compound of Formula (28) can be performed in a suitable solvent, in the presence of a copper halide and a palladium catalyst.
  • solvents examples include ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • ketones such as acetone and methyl ethyl ketone
  • ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme
  • aliphatic acids such as acetic acid and formic acid
  • esters such as methyl acetate and ethyl
  • copper halides examples include copper (I) chloride, copper (I) bromide, and copper (I) iodide.
  • palladium catalysts examples include palladium compounds such as tetrakis(triphenylphosphine)palladium (0); and dichlorobis(triphenylphosphine)palladium (II).
  • a basic compound may be added, as required.
  • Examples of basic compounds include triethylamine, diisopropylethylamine, pyridine, and diethylamine.
  • the basic compound can be typically used in an amount of 0.01 to 10 mole, and preferably 0.01 to 1 moles, per mole of the compound of Formula (23).
  • the reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 180° C.
  • the reaction is typically completed in about 10 minutes to about 30 hours.
  • reaction converting the compound of Formula (28) to the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (25) to the compound of Formula (26) shown in Reaction Formula 16 above.
  • reaction of the compound of Formula (3a) with the compound of Formula (8) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.
  • reaction of the compound of Formula (3a) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • the compound of Formula (3) which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.
  • R 7b is a nitrogen-containing heterocyclic group optionally having one or more substituents; and X B1 is lower alkylene.
  • R 7b examples include, among groups represented by the group R 7 mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds having an N—H bond, and groups optionally having one or more substituents.
  • Examples of “lower alkylene” represented by X B1 include alkylene groups with 2 to 4 carbon atoms, such as ethylene and trimethylene.
  • reaction of the compound of Formula (29) with the compound of Formula (30) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • reaction converting the compound of Formula (31) to the compound of Formula (3d) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (7) to the compound of Formula (1c) shown in Reaction Formula 4 above.
  • R 7b is the same as above;
  • X B2 is lower alkylene; and
  • R 12 and R 13 are each independently lower alkyl, or R 12 and R 13 are linked to form lower alkylene.
  • lower alkyl represented by R 12 and R 13 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and n-propyl.
  • lower alkylene formed by R 12 and R 13 when they are linked include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • Examples of “lower alkylene” represented by X B2 include alkylene groups with 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • reaction of the compound of Formula (29) with the compound of Formula (32) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • reaction converting the compound of Formula (33) to the compound of Formula (8a) can be performed by hydrolysis of the compound (33).
  • This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acidic compound.
  • solvents include water; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, and tert-butanol
  • ketones such as acetone and methyl ethyl ket
  • acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS), and like sulfonic acids. These acids may be used singly or in a combination of two or more.
  • the hydrolytic reaction advantageously proceeds typically at about 0 to about 100° C., and preferably at about 0 to about 80° C.
  • the reaction is typically completed in about 10 minutes to about 30 hours.
  • a 1b is the same as above; and Ms is methanesulfonyl (CH 3 SO 2 —).
  • the reaction converting the compound of Formula (34) to the compound of Formula (35) is performed by methanesulfonylation (mesylation) of the compound of Formula (34) using a conventional method.
  • the compound of Formula (35) can be produced by reacting the compound of Formula (34) with trifluoromethanesulfonic anhydride in a suitable solvent (e.g., dichloromethane), in the presence of a basic compound (e.g., triethylamine).
  • the reaction converting the compound of Formula (35) to the compound of Formula (36) is performed by iodination of the compound of Formula (35) with an iodinating agent such as sodium iodide, in a suitable solvent (e.g., acetone).
  • an iodinating agent such as sodium iodide
  • the reaction converting the compound of Formula (36) to the compound of Formula (27) can be performed by reacting the compound of Formula (36) with potassium phthalimide in a suitable solvent (e.g., N,N-dimethylformamide).
  • a suitable solvent e.g., N,N-dimethylformamide
  • the compound of Formula (27) can be directly produced by reacting the compound of Formula (34) with phthalimide under the Mitsunobu reaction conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).
  • DEAD diethyl azodicarboxylate
  • triphenylphosphine triphenylphosphine
  • the compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • the compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • the starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.
  • those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids.
  • acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds.
  • basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • one or more atoms can be substituted with one or more isotopic atoms.
  • isotopic atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 14 N, 18 O, etc.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • compositions can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; star
  • Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • a solution, emulsion or suspension is sterilized and preferably made isotonic with blood.
  • Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc.
  • the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • the proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • the route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.
  • Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required.
  • Suppositories are administered intrarectally.
  • the dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • the compound of the present invention When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.).
  • the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • the compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels.
  • the compound of the invention has characteristics as an atrial-selective K + channel-blocking agent.
  • the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents.
  • the compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia).
  • the compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • the compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • the compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • the present inventors conducted extensive research to develop a compound that blocks the I Kur current (Kv1.5 channel) and/or the I KA C h current (GIRK1/4 channel) potently and more selectively than other K + channels.
  • the inventors found that a novel amino compound represented by General Formula (1) below could be the desired compound.
  • the present invention has been accomplished based on the above findings.
  • the present invention provides amino compounds, and pharmaceutical compositions comprising the amino compounds as summarized in items 1 to 7 below.
  • R 1 and R 2 are each independently hydrogen or organic group
  • X A and X B are each independently a bond, alkylene, alkenylene, —CO—, —SO 2 —, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C( ⁇ S)—, —SO 2 —, —CO—, —O—, —NH—, —CONH— and —SO 2 NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in X A and X B is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl; A 1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo; R 3 is (i) a heterocyclic group which is optional
  • R 4 and R 5 are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, or lower alkanoyl; or R 4 and R 5 may be linked to form a ring together with the neighboring nitrogen, and the ring may optionally have one or more substituents.
  • Item 2 A pharmaceutical composition comprising an amino compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 3 A pharmaceutical composition according to Item 1 for preventing and/or treating arrhythmia.
  • Item 4 An amino compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 5 Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 6 Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 7 A method of preventing and/or treating arrhythmia, comprising administering to a patient an amino compound represented by Formula (1) or a salt thereof according to Item 1.
  • one or more may be preferably 1 to 6, more preferably 1 to 3.
  • lower alkyl examples include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • alkylene examples include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.
  • lower alkylene examples include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • alkenylene examples include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.
  • lower alkenylene examples include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • lower alkylidene examples include linear or branched alkylidene groups having 1 to 6 carbon atoms, such as methylidene, ethylidene, propylidene, and butylidene.
  • cyclo lower alkyl examples include linear or branched cyclo alkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • lower alkoxy examples include linear or branched alkoxy groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • halogen examples include fluorine, chlorine, bromine, and iodine.
  • lower alkylenedioxy examples include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • lower alkanoyl examples include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • lower alkoxycarbonyl examples include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • aralkyl group examples include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.
  • organic group examples include lower alkyl, lower alkoxy, cyclo lower alkyl, amino, lower alkyl thio, aryl, and heterocyclic group, each of which is optionally substituted.
  • aryl group examples include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, naphthyl and tetrahydronaphthyl, indenyl, and dihydroindenyl.
  • heterocyclic group examples include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. More preferable examples of heterocyclic groups include the following (a) to (o):
  • azabicyclooctanyl e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl
  • heterocyclic group may be substituted by one or more suitable substituents.
  • Substituents of “aryl group which is optionally substituted” represented by R 1 and R 2 are each independently one or more substituents selected from the group consisting of:
  • Substituents of “heterocyclic group which is optionally substituted” represented by R 1 and R 2 are each independently one or more substituents selected from the group consisting of:
  • Substituents of “lower alkyl group which is optionally substituted” represented by R 1 and R 2 are each independently one or more substituents selected from the group consisting of oxo and phenyl.
  • Substituents of “cyclo lower alkyl group which is optionally substituted” represented by R 1 and R 2 are each independently one or more substituents selected from the group consisting of lower alkyl phenyl and phenyl.
  • Substituents of “amino group which is optionally substituted” represented by R 1 and R 2 are each independently one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and phenyl lower alkyl.
  • Substituents of “dihydroindenyl group which is optionally substituted” represented by R 1 and R 2 are each independently one or more oxos.
  • R 1 and R 2 are each independently selected from the group consisting of the following substituents (1) to (69):
  • aryl group which is optionally substituted for R 1 and R 2 include the substituents (4), (5) and (53).
  • heterocyclic group which is optionally substituted for R 1 and R 2 include the substituents (6) to (52) and (57) to (69).
  • Examples of X A and X B include a bond, lower alkylene, lower alkenylene, —CO—, —SO 2 —, -lower alkylene-SO 2 —, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-
  • Either of the two bonds in X A may be bonded to R 1 or N, and either of the two bonds in X B may be bonded to R 2 or N.
  • Examples of “lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo” represented by A 1 are C 1-6 alkylene and —CO—C 2-6 alkylene-.
  • heterocyclic groups of “heterocyclic group which is optionally substituted” represented by R 3 include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, quinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, indolyl, 2,3-dihydroindolyl, isoindolyl, 1,3-dihydroisoindolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzo[d]isothiazolyl, 2,3-dihydrobenzo[
  • substituents of “substituted heterocyclic group” represented by R 3 include the substituents (h1) to (h17) and (h20) to (h24), which are mentioned as substituents of heterocyclic groups represented by R 1 and R 2 .
  • preferable substituents are (h1), (h2), (h5), (h6), (h8), (h10), (h11), (h12) and (h20), and more preferable substituents are (h1) and/or (h2).
  • aryl groups of “aryl group which is substituted” represented by R 3 include those as defined above.
  • R 4 and R 5 in General Formula (2) are linked to form a ring together with the neighboring nitrogen, examples of the group —N R 4 R 5 include the following:
  • Each of the ring may optionally have one or more substituents selected from the group consisting of oxo; lower alkyl; phenyl lower alkyl; halo-phenyl lower alkyl; and amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, phenyl and halo-phenyl.
  • amino compound of the present invention represented by General Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification.
  • amino compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • R 1 , R 2 , R 3 , X A , X B and A 1 are the same as above; and X 1 is a leaving group.
  • reaction of the compound of Formula (3) with the compound of Formula (4) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.
  • Examples of the leaving groups represented by X 1 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • halogen atoms e.g., chlorine, bromine, iodine, and like atoms
  • lower alkanesulfonyloxy e.g., methanesulfonyloxy
  • halo substituted lower alkane sulfonyloxy e.g., trifluoromethanesulfonyloxy
  • inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
  • a wide variety of known basic compounds can be used as the basic compound.
  • usable basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine, tripropylamine, pyridine, quinoline, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octan
  • the above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • an alkali metal iodide such as potassium iodide or sodium iodide
  • the compound of Formula (4) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (3).
  • the amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (3).
  • the reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • R 1 , R 2 , R 3 , X A and A 1 are the same as above; and R 2a is hydrogen or lower alkyl.
  • Examples of lower alkyl groups represented by R 2a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.
  • reaction between the compound of Formula (1b) and the compound of Formula (5) is performed, for example, in an inert solvent or suitable solvent, in the presence of a reducing agent.
  • Examples of usable solvents include water; lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetonitrile, formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol
  • aliphatic acids such as acetonitrile, formic acid, and acetic acid
  • ethers
  • reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, and lithium aluminium hydride; and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts and hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • aliphatic acids such as formic acid
  • aliphatic acid alkali metal salts such as sodium formate
  • hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, and lithium aluminium hydride
  • catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black,
  • a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours.
  • the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1b).
  • a suitable reaction temperature is typically about ⁇ 80 to about 100° C., and preferably about ⁇ 80 to about 70° C.
  • the reaction is typically completed in about 30 minutes to about 60 hours.
  • the hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1b).
  • lithium aluminium hydride is used as a hydride reducing agent
  • a solvent such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene.
  • an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine
  • a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).
  • the reaction is typically performed at about ⁇ 30 to about 100° C., and preferably about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen doner such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
  • a hydrogen doner such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.
  • the reaction is typically completed in about 1 to about 12 hours.
  • the catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1b).
  • the compound of Formula (5) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1b).
  • the compound of Formula (5) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.
  • R 1 , R 2 , R 3 , X A , X B , A 1 and X 1 are the same as above.
  • reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed by the known “Ullmann condensation”, “Palladium coupling reaction”, etc.
  • the reaction can be preferably adopted especially when X B is a bond and R 2 is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted.
  • the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of transition metal compound (e.g., Pd(OAc) 2 , Pd 2 (dba) 3 and copper iodide), a basic compound (e.g., sodium tert-butoxide, K 3 PO 4 and Cs 2 CO 3 ), and if necessary a phosphine (e.g., xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).
  • a solvent e.g., toluene
  • the reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the compound of Formula (3) which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.
  • R 1 , R 2 , R 2a , X A , X B and X 1 are the same as above.
  • reaction of the compound of Formula (3a) with the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above.
  • reaction of the compound of Formula (3a) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • R 1 , R 2 , R 3 , X A , X B and A 1 are the same as above.
  • the reaction of the compound of Formula (8) with the compound of Formula (9) can be performed by the known “Mitsunobu reaction” conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).
  • DEAD diethyl azodicarboxylate
  • triphenylphosphine triphenylphosphine
  • R 1 , R 2 , R 3 , X A , X B , X 1 and A 1 are the same as above.
  • the reaction of the compound of Formula (10) with the compound of Formula (9) can be performed by the known O-alkylation reaction.
  • the reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K 2 CO 3 and Cs 2 CO 3 ).
  • an inert solvent e.g., DMF, THF, dioxane and acetonitrile
  • a basic compound e.g., K 2 CO 3 and Cs 2 CO 3
  • the reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • R 1 , R 2 , R 3 , X A and X B are the same as above; and A 10 is a divalent residue which is obtained by removing —CH 2 — from group A 1 .
  • reaction of the compound of Formula (3) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above,
  • R 3 , X 1 , X 2 and A 1 are the same as above.
  • reaction of the compound of Formula (9) with the compound of Formula (15) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.
  • reaction of the compound of Formula (9) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.
  • the reaction of the compound of Formula (4) with the compound of Formula (13) can be performed by the known N-alkylation reaction.
  • the reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K 2 CO 3 and Cs 2 CO 3 ).
  • an inert solvent e.g., DMF, THF, dioxane and acetonitrile
  • a basic compound e.g., K 2 CO 3 and Cs 2 CO 3
  • the N-alkylation reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the reaction converting the compound of Formula (14) to the compound of Formula (1e) can be performed by the known method.
  • the reaction can be performed in the presence of hydrazine.
  • R 1 , R 2 , X A , X B , X 1 and A 1 are the same as above; and P is a hydroxyl-protecting group and X 2 is a leaving group.
  • hydroxyl-protecting groups represented by P include tetrahydropyran-2-yl, methoxymethyl, benzyl.
  • Examples of the leaving groups represented by X 2 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • halogen atoms e.g., chlorine, bromine, iodine, and like atoms
  • lower alkanesulfonyloxy e.g., methanesulfonyloxy
  • halo substituted lower alkane sulfonyloxy e.g., trifluoromethanesulfonyloxy
  • the halogen atom represented by X 2 is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X 1 .
  • reaction of the compound of Formula (3) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • reaction of the compound of Formula (3) with the compound of Formula (17) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • the reaction converting the compound of Formula (18) to the compound of Formula (8) can be performed under the known deprotection method depending on the type of the protecting group (P).
  • the compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • the compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • the starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a usual purification procedure such as column chromatography, recrystallization, etc.
  • those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids.
  • acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds.
  • basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • one or more atoms can be substituted with one or more isotopic atoms.
  • isotopic atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 14 N, 18 O, etc.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into usual pharmaceutical preparations, using usually employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • compositions can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; star
  • Such tablets may be coated with usual coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • a solution, emulsion or suspension is sterilized and preferably made isotonic with blood.
  • Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc.
  • the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain usual solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • the proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is usually preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • the route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.
  • Injections are intravenously administered singly or as mixed with usual injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required.
  • Suppositories are administered intrarectally.
  • the dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is usually about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • the compound of the present invention When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.).
  • the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • the compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels.
  • the compound of the invention has characteristics as an atrial-selective K + channel-blocking agent.
  • the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents.
  • the compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia).
  • the compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • the compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • the compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • the present inventors conducted extensive research to develop a compound that blocks the I Kur current (Kv1.5 channel) and/or the I KA C h current (GIRK1/4 channel) potently and more selectively than other K + channels.
  • a novel benzodiazepine compound represented by General Formula (1) below could be the desired compound.
  • the present invention has been accomplished based on the above findings.
  • the present invention provides benzodiazepine compounds, and pharmaceutical compositions comprising the benzodiazepine compounds as summarized in items 1 to 7 below.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or lower alkyl; R 2 and R 3 may be linked to form lower alkylene; A 1 is lower alkylene optionally substituted with one or more hydroxyls; and R 5 is an aryl or heterocyclic group, each of which is optionally substituted.
  • Item 2 A pharmaceutical composition comprising a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 3 A pharmaceutical composition according to Item 2 for preventing and/or treating arrhythmia.
  • Item 4 A benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 5 Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 6 Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 7 A method of preventing and/or treating arrhythmia, comprising administering to a patient a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1.
  • one or more may be preferably 1 to 6, and more preferably 1 to 3.
  • lower alkyl examples include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • lower alkylene examples include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • lower alkenylene examples include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • cyclo lower alkyl examples include linear or branched cyclo alkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • lower alkoxy examples include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • halogen examples are fluorine, chlorine, bromine, and iodine.
  • lower alkylenedioxy examples include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • lower alkanoyl examples include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • lower alkoxycarbonyl examples include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • aralkyl group examples include groups wherein aryl groups are substituted on the alkyl groups, such as benzyl and phenethyl.
  • aryl group examples include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.
  • heterocyclic group examples include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen.
  • heterocyclic groups include the followings (a) to (m) groups:
  • 1,4-dihydroquinolyl, etc. tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydr
  • furopyridyl e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-
  • Substituents of “aryl and heterocyclic group, each of which is optionally substituted” represented by R 5 are each independently one or more substituents selected from the group consisting of:
  • heterocyclic group in Item (7) above can be selected from the above-mentioned groups (a) to (m).
  • R 1 , R 2 , R 3 , and R 4 are each independently lower alkyl; A 1 is lower alkylene; and R 5 is piperidyl, piperazinyl, indolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydroindolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,
  • the benzodiazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification.
  • the benzodiazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and A 1 are the same as above, and X 1 is halogen or hydroxyl.
  • reaction of the compound of Formula (2) with the compound of Formula (3) wherein X 1 is halogen can be performed in a general inert solvent or without using any solvent in the presence or absence of a basic compound.
  • inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixed solvents of such solvents.
  • ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol di
  • the basic compound may be selected from various known compounds.
  • examples of such compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]octane (DAB
  • the above reaction may be performed by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • an alkali metal iodide such as potassium iodide or sodium iodide
  • the compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably 0.5 to 10 moles, per mole of the compound of Formula (2).
  • the basic compound is typically used in an amount of 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).
  • the reaction is typically performed at a temperature of 0° C. to 250° C., and preferably 0° C. to 200° C., and is typically completed in about 1 to about 80 hours.
  • reaction of the compound of Formula (2) with the compound of Formula (3) wherein X 1 is hydroxyl is performed in a suitable solvent in the presence of a condensing agent.
  • solvents usable herein include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; aprotic polar solvents such as acetonitrile, pyridine, acetone, N,N-dimethyl formamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures of such solvents
  • condensing agents include azocarboxylates such as di-tert-butyl azodicarboxylate, N,N,N′,N′-tetramethyl azodicarboxamide, 1,1′-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate; and phosphorus compounds such as triphenylphosphine and tri-n-butylphosphine.
  • azocarboxylates such as di-tert-butyl azodicarboxylate, N,N,N′,N′-tetramethyl azodicarboxamide, 1,1′-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate
  • phosphorus compounds such as triphenylphosphine and tri-n-butylphosphine.
  • the compound (3) is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).
  • the condensing agent is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).
  • the reaction proceeds typically at 0 to 200° C., and preferably at about 0 to about 150° C., and is completed in about 1 to about 10 hours.
  • R 1 , R 2 , R 3 , R 4 , and A 1 are the same as above;
  • R 5a is a nitrogen-containing heterocyclic group optionally having substituent(s); and
  • X 2 is a halogen atom.
  • R 5a examples include, among groups represented by the group R 5 mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds with an N—H bond, the groups optionally having substituent(s).
  • reaction of the compound of Formula (4) with the compound of Formula (5) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.
  • halogen atoms represented by X 2 include chlorine, bromine, iodine, and like atoms.
  • inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
  • aromatic hydrocarbons such as
  • a wide variety of known basic compounds can be used as the basic compound.
  • Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]oct
  • the above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • an alkali metal iodide such as potassium iodide or sodium iodide
  • the compound of Formula (5) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (4).
  • the amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (4).
  • the reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • R 2 , R 3 , R 4 , and X 2 are as defined above; R 1a is lower alkyl; R 7 is lower alkoxy; and R 6 is lower alkoxycarbonyl.
  • Examples of lower alkyl groups represented by R 1a include alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and propyl groups.
  • Examples of lower alkoxycarbonyl groups represented by R 6 include (C 1-6 alkoxy)carbonyl groups, such as methoxycarbonyl, and ethoxycarbonyl.
  • Examples of lower alkoxy groups represented by R 7 include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy.
  • the compound of Formula (7) is reacted with the carboxylic acid compound of Formula (8) through a general amide bond formation reaction.
  • Conditions for known amide bond formation reactions can be easily employed in the amide formation reaction.
  • reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (8) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (7); (ii) an active ester method, in which Carboxylic Acid (8) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like, or an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (7); (iii) a carbodiimide method, in which Carboxylic Acid (8) is subjected to a condensation reaction with Amine (7) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-e
  • the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound.
  • Any solvents used for conventional mixed acid anhydride methods are usable.
  • Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.
  • organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyld
  • Carboxylic Acid (8), an alkyl halocarboxylate, and Amine (7) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (8) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (7).
  • the reaction is typically performed at about ⁇ 20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.
  • Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound.
  • Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (7) mentioned above as one of the other methods (iv).
  • a suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (7).
  • WSC is used as an activating agent
  • addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously.
  • the reaction is typically performed at about ⁇ 20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.
  • a basic compound in a suitable solvent.
  • usable basic compounds include a wide variety of known basic compounds, such as those for use in the method (i) above.
  • usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, and methylcellosolve; acetonitrile; pyridine; acetone; and water.
  • the ratio of the carboxylic acid halide to Amine (7) is not limited and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (7).
  • the reaction is typically performed at about ⁇ 20 to about 180° C., and preferably at about 0 to about 150° C., and typically completed in about 5 minutes to about 30 hours.
  • the amide bond formation reaction shown in Reaction Formula 3 above can also be performed by reacting Carboxylic Acid (8) with Amine (7) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.
  • a phosphorus compound serving as a condensing agent such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • the reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (7), typically at about ⁇ 20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (8) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (7).
  • the reaction converting the compound of Formula (9) to the compound of Formula (10) can be performed by, for example, [1] reducing the compound of Formula (9) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (9) in a suitable inert solvent using as a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof.
  • Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel.
  • the reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (9).
  • the reaction temperature is typically about ⁇ 20 to about 150° C., and preferably about 0 to about 100° C.
  • the hydrogen pressure is typically about 1 to 10 atm.
  • the reaction is typically completed in about 0.5 to about 100 hours.
  • An acid such as hydrochloric acid may be added to the reaction.
  • alkali metal hydroxide such as sodium hydroxide
  • a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride or the like
  • inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof.
  • Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used.
  • the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours.
  • a reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (9).
  • reaction converting the compound of Formula (10) to the compound of Formula (6b) is performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8).
  • reaction of the compound of Formula (6b) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • R 1 , R 2 , R 3 , R 4 , and R 7 are the same as above.
  • reaction of the compound of Formula (12) with the compound of Formula (13) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8) shown in Reaction Formula 3 above.
  • R 1 , R 2 , R 3 , R 4 , R 7 , A 1 , and X 2 are the same as above; and X 3 is a halogen atom.
  • reaction converting the compound of Formula (6) to the compound of Formula (2) can be performed in a suitable solvent in the presence of an acid.
  • solvents examples include water; lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof.
  • lower (C 1-6 ) alcohols such as methanol, ethanol, and isopropanol
  • ethers such as dioxane, tetrahydrofuran, and diethylether
  • halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride
  • polar solvents such as acetonitrile
  • acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.
  • the reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours.
  • the amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (6).
  • halogen atoms represented by X 3 include chlorine, bromine, iodine, and like atoms.
  • the halogen atom represented by X 3 is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X 2 .
  • reaction of the compound of Formula (2) with the compound of Formula (14) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above, wherein X 1 is a halogen atom.
  • the compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • the compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • the starting material compounds and object compounds represented by each of the reaction formulae can be used in a suitable salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.
  • those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids.
  • acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds.
  • basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • one or more atoms can be substituted with one or more isotopic atoms.
  • isotopic atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 14 N, 18 O, etc.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • compositions can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; star
  • Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • a solution, emulsion or suspension is sterilized and preferably made isotonic with blood.
  • Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc.
  • the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • the proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • the route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.
  • Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required.
  • Suppositories are administered intrarectally.
  • the dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • the compound of the present invention When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.).
  • the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • the compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels.
  • the compound of the invention has characteristics as an atrial-selective K + channel-blocking agent.
  • the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents.
  • the compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia).
  • the compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • the compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • the compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
  • Trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.12 g)
  • zinc cyanide 70 mg
  • tris (dibenzylideneacetone) dipalladium 7 mg
  • 1,1′-bis (diphenylphosphino) ferrocene 8 mg
  • zinc powder (2 mg) were added to DMF (1 ml), and the mixture was heated for 20 minutes at 170° C. (microwave reactor).
  • the reaction liquid was cooled to room temperature, and subjected to celite filtration.
  • Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione (0.3 g), dichlorobis(triphenyl phosphine)palladium (II)(53 mg), copper(I) iodide (29 mg), and triethylamine (0.39 ml) were added to DMF (4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes.
  • the reaction liquid was cooled to room temperature, and subjected to celite filtration.
  • the purified product was condensed under reduced pressure to give the title compound (0.51 g) as a yellowish-white solid.
  • Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis (triphenylphosphine) palladium (II)(35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration.
  • Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
  • Methanesulfonic acid 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl ester
  • Hydrazine hydrate (0.5 ml) was added to a methanol solution (60 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-tri methyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (1.93 g).
  • the mixture was stirred for 5.5 hours while heated under reflux. After cooled to room temperature, a 1N-sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound (1.2 g) as a yellow solid.
  • the reaction mixture was condensed under reduced pressure.
  • the purified product was condensed under reduced pressure.
  • a 6N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.43 g) as a white solid.
  • Triethylamine (0.1 ml) and 4-pyridine carbaldehyde (0.094 ml) were added to a methanol solution (10 ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione hydrochloride (0.26 g).
  • the mixture was stirred at room temperature for 1 hour.
  • Sodium borohydride (0.11 g) was added, and the mixture was further stirred at room temperature overnight.
  • the purified product was condensed under reduced pressure to give the title compound (0.21 g) as a colorless oily matter.
  • Trimethyl orthoformate (9 ml) was added to a methanol solution (50 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.2 g) and 3-(2-aminoethyl)pyridine (1.0 g). The mixture was stirred at room temperature for 2 hours.

Abstract

The present invention provides a novel diazepine compound that blocks the IKur current or the Kv1.5 channel potently and more selectively than other K+ channels. The present invention relates to a diazepine compound represented by General Formula (1)
Figure US20140343277A1-20141120-C00001
  • or a salt thereof,
  • wherein R1, R2, R3, and R4 are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl;
  • R2 and R3 may be linked to form lower alkylene;
  • A1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo;
  • Y1 and Y2 are each independently —N═ or —CH═;
  • and
  • R5 is group represented by
Figure US20140343277A1-20141120-C00002
  • wherein R6 and R7 are each independently hydrogen or organic group;
  • R6 and R7 may be linked to form a ring together with the neighboring group —XA—N—XB—;
  • XA and XB are each independently a bond, lower alkylene, etc.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a Divisional Application of U.S. application Ser. No. 13/388, 442, filed on Apr. 23, 2012, which is a National Stage of International Application No. PCT/JP2010/064545, filed on Aug. 20, 2010, which claims priorities from U.S. Patent Application Nos. 61/235,973 filed on Aug. 21, 2009, 61/235,981 filed on Aug. 21, 2009, 61/235,983 filed on Aug. 21, 2009 and 61/359,686 filed on Jun. 29, 2010, the contents of all of which are incorporated herein by reference in their entirety.
    • TECHNICAL FIELD
  • The present invention relates to a nitrogen-containing compound and a pharmaceutical composition containing the same.
    • BACKGROUND ART
  • Atrial fibrillation (hereinafter referred to as “AF”) is the most frequently observed type of arrhythmia in clinical examinations. Although not a lethal arrhythmia, AF causes cardiogenic cerebral embolism, and is therefore recognized as an arrhythmia that greatly affects vital prognoses and QOL. It is known that the onset of AF increases with age, and that repeated AF strokes lead to chronic (serious) AF (The Journal of American Medical Association, 285, 2370-2375 (2001) and Circulation, 114, 119-123 (2006)).
  • To prevent chronic AF, which causes difficulty in restoring sinus rhythm and increases the risk of cardiogenic cerebral embolism, early defibrillation and subsequent prevention of recurrence (maintenance of the sinus rhythm) are required. Antiarrhythmic drugs (classes I and III) are most commonly used as pharmacotherapy, but these drugs achieve insufficient therapeutic effects, while causing serious side effects such as a proarrhythmic effect (Am. J. Cardiol., 72, B44-B49 (1993)).
  • The onset of AF is triggered by atrial premature contraction with underlining causes such as intra-atrial conduction delay, shortening and heterogeneity of the atrial refractory period (Nature Reviews DRUG DISCOVERY 4, 899-910 (2005)). It is known that the prolongation of refractory period of atrial muscle can terminate AF (defibrillation) or prevent the occurrence of AF. The action potential duration of the mammalian cardiac muscle is predominantly determined by voltage-dependent K+ channels. Inhibition of the K+ channel prolongs myocardial action potential duration, which results in prolongation of the refractory period (Nature Reviews DRUG DISCOVERY 5, 1034-49 (2006)). The action mechanism of class III antiarrhythmic drugs (e.g., Dofetilide) is to inhibit rapid delayed rectifier K+ current (IKr), K+ current encoded by HERG. However, since IKr is present in both the atria and ventricles, such drugs might cause ventricular arrhythmias, such as torsades de pointes (Trends Pharmacol. soc., 22, 240-246 (2001)).
  • Ultra-rapid delayed rectifier K+ current (IKur), K+ current encoded by Kv1.5, has been identified as K+ channel that is specifically expressed only in human atria (Cric. Res., 73, 1061-1076 (1993), J. Physiol., 491, 31-50 (1996) and Cric. Res., 80, 572-579 (1997)). Muscarine potassium current (IKACh) encoded by two genes called GIRK1 and GIRK4 is known as a K+ channel specifically expressed inhuman atria (Nature 374, 135-141 (1995)). Accordingly, a pharmacologically acceptable substance that selectively blocks the IKur current (the Kv1.5 channel) or the IKACh current (GIRK1/4 channel) can act selectively on the atrial muscle and is considered effective to exclude the proarrhythmic effect caused by prolonged action potential duration of the ventricular muscle.
    • SUMMARY OF INVENTION
  • The present specification discloses three inventions (three nitrogen-containing compounds each having a different structure). The inventions are respectively expressed as a “First Invention”, “Second Invention”, and “Third Invention”, which are described in detail below.
    • 1. First Invention (Diazepine Compound)
  • The present inventors conducted extensive research to develop a compound that blocks the IKur current (Kv1.5 channel) and/or the IKACh current (GIRK1/4 channel) potently and more selectively than other K+ channels. As a result, the inventors found that a novel diazepine compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.
  • The present invention provides diazepine compounds, and pharmaceutical compositions comprising the diazepine compounds as summarized in items 1 to 16 below.
  • Item 1. A diazepine compound represented by General Formula (1)
  • Figure US20140343277A1-20141120-C00003
  • or a salt thereof,
    wherein R1, R2, R3, and R4 are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl;
    R2 and R3 may be linked to form lower alkylene;
    A1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo;
    Y1 and Y2 are each independently —N═ or —CH═;
    R5 is group represented by
  • Figure US20140343277A1-20141120-C00004
  • wherein R6 and R7 are each independently hydrogen or an organic group;
    R6 and R7 may be linked to form a ring together with the neighboring group —XA—N—XB—;
    XA and XB are each independently a bond, alkylene, alkenylene, —CO—, —SO2—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO2—, —CO—, —O—, —NH—, —CONH— and —SO2NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in XA and XB is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl.
  • Item 2. A diazepine compound or a salt thereof according to Item 1, wherein R6 and R7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or heterocyclic group, each of which is optionally substituted, and XA and XB are each independently a bond, lower alkylene, lower alkenylene, —CO—, —SO2—, -lower alkylene-SO2—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO2—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO2—N(lower alkyl)-lower alkylene-, —SO2—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, lower alkylene-N(phenyl lower alkyl)-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, or —CO-lower alkylene-O—CO-lower alkylene-O—.
  • Item 3. A diazepine compound or a salt thereof according to Item 2, wherein R6 and R7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, each of which is optionally substituted.
  • Item 4. A diazepine compound or a salt thereof according to Item 3, wherein R6 and R7 are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, naphthyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, benzothienyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzisoxazolyl, pyrazolo[2,3-a]pyridyl, indolizinyl, 2,3-dihydroindolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, pyrido[2,3-d]imidazolyl, chromanyl, 5,6,7,8-tetrahydroisoquinolyl, 3,4-dihydro-1H-isoquinolyl, 3,4-dihydroisoquinolyl, naphthyridinyl, 1,4-benzodioxanyl, cinnolinyl, quinoxalinyl, 2,3-dihydrobenz-1,4-oxazinyl, azetidinyl, 1,2,4-oxadiazolyl and azepanyl, each of which is optionally substituted.
  • Item 5. A diazepine compound or a salt thereof according to Item 4, wherein R6 and R7 are each independently selected from the group consisting of the following substituents (1) to (54):
  • (1) hydrogen;
    (2) lower alkyl;
    (3) cyclo lower alkyl optionally substituted with one or more phenyl lower alkoxys;
    (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-27):
      • (4-1) cyano;
      • (4-2) hydroxyl;
      • (4-3) halogen;
      • (4-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, lower alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;
      • (4-5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino;
      • (4-6) pyridyl;
      • (4-7) thienyl;
      • (4-8) piperazinyl optionally substituted with one or more lower alkyls;
      • (4-9) phenyl;
      • (4-10) pyrazolyl optionally substituted with one or more lower alkyls;
      • (4-11) pyrimidinyl optionally substituted with one or more lower alkyls;
      • (4-12) piperidyl optionally substituted with one or more lower alkyls;
      • (4-13) furyl;
      • (4-14) carboxy;
      • (4-15) lower alkoxycarbonyl;
      • (4-16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and lower alkylsulfonyl;
      • (4-17) lower alkylthio;
      • (4-18) triazolyl;
      • (4-19) imidazolyl;
      • (4-20) pyrrolidinyl optionally substituted with one or more oxos;
      • (4-21) lower alkylsulfonyl;
      • (4-22) lower alkylenedioxy optionally substituted with one or more halogens;
      • (4-23) nitro;
      • (4-24) oxazolyl;
      • (4-25) thiazolyl optionally substituted with one or more lower alkyls;
      • (4-26) lower alkanoyl; and
      • (4-27) morpholinyl;
        (5) naphthyl;
        (6) furyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl and phenyl;
        (7) thienyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl and furyl;
        (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl and halogen;
        (9) pyrazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen or lower alkoxy; cyclo lower alkyl; halogen; phenyl optionally substituted with lower alkoxy; furyl and thienyl;
        (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
        (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, thienyl and furyl;
        (12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen or lower alkoxy; phenyl; phenoxy and lower alkanoylamino;
        (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl;
        (14) triazolyl optionally substituted with one or more lower alkyls;
        (15) pyridyl optionally substituted with one or more substituents selected from the group consisting of the following (15-1) to (15-14):
      • (15-1) halogen;
      • (15-2) cyano;
      • (15-3) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl;
      • (15-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;
      • (15-5) oxo;
      • (15-6) hydroxyl;
      • (15-7) lower alkoxy optionally substituted with one or more phenyls;
      • (15-8) pyrrolidinyl;
      • (15-9) lower alkanoyl;
      • (15-10) morpholinyl;
      • (15-11) phenoxy;
      • (15-12) pyrazolyl;
      • (15-13) thienyl; and
      • (15-14) N-oxide
        (16) pyrimidinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
        (17) pyridazinyl;
        (18) pyrazinyl optionally substituted with one or more phenyl lower alkoxys;
        (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more halogens;
        (20) thieno[2,3-b]pyrazinyl;
        (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one or more phenyls;
        (22) benzothiazolyl optionally substituted with one or more lower alkyls;
        (23) indolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and halogen;
        (24) imidazo[1,2-a]pyridyl or imidazo[1,5-a]pyridyl, each of which is optionally substituted with one or more lower alkyls;
        (25) benzothienyl optionally substituted with one or more lower alkyls;
        (26) benzimidazolyl optionally substituted with one or more lower alkyls;
        (27) 2,3-dihydrobenzo[b]furyl;
        (28) benzofuryl optionally substituted with one or more halogens;
        (29) indazolyl optionally substituted with one or more lower alkyls;
        (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl optionally substituted with lower alkoxy;
        (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl optionally substituted with halogen or lower alkoxy, halogen, furyl, pyridyl and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and lower alkoxy;
        (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl;
        (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (34) thieno[2,3-b]pyridyl;
        (35) benzo[1,3]dioxolyl optionally substituted with one or more halogens;
        (36) benzisoxazolyl;
        (37) pyrazolo[2,3-a]pyridyl;
        (38) indolizinyl;
        (39) 2,3-dihydroindolyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl and lower alkanoyl;
        (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halogen and oxo;
        (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more oxos;
        (42) quinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyls, lower alkoxy, lower alkyl and oxo
        (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, pyridyl lower alkyl, aralkyl, lower alkoxy and oxo;
        (44) 1,2-dihydroquinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyls, lower alkoxy, lower alkyl and oxo;
        (45) chromanyl optionally substituted with one or more lower alkyls;
        (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one or more oxos;
        (47) 3,4-dihydroisoquinolyl optionally substituted with one or more oxos;
        (48) naphthyridinyl;
        (49) 1,4-benzodioxanyl;
        (50) cinnolinyl;
        (51) quinoxalinyl;
        (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo;
        (53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo; and
        (54) piperidyl optionally substituted with one or more aryl carbonyls.
  • Item 6. A diazepine compound or a salt thereof according to Item 5, wherein R6 and R7 are each independently (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35), (40a), (40b), (42a), (43a), (44a), and (53):
  • (1) hydrogen;
    (4a) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1), (4-2), (4-4), (4a-5), (4-10), (4a-16), (4-18), (4-19), (4-23), (4-26), and (4-27):
      • (4-1) cyano;
      • (4-2) hydroxyl;
      • (4-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, lower alkoxy, imidazolyl, and morpholinyl;
      • (4a-5) lower alkoxy;
      • (4-10) pyrazolyl optionally substituted with one or more lower alkyls;
      • (4a-16) amino optionally substituted with one or more lower alkylsulfonyls;
      • (4-18) triazolyl;
      • (4-19) imidazolyl;
      • (4-23) nitro;
      • (4-26) lower alkanoyl; and
      • (4-27) morpholinyl;
        (6a) furyl optionally substituted with one or more lower alkyls optionally substituted with halogen;
        (7a) thienyl optionally substituted with one or more lower alkyls;
        (8a) imidazolyl optionally substituted with one or more lower alkyls;
        (9a) pyrazolyl optionally substituted with one or more lower alkyls optionally substituted with lower alkoxy;
        (10a) oxazolyl optionally substituted with one or more lower alkyls;
        (11a) isoxazolyl optionally substituted with one or more lower alkyls;
        (12a) thiazolyl optionally substituted with one or more lower alkyls optionally substituted with halogen;
        (15a) pyridyl optionally substituted with one or more substituents selected from the group consisting of the following (15-1) to (15-5), (15a-7), (15-9), (15-11), (15-12) and (15-14):
      • (15-1) halogen;
      • (15-2) cyano;
      • (15-3) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl;
      • (15-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;
      • (15-5) oxo;
      • (15a-7) lower alkoxy;
      • (15-9) lower alkanoyl;
      • (15-11) phenoxy;
      • (15-12) pyrazolyl; and
      • (15-14) N-oxide
        (16a) pyrimidinyl optionally substituted with one or more lower alkyls;
        (17) pyridazinyl
        (18) pyrazinyl optionally substituted with one or more phenyl lower alkoxys;
        (23a) indolyl optionally substituted with one or more lower alkyls;
        (24a) imidazo[1,2-a]pyridyl;
        (24b) imidazo[1,5-a]pyridyl optionally substituted with one or more lower alkyls;
        (26) benzimidazolyl optionally substituted with one or more lower alkyls;
        (29) indazolyl optionally substituted with one or more lower alkyls;
        (30a) furo[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (31a) furo[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (31b) 4,5-dihydrofuro[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl optionally substituted with halogen or lower alkoxy;
        (32a) thieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (32b) 6,7-dihydrothieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl;
        (33a) thieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (35a) benzo[1,3]dioxolyl;
        (40a) isoquinolyl optionally substituted with one or more oxos;
        (40b) 1,2-dihydroisoquinolyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (42a) quinolyl optionally substituted with one or more oxos;
        (43a) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of aralkyl (e.g., phenyl lower alkyl, etc.), pyridyl lower alkyl and oxo;
        (44) 1,2-dihydroquinolyl optionally substituted with one or more oxos; and
        (53) 2,3-dihydrobenzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo.
  • Item 7. A diazepine compound or a salt thereof according to Item 6, wherein R6 and R7 are each independently phenyl, pyridyl, pyrazolyl, indolyl, 4,5-dihydrofuro[3,2-c]pyridyl, and 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or two substituents selected from the group consisting of oxo, lower alkyl, lower alkoxy lower alkyl, and lower alkylsulfonylamino.
  • Item 8. A diazepine compound or a salt thereof according to Item 7, which is selected from the group consisting of the following compounds:
    • 1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydro benzo[b][1,4]diazepine-2,4-dione,
    • 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide,
    • N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide,
    • 7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • N-(2-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)(2-pyridin-3-ylethyl)amino]methyl}-phenyl)methanesulfonamide,
    • 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide.
  • Item 9. A diazepine compound according to Item 8, which is selected from the group consisting of the following compounds:
    • 1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
    • 1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
    • 1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
    • 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino}ethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
    • 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
    • N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide hydrochloride,
    • N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide,
    • 7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride,
    • N-(2-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)(2-pyridin-3-ylethyl)amino]methyl}phenyl)methanesulfonamide dihydrochloride,
    • 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,
    • 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, and
    • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride.
  • Item 10. A diazepine compound or a salt thereof according to Item 1, wherein Y1 and Y2 are each —CH═.
  • Item 11. A pharmaceutical composition comprising a diazepine compound or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 12. A pharmaceutical composition according to Item 11 for preventing and/or treating arrhythmia.
  • Item 13. A diazepine compound or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 14. Use of a diazepine compound or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 15. Use of a diazepine compound or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 16. A method of preventing and/or treating arrhythmia, comprising administering to a patient a diazepine compound or a salt thereof according to Item 1.
  • The groups represented by, or substituents of, R1, R2, R3, R4, R5, R6, R7, A1, XA, XB, Y1 and Y2 in the specification are described below.
  • The term “one or more” may be preferably 1 to 6, more preferably 1 to 3.
  • Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • Examples of “alkylene” include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.
  • Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • Examples of “alkenylene” include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.
  • Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclohexylmethyl.
  • Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • Examples of “halogen” are fluorine, chlorine, bromine, and iodine.
  • Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • Examples of “aralkyl group” include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.
  • Examples of “organic group” include lower alkyl, cyclo lower alkyl, aryl, and heterocyclic group, each of which is optionally substituted.
  • Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.
  • Examples of “aroyl group” include benzoyl and naphthoyl.
  • Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. Examples of preferable heterocyclic groups include the following (a) to (n):
  • (a) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, tetrahydropyridyl (e.g., 1,2,3,6-tetrahydropyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
  • (b) saturated 3 to 8-membered, preferably 5 or 7-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azepanyl, 1,4-diazepanyl, etc.;
  • (c) saturated or unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, decahydroquinolyl, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazolyl, etc.), quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl (e.g. benzo[d][1,2,3]triazolyl, etc.), tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, imidazo[1,5-a]pyridyl, etc.), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.), tetrahydropyridoindolyl (e.g., 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, etc.), azabicyclooctanyl (e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl), etc.;
  • (d) saturated or unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl, etc.), tetrahydrofuryl, etc.;
  • (e) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;
  • (f) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
  • (g) saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;
  • (h) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), furopyrrolyl (e.g., furo[3,2-b]pyrrolyl etc.), etc.;
  • (i) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), isothiazolyl, etc.;
  • (j) saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
  • (k) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;
  • (l) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl, etc.);
  • (m) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.; and
  • (n) saturated or unsaturated 7- to 12-membered heterocyclic spiro groups containing 1 to 2 nitrogen atom(s), for example, azaspiroundecanyl (e.g., 3-azaspiro[5.5]undecanyl), etc.; and the like;
  • wherein said heterocyclic groups may be substituted with one or more suitable substituents.
  • Examples of more preferable heterocyclic groups include piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, benzothienyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzisoxazolyl, pyrazolo[2,3-a]pyridyl, indolizinyl, 2,3-dihydroindolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, pyrido[2,3-d]imidazolyl, chromanyl, 5,6,7,8-tetrahydroisoquinolyl, 3,4-dihydro-1H-isoquinolyl, 3,4-dihydroisoquinolyl, naphthyridinyl, 1,4-benzodioxanyl, cinnolinyl, quinoxalinyl, 2,3-dihydrobenz-1,4-oxazinyl, azetidinyl, 1,2,4-oxadiazolyl, and azepanyl, each of which is optionally substituted.
  • Substituents of “aryl group which is optionally substituted” represented by R6 and R7 are independently one or more substituents selected from the group consisting of:
  • (a1) cyano;
    (a2) hydroxyl;
    (a3) halogen;
    (a4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, lower alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;
    (a5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino;
    (a6) pyridyl;
    (a7) thienyl;
    (a8) piperazinyl optionally substituted with one or more lower alkyls;
    (a9) phenyl;
    (a10) pyrazolyl optionally substituted with one or more lower alkyls;
    (a11) pyrimidinyl optionally substituted with one or more lower alkyls;
    (a12) piperidyl optionally substituted with one or more lower alkyls;
    (a13) furyl;
    (a14) carboxy;
    (a15) lower alkoxycarbonyl;
    (a16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl;
    (a17) lower alkylthio;
    (a18) triazolyl;
    (a19) imidazolyl;
    (a20) pyrrolidinyl optionally substituted with one or more oxos;
    (a21) lower alkylsulfonyl;
    (a22) lower alkylenedioxy optionally substituted with one or more halogens;
    (a23) nitro;
    (a24) oxazolyl;
    (a25) thiazolyl optionally substituted with one or more lower alkyls;
    (a26) lower alkanoyl;
    (a27) sulfo; and
    (a28) morpholinyl.
  • Substituents of “heterocyclic group which is optionally substituted” represented by R6 and R7 are independently one or more substituents selected from the group consisting of:
  • (h1) oxo;
    (h2) lower alkyl optionally substituted with one or more substitutents selected from the group consisting of the following (h2-1) to (h2-10):
      • (h2-1) halogen;
      • (h2-2) hydroxyl;
      • (h2-3) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, cyclo lower alkyl and lower alkanoyl;
      • (h2-4) pyridyl;
      • (h2-5) lower alkanoyloxy;
      • (h2-6) lower alkoxy;
      • (h2-7) aryloxy;
      • (h2-8) pyrimidinyl;
      • (h2-9) pyrrolidinyl optionally substituted with one or more hydroxyls; and
      • (h2-10) imidazolyl optionally substituted with one or more lower alkyls;
        (h3) cyclo lower alkyl;
        (h4) lower alkoxy optionally substituted with one or more substitutents selected from the group consisting of pyridyl and aryl;
        (h5) aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with one or more halogens; lower alkoxy; lower alkanoyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino; lower alkyl amino, aryl and cyano;
        (h6) aralkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano and oxo;
        (h7) heterocyclic group optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano and oxo;
        (h8) hydroxyl;
        (h9) halogen;
        (h10) carboxy;
        (h11) lower alkanoyl;
        (h12) lower alkoxycarbonyl;
        (h13) lower alkylenedioxy;
        (h14) cyano;
        (h15) nitro;
        (h16) sulfo;
        (h17) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, aryl, aroyl, lower alkylsulfonyl and lower alkanoyl;
        (h18) lower alkylthio;
        (h19) lower alkylsulfonyl; and
        (h20) aryloxy.
  • Preferable substituents represented by R6 and R7 are each independently selected from the group consisting of the following substituents (1) to (54):
  • (1) hydrogen;
    (2) lower alkyl;
    (3) cyclo lower alkyl optionally substituted with one or more phenyl lower alkoxys;
    (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-27):
      • (4-1) cyano;
      • (4-2) hydroxyl;
      • (4-3) halogen;
      • (4-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, lower alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;
      • (4-5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino;
      • (4-6) pyridyl;
      • (4-7) thienyl;
      • (4-8) piperazinyl optionally substituted with one or more lower alkyls;
      • (4-9) phenyl;
      • (4-10) pyrazolyl optionally substituted with one or more lower alkyls;
      • (4-11) pyrimidinyl optionally substituted with one or more lower alkyls;
      • (4-12) piperidyl optionally substituted with one or more lower alkyls;
      • (4-13) furyl;
      • (4-14) carboxy;
      • (4-15) lower alkoxycarbonyl;
      • (4-16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and lower alkylsulfonyl;
      • (4-17) lower alkylthio;
      • (4-18) triazolyl;
      • (4-19) imidazolyl;
      • (4-20) pyrrolidinyl optionally substituted with one or more oxos;
      • (4-21) lower alkylsulfonyl;
      • (4-22) lower alkylenedioxy optionally substituted with one or more halogens;
      • (4-23) nitro;
      • (4-24) oxazolyl;
      • (4-25) thiazolyl optionally substituted with one or more lower alkyls;
      • (4-26) lower alkanoyl; and
      • (4-27) morpholinyl;
        (5) naphthyl;
        (6) furyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl and phenyl;
        (7) thienyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl and furyl;
        (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl and halogen;
        (9) pyrazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen or lower alkoxy; cyclo lower alkyl; halogen; phenyl optionally substituted with lower alkoxy; furyl and thienyl;
        (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
        (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, thienyl and furyl;
        (12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen or lower alkoxy; phenyl; phenoxy and lower alkanoylamino;
        (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl;
        (14) triazolyl optionally substituted with one or more lower alkyls;
        (15) pyridyl optionally substituted with one or more substituents selected from the group consisting of the following (15-1) to (15-14):
      • (15-1) halogen;
      • (15-2) cyano;
      • (15-3) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl;
      • (15-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;
      • (15-5) oxo;
      • (15-6) hydroxyl;
      • (15-7) lower alkoxy optionally substituted with one or more phenyls;
      • (15-8) pyrrolidinyl;
      • (15-9) lower alkanoyl;
      • (15-10) morpholinyl;
      • (15-11) phenoxy;
      • (15-12) pyrazolyl;
      • (15-13) thienyl; and
      • (15-14) N-oxide;
        (16) pyrimidinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
        (17) pyridazinyl;
        (18) pyrazinyl optionally substituted with one or more phenyl lower alkoxys;
        (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more halogens;
        (20) thieno[2,3-b]pyrazinyl;
        (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one or more phenyls;
        (22) benzothiazolyl optionally substituted with one or more lower alkyls;
        (23) indolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and halogen;
        (24) imidazo[1,2-a]pyridyl or imidazo[1,5-a]pyridyl, each of which is optionally substituted with one or more lower alkyls;
        (25) benzothienyl optionally substituted with one or more lower alkyls;
        (26) benzimidazolyl optionally substituted with one or more lower alkyls;
        (27) 2,3-dihydrobenzo[b]furyl;
        (28) benzofuryl optionally substituted with one or more halogens;
        (29) indazolyl optionally substituted with one or more lower alkyls;
        (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl optionally substituted with lower alkoxy;
        (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl optionally substituted with halogen or lower alkoxy, halogen, furyl, pyridyl and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and lower alkoxy;
        (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl;
        (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (34) thieno[2,3-b]pyridyl;
        (35) benzo[1,3]dioxolyl optionally substituted with one or more halogens;
        (36) benzisoxazolyl;
        (37) pyrazolo[2,3-a]pyridyl;
        (38) indolizinyl;
        (39) 2,3-dihydroindolyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl and lower alkanoyl;
        (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halogen and oxo;
        (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more oxos;
        (42) quinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyls, lower alkoxy, lower alkyl and oxo (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, pyridyl lower alkyl, aralkyl (e.g., phenyl lower alkyl), lower alkoxy and oxo;
        (44) 1,2-dihydroquinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyls, lower alkoxy, lower alkyl and oxo;
        (45) chromanyl optionally substituted with one or more lower alkyls;
        (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one or more oxos;
        (47) 3,4-dihydroisoquinolyl optionally substituted with one or more oxos;
        (48) naphthyridinyl;
        (49) 1,4-benzodioxanyl;
        (50) cinnolinyl;
        (51) quinoxalinyl;
        (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo;
        (53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo; and
        (54) piperidyl optionally substituted with one or more aryl carbonyls (e.g., phenyl carbonyl).
  • Examples of more preferable substituents represented by R6 and R7 include the following substituents (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35a), (40a), (40b), (42a), (43a), (44a), and (53):
  • (1) hydrogen;
    (4a) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1), (4-2), (4a-4), (4a-5), (4-10), (4a-16), (4-18), (4-19), (4-23), (4-26) and (4-27):
      • (4-1) cyano;
      • (4-2) hydroxyl;
      • (4a-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, lower alkoxy, imidazolyl and morpholinyl;
      • (4a-5) lower alkoxy;
      • (4-10) pyrazolyl optionally substituted with one or more lower alkyls;
      • (4a-16) amino optionally substituted with one or more lower alkylsulfonyls;
      • (4-18) triazolyl
      • (4-19) imidazolyl;
      • (4-23) nitro;
      • (4-26) lower alkanoyl; and
      • (4-27) morpholinyl;
        (6a) furyl optionally substituted with one or more lower alkyls optionally substituted with halogen;
        (7a) thienyl optionally substituted with one or more lower alkyls;
        (8a) imidazolyl optionally substituted with one or more lower alkyls;
        (9a) pyrazolyl optionally substituted with one or more lower alkyls optionally substituted with lower alkoxy;
        (10a) oxazolyl optionally substituted with one or more lower alkyls;
        (11a) isoxazolyl optionally substituted with one or more lower alkyls;
        (12a) thiazolyl optionally substituted with one or more lower alkyls optionally substituted with halogen;
        (15a) pyridyl optionally substituted with one or more substituents selected from the group consisting of the following (15-1) to (15-5), (15a-7), (15-9), (15-11), (15-12) and (15-14):
      • (15-1) halogen;
      • (15-2) cyano;
      • (15-3) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl;
      • (15-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;
      • (15-5) oxo;
      • (15a-7) lower alkoxy;
      • (15-9) lower alkanoyl;
      • (15-11) phenoxy;
      • (15-12) pyrazolyl; and
      • (15-14) N-oxide;
        (16a) pyrimidinyl optionally substituted with one or more lower alkyls;
        (17) pyridazinyl;
        (18) pyrazinyl optionally substituted with one or more phenyl lower alkoxys;
        (23a) indolyl optionally substituted with one or more lower alkyls;
        (24a) imidazo[1,2-a]pyridyl;
        (24b) imidazo[1,5-a]pyridyl optionally substituted with one or more lower alkyls;
        (26) benzimidazolyl optionally substituted with one or more lower alkyls;
        (29) indazolyl optionally substituted with one or more lower alkyls;
        (30a) furo[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (31a) furo[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (31b) 4,5-dihydrofuro[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl optionally substituted with halogen or lower alkoxy;
        (32a) thieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (32b) 6,7-dihydrothieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl;
        (33a) thieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (35a) benzo[1,3]dioxolyl;
        (40a) isoquinolyl optionally substituted with one or more oxos;
        (40b) 1,2-dihydroisoquinolyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
        (42a) quinolyl optionally substituted with one or more oxos;
        (43a) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of aralkyl (e.g., phenyl lower alkyl), pyridyl lower alkyl and oxo;
        (44a) 1,2-dihydroquinolyl optionally substituted with one or more oxos; and
        (53) 2,3-dihydrobenzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo.
  • Preferred embodiments of the diazepine compound of Formula (1) are described below.
  • R1, R2, R3 and R4 are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl, and preferably hydrogen, C1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl), C1-6 cyclo alkyl (e.g., cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl), or C1-6 alkoxy C1-6 alkyl (e.g., 2-methoxyethyl and 2-ethoxyethyl).
    • Both Y1 and Y2 are —C═.
  • A1 is lower alkylene, and preferably C1-6 alkylene such as methylene, ethylene, trimethylene, or tetramethylene. XA and XB are each independently lower alkylene, which is preferably C1-6 alkylene such as methylene, ethylene, trimethylene, or tetramethylene; a bond; —CO—; or —SO2—.
  • R6 and R7 are each independently a group selected from (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30b), (31b), (32b), (33b), (35a), (40b), (42a), (43a), (44a), and (53):
  • Examples of XA and XB include a bond, lower alkylene, lower alkenylene, —CO—, —SO2—, -lower alkylene-SO2—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO2—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO2—N(lower alkyl)-lower alkylene-, —SO2—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, lower alkylene-N(phenyl lower alkyl)-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, and —CO-lower alkylene-O—CO-lower alkylene-O—.
  • Preferred examples of XA and XB include a bond, lower alkylene, lower alkenylene, —CO—, —SO2—, -lower alkylene-SO2—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, and —O-lower alkylene-.
  • Either of the two bonds in XA may be bonded to R1 or N, and either of the two bonds in XB may be bonded to R2 or N.
  • The ring formed when R6 and R7 are linked together with the neighboring group —XA—N—XB— is a nitrogen-containing heterocyclic group optionally having one or more substituents. Examples of the nitrogen-containing heterocyclic group include the above-mentioned heterocyclic groups (a) to (c), (f) to (j), and (m) to (n). Examples of substituents of the nitrogen-containing heterocyclic group optionally having one or more substituents include the above-mentioned substituents (h1) to (h20).
  • The diazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the diazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • Figure US20140343277A1-20141120-C00005
  • wherein R1, R2, R3, R4, R5, A1, Y1 and Y2 are the same as above, and X1 is a leaving group.
  • The reaction of the compound of Formula (2) with the compound of Formula (3) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound and/or catalyst.
  • Examples of the leaving groups represented by X1 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkane sulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C1-6) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • A wide variety of known basic compounds can be used as the basic compound. Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.
  • Examples of the catalyst include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone) palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone) palladium, copper iodide/bis(triphenylphosphine) palladium dichloride, tris(dibenzylideneacetone) dipalladium, R-tris (dibenzylideneacetone)-dipalladium, S-tris (dibenzylideneacetone) dipalladium, palladium(II) acetate, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), and tetrakis (triphenylphosphine) palladium.
  • Additives (ligands etc.) can be used together with the catalyst. Examples of the additive include compounds such as R-2,2′-bis diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), and 2,2-bis(diphenylimidazolidinyliden), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.
  • The above reaction may be performed by adding to the reaction system, as required, an alkali metal iodide serving as a reaction accelerator, such as potassium iodide or sodium iodide.
  • The compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (2).
  • The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).
  • The catalyst is appropriately used in a typical catalytic amount, preferably 0.0001 to 1 moles, and more preferably 0.001 to 0.5 moles, per mole of the compound (2).
  • The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • Figure US20140343277A1-20141120-C00006
  • wherein R1, R2, R3, R4, Y1 and Y2 are the same as above.
  • The reaction converting the compound of Formula (4) to the compound of Formula (1a) can be performed by catalytic reduction of the compound of Formula (4) in a suitable solvent, in the presence of a catalytic hydrogenation reducing agent.
  • The solvent is not limited as long as it does not adversely affect the reduction reaction. Examples of such solvents include carboxylic acids such as formic acid and acetic acid; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; and lower (e.g., C1-6) alcohols such as methanol, ethanol, and isopropanol.
  • Examples of catalytic hydrogenation reducing agents include palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • The amount of catalytic hydrogenation reducing agent is typically 0.1 to 40 wt %, and preferably 1 to 20 wt %, based on the compound of Formula (4).
  • The reaction can be typically performed in a hydrogen atmosphere at atmospheric pressure to about 20 atm, and preferably atmospheric pressure to 10 atm; or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction temperature may typically be about −30 to about 100° C., and preferably about 0 to about 60° C.
  • Figure US20140343277A1-20141120-C00007
  • wherein R1, R2, R3, R4, Y1 and Y2 are the same as above; and R8 is lower alkyl.
  • The reaction converting the compound of Formula (5) to the compound of Formula (6) can be performed in a general inert solvent or without using any solvent, in the presence of an azide compound, a basic compound, and a lower (C1-6) alcohol (R8OH).
  • Examples of “lower alkyl” represented by R8 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and tert-butyl, with tert-butyl being preferred.
  • Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • Examples of azide compounds include sodium azide, lithium azide, and diphenylphosphoryl azide (DPPA).
  • Examples of usable basic compounds include organic bases such as triethylamine; tripropylamine; diisopropylethylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • In the reaction, a carboxylic azide is produced from the carboxylic compound of Formula (5) and an azide compound, and the carboxylic azide undergoes subsequent Curtius rearrangement to produce an isocyanate. The isocyanate reacts with a lower (C1-6) alcohol (R8OH) to produce a urethane compound of Formula (6).
  • Next, the reaction converting the compound of Formula (6) to the compound of Formula (1b) can be performed by solvolysis in a suitable solvent, in the presence of an acid or basic compound.
  • Examples of usable solvents include water; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, and mixtures thereof.
  • Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, thioglycolic acid, trifluoroacetic acid, and sulfonic acids such as p-toluenesulfonic acid. These acids may be used singly or in a combination of two or more.
  • Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.
  • The amount of acid or basic compound is typically at least 1 mole, and preferably about 1 to about 10 moles, per mole of the compound of Formula (6).
  • The solvolysis reaction (particularly the hydrolysis) advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 10 minutes to about 80 hours.
  • Particularly when R8 is tert-butyl, the solvolysis can be easily accomplished using the above-mentioned acids (particularly hydrochloric acid and the like) to produce the compound of Formula (1b).
  • Alternatively, the compound of Formula (5) can be directly converted to the compound of Formula (1b). This reaction can be performed by reacting the compound (5) with an azide compound in a general inert solvent or without using any solvent, in the presence of a basic compound, followed by treating the product with water. In this reaction, an isocyanate is produced from the above-mentioned carboxylic compound of Formula (5) and azide compound, and the isocyanate is hydrolyzed to produce the amine compound of Formula (1b).
  • Figure US20140343277A1-20141120-C00008
  • wherein R1, R2, R3, R4, Y1 and Y2 are the same as above; and A1a is lower alkylene with 3 or more carbon atoms.
  • Examples of “lower alkylene with 3 or more carbon atoms” represented by A1a include alkylene groups with 3 to 6 carbon atoms, such as trimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • The reaction converting the compound of Formula (7) to the compound of Formula (1c) can be performed by reacting the compound (7) with hydrazine in a suitable solvent, or by hydrolysis. Here, hydrazine hydrate may be used as the hydrazine.
  • Examples of solvents used in reacting the hydrazine include water; halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate and ethyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; and mixtures thereof.
  • The amount of hydrazine is typically at least about 1 mole, and preferably about 1 to about 5 moles, per mole of the compound of Formula (7).
  • The reaction is performed typically at about 0 to about 120° C., and preferably at about 0 to about 100° C., and is typically completed in about 0.5 to about 5 hours.
  • Figure US20140343277A1-20141120-C00009
  • wherein R1, R2, R3, R4, R6, R7, XA, A1, Y1 and Y2 are the same as above; and R7a is hydrogen or lower alkyl.
    Examples of “lower alkyl” represented by R7a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • The reaction between the compound of Formula (1d) and the compound of Formula (8) is performed, for example, in a suitable solvent or without using any solvent, in the presence of a reducing agent.
  • Examples of usable solvents include water; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; acetonitrile; and mixtures thereof.
  • Examples of reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, lithium aluminium hydride, and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts with hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • When an aliphatic acid such as formic acid, or an aliphatic acid alkali metal salt such as sodium formate is used as a reducing agent, a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours. Preferably, the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1d).
  • When a hydride reducing agent is used, a suitable reaction temperature is typically about −80 to about 100° C., and preferably about −80 to about 70° C. The reaction is typically completed in about 30 minutes to about 60 hours. The hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1d). Particularly when lithium aluminium hydride is used as a hydride reducing agent, it is preferable to use as a solvent an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system may be added an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine; or a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).
  • When a catalytic hydrogenation reducing agent is used, the reaction is typically performed at about −30 to about 100° C., and preferably at about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction is typically completed in about 1 to about 12 hours. The catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1d).
  • In the reaction of the compound of Formula (1d) and the compound of Formula (8), the compound of Formula (8) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1d).
  • The compound of Formula (8) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.
  • Figure US20140343277A1-20141120-C00010
  • wherein R1, R2, R3, R4, R6, R7, XA, XB, A1, XB, Y1 and Y2 are the same as above.
  • The reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • Alternatively, the reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed by the known “Ullmann condensation” etc. The reaction can be preferably adopted especially when XB is a bond and R7 is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted. For example, the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of copper compound (e.g., copper oxides, copper halides such as copper iodide), a basic compound (e.g., sodium tert-butoxide, K3PO4 and Cs2CO3), and if necessary a phosphine (e.g., triphenylphosphine, xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).
  • The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • Figure US20140343277A1-20141120-C00011
  • wherein R1, R2, R3, R4, R5, Y1 and Y2 are the same as above.
  • The reaction of the compound of Formula (10) with the compound of Formula (3) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.
  • Figure US20140343277A1-20141120-C00012
  • wherein R2, R3, R4, R5, A1, X1, Y1 and Y2 are the same as above; and R1a is lower alkyl.
  • Examples of “lower alkyl” represented by R1a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
  • The reaction of the compound of Formula (1 g) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • In this reaction, when R4 is hydrogen in the compound of Formula (1 g), a compound may be obtained wherein the 1- and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R1a.
  • Figure US20140343277A1-20141120-C00013
  • wherein R1a, R4, R5, A1, X1, Y1 and Y2 are the same as above.
  • The reaction of the compound of Formula (1i) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • In this reaction, when R4 is hydrogen in the compound of Formula (1i), a compound may be obtained wherein the 1-, 3-, and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R1a.
  • Figure US20140343277A1-20141120-C00014
  • wherein R1, R4, R5, A1, X1, Y1 and Y2 are the same as above; and R2a is lower alkyl.
  • Examples of “lower alkyl” represented by R2a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
  • The reaction of the compound of Formula (1k) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • In this reaction, when R1 and/or R4 is hydrogen in the compound of Formula (1k), a compound may be obtained wherein the 1-, 3-, and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R2a.
  • Figure US20140343277A1-20141120-C00015
  • wherein R2, R3, R4, R1a, X1, Y1 and Y2 are the same as above; R9 is lower alkoxy; and R10 is lower alkoxycarbonyl.
  • Examples of “lower alkoxy” represented by R9 include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, and ethoxy. Examples of “lower alkoxycarbonyl” represented by R10 include (C1-6 alkoxy) carbonyl groups, such as methoxycarbonyl, ethoxycarbonyl.
  • In the reaction of the compound of Formula (13) with the compound of Formula (14), the compound of Formula (13) is reacted with the carboxylic acid compound of Formula (14) through a general amide bond formation reaction. Conditions for known amide bond formation reactions can be easily employed in this amide formation reaction. For example, the following reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (14) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (13); (ii) an active ester method, in which Carboxylic Acid (14) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or to an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (13); (iii) a carbodiimide method, in which Carboxylic Acid (14) is subjected to a condensation reaction with Amine (13) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), or carbonyldiimidazole; and (iv) other methods, for example, a method in which Carboxylic Acid (14) is converted to a carboxylic anhydride using a dehydrating agent such as acetic anhydride, and the carboxylic anhydride is reacted with Amine (13), a method in which an ester of Carboxylic Acid (14) with a lower (C1-6) alcohol is reacted with Amine (13) at a high pressure and a high temperature, and a method in which an acid halide of Carboxylic Acid (14), i.e., a carboxylic acid halide, is reacted with Amine (13).
  • Generally, the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound. Any solvents used for conventional mixed acid anhydride methods are usable. Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.
  • Examples of alkyl halocarboxylates usable in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. In this method, Carboxylic Acid (14), an alkyl halocarboxylate, and Amine (13) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (14) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (13).
  • The reaction is typically performed at about −20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.
  • Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound. Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (13) mentioned above as one of the other methods (iv). A suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (13). When WSC is used as an activating agent, the addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously. The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.
  • When the method in which a carboxylic acid halide is reacted with Amine (13), mentioned above as one of the other methods (iv), is employed, the reaction is performed in the presence of a basic compound in a suitable solvent. Examples of usable basic compounds include a wide variety of known basic compounds, such as those for use in the Schotten-Baumann reaction described above. In addition to those usable in the mixed acid anhydride method, usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; acetone; and water. The ratio of the carboxylic acid halide to Amine (13) is not limited, and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (13). The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 30 hours.
  • The amide bond formation reaction shown in Reaction Formula 11 can also be performed by reacting Carboxylic Acid (14) with Amine (13) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis (2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.
  • The reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (13), typically at about −20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (14) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (13).
  • The reaction converting the compound of Formula (15) to the compound of Formula (16) can be performed by, for example, [1] reducing the compound of Formula (15) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (15) in a suitable inert solvent using a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • When Method [1] in which a catalytic hydrogenation reducing agent is used, examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof. Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel. The reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (15). The reaction temperature is typically about −20 to about 150° C., and preferably about 0 to about 100° C. The hydrogen pressure is typically about 1 to 10 atm. The reaction is typically completed in about 0.5 to about 100 hours. An acid such as hydrochloric acid may be added to the reaction.
  • When Method [2] above is used, a mixture of iron, zinc, tin, or tin (II) chloride, with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, iron (II) sulfate, zinc, or tin, with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride, can be used as a reducing agent. Examples of inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof. Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used. For example, when a mixture of tin (II) chloride and hydrochloric acid is used as a reducing agent, the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours. A reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (15).
  • The reaction converting the compound of Formula (16) to the compound of Formula (17) is performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14).
  • The reaction of the compound of Formula (17) with the compound of Formula (11) is performed under the same reaction conditions as those for the reaction of the compound of Formula (1 g) with the compound of Formula (11) in Reaction Formula 8.
  • Figure US20140343277A1-20141120-C00016
  • wherein R1, R2a, R4, R9, X1, Y1 and Y2 are the same as above.
  • The reaction of the compound of Formula (19) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • When R1 and/or R4 is hydrogen in the reaction of the compound of Formula (19) with the compound of Formula (12), the hydrogen atom may be replaced with R2a.
  • The compound of Formula (18) can also be produced according to the process shown in the following Reaction Formula 13.
  • Figure US20140343277A1-20141120-C00017
  • wherein R1, R2, R3, R4, R9, Y1 and Y2 are the same as above.
  • The reaction of the compound of Formula (20) with the compound of Formula (21) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14) shown in Reaction Formula 11 above.
  • Figure US20140343277A1-20141120-C00018
  • wherein R1, R2, R3, R4, R9, Y1 and Y2 are the same as above; and Tf is trifluoromethanesulfonyl (CF3SO2—).
  • The reaction converting the compound of Formula (18) to the compound of Formula (22) can be performed in a suitable solvent in the presence of an acid.
  • Examples of solvents include water; lower (C1-6) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.
  • The reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours. The amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (18).
  • The reaction converting the compound of Formula (22) to the compound of Formula (23) is performed by reacting the compound of Formula (22) with trifluoromethanesulfonic anhydride in a suitable solvent, in the presence or absence of a basic compound.
  • Examples of solvents include ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • Figure US20140343277A1-20141120-C00019
  • wherein R1, R2, R3, R4, Tf, Y1 and Y2 are the same as above; M is a metal, for example, Na, K, Ag, Zu, Cu, and the like; and X is a positive number.
  • The reaction converting the compound of Formula (23) to the compound of Formula (4) can be performed by reacting the compound of Formula (23) with a cyano metal in a suitable solvent, in the presence of a catalyst.
  • Examples of metal cyanides (M(CN)x) include sodium cyanide, potassium cyanide, silver cyanide, zinc cyanide, and cuprous cyanide.
  • Examples of solvents usable in this reaction include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of catalysts include palladium compounds such as tetrakis (triphenylphosphine) palladium (0); dichlorobis (triphenylphosphine) palladium (II); and tris (dibenzylideneacetone) dipalladium (0).
  • A ligand such as 1,1′-bis (diphenylphosphino) ferrocene or zinc dust may be added, as required, in order to promote the reaction.
  • The catalyst can be typically used in an amount of 0.01 to 1 mole, and preferably 0.01 to 0.5 moles, per mole of the compound of Formula (23).
  • The metal cyanide can be typically used in an amount of at least 1 mole, and preferably 1 to 3 moles, per mole of the compound of Formula (23).
  • The reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C. The reaction is typically completed in about 1 hour to about 1 week.
  • The reaction converting the compound of Formula (4) to the compound of Formula (10) is performed in a suitable solvent, in the presence of a reducing agent.
  • Examples of solvents include aliphatic acids such as formic acid; ethers such as dioxane, tetrahydrofuran, diethylether, and diethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • Examples of reducing agents include alkylaluminum hydrides such as diisobutylaluminum hydride; and Raney nickel. The reducing agent is typically used in an amount at least equal to, and preferably from an equal weight to 5 times the weight of the compound of Formula (4).
  • The reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C. The reaction is typically completed in about 0.5 to about 20 hours.
  • Figure US20140343277A1-20141120-C00020
  • wherein R1, R2, R3, R4, Tf, Y1 and Y2 are the same as above; and R11 is lower alkyl.
  • Examples of “lower alkyl” represented by R11 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, and ethyl.
  • The reaction converting the compound of Formula (23) and the compound of Formula (24) to the compound of Formula (25) can be performed in a suitable solvent, in the presence of a catalyst.
  • Examples of usable solvents include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • Preferable as the catalyst are palladium compounds, for example, tetrakis(triphenylphosphine)palladium (0); dichlorobis(triphenylphosphine)palladium (II); and the like. The catalyst is typically used in an amount of about 0.01 to about 1 mole, and preferably about 0.01 to about 0.5 moles, per mole of the compound of Formula (23).
  • Further, a basic compound such as triethylamine, pyridine, may be added, as required.
  • The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.
  • The reaction converting the compound of Formula (25) to the compound of Formula (26) can be performed by catalytic reduction of the compound of Formula (25) in a suitable solvent in a hydrogen atmosphere.
  • Known hydrogenolysis methods can be widely employed in hydrogenolysis. Examples of such hydrogenolysis methods include chemical reduction and catalytic reduction.
  • Catalysts suitable for use in catalytic reduction include platinum catalysts, such as platinum plates, spongy platinum, platinum black, colloid platinum, platinum oxide, and platinum wires; palladium catalysts, such as spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, and palladium/barium carbonate; nickel catalysts, such as reduced nickel, nickel oxide, and Raney nickel; cobalt catalysts, such as reduced cobalt and Raney cobalt; and iron catalysts, such as reduced iron.
  • The amount of the catalyst used for catalytic reduction is not limited, and may be an amount generally used.
  • The reaction temperature is typically 0 to 120° C., preferably room temperature to about 100° C., and more preferably room temperature to 80° C. The reaction time is typically 30 minutes to 24 hours, preferably 30 minutes to 10 hours, and more preferably 30 minutes to 4 hours.
  • The reaction converting the compound of Formula (26) to the compound of Formula (5) can be performed by hydrolysis of the compound (26).
  • This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acid or basic compound.
  • Examples of solvents include water; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and like sulfonic acids. These acids may be used singly or in a combination of two or more.
  • Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.
  • The hydrolytic reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C. The reaction is typically completed in about 10 minutes to about 30 hours.
  • Figure US20140343277A1-20141120-C00021
  • wherein R1, R2, R3, R4, Tf, Y1 and Y2 are the same as above; and A1b is lower alkylene.
  • Examples of “lower alkylene” represented by A1b include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • The reaction converting the compound of Formula (23) and the compound of Formula (27) to the compound of Formula (28) can be performed in a suitable solvent, in the presence of a copper halide and a palladium catalyst.
  • Examples of solvents include ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of copper halides include copper (I) chloride, copper (I) bromide, and copper (I) iodide.
  • Examples of palladium catalysts include palladium compounds such as tetrakis(triphenylphosphine)palladium (0); and dichlorobis(triphenylphosphine)palladium (II).
  • A basic compound may be added, as required. Examples of basic compounds include triethylamine, diisopropylethylamine, pyridine, and diethylamine. The basic compound can be typically used in an amount of 0.01 to 10 mole, and preferably 0.01 to 1 moles, per mole of the compound of Formula (23).
  • The reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 180° C. The reaction is typically completed in about 10 minutes to about 30 hours.
  • The reaction converting the compound of Formula (28) to the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (25) to the compound of Formula (26) shown in Reaction Formula 16 above.
  • Figure US20140343277A1-20141120-C00022
  • wherein R6, R7, R8, XA, XB, and X1 are the same as above.
  • The reaction of the compound of Formula (3a) with the compound of Formula (8) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.
  • The reaction of the compound of Formula (3a) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.
  • The compound of Formula (3), which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.
  • Figure US20140343277A1-20141120-C00023
  • wherein R7b is a nitrogen-containing heterocyclic group optionally having one or more substituents; and
    XB1 is lower alkylene.
  • Examples of R7b include, among groups represented by the group R7 mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds having an N—H bond, and groups optionally having one or more substituents.
  • Examples of “lower alkylene” represented by XB1 include alkylene groups with 2 to 4 carbon atoms, such as ethylene and trimethylene.
  • The reaction of the compound of Formula (29) with the compound of Formula (30) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • The reaction converting the compound of Formula (31) to the compound of Formula (3d) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (7) to the compound of Formula (1c) shown in Reaction Formula 4 above.
  • Figure US20140343277A1-20141120-C00024
  • wherein R7b is the same as above; XB2 is lower alkylene; and R12 and R13 are each independently lower alkyl, or R12 and R13 are linked to form lower alkylene.
  • Examples of “lower alkyl” represented by R12 and R13 include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and n-propyl. Examples of “lower alkylene” formed by R12 and R13 when they are linked include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • Examples of “lower alkylene” represented by XB2 include alkylene groups with 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.
  • The reaction of the compound of Formula (29) with the compound of Formula (32) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • The reaction converting the compound of Formula (33) to the compound of Formula (8a) can be performed by hydrolysis of the compound (33).
  • This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acidic compound.
  • Examples of solvents include water; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS), and like sulfonic acids. These acids may be used singly or in a combination of two or more.
  • The hydrolytic reaction advantageously proceeds typically at about 0 to about 100° C., and preferably at about 0 to about 80° C. The reaction is typically completed in about 10 minutes to about 30 hours.
  • Figure US20140343277A1-20141120-C00025
  • wherein A1b is the same as above; and Ms is methanesulfonyl (CH3SO2—).
  • The reaction converting the compound of Formula (34) to the compound of Formula (35) is performed by methanesulfonylation (mesylation) of the compound of Formula (34) using a conventional method. Typically, the compound of Formula (35) can be produced by reacting the compound of Formula (34) with trifluoromethanesulfonic anhydride in a suitable solvent (e.g., dichloromethane), in the presence of a basic compound (e.g., triethylamine).
  • The reaction converting the compound of Formula (35) to the compound of Formula (36) is performed by iodination of the compound of Formula (35) with an iodinating agent such as sodium iodide, in a suitable solvent (e.g., acetone).
  • The reaction converting the compound of Formula (36) to the compound of Formula (27) can be performed by reacting the compound of Formula (36) with potassium phthalimide in a suitable solvent (e.g., N,N-dimethylformamide).
  • Alternatively, the compound of Formula (27) can be directly produced by reacting the compound of Formula (34) with phthalimide under the Mitsunobu reaction conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).
  • The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.
  • The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • The starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.
  • Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O, etc.
  • The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.
  • Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.
  • The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K+ channel-blocking agent.
  • Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
    • 2. Second Invention (Amino Compound)
  • The present inventors conducted extensive research to develop a compound that blocks the IKur current (Kv1.5 channel) and/or the IKACh current (GIRK1/4 channel) potently and more selectively than other K+ channels. As a result, the inventors found that a novel amino compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.
  • The present invention provides amino compounds, and pharmaceutical compositions comprising the amino compounds as summarized in items 1 to 7 below.
  • Item 1. An amino compound represented by General Formula (1):
  • Figure US20140343277A1-20141120-C00026
  • or a salt thereof,
    wherein R1 and R2 are each independently hydrogen or organic group; XA and XB are each independently a bond, alkylene, alkenylene, —CO—, —SO2—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO2—, —CO—, —O—, —NH—, —CONH— and —SO2NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in XA and XB is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl;
    A1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo;
    R3 is (i) a heterocyclic group which is optionally substituted with one or more substituents, or
    (ii) an aryl group substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, carboxyl, halo-lower alkyl, lower alkanoyl lower alkyl, phenyl lower alkyl, cyclo lower alkyl, lower alkoxy, halo lower alkoxy, phenyl lower alkoxy, phenoxy, cyano, hydroxyl, halogen, nitro, lower alkyl thio, lower alkanoyl, lower alkoxy carbonyl, lower alkenyl, phenyl, triazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzo[d]oxazolyl, benzo[d]thiazolyl and the group represented by General Formula (2):
  • Figure US20140343277A1-20141120-C00027
  • wherein Y is a bond, lower alkylene, or —CO—; R4 and R5 are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, or lower alkanoyl; or R4 and R5 may be linked to form a ring together with the neighboring nitrogen, and the ring may optionally have one or more substituents.
  • Item 2. A pharmaceutical composition comprising an amino compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 3. A pharmaceutical composition according to Item 1 for preventing and/or treating arrhythmia.
  • Item 4. An amino compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 5. Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 6. Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 7. A method of preventing and/or treating arrhythmia, comprising administering to a patient an amino compound represented by Formula (1) or a salt thereof according to Item 1.
  • The groups represented by, or substituents of, R1, R2, R3, R4, R5, A1, XA, XB and Y in the specification are described below.
  • The term “one or more” may be preferably 1 to 6, more preferably 1 to 3.
  • Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • Examples of “alkylene” include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.
  • Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • Examples of “alkenylene” include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.
  • Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • Examples of “lower alkylidene” include linear or branched alkylidene groups having 1 to 6 carbon atoms, such as methylidene, ethylidene, propylidene, and butylidene.
  • Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • Examples of “halogen” include fluorine, chlorine, bromine, and iodine.
  • Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • Examples of “aralkyl group” include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.
  • Examples of “organic group” include lower alkyl, lower alkoxy, cyclo lower alkyl, amino, lower alkyl thio, aryl, and heterocyclic group, each of which is optionally substituted.
  • Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, naphthyl and tetrahydronaphthyl, indenyl, and dihydroindenyl.
  • Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. More preferable examples of heterocyclic groups include the following (a) to (o):
  • (a) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
  • (b) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, 1,4-diazepanyl, etc.;
  • (c) saturated or unsaturated condensed 7- to 14-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, decahydroquinolyl, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazolyl, etc.), quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl (e.g. benzo[d][1,2,3]triazolyl, etc.), tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, etc.,), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.) tetrahydropyridoindolyl (e.g., 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, etc.), etc.;
  • (d) saturated or unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl, etc.), tetrahydrofuryl, etc.;
  • (e) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;
  • (f) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
  • (g) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;
  • (h) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), furopyrrolyl (e.g., furo[3,2-b]pyrrolyl etc.) etc.;
  • (i) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), isothiazolyl, etc.;
  • (j) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
  • (k) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;
  • (l) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl), etc.;
  • (m) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzo[d]isothiazolyl, 2,3-dihydro benzo[d]isothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.;
  • (n) saturated or unsaturated 7- to 12-membered heterocyclic spiro groups containing 1 to 2 nitrogen atom(s), for example, azaspiroundecanyl (e.g., 3-azaspiro[5.5]undecanyl), etc.; and
  • (O) saturated 7- to 12-membered hetero bicyclic groups containing 1 to 3 nitrogen atom(s), for example, azabicyclooctanyl (e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl), etc;
  • wherein said heterocyclic group may be substituted by one or more suitable substituents.
  • Substituents of “aryl group which is optionally substituted” represented by R1 and R2 are each independently one or more substituents selected from the group consisting of:
  • (a1) cyano;
    (a2) hydroxyl;
    (a3) halogen;
    (a4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, hydroxyl, imidazolyl, morpholinyl, triazolyl and phenyl;
    (a5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of halogen, amino, lower alkyl amino and phenyl;
    (a6) pyridyl;
    (a7) thienyl;
    (a8) piperazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and halo phenyl lower alkyl;
    (a9) phenyl;
    (a10) pyrazolyl optionally substituted with one or more lower alkyl;
    (a11) pyrimidinyl optionally substituted with one or more lower alkyls;
    (a12) piperidyl optionally substituted with one or more lower alkyls;
    (a13) furyl;
    (a14) carboxy;
    (a15) lower alkoxycarbonyl;
    (a16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, phenyl, lower alkanoyl and lower alkylsulfonyl;
    (a17) lower alkylthio;
    (a18) triazolyl;
    (a19) imidazolyl;
    (a20) pyrrolidinyl optionally substituted with one or more oxos;
    (a21) lower alkylsulfonyl;
    (a22) lower alkylenedioxy optionally substituted with one or more halogens;
    (a23) nitro;
    (a24) oxazolyl;
    (a25) thiazolyl optionally substituted with one or more lower alkyls;
    (a26) lower alkanoyl;
    (a27) sulfo;
    (a28) carbamoyl optionally substituted with one or two lower alkyls;
    (a29) phenoxy;
    (a30) isoxazolyl;
    (a31) pyrrolyl;
    (a32) lower alkenyl;
    (a33) cyclo lower alkyl;
    (a34) benzo[d]oxazolyl; and
    (a35) oxo.
  • Substituents of “heterocyclic group which is optionally substituted” represented by R1 and R2 are each independently one or more substituents selected from the group consisting of:
  • (h1) oxo;
    (h2) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, phenyl amino, cyclo lower alkyl, lower alkoxy, pyridyl, mono- or di-lower alkyl amino, hydroxyl, lower alkyl substituted isoxazolyl, 1,3-dioxolanyl, lower alkyl substituted piperidinyl, mono or di lower alkyl amino, fulyl, imidazolyl, morpholinyl, lower alkyl substituted 1,4-diazepanyl, phenyl thiazolyl, phenyl lower alkyl tetrazolyl, lower alkyl tetrazolyl, quinolyl, pyrrolyl, imidazolyl, 2,3-dihydrobenzofuryl and benzodioxolyl;
    (h3) cyclo lower alkyl;
    (h4) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of pyridyl, halo-lower alkoxy phenyl, halo phenyl, phenyl, and halo-lower alkyl phenyl;
    (h5) aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkoxy, halo lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, and cyano;
    (h6) aralkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano, phenyl, and oxo, on the aryl and/or lower alkyl group of aralkyl;
    (h7) heterocyclic group optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano, phenyl, and oxo;
    (h8) hydroxyl;
    (h9) halogen;
    (h10) carboxy;
    (h11) lower alkanoyl;
    (h12) lower alkoxycarbonyl;
    (h13) lower alkylenedioxy;
    (h14) cyano;
    (h15) nitro;
    (h16) sulfo;
    (h17) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, mono- or di-lower alkyl amino lower alkyl, (lower alkyl)(phenyl)amino lower alkyl, lower alkyl substituted phenoxy lower alkyl, phenyl lower alkyl, cyclo lower alkyl lower alkyl, lower alkyoxy phenyl lower alkyl, lower alkyl phenyl lower alkyl, triazolyl lower alkyl, halo substituted phenyl, halo-lower alkyl substituted phenyl, halo-lower alkoxy substituted phenyl, piperazinyl lower alkyl carbonyl, phenyl lower alkyl carbonyl and lower alkoxy dihydroindenyl;
    (h18) lower alkylthio;
    (h19) lower alkylsulfonyl;
    (h20) lower alkenyl optionally substituted with one or more phenyls;
    (h21) benzo[d][1,3]dioxolyl carbonyl;
    (h22) 2,3-dihydroindenyl;
    (h23) phenoxy substituted with one or more substituents selected from the group consisting of halo-lower alkoxy and halogen;
    (h24) lower alkylidene substituted with one or more lower alkoxy phenyls;
  • Substituents of “lower alkyl group which is optionally substituted” represented by R1 and R2 are each independently one or more substituents selected from the group consisting of oxo and phenyl.
  • Substituents of “cyclo lower alkyl group which is optionally substituted” represented by R1 and R2 are each independently one or more substituents selected from the group consisting of lower alkyl phenyl and phenyl.
  • Substituents of “amino group which is optionally substituted” represented by R1 and R2 are each independently one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and phenyl lower alkyl.
  • Substituents of “dihydroindenyl group which is optionally substituted” represented by R1 and R2 are each independently one or more oxos.
  • Preferable substituents represented by R1 and R2 are each independently selected from the group consisting of the following substituents (1) to (69):
  • (1) hydrogen;
    (2) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo and phenyl;
    (3) cyclo lower alkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl phenyl and phenyl;
    (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-25):
    (4-1) cyano;
    (4-2) hydroxyl;
    (4-3) halogen;
    (4-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, imidazolyl, hydroxyl, triazolyl (e.g, 1,2,4-triazolyl) and morpholinyl;
    (4-5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino;
    (4-6) pyridyl;
    (4-7) thienyl;
    (4-8) piperazinyl optionally substituted with one or more lower alkyls;
    (4-9) phenyl;
    (4-10) pyrazolyl optionally substituted with one or more lower alkyls;
    (4-11) pyrimidinyl optionally substituted with one or more lower alkyls;
    (4-12) piperidyl optionally substituted with one or more lower alkyls;
    (4-13) furyl;
    (4-14) carboxy;
    (4-15) lower alkoxycarbonyl;
    (4-16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and lower alkylsulfonyl;
    (4-17) lower alkylthio;
    (4-18) triazolyl;
    (4-19) imidazolyl;
    (4-20) pyrrolidinyl optionally substituted with one or more oxos;
    (4-21) lower alkylsulfonyl;
    (4-22) lower alkylenedioxy optionally substituted with one or more halogens;
    (4-23) nitro;
    (4-24) oxazolyl;
    (4-25) thiazolyl optionally substituted with one or more lower alkyls;
    (4-26) phenoxy; and
    (4-27) carbamoyl optionally substituted with one or two lower alkyls;
    (5) naphthyl;
    (6) furyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl, and phenyl;
    (7) thienyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl, and furyl;
    (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, and halogen;
    (9) pyrazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, halogen, phenyl optionally substituted with lower alkoxy, furyl, and thienyl;
    (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
    (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, thienyl, and furyl;
    (12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with lower alkoxy, phenyl, and lower alkanoylamino;
    (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl;
    (14) triazolyl optionally substituted with one or more lower alkyls;
    (15) pyridyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, oxo, hydroxyl, lower alkoxy, halogen, pyrrolidinyl, morpholinyl, thienyl, piperazinyl lower alkyl carbonyl amino;
    (16) pyrimidinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
    (17) pyridazinyl;
    (18) pyrazinyl;
    (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more halogens;
    (20) thieno[2,3-b]pyrazinyl;
    (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one or more phenyls;
    (22) benzothiazolyl optionally substituted with one or more lower alkyls;
    (23) indolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and halogen;
    (24) imidazo[1,2-a]pyridyl optionally substituted with one or more lower alkyls;
    (25) benzothienyl optionally substituted with one or more lower alkyls;
    (26) benzimidazolyl optionally substituted with one or more lower alkyls;
    (27) 2,3-dihydrobenzo[b]furyl;
    (28) benzofuryl optionally substituted with one or more halogens;
    (29) indazolyl optionally substituted with one or more lower alkyls;
    (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
    (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl optionally substituted with halogen, halogen, furyl, pyridyl, and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and lower alkoxy;
    (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl;
    (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
    (34) thieno[2,3-b]pyridyl;
    (35) benzo[1,3]dioxolyl optionally substituted with one or more halogens;
    (36) benzisoxazolyl;
    (37) pyrazolo[2,3-a]pyridyl;
    (38) indolizinyl;
    (39) 2,3-dihydroindolyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, and lower alkanoyl;
    (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, lower alkoxy and oxo;
    (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more oxos;
    (42) 1,2-dihydroquinolyl optionally substituted with one or more substituents selected from the group consisting of lower alkoxy and oxo;
    (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkoxy;
    (44) quinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyl, lower alkoxy, lower alkyl, and oxo;
    (45) chromanyl optionally substituted with one or more lower alkyls;
    (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one or more oxos;
    (47) 3,4-dihydroisoquinolyl optionally substituted with one or more oxos;
    (48) naphthyridinyl;
    (49) 1,4-benzodioxanyl;
    (50) cinnolinyl;
    (51) quinoxalinyl;
    (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo;
    (53) 2,3-dihydroindenyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkoxy;
    (54) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and phenyl lower alkyl;
    (55) lower alkoxy;
    (56) lower alkylthio;
    (57) decahydroquinolyl;
    (58) piperazinyl optionally substituted with one or more substituents selected from the group consisting of
    (58-1) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkoxy, 1,3-dioxolanyl, lower alkyl-substituted piperidyl, furyl, imidazolyl, phenyl amino, phenyl-substituted thiazolyl, phenyl lower alkyl-substituted tetrazolyl, lower alkyl-substituted tetrazolyl, quinolyl, pyrrolyl, mono- or di-lower alkyl amino, pyridyl and benzo[d][1,3]dioxolyl;
    (58-2) oxo;
    (58-3) halo-lower alkyl substituted phenyl amino;
    (58-4) cyclo lower alkyl;
    (58-5) 2,3-dihydroindenyl;
    (58-6) phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo-lower alkyl and halo-lower alkoxy; and
    (58-7) phenyl lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, halo-lower alkyl, halo-lower alkoxy and pyridyl, on the benzene ring and/or lower alkyl of phenyl lower alkyl;
    (59) 1,4-diazepanyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, pyridyl and morpholinyl lower alkyl;
    (60) piperidyl optionally substituted with one or more substituents selected from the group consisting of:
    (60-1) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, mono- or di-lower alkylamino, 2,3-dihydrobenzofuryl and imidazolyl;
    (60-2) amino optionally substituted with one or two substituents selected from the group consisting of lower alkyl, halo-phenyl, halo-lower alkoxy-substituted phenyl, mono- or di-lower alkyl amino lower alkyl, lower alkyl-substituted phenoxy lower alkyl, phenyl lower alkyl, phenyl lower alkyl carbonyl, cyclo lower alkyl lower alkyl, lower alkoxy phenyl lower alkyl, 1,2,4-triazolyl lower alkyl, pyridyl phenyl, (phenyl)(lower alkyl)amino lower alkyl, lower alkoxy-substituted 2,3-dihydro-1H-indenyl and lower alkyl phenyl lower alkyl;
    (60-3) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of phenyl, halo-phenyl, halo-lower alkoxy-substituted phenyl, halo-lower alkyl substituted phenyl and pyridyl;
    (60-4) phenoxy optionally substituted with one or more substituents selected from the group consisting of halogen, and halo-lower alkoxy;
    (60-5) phenyl lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, lower alkoxy and amino, on the benzene ring and/or lower alkyl of phenyl lower alkyl;
    (60-6) lower alkoxy phenyl lower alkylidene;
    (60-7) phenyl imidazolyl;
    (60-8) phenyl morpholinyl; and
    (60-9) phenyl;
    (61) morpholinyl optionally substituted with one or more mono- or di-lower alkyl amino-substituted piperidyl lower alkyls;
    (62) benzo[d][1,2,3]triazolyl optionally substituted with one or more lower alkyls;
    (63) 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl;
    (64) 2,3,4,9-tetrahydropyrido[3,4-b]indolyl);
    (65) 3-azaspiro[5,5]undecanyl;
    (66) 8-azabicyclo[3,2,1]octanyl;
    (67) tetrahydro-2H-pyranyl;
    (68) furo[3,2-b]pyrrolyl optionally substituted with one or more lower alkyls; and
    (69) tetrahydrofuryl.
  • Preferable examples of “aryl group which is optionally substituted” for R1 and R2 include the substituents (4), (5) and (53).
  • Preferable examples of “heterocyclic group which is optionally substituted” for R1 and R2 include the substituents (6) to (52) and (57) to (69).
  • Examples of XA and XB include a bond, lower alkylene, lower alkenylene, —CO—, —SO2—, -lower alkylene-SO2—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO2—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO2—N(lower alkyl)-lower alkylene-, —SO2—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, and —CO-lower alkylene-O—CO—.
  • Either of the two bonds in XA may be bonded to R1 or N, and either of the two bonds in XB may be bonded to R2 or N.
  • Examples of “lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo” represented by A1 are C1-6 alkylene and —CO—C2-6 alkylene-.
  • Examples of heterocyclic groups of “heterocyclic group which is optionally substituted” represented by R3 include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, quinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, indolyl, 2,3-dihydroindolyl, isoindolyl, 1,3-dihydroisoindolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzo[d]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3,4,5-tetrahydrobenz[f]1,4-thiazepinyl, 1,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, benzo[d][1,3]oxathiolyl, 2H-chromenyl, 2H-pyranyl, benzofuryl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 2,3,4,5-tetrahydrobenzo[e][1,4]diazepinyl, 2,3,4,5-tetrahydrobenzo[b]azepinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3,4,5-tetrahydrobenzo[c]azepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepinyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c][1,2,5]oxadiazolyl, 2H-pyranyl, 3,4-dihydroisoquinolyl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinyl, 1,2,3,5-tetrahydrobenzo[e][1,4]oxazepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, dibenzo[b,d]furyl, 9H-carbazolyl, benzo[c][1,2,5]oxadiazolyl, 1,2,3,4,5,6-hexahydrobenzo[b]azocinyl, 2,3-dihydrobenzofuryl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 2,4-dihydro-1H-benzo[d][1,3]oxazinyl, and benzo[b]thiophenyl.
  • Examples of substituents of “substituted heterocyclic group” represented by R3 include the substituents (h1) to (h17) and (h20) to (h24), which are mentioned as substituents of heterocyclic groups represented by R1 and R2. Among these, preferable substituents are (h1), (h2), (h5), (h6), (h8), (h10), (h11), (h12) and (h20), and more preferable substituents are (h1) and/or (h2).
  • Examples of aryl groups of “aryl group which is substituted” represented by R3 include those as defined above.
  • When R4 and R5 in General Formula (2) are linked to form a ring together with the neighboring nitrogen, examples of the group —N R4R5 include the following:
  • Figure US20140343277A1-20141120-C00028
  • Each of the ring may optionally have one or more substituents selected from the group consisting of oxo; lower alkyl; phenyl lower alkyl; halo-phenyl lower alkyl; and amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, phenyl and halo-phenyl.
  • The amino compound of the present invention represented by General Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the amino compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • Figure US20140343277A1-20141120-C00029
  • wherein R1, R2, R3, XA, XB and A1 are the same as above; and X1 is a leaving group.
  • The reaction of the compound of Formula (3) with the compound of Formula (4) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.
  • Examples of the leaving groups represented by X1 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C1-6) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • A wide variety of known basic compounds can be used as the basic compound. Examples of usable basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine, tripropylamine, pyridine, quinoline, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.
  • The above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • The compound of Formula (4) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (3).
  • The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (3).
  • The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • Figure US20140343277A1-20141120-C00030
  • wherein R1, R2, R3, XA and A1 are the same as above; and R2a is hydrogen or lower alkyl.
  • Examples of lower alkyl groups represented by R2a include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.
  • The reaction between the compound of Formula (1b) and the compound of Formula (5) is performed, for example, in an inert solvent or suitable solvent, in the presence of a reducing agent.
  • Examples of usable solvents include water; lower (C1-6) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetonitrile, formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.
  • Examples of reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, and lithium aluminium hydride; and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts and hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.
  • When an aliphatic acid such as formic acid, or an aliphatic acid alkali metal salt such as sodium formate is used as a reducing agent, a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours. Preferably, the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1b).
  • When a hydride reducing agent is used, a suitable reaction temperature is typically about −80 to about 100° C., and preferably about −80 to about 70° C. The reaction is typically completed in about 30 minutes to about 60 hours. The hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1b). Particularly when lithium aluminium hydride is used as a hydride reducing agent, it is preferable to use as a solvent an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system of the reaction may be added an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine; or a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).
  • When a catalytic hydrogenation reducing agent is used, the reaction is typically performed at about −30 to about 100° C., and preferably about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen doner such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction is typically completed in about 1 to about 12 hours. The catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1b).
  • In the reaction of the compound of Formula (1b) and the compound of Formula (5), the compound of Formula (5) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1b).
  • The compound of Formula (5) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.
  • Figure US20140343277A1-20141120-C00031
  • wherein R1, R2, R3, XA, XB, A1 and X1 are the same as above.
  • The reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • Alternatively, the reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed by the known “Ullmann condensation”, “Palladium coupling reaction”, etc. The reaction can be preferably adopted especially when XB is a bond and R2 is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted. For example, the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of transition metal compound (e.g., Pd(OAc)2, Pd2(dba)3 and copper iodide), a basic compound (e.g., sodium tert-butoxide, K3PO4 and Cs2CO3), and if necessary a phosphine (e.g., xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).
  • The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • The compound of Formula (3), which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.
  • Figure US20140343277A1-20141120-C00032
  • wherein R1, R2, R2a, XA, XB and X1 are the same as above.
  • The reaction of the compound of Formula (3a) with the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above.
  • The reaction of the compound of Formula (3a) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • Figure US20140343277A1-20141120-C00033
  • wherein R1, R2, R3, XA, XB and A1 are the same as above.
  • The reaction of the compound of Formula (8) with the compound of Formula (9) can be performed by the known “Mitsunobu reaction” conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).
  • Figure US20140343277A1-20141120-C00034
  • wherein R1, R2, R3, XA, XB, X1 and A1 are the same as above.
  • The reaction of the compound of Formula (10) with the compound of Formula (9) can be performed by the known O-alkylation reaction. For example, The reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K2CO3 and Cs2CO3).
  • The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • Figure US20140343277A1-20141120-C00035
  • wherein R1, R2, R3, XA and XB are the same as above; and A10 is a divalent residue which is obtained by removing —CH2— from group A1.
  • The reaction of the compound of Formula (3) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above,
  • Figure US20140343277A1-20141120-C00036
  • wherein R3, X1, X2 and A1 are the same as above.
  • The reaction of the compound of Formula (9) with the compound of Formula (15) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.
  • The reaction of the compound of Formula (9) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.
  • The reaction of the compound of Formula (4) with the compound of Formula (13) can be performed by the known N-alkylation reaction. For example, The reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K2CO3 and Cs2CO3).
  • The N-alkylation reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • The reaction converting the compound of Formula (14) to the compound of Formula (1e) can be performed by the known method. For example, The reaction can be performed in the presence of hydrazine.
  • Figure US20140343277A1-20141120-C00037
  • wherein R1, R2, XA, XB, X1 and A1 are the same as above; and P is a hydroxyl-protecting group and X2 is a leaving group.
  • Examples of hydroxyl-protecting groups represented by P include tetrahydropyran-2-yl, methoxymethyl, benzyl.
  • Examples of the leaving groups represented by X2 include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.
  • When X1 and X2 are both halogen atoms, the halogen atom represented by X2 is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X1.
  • The reaction of the compound of Formula (3) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • The reaction of the compound of Formula (3) with the compound of Formula (17) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.
  • The reaction converting the compound of Formula (18) to the compound of Formula (8) can be performed under the known deprotection method depending on the type of the protecting group (P).
  • The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.
  • The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • The starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a usual purification procedure such as column chromatography, recrystallization, etc.
  • Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O, etc.
  • The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into usual pharmaceutical preparations, using usually employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.
  • Such tablets may be coated with usual coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain usual solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is usually preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with usual injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.
  • The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is usually about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K+ channel-blocking agent.
  • Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
    • 3. Third Invention (Benzodiazepine Compound)
  • The present inventors conducted extensive research to develop a compound that blocks the IKur current (Kv1.5 channel) and/or the IKACh current (GIRK1/4 channel) potently and more selectively than other K+ channels. As a result, the inventors found that a novel benzodiazepine compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.
  • The present invention provides benzodiazepine compounds, and pharmaceutical compositions comprising the benzodiazepine compounds as summarized in items 1 to 7 below.
  • Item 1. A benzodiazepine compound represented by General Formula (1):
  • Figure US20140343277A1-20141120-C00038
  • or a salt thereof,
    wherein R1, R2, R3, and R4 are each independently hydrogen or lower alkyl; R2 and R3 may be linked to form lower alkylene;
    A1 is lower alkylene optionally substituted with one or more hydroxyls; and R5 is an aryl or heterocyclic group, each of which is optionally substituted.
  • Item 2. A pharmaceutical composition comprising a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.
  • Item 3. A pharmaceutical composition according to Item 2 for preventing and/or treating arrhythmia.
  • Item 4. A benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.
  • Item 5. Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.
  • Item 6. Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.
  • Item 7. A method of preventing and/or treating arrhythmia, comprising administering to a patient a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1.
  • The groups represented by, or substituents of, R1, R2, R3, R4, R5 and A1 in the specification are described below.
  • The term “one or more” may be preferably 1 to 6, and more preferably 1 to 3.
  • Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
  • Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene.
  • Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.
  • Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.
  • Examples of “halogen” are fluorine, chlorine, bromine, and iodine.
  • Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.
  • Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.
  • Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.
  • Examples of “aralkyl group” include groups wherein aryl groups are substituted on the alkyl groups, such as benzyl and phenethyl.
  • Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.
  • Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. Examples of preferable heterocyclic groups include the followings (a) to (m) groups:
  • (a) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
  • (b) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, etc.;
  • (c) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, etc.,), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.), etc.;
  • (d) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, etc.;
  • (e) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;
  • (f) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
  • (g) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;
  • (h) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), etc.;
  • (i) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), etc.;
  • (j) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
  • (k) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;
  • (l) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl, etc.); and
  • (m) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.; wherein said heterocyclic groups may be substituted by one or more suitable substituents.
  • Substituents of “aryl and heterocyclic group, each of which is optionally substituted” represented by R5 are each independently one or more substituents selected from the group consisting of:
  • (1) oxo;
    (2) lower alkyl optionally substituted with one or more halogens or heterocyclic groups optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo;
    (3) cyclo lower alkyl;
    (4) lower alkoxy;
    (5) aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; and cyano;
    (6) aralkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo;
    (7) a heterocyclic group optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo;
    (8) hydroxyl;
    (9) halogen;
    (10) carboxy;
    (11) lower alkanoyl;
    (12) lower alkoxycarbonyl;
    (13) lower alkylenedioxy;
    (14) cyano;
    (15) nitro;
    (16) sulfo;
    (17) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl;
    (18) lower alkylsulfonyl; and
    (19) lower alkyl thio.
  • The “heterocyclic group” in Item (7) above can be selected from the above-mentioned groups (a) to (m).
  • Examples of preferable benzodiazepine compounds represented by General Formula (1) include those wherein:
  • R1, R2, R3, and R4 are each independently lower alkyl;
    A1 is lower alkylene; and R5 is piperidyl, piperazinyl, indolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydroindolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, or pyrido[2,3-d]imidazolyl; each of which is optionally substituted with one or more substituents selected from the group consisting of:
    (1) oxo;
    (2a) lower (C1-3) alkyl optionally substituted with 6,7-dihydrofuro[2,3-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl;
    (4a) C1-3 alkoxy;
    (5a) phenyl;
    (6a) benzyl;
    (7a) pyridyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxy;
    (9) halogen;
    (10) carboxy;
    (12a) C1-3 alkoxycarbonyl; and
    (13a) C1-4 alkylenedioxy.
  • The benzodiazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the benzodiazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.
  • Figure US20140343277A1-20141120-C00039
  • wherein R1, R2, R3, R4, R5, and A1 are the same as above, and X1 is halogen or hydroxyl.
  • The reaction of the compound of Formula (2) with the compound of Formula (3) wherein X1 is halogen can be performed in a general inert solvent or without using any solvent in the presence or absence of a basic compound.
  • Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C1-6) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixed solvents of such solvents.
  • The basic compound may be selected from various known compounds. Examples of such compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.
  • The above reaction may be performed by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • The compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably 0.5 to 10 moles, per mole of the compound of Formula (2).
  • The basic compound is typically used in an amount of 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).
  • The reaction is typically performed at a temperature of 0° C. to 250° C., and preferably 0° C. to 200° C., and is typically completed in about 1 to about 80 hours.
  • The reaction of the compound of Formula (2) with the compound of Formula (3) wherein X1 is hydroxyl is performed in a suitable solvent in the presence of a condensing agent.
  • Examples of solvents usable herein include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; aprotic polar solvents such as acetonitrile, pyridine, acetone, N,N-dimethyl formamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures of such solvents.
  • Examples of condensing agents include azocarboxylates such as di-tert-butyl azodicarboxylate, N,N,N′,N′-tetramethyl azodicarboxamide, 1,1′-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate; and phosphorus compounds such as triphenylphosphine and tri-n-butylphosphine.
  • In this reaction, the compound (3) is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).
  • The condensing agent is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).
  • The reaction proceeds typically at 0 to 200° C., and preferably at about 0 to about 150° C., and is completed in about 1 to about 10 hours.
  • Figure US20140343277A1-20141120-C00040
  • wherein R1, R2, R3, R4, and A1 are the same as above; R5a is a nitrogen-containing heterocyclic group optionally having substituent(s); and X2 is a halogen atom.
  • Examples of R5a include, among groups represented by the group R5 mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds with an N—H bond, the groups optionally having substituent(s).
  • The reaction of the compound of Formula (4) with the compound of Formula (5) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.
  • Examples of halogen atoms represented by X2 include chlorine, bromine, iodine, and like atoms.
  • Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.
  • A wide variety of known basic compounds can be used as the basic compound. Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.
  • The above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.
  • The compound of Formula (5) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (4).
  • The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (4).
  • The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.
  • Figure US20140343277A1-20141120-C00041
  • wherein R2, R3, R4, and X2 are as defined above; R1a is lower alkyl; R7 is lower alkoxy; and R6 is lower alkoxycarbonyl.
  • Examples of lower alkyl groups represented by R1a include alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and propyl groups.
  • Examples of lower alkoxycarbonyl groups represented by R6 include (C1-6 alkoxy)carbonyl groups, such as methoxycarbonyl, and ethoxycarbonyl.
  • Examples of lower alkoxy groups represented by R7 include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy.
  • In the reaction of the compound of Formula (7) with the compound of Formula (8), the compound of Formula (7) is reacted with the carboxylic acid compound of Formula (8) through a general amide bond formation reaction. Conditions for known amide bond formation reactions can be easily employed in the amide formation reaction. For example, the following reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (8) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (7); (ii) an active ester method, in which Carboxylic Acid (8) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like, or an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (7); (iii) a carbodiimide method, in which Carboxylic Acid (8) is subjected to a condensation reaction with Amine (7) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), carbonyldiimidazole or the like; and (iv) other methods, for example, a method in which Carboxylic Acid (8) is converted to a carboxylic anhydride using a dehydrating agent such as acetic anhydride, and the carboxylic anhydride is reacted with Amine (7), a method in which an ester of Carboxylic Acid (8) with a lower alcohol is reacted with Amine (7) at a high pressure and a high temperature, and a method in which an acid halide of Carboxylic Acid (8), i.e., a carboxylic acid halide, is reacted with Amine (7).
  • Generally, the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound. Any solvents used for conventional mixed acid anhydride methods are usable. Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.
  • Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.
  • Examples of alkyl halocarboxylates usable in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. In this method, Carboxylic Acid (8), an alkyl halocarboxylate, and Amine (7) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (8) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (7).
  • The reaction is typically performed at about −20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.
  • Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound. Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (7) mentioned above as one of the other methods (iv). A suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (7). When WSC is used as an activating agent, addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously. The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.
  • When the method in which a carboxylic acid halide is reacted with Amine (7), mentioned above as one of the other methods (iv), is employed, the reaction is performed in the presence of a basic compound in a suitable solvent. Examples of usable basic compounds include a wide variety of known basic compounds, such as those for use in the method (i) above. In addition to those usable in the mixed acid anhydride method, usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, and methylcellosolve; acetonitrile; pyridine; acetone; and water. The ratio of the carboxylic acid halide to Amine (7) is not limited and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (7). The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and typically completed in about 5 minutes to about 30 hours.
  • The amide bond formation reaction shown in Reaction Formula 3 above can also be performed by reacting Carboxylic Acid (8) with Amine (7) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.
  • The reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (7), typically at about −20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (8) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (7).
  • The reaction converting the compound of Formula (9) to the compound of Formula (10) can be performed by, for example, [1] reducing the compound of Formula (9) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (9) in a suitable inert solvent using as a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.
  • When Method [1] in which a catalytic hydrogenation reducing agent is used, examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof. Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel. The reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (9). The reaction temperature is typically about −20 to about 150° C., and preferably about 0 to about 100° C. The hydrogen pressure is typically about 1 to 10 atm. The reaction is typically completed in about 0.5 to about 100 hours. An acid such as hydrochloric acid may be added to the reaction.
  • When Method [2] above is used, a mixture of iron, zinc, tin, or tin (II) chloride with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, iron (II) sulfate, zinc, or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride or the like, can be used as a reducing agent. Examples of inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof. Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used. For example, when a mixture of tin (II) chloride and hydrochloric acid is used as a reducing agent, the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours. A reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (9).
  • The reaction converting the compound of Formula (10) to the compound of Formula (6b) is performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8).
  • The reaction of the compound of Formula (6b) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.
  • Figure US20140343277A1-20141120-C00042
  • wherein R1, R2, R3, R4, and R7 are the same as above.
  • The reaction of the compound of Formula (12) with the compound of Formula (13) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8) shown in Reaction Formula 3 above.
  • Figure US20140343277A1-20141120-C00043
  • wherein R1, R2, R3, R4, R7, A1, and X2 are the same as above; and X3 is a halogen atom.
  • The reaction converting the compound of Formula (6) to the compound of Formula (2) can be performed in a suitable solvent in the presence of an acid.
  • Examples of solvents include water; lower (C1-6) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.
  • The reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours. The amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (6).
  • Examples of halogen atoms represented by X3 include chlorine, bromine, iodine, and like atoms. The halogen atom represented by X3 is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X2.
  • The reaction of the compound of Formula (2) with the compound of Formula (14) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above, wherein X1 is a halogen atom.
  • The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.
  • In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.
  • The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.
  • The starting material compounds and object compounds represented by each of the reaction formulae can be used in a suitable salt form.
  • Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.
  • Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.
  • Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O, etc.
  • The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.
  • Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.
  • The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
  • To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.
  • Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
  • To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.
  • To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.
  • To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.
  • The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.
  • For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.
  • The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.
  • Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.
  • When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.
  • The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K+ channel-blocking agent.
  • Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.
  • The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).
    • DESCRIPTION OF EMBODIMENTS
  • The following Examples are intended to illustrate the present invention in further detail.
    • 1. First Invention Reference Example 1 Synthesis of 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of N-(2-amino-5-methoxyphenyl)-N-methylmalonamic acid ethyl ester (266 mg). The mixture was stirred at 65° C. for 2.5 hours. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm: 3.36 (2H, s), 3.43 (3H, s), 3.84 (3H, s), 6.79-6.83 (1H, m), 7.06-7.09 (1H, m), and 8.72 (1H, br-s).
    • Reference Example 2 Synthesis of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium hydride (60% in oil, 44 mg) was suspended in of DMF (8 ml), and was cooled to 0° C. in an ice water bath. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Ethyl iodide (187 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness to give the title compound (190.2 mg) as a yellow solid.
  • 1H-NMR (CDCl3) δppm: 1.11 (3H, t, J=7.1 Hz), 3.32 (2H, m), 3.59-3.68 (1H, m), 3.85 (3H, s), 4.18-4.30 (1H, m), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H, dd, J=9.0 and 2.8 Hz), 7.26 (1H, d, J=9.0 Hz).
    • Reference Example 3 Synthesis of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium hydride (60% in oil, 76 mg) was suspended in of DMF (8 ml). 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (190 mg) was added thereto at 0° C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.19 ml) was added thereto, and the mixture was stirred at room temperature for three days. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed to dryness to give the title compound (169 mg) as yellow powder.
  • 1H-NMR (CDCl3) δppm: 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.65-3.76 (1H, m), 3.85 (3H, s), 4.12-4.24 (1H, m), 6.73 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), and 7.22 (1H, d, J=9.0 Hz).
    • Reference Example 4 Synthesis of 7-methoxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium hydride (60% in oil, 128 mg) was suspended in of DMF (10 ml). 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (176 mg) was added thereto at 0° C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.25 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from hexane to give the title compound (161.6 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm: 0.87 (3H, s), 1.54 (3H, s), 3.40 (3H, s), 3.42 (3H, s), 3.84 (3H, s), 6.73 (1H, s), 6.84 (1H, d, J=8.9 Hz), 7.14 (1H, d, J=8.9 Hz).
    • Reference Example 5 Synthesis of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1.0M-boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg) at 0° C. The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture, and extraction was performed using a dichloromethane/methanol mixture (dichloromethane:methanol=10:1). The organic layer was dried over anhydrous sodium sulfate, and condensed to dryness under reduced pressure to give the title compound (156.4 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm: 0.90 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.55 (3H, s), 3.41 (3H, s), 3.66-3.78 (1H, m), 4.12-4.23 (1H, m), 6.79 (1H, d, J=2.7 Hz), 6.84 (1H, dd, J=8.8 and 2.7 Hz), 6.88 (1H, s), 7.18 (1H, d, J=8.8 Hz).
    • Reference Example 6 Synthesis of 7-hydroxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Reference Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.90 (3H, s), 1.49 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 6.73 (1H, d, J=2.7 Hz), 6.80 (1H, dd, J=8.9 and 2.7 Hz), 7.13 (1H, d, J=8.9 Hz).
    • Reference Example 7 Synthesis of trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester
  • A dichloromethane solution (50 ml) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.6 g) was cooled with ice. After adding of triethylamine (1.5 ml) to the solution, trifluoromethane sulfonic anhydride (1.9 ml) was added, and the mixture was stirred at room temperature for 4 hours. Triethylamine (0.75 ml) and trifluoromethane sulfonic anhydride (0.75 ml) were further added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→5:5). The purified product was condensed to dryness under reduced pressure to give the title compound (3.4 g) as a white solid (yield=86%).
  • 1H-NMR (CDCl3) δppm: 0.87 (3H, s), 1.23 (3H, t, J=7.2 Hz), 1.52 (3H, s), 3.42 (3H, s), 3.81-3.91 (1H, m), 4.04-4.14 (1H, m), 7.15-7.22 (2H, m), 7.40 (1H, d, J=8.9 Hz).
    • Reference Example 8 Synthesis of trifluoromethanesulfonic acid 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester
  • The synthesis of the title compound was performed in the same manner as in Reference Example 7 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.29 (1H, d, J=12.7 Hz), 3.43 (6H, s), 3.48 (1H, d, J=12.7 Hz), 7.21-7.26 (2H, m), 7.38-7.41 (1H, m).
    • Reference Example 9 Synthesis of trifluoromethanesulfonic acid 1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester
  • The synthesis of the title compound was performed in the same manner as in Reference Example 7 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.88 (3H, s), 1.56 (3H, s), 3.44 (3H, s), 3.45 (3H, s), 7.16-7.21 (2H, m), 7.33 (1H, d, J=8.9 Hz).
    • Reference Example 10 Synthesis of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • Trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.12 g), zinc cyanide (70 mg), tris (dibenzylideneacetone) dipalladium (7 mg), 1,1′-bis (diphenylphosphino) ferrocene (8 mg), and zinc powder (2 mg) were added to DMF (1 ml), and the mixture was heated for 20 minutes at 170° C. (microwave reactor). The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100). The purified product was condensed under reduced pressure to give the title compound (77 mg) as a white solid.
  • 1H-NMR (CDCl3) δppm: 0.88 (3H, s), 1.25 (3H, t, J=7.1 Hz), 1.55 (3H, s), 3.44 (3H, s), 3.89-3.95 (1H, m), 4.05-4.11 (1H, m), 7.43 (1H, d, J=9.1 Hz), 7.53-7.56 (2H, m).
    • Reference Example 11 Synthesis of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.25 (1H, d, J=12.7 Hz), 3.438 (3H, s), 3.444 (3H, s), 3.50 (1H, d, J=12.7 Hz), 7.42 (1H, J=8.4 Hz), 7.57-7.62 (2H, m).
    • Reference Example 12 Synthesis of 1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.88 (3H, s), 1.56 (3H, s), 3.45 (3H, s), 3.46 (3H, s), 7.34-7.37 (1H, m), 7.53-7.57 (2H, m).
    • Reference Example 13 Synthesis of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) and Raney nickel (3.0 g) were suspended in formic acid (10 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→20:80). The purified product was condensed under reduced pressure to give the title compound (0.92 g) as a yellowish-white solid (yield=92%).
  • 1H-NMR (CDCl3) δppm: 0.88 (3H, s), 1.26 (3H, t, J=7.1 Hz), 1.56 (3H, s), 3.48 (3H, s), 3.92-3.99 (1H, m), 4.07-4.15 (1H, m), 7.50 (1H, d, J=8.9 Hz), 7.77-7.80 (2H, m), 10.01 (1H, s).
    • Reference Example 14 Synthesis of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione (0.3 g), dichlorobis(triphenyl phosphine)palladium (II)(53 mg), copper(I) iodide (29 mg), and triethylamine (0.39 ml) were added to DMF (4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70). The purified product was condensed under reduced pressure to give the title compound (0.51 g) as a yellowish-white solid.
  • 1H-NMR (CDCl3) δppm: 0.84 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.84 (2H, t, J=6.3 Hz), 3.38 (3H, s), 3.68-3.80 (1H, m), 3.99 (2H, t, J=6.3 Hz), 4.00-4.15 (1H, m), 7.19-7.20 (3H, m), 7.73-7.76 (2H, m), 7.87-7.89 (2H, m).
    • Reference Example 15 Synthesis of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-prop-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Reference Example 14 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.38 (3H, s), 3.71-3.89 (1H, m), 4.03-4.18 (1H, m) 4.70 (2H, s), 7.20-7.31 (3H, m), 7.75-7.78 (2H, m), 7.90-7.93 (2H, m).
    • Reference Example 16 Synthesis of (E)-3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)acrylic acid ethyl ester
  • Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis (triphenylphosphine) palladium (II)(35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound (0.36 g) as a pale yellow solid.
  • 1H-NMR (CDCl3) δppm: 0.88 (3H, s), 1.22 (3H, t, J=7.2 Hz), 1.35 (3H, t, J=7.1 Hz), 1.55 (3H, s), 3.44 (3H, s), 3.81-3.90 (1H, m), 4.08-4.25 (1H, m), 4.13 (2H, q, J=7.1 Hz), 6.45 (1H, d, J=16.0 Hz), 7.25-7.27 (1H, m), 7.32-7.37 (2H, m), 7.65 (1H, d, J=16.0 Hz).
    • Reference Example 17 Synthesis of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid ethyl ester
  • 10% Palladium on carbon (0.1 g) was added to a methanol solution (10 ml) of (E)-3-(1-ethyl 3,3,5-trimethyl 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)acrylic acid ethyl ester (0.36 g). The mixture was subjected to catalytic reduction at room temperature and under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (0.29 g) as a brown solid.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.23 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.65 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 3.40 (3H, s), 3.77-3.90 (1H, m), 4.01-4.21 (3H, m), 7.07-7.11 (2H, m), 7.21-7.26 (1H, m).
    • Reference Example 18 Synthesis of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid
  • 50% Sodium hydroxide aqueous solution (1 ml) was added to a methanol (20 ml) solution of 3-(1-ethyl 3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) propionic acid ethyl ester (1.1 g). The mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by washing with ether. A hydrochloric acid was added to the aqueous layer, followed by extraction using ethyl acetate and drying using magnesium sulfate. The dried product was condensed under reduced pressure to give the title compound (0.97 g) as a colorless oily matter.
  • 1H-NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.52 (3H, s), 2.72 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 3.40 (3H, s), 3.72-3.88 (1H, m), 4.03-4.21 (1H, m), 7.09-7.13 (2H, m), 7.23-7.26 (1H, m).
    • Reference Example 19 Synthesis of 2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl carbamic acid tert-butyl ester
  • Diphenylphosphoryl azide (1.0 ml) and tert-butanol (10 ml) were added to a THF solution (10 ml) of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid (0.97 g) and triethylamine (0.67 ml). The mixture was stirred at 100° C. overnight. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.43 (9H, s), 1.53 (3H, s), 2.83 (2H, t, J=7.1 Hz), 3.38 (2H, t, J=7.1 Hz), 3.41 (3H, s), 3.71-3.85 (1H, m), 4.03-4.19 (1H, m), 4.57 (1H, br), 7.06-7.11 (2H, m), 7.22-7.27 (1H, m).
    • Reference Example 20 Synthesis of 5-(2,2-dihydroxyethyl)-5H-furo[3,2-c]pyridin-4-one
  • Sodium hydride (60% in oil, 0.36 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one (1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal (2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.90 g) as a white solid.
  • 1H-NMR (DMSO-d6) δppm: 3.88 (d, J=5.4 Hz, 2H), 4.95-5.03 (m, 1H), 6.08 (d, J=6.4 Hz, 2H), 6.69 (dd, J=7.4, 0.8 Hz, 1H), 6.94 (dd, J=2.1 and 0.8 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H).
    • Reference Example 21 Synthesis of 5-(2,2-dihydroxy-ethyl)-7-methyl-5H-furo[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.28 (3H, d, J=1.0 Hz), 3.85 (2H, d, J=5.4 Hz), 4.95-5.02 (1H, m), 6.06 (2H, d, J=6.3 Hz), 6.95 (1H, d, J=2.1 Hz), 7.33 (1H, d, J=1.0 Hz), 7.90 (1H, d, J=2.1 Hz).
    • Reference Example 22 Synthesis of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 2.36 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 4.94-4.98 (m, 1H), 6.04 (d, J=6.4 Hz, 2H), 6.52 (s, 1H), 6.59 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.4 H, 1H).
    • Reference Example 23 Synthesis of 5-(2,2-dihydroxyethyl)-2,3-dimethyl-5H-furo[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 2.18 (3H, s), 2.28 (3H, s), 3.84 (2H, d, J=5.4 Hz), 4.95-5.02 (1H, m), 6.04 (2H, d, J=6.2 Hz), 6.53 (1H, d, J=7.4 Hz), 7.38 (1H, d, J=7.4 Hz).
    • Reference Example 24 Synthesis of 5-(2,2-dihydroxyethyl)-2,7-dimethyl-5H-furo[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 2.14 (3H, s), 2.39 (3H, s), 3.82 (2H, d, J=5.4 Hz), 4.95-5.01 (1H, m), 6.10 (2H, d, J=6.2 Hz), 6.55 (1H, s), 7.24 (1H, s).
    • Reference Example 25 Synthesis of 6-(2,2-dihydroxyethyl)-4-methyl-6H-furo[2,3-c]pyridin-7-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 2.17 (3H, s), 3.86 (2H, d, J=5.4 Hz), 4.95-5.01 (1H, m), 6.06 (2H, d, J=6.2 Hz), 6.92 (1H, d, J=1.8 Hz), 7.17 (1H, s), 8.10 (1H, d, J=1.8 Hz).
    • Reference Example 26 Synthesis of 5-(2,2-dihydroxyethyl)-5H-thieno[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 3.90 (d, J=6.3 Hz, 2H), 4.99-5.04 (m, 1H), 6.07 (d, J=6.3 Hz, 2H), 6.86 (d, J=7.2 Hz, 1H), 7.41-7.49 (m, 2H), 7.57-7.64 (m, 1H).
    • Reference Example 27 Synthesis of 6-(2,2-dihydroxyethyl)-6H-thieno[2,3-c]pyridin-7-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 3.98 (d, J=5.3 Hz, 2H), 5.11-5.16 (m, 1H), 6.04 (d, J=6.4 Hz, 1H), 6.66 (d, J=7.1 Hz, 2H), 7.27 (d, J=5.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.84 (d, J=5.2H, 1H).
    • Reference Example 28 (1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-acetonitrile
  • To a solution of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.11 g) in DMF (15 ml) was added sodium cyanide (0.59 g) at room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.84 g) as a pale yellow oil.
  • 1H NMR (CDCl3), δppm: 0.85 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.54 (3H, s), 3.43 (3H, s), 3.77-3.86 (3H, m), 4.09-4.19 (1H, m), 7.21-7.24 (2H, m), 7.34 (1H, d, J=8.3 Hz).
    • Reference Example 29 2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-2-methyl-propionitrile
  • (1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-acetonitrile (0.84 g) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 0.259 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.405 ml) was added thereto, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.9 g) as a white powder.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.20 (3H, t, J=7.06 Hz), 1.54 (3H, s), 1.77 (6H, s), 3.45 (3H, s), 3.78-3.87 (1H, m), 4.09-4.18 (1H, m), 7.34 (3H, s).
    • Reference Example 30 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid
  • To a t-butanol (20 ml) and H2O (5 ml) solution of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.25 g) and 2-methyl-2-butene (3.25 ml) were added sodium dihydrogenphosphate (0.92 g) and sodium chlorite (2.081 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure to give the title compound (0.98 g) as a white powder.
  • mp: 296-299° C.
    • Reference Example 31 7-Bromomethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
  • 1H NMR (CDCl3), δppm: 0.85 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.77-3.87 (1H, m), 4.08-4.17 (1H, m), 4.49 (2H, s), 7.28-7.29 (3H, m).
    • Reference Example 32 1-Ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • 3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid (1.0 g) was dissolved in THF (20 ml) and was cooled to 0° C. in ice water bath. Triethylamine (0.525 ml) and ethyl chloroformate (0.325 ml) were added to this solution and stirred for 30 minutes at same temperature. Sodium borohydride (0.36 g) was added to the mixture under cooling in ice methanol bath. Methanol (0.64 ml) was added dropwise to the mixture and stirred for 1 hour at same temperature. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.71 g) as a colorless oil.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.88-1.95 (2H, m), 2.76 (2H, t, J=7.8 Hz), 3.41 (3H, s), 3.71 (2H, t, J=6.3 Hz), 3.74-3.83 (1H, m), 4.10-4.19 (1H, m), 7.07 (1H, d, J=1.8 Hz), 7.11 (1H, dd, J=8.3 and 1.8 Hz), 7.23 (1H, d, J=8.3 Hz)
    • Reference Example 33 1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 184-185° C.
    • Reference Example 34 1-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 204-205° C.
    • Reference Example 35 1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 163-166° C.
    • Reference Example 36 1-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 154-155° C.
    • Reference Example 37 1-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.43 (2H, br), 1.07 (2H, br), 1.66 (3H, br), 3.17-3.23 (1H, m), 7.35 (1H, br), 7.50-7.56 (2H, m), 8.67 (1H, br).
    • Reference Example 38 1-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.22-0.23 (2H, m), 0.46-0.48 (2H, m), 0.98-1.07 (1H, m), 3.90 (1H, br-d), 7.38-7.54 (3H, m), 9.42 (1H, br).
    • Reference Example 39 1-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.44 (2H, br), 1.08 (2H, br), 1.30 (6H, br), 3.20-3.25 (1H, m), 7.49 (1H, d, J=1.8 Hz), 7.58 (1H, d, J=8.4 Hz), 7.78 (1H, dd, J=8.4, 1.8 Hz), 9.98 (1H, s).
    • Reference Example 40 1-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 124-125° C.
    • Reference Example 41 1-Cyclopropyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • 1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) was dissolved in DMF (10 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 0.167 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.261 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and was cooled to 0° C. in ice water bath. The precipitated insoluble matter was separated and dried to give the title compound (0.61 g) as a white powder.
  • 1H NMR (CDCl3), δppm: 0.10-0.17 (1H, m), 0.66-0.73 (1H, m), 0.82-0.92 (1H, m), 0.89 (3H, s), 1.21-1.29 (1H, m), 1.55 (3H, s), 3.16-3.22 (1H, m), 3.41 (3H, s), 7.50-7.57 (3H, m).
    • Reference Example 42 1-Isobutyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.72 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.86 (3H, s), 1.55 (3H, s), 1.77-1.88 (1H, m), 3.35 (1H, dd, J=13.7, 6.6 Hz), 3.45 (3H, s), 4.40 (1H, dd, J=13.7, 8.4 Hz), 7.41 (1H, d, J=8.4 Hz), 7.53-7.57 (2H, m).
    • Reference Example 43 1-(2-Methoxy-ethyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.89 (3H, s), 1.55 (3H, s), 3.32 (3H, s), 3.43 (3H, s), 3.59 (1H, ddd, J=10.4, 5.0, 3.7 Hz), 3.75 (1H, ddd, J=10.4, 7.8, 3.4 Hz), 3.94 (1H, ddd, J=14.4, 7.8, 3.7 Hz), 4.12 (1H, ddd, J=14.4, 5.0, 3.4 Hz), 7.52-7.55 (2H, m), 7.81-7.84 (1H, m).
    • Reference Example 44 5-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 252-253° C.
    • Reference Example 45 5-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 219-220° C.
    • Reference Example 46 5-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 234-236° C.
    • Reference Example 47 5-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 247-248° C.
    • Reference Example 48 Methanesulfonic acid 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl ester
  • The synthesis of the title compound was obtained from 1-ethyl-7-(3-hydroxypropyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine and methanesulfonyl chloride in a conventional matter.
  • 1H NMR (CDCl3), δppm: 0.86 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.05-2.16 (2H, m), 2.79 (2H, t, J=7.6 Hz), 3.03 (3H, s), 3.42 (3H, s), 3.74-3.83 (1H, m), 4.10-4.18 (1H, m), 4.26 (2H, t, J=6.2 Hz), 7.07 (1H, dd, J=8.3 and 2.0 Hz), 7.10 (1H, d, J=2.0 Hz), 7.25 (1H, d, J=8.3 Hz).
    • Reference Example 49 1-Cyclopropyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.10-0.20 (1H, m), 0.66-0.73 (1H, m), 0.73-0.94 (1H, m), 0.89 (3H, s), 1.21-1.28 (1H, m), 1.55 (3H, s), 3.91-3.45 (1H, m), 3.45 (3H, s), 7.57 (1H, d, 8.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.79 (1H, dd, J=8.4, 1.8 Hz), 10.01 (1H, s).
    • Reference Example 50 1-Isobutyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.71 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.86 (3H, s), 1.53 (3H, s), 1.76-1.90 (1H, m), 3.39 (1H, dd, J=13.6, 6.6 Hz), 3.49 (3H, s), 4.42 (1H, dd, J=13.6, 8.4 Hz), 7.47 (1H, d, J=9.0 Hz), 7.76-7.79 (2H, m), 10.01 (1H, s).
    • Reference Example 51 1-(2-Methoxy-ethyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.88 (3H, s), 1.55 (3H, s), 3.31 (3H, s), 3.48 (3H, s), 3.60 (1H, ddd, J=10.4, 5.2, 4.1 Hz), 3.74 (1H, ddd, J=10.4, 7.1, 4.1 Hz), 4.01-4.15 (2H, m), 7.75-7.78 (2H, m), 7.80-7.83 (1H, m), 10.01 (1H, s).
    • Reference Example 52 5-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 208-211° C.
    • Reference Example 53 5-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 183-188° C.
    • Reference Example 54 1,3,3-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaz epine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 289-294° C.
    • Reference Example 55 1-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 215-218° C.
    • Reference Example 56 3,3,5-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 250-251° C.
    • Reference Example 57 5-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.
  • mp: 241-247° C.
    • Reference Example 58 1,3,3-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 208-210° C.
    • Reference Example 59 1-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.07 (3H, br), 1.29 (3H, t, J=7.1 Hz), 1.57 (3H, br), 4.57 (2H, q, J=7.1 Hz), 7.50 (1H, d, J=8.5 Hz), 7.57 (1H, br), 7.77 (1H, dd, J=8.5, 1.8 Hz), 8.42 (1H, br). 9.99 (1H, s).
    • Reference Example 60 3,3,5-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 197-202° C.
    • Reference Example 61 5-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • mp: 188-191° C.
    • Reference Example 62 5-Cyclopropylmethyl-1-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.15-0.24 (2H, m), 0.38-0.51 (2H, m), 0.87 (3H, s), 0.93-1.01 (1H, m), 1.55 (3H, s), 3.32 (3H, s), 3.53-3.62 (1H, m), 3.73-3.79 (1H, m), 3.97-4.04 (1H, m), 4.06-4.13 (1H, m), 7.55 (1H, dd, J=8.5, 1.9 Hz), 7.66 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=8.5 Hz).
    • Reference Example 63 1-Cyclopropylmethyl-5-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.14-0.22 (2H, m), 0.38-0.49 (2H, m), 0.87 (3H, s), 0.93-1.02 (1H, m), 1.55 (3H, s), 3.34 (3H, s), 3.53-3.65 (1H, m), 3.77-3.83 (1H, m), 3.91-3.98 (1H, m), 4.05-4.13 (1H, m), 7.45 (1H, d, J=8.5 Hz), 7.53 (1H, dd, J=8.5, 1.9 Hz), 8.10 (1H, d, J=1.9 Hz).
    • Reference Example 64 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile
  • The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.03-0.19 (3H, m), 0.27-0.41 (2H, m), 0.61-0.68 (1H, m), 0.81-0.93 (1H, m), 0.88 (3H, s), 1.21-1.29 (2H, m), 1.54 (3H, s), 3.06-3.26 (1H, m), 3.42 (1H, dd, J=14.3, 6.8 Hz), 4.31 (1H, dd, J=14.3, 7.5 Hz), 7.38 (1H, d, J=8.5. Hz), 7.53 (1H, dd, J=8.5, 1.8 Hz), 7.72 (1H, d, J=1.8 Hz).
    • Reference Example 65 5-Cyclopropylmethyl-1-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.13-0.25 (2H, m), 0.37-0.48 (2H, m), 0.87 (3H, s), 0.96-1.03 (1H, m), 1.55 (3H, s), 3.32 (3H, s), 3.54-3.59 (1H, m), 3.66 (1H, dd, J=14.2, 6.4 Hz), 3.75 (1H, ddd, J=10.3, 7.2, 4.7 Hz), 4.04-4.19 (3H, m), 7.78 (1H, dd, J=8.4, 1.7 Hz), 7.82 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=1.7 Hz), 10.0 (1H, s).
    • Reference Example 66 1-Cyclopropylmethyl-5-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.14-0.24 (2H, m), 0.38-0.50 (2H, m), 0.87 (3H, s), 0.97-1.07 (1H, m), 1.55 (3H, s), 3.33 (3H, s), 3.53-3.59 (1H, m), 3.65 (1H, dd, J=14.2, 6.4 Hz), 3.73-3.79 (1H, m), 4.03-4.16 (3H, m), 7.51 (1H, d, J=8.4 Hz), 7.79 (1H, dd, J=8.4, 1.9 Hz), 8.19 (1H, d, J=1.9 Hz), 10.0 (1H, s).
    • Reference Example 67 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde
  • The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.09-0.07 (1H, m), 0.09-0.20 (2H, m), 0.27-0.40 (2H, m), 0.62-0.68 (1H, m), 0.83-0.92 (1H, m), 0.88 (3H, s), 1.20-1.28 (2H, m), 1.54 (3H, s), 3.27-3.33 (1H, m), 3.45 (1H, dd, J=14.3, 6.8 Hz), 4.34 (1H, dd, J=14.3, 7.5 Hz), 7.43 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=8.4, 1.9 Hz), 7.92 (1H, d, J=1.9 Hz), 10.0 (1H, s).
    • Example 1 Synthesis of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 10% Palladium on carbon (0.52 g) was added to a methanol solution (50 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl) but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.2 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (1.93 g) as a brown solid.
  • 1H-NMR (CDCl3) δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.61-1.79 (4H, m), 2.68 (2H, t, J=7.0 Hz), 3.40 (3H, s), 3.71-3.81 (3H, m), 4.01-4.18 (1H, m), 7.02-7.08 (2H, m), 7.20 (1H, d, J=8.3 Hz), 7.70-7.74 (2H, m), 7.83-7.86 (2H, m).
    • Example 2 Synthesis of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Hydrazine hydrate (0.5 ml) was added to a methanol solution (60 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-tri methyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (1.93 g). The mixture was stirred for 5.5 hours while heated under reflux. After cooled to room temperature, a 1N-sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound (1.2 g) as a yellow solid.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.47-1.58 (2H, m), 1.52 (3H, s), 1.62-1.73 (4H, m), 2.66 (2H, t, J=7.6 Hz), 2.76 (2H, t, J=7.0 Hz), 3.41 (3H, s), 3.71-3.84 (1H, m), 4.03-4.18 (1H, m), 7.02-7.09 (2H, m), 7.21 (1H, d, J=8.3 Hz).
    • Example 3 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 4-Pyridine carbaldehyde (0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.
  • 1H-NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.47-1.58 (2H, m), 1.53 (3H, s), 1.53-1.60 (2H, m), 1.62-1.71 (2H, m), 2.62-2.68 (4H, m), 3.40 (3H, s), 3.69-3.81 (3H, m), 4.03-4.19 (1H, m), 7.01 (1H, d, J=1.9 Hz), 7.06 (1H, dd, J=8.3, 1.9 Hz), 7.21 (1H, d, J=8.3 Hz), 7.25-7.28 (2H, m), 8.53-3.56 (2H, m).
    • Example 4 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(4-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}butyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • (2-Methyl-4-oxo-4H-furo[3,2-c]pyridin 5-yl)acetaldehyde (0.18 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (0.38 g). The mixture was stirred for 30 minutes at room temperature. sodium triacetoxyborohydride (0.32 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was condensed under reduced pressure. A 6N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.43 g) as a white solid.
  • 1H-NMR (DMSOd6) δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.30 (3H, s), 1.56 (2H, br), 1.76 (2H, br), 2.38 (3H, s), 2.59 (2H, t, J=7.6 Hz), 3.13 (2H, br), 3.31 (3H, s), 3.22-3.38 (2H, m), 3.40-3.55 (1H, m), 3.99-4.08 (1H, m), 4.42 (2H, br), 4.64 (2H, br), 6.56 (1H, s), 6.75 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.38 (1H, d, J=8.4 Hz), 7.63 (1H, br), 8.22 (2H, br), 8.92 (2H, br).
    • Example 5 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{4-[(2-methylpyridin-3-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.52-1.61 (2H, m), 1.63-1.70 (2H, m), 2.56 (3H, s), 2.62-2.73 (4H, m), 3.40 (3H, s), 3.68-3.81 (3H, m), 4.02-4.19 (1H, m), 7.01-7.11 (3H, m), 7.20 (1H, d, J=8.3 Hz), 7.58-7.61 (1H, m), 8.38-8.40 (1H, m).
    • Example 6 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(4-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}butyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.31 (3H, s), 1.59 (2H, br), 1.74 (2H, br), 2.50 (3H, s), 2.61 (2H, t, J=7.6 Hz), 2.80 (2H, br), 3.10 (2H, br), 3.31 (3H, s), 3.55-3.70 (1H, m), 3.95-4.08 (1H, m), 4.37 (4H, br), 6.56 (1H, s), 6.82 (1H, br), 6.95 (1H, s), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.39 (1H, d, J=8.4 Hz), 7.68 (1H, br), 7.81 (1H, br), 7.91 (1H, br), 8.71 (2H, br).
    • Example 7 Synthesis of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 1 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.80 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.00-2.13 (2H, m), 2.72 (2H, t, J=7.7 Hz), 3.42 (3H, s), 3.68-3.73 (3H, m), 3.98-4.11 (1H, m), 7.07-7.10 (2H, m), 7.17-7.20 (1H, m), 7.70-7.75 (2H, m), 7.82-7.85 (2H, m).
    • Example 8 Synthesis of 7-(3-aminopropyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.84 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.54 (3H, s), 1.76 (2H, br), 1.74-1.91 (2H, m), 2.71 (2H, t, J=8.2 Hz), 2.84 (2H, t, J=7.0 Hz), 3.42 (3H, s), 3.81-3.95 (1H, m), 4.08-4.19 (1H, m), 7.09-7.14 (2H, m), 7.22-7.26 (1H, m).
    • Example 9 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.81 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.78-1.91 (2H, m), 2.66-2.74 (4H, m), 3.39 (3H, s), 3.71-3.89 (3H, m), 4.05-4.16 (1H, m), 7.02-7.10 (3H, m), 7.19-7.26 (2H, m), 8.52-8.56 (2H, m).
    • Example 10 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.05 (2H, br), 2.38 (3H, s), 2.60 (2H, br), 3.04 (2H, br), 3.31 (3H, s), 3.25-3.50 (2H, m), 3.40-3.65 (1H, m), 3.91-4.08 (1H, m), 4.38 (2H, br), 4.58 (2H, br), 6.55 (1H, s), 6.75 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.38 (1H, d, J=8.4 Hz), 7.63 (1H, d, J=7.4 Hz), 8.17 (2H, br), 8.88 (2H, br).
    • Example 11 Synthesis of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • A 4N-hydrogen chloride ethyl acetate solution (6 ml) was added to an ethyl acetate solution (20 ml) of [2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)ethyl]carbamic acid tert-butyl ester (0.38 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure to give the title compound (0.26 g) as a pale orange amorphous solid.
  • 1H-NMR (DMSO-d6) δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.39 (3H, s), 2.91-3.00 (2H, m), 3.02-3.13 (2H, m), 3.38 (3H, s), 3.68-3.83 (1H, m), 3.95-4.11 (1H, m), 7.11-7.16 (1H, m), 7.23 (1H, br), 7.31-7.35 (1H, m), 8.06 (3H, br).
    • Example 12 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(pyridin-4-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Triethylamine (0.1 ml) and 4-pyridine carbaldehyde (0.094 ml) were added to a methanol solution (10 ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione hydrochloride (0.26 g). The mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.11 g) was added, and the mixture was further stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.21 g) as a colorless oily matter.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.86 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.82-2.94 (4H, m), 3.40 (3H, s), 3.73-3.85 (1H, m), 3.84 (2H, s), 4.02-4.18 (1H, m), 7.05-7.11 (2H, m), 7.20-7.26 (3H, m), 8.52-8.55 (2H, m).
    • Example 13 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.52 (3H, s), 2.82-2.88 (2H, m), 2.93-2.99 (2H, m), 3.40 (3H, s), 3.75-3.82 (1H, m), 3.81 (3H, s), 4.11-4.18 (1H, m), 7.06-7.12 (2H, m), 7.22-7.26 (2H, m), 7.53-7.57 (1H, m), 8.37-8.40 (1H, m).
    • Example 14 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.33 (3H, s), 2.82-2.87 (2H, m), 2.93-2.99 (2H, m), 3.39 (3H, s), 3.75-3.84 (1H, m), 3.82 (3H, s), 4.10-4.20 (1H, m), 7.06-7.12 (3H, m), 7.21-7.26 (1H, m), 8.38 (1H, d, J=4.9 Hz), 8.41 (1H, s).
    • Example 15 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride.
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.69 (3H, s), 1.02 (3H, t, J=7.1 Hz), 1.31 (3H, s), 2.39 (3H, s), 3.08 (2H, br), 3.29 (3H, s), 3.11-3.42 (2H, m), 3.42-3.70 (3H, m), 3.91-4.10 (1H, m), 4.36 (2H, br), 4.57 (2H, br), 6.54 (1H, s), 6.71 (1H, d, J=7.2 Hz), 7.15-7.20 (1H, m), 7.30 (1H, s), 7.37-7.40 (1H, m), 7.60-7.63 (1H, m), 8.16 (2H, br), 8.86 (2H, br).
    • Example 16 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.70 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.50 (3H, s), 2.84 (2H, br), 3.14 (2H, br), 3.34 (3H, s), 3.25-3.45 (2H, m), 3.50-3.70 (1H, m), 3.90-4.08 (1H, m), 4.38 (2H, br), 4.47 (2H, br), 6.76 (1H, d, J=7.1 Hz), 6.93 (1H, s), 7.23 (1H, d, J=8.2 Hz), 7.36 (1H, s), 7.40 (1H, d, J=8.2 Hz), 7.69 (1H, br), 7.82 (1H, br), 7.90 (1H, d, J=2.1 Hz), 8.71 (2H, br).
    • Example 17 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.72 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.40 (3H, s), 2.51 (3H, s), 2.89 (4H, br), 3.31 (3H, s), 3.50 (2H, br), 3.72-3.77 (1H, m), 4.02-4.07 (1H, m), 4.42 (2H, br), 4.61 (2H, br), 6.54 (1H, s), 6.70 (1H, br), 7.23 (1H, br), 7.34 (1H, s), 7.40 (1H, br), 7.64 (1H, br), 7.86 (1H, br), 8.73 (2H, br).
    • Example 18 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.39 (3H, s), 2.51 (3H, s), 2.74 (2H, br), 3.15 (2H, br), 3.33 (3H, s), 3.51 (2H, br), 3.72-3.77 (1H, m), 4.02-4.07 (1H, m), 4.42 (2H, br), 4.75 (2H, br), 6.53 (1H, s), 6.70 (1H, br), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.42-7.44 (1H, m), 7.64 (1H, br), 7.86 (1H, br), 8.76 (1H, br), 9.20 (1H, br).
    • Example 19 Synthesis of 7-aminomethyl-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 10% Palladium on carbon (0.1 g) was added to an acetic acid solution (20 ml) of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (0.3 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (0.17 g) as a yellowish white solid.
  • 1H NMR (CDCl3) δppm: 3.28 (1H, d, J=12.4 Hz), 3.42 (3H, s), 3.44 (3H, s), 3.38-3.42 (1H, m), 3.94 (2H, s), 7.26-7.29 (3H, m).
    • Example 20 Synthesis of 7-aminomethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.75-3.82 (1H, m), 3.93 (2H, s), 4.13-4.19 (1H, m), 7.20-7.23 (1H, m), 7.25-7.27 (2H, m).
    • Example 21 Synthesis of 7-aminomethyl-1,3,3,5-tetramethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.85 (3H, s), 1.54 (3H, s), 3.42 (3H, s), 3.44 (3H, s), 3.93 (2H, s), 7.18-7.26 (3H, m).
    • Example 22 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.69-3.82 (1H, m), 3.84 (2H, s), 3.87 (2H, s), 4.04-4.20 (1H, m), 7.23-7.26 (3H, m), 7.29-7.32 (2H, m), 8.56-8.58 (2H, m).
    • Example 23 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.56 (3H, s), 3.42 (3H, s), 3.77-3.88 (1H, m), 3.84 (2H, s), 3.88 (2H, s), 4.09-4.18 (1H, m), 7.11-7.15 (1H, m), 7.24-7.29 (3H, m), 7.63-7.65 (1H, m), 8.41-8.43 (1H, m).
    • Example 24 Synthesis of 1,5-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 2.59 (3H, s), 3.27 (1H, d, J=12.4 Hz), 3.37-3.43 (7H, m), 3.82 (2H, s), 3.86 (2H, s), 7.10-7.14 (1H, m), 7.23-7.26 (3H, m), 7.61-7.65 (1H, m), 8.39-8.42 (1H, m).
    • Example 25 Synthesis of 1,3,3,5-tetramethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.85 (3H, s), 1.54 (3H, s), 2.56 (3H, s), 3.43 (3H, s), 3.44 (3H, s), 3.82 (2H, s), 3.88 (2H, s), 7.11-7.15 (1H, m), 7.20-7.26 (3H, m), 7.62-7.64 (1H, m), 8.41-8.43 (1H, m).
    • Example 26 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[[[2-(pyridin-3-yl)ethyl]amino]methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Trimethyl orthoformate (9 ml) was added to a methanol solution (50 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.2 g) and 3-(2-aminoethyl)pyridine (1.0 g). The mixture was stirred at room temperature for 2 hours.
  • The reaction liquid was condensed under reduced pressure, and a methanol solution (50 ml) of the residue was cooled with ice. Sodium borohydride (0.34 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction liquid, followed by concentration under reduced pressure. The residue was extracted by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (2.5 g) as a colorless oily matter.
  • 1H NMR (CDCl3) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.80-2.90 (2H, m), 2.90-2.99 (2H, m), 3.39 (3H, s), 3.72-3.90 (1H, m), 3.83 (2H, s), 4.06-4.22 (1H, m), 7.14-7.20 (2H, m), 7.20-7.28 (2H, m), 7.54 (1H, td, J=2.0, 7.8 Hz), 8.45-8.53 (2H, m).
    • Example 27 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium borohydride (0.15 g) was added to a methanol solution (150 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.1 g) and 5-(2-aminoethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one (1.0 g), and the mixture was stirred at room temperature overnight. The reaction liquid was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure.
  • The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (1.1 g) as a colorless amorphous solid.
  • 1H NMR (CDCl3) δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.15 (1H, br), 2.42 (3H, s), 3.02-3.10 (2H, m), 3.36 (3H, s), 3.75-3.81 (1H, m), 3.86 (2H, s), 4.09-4.20 (3H, m), 6.49 (1H, d, J=6.7 Hz), 6.53 (1H, d, J=1.9 Hz), 7.15-7.21 (4H, m).
    • Example 28 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.80 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.95 (2H, br), 3.36 (3H, s), 3.74-3.82 (1H, m), 3.86 (2H, br), 4.02-4.14 (1H, m), 4.20 (2H, br), 6.57 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=2.0 Hz), 7.14-7.26 (4H, m), 7.50 (1H, d, J=2.0 Hz).
    • Example 29 Synthesis of 7,7′-azanediylbis(methylene)bis(1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4-dione)
  • 10% Palladium on carbon (0.3 g) was added to an acetic acid solution (20 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.4 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (0.19 g) as a colorless oily matter.
  • 1H-NMR (CDCl3) δppm: 0.84 (6H, s), 1.19 (6H, t, J=7.1 Hz), 1.54 (6H, s), 3.43 (6H, s), 3.71-3.92 (2H, m), 3.87 (4H, s), 4.01-4.18 (2H, m), 7.24-7.27 (6H, m).
    • Example 30 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}methyl)-1,5-dihydro benzo[b][1,4]diazepine-2,4-dione
  • 5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.21 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.42 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (0.47 g) as a white powder.
  • mp: 143 to 145° C.
    • Example 31 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 153 to 154° C.
    • Example 32 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 172 to 173° C.
    • Example 33 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[3-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)propyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.66 (3H, s), 1.04 (3H, br), 1.33 (3H, s), 2.29 (2H, br), 2.41 (3H, s), 2.80 (3H, br). 3.08 (2H, br), 3.33 (3H, s), 3.73-3.79 (1H, m), 3.93-4.01 (3H, m), 4.46 (2H, br), 4.57 (2H, br), 6.56 (1H, s), 6.67 (1H, d, J=6.2 Hz), 7.42-7.44 (1H, m), 7.48-7.59 (2H, m), 7.88 (2H, br), 8.76 (1H, br), 8.93 (1H, br).
    • Example 34 Synthesis of 7,7′-(pyridin-4-ylmethylazanediyl)bis(methylene)bis(1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4-dione) dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.69 (6H, s), 1.07 (6H, t, J=7.1 Hz), 1.32 (6H, s), 3.35 (6H, s), 3.74-3.81 (2H, m), 3.94-4.04 (2H, m), 4.52 (2H, br), 4.82 (4H, s), 7.45-7.47 (4H, m), 8.08 (2H, d, J=6.7 Hz), 8.05-8.40 (2H, m), 8.88 (2H, d, J=6.7 Hz).
    • Example 35 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.67 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.41-2.59 (5H, m), 2.83 (2H, br), 3.25 (3H, s), 3.61-3.83 (3H, m), 3.92-3.97 (1H, m), 4.16 (2H, br), 6.58 (1H, br), 7.22 (2H, br), 7.40 (2H, br), 7.48-7.63 (2H, m), 7.67-7.68 (1H, m), 7.71-7.75 (1H, m), 8.10-8.12 (1H, m), 8.24 (1H, br), 8.44 (1H, br).
    • Example 36 Synthesis of 1,5-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.38 (3H, s), 2.51 (3H, s), 2.54 (2H, br), 2.75 (2H, br), 3.05 (1H, d, J=12.4 Hz), 3.26 (6H, s), 3.32 (1H, d, J=12.4 Hz), 3.75 (2H, br), 4.14 (2H, br), 6.45 (1H, br), 6.63 (1H, br), 7.24 (1H, br), 7.33 (1H, br), 7.50 (2H, br), 7.68 (1H, br), 8.25 (1H, br), 8.56 (1H, br).
    • Example 37 Synthesis of 1,3,3,5-tetramethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.70 (3H, s), 1.34 (3H, s), 2.51 (3H, s), 2.55 (2H, br), 2.82 (2H, br), 3.30 (6H, s), 3.78 (2H, br), 4.19 (2H, br), 6.73 (1H, br), 6.88 (1H, br), 7.31 (3H, br), 7.60 (2H, br), 7.91 (1H, d, J=2.0 Hz), 8.26 (1H, br), 8.56 (1H, br).
    • Example 38 Synthesis of 1,3,3,5-tetramethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.70 (3H, s), 1.34 (3H, s), 2.41 (3H, s), 2.51 (3H, s), 2.56 (2H, br), 2.79 (2H, br), 3.30 (6H, s), 3.77 (2H, br), 4.15 (2H, br), 6.46 (1H, br), 6.63 (1H, br), 7.31 (3H, br), 7.50 (1H, br), 7.68 (1H, br), 8.24 (1H, br), 8.56 (1H, br).
    • Example 39 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.92 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of (2-pyridine 3-ylethyl)pyridin-4-ylmethylamine (0.81 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.90 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.83 g) as a white solid
  • 1H-NMR (DMSO-d6) δppm: 0.68 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.33 (3H, s), 3.00 (2H, br), 3.32 (3H, s), 3.10-3.45 (4H, m), 3.74-3.79 (1H, m), 3.94-4.00 (3H, m), 7.43 (2H, br), 7.98-8.02 (2H, m), 8.45 (1H, d, J=8.0 Hz), 8.82-8.88 (6H, m).
    • Example 40 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • Benzoyl chloride (0.13 ml) was added to an acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g) and triethylamine (0.17 ml) under ice cooling. The mixture was stirred at room temperature overnight. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=91:9). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.87 ml) was added to an isopropyl alcohol solution (10 ml) of the residue, and the liquid was condensed under reduced pressure. The residue was recrystallized from the ethanol-ether mixture to give the title compound (0.26 g) as a pale brown white powder.
  • 1H NMR (DMSO-d6) δppm: 0.73 (3H, bs), 0.98-1.14 (3H, m), 1.34 (3H, s), 2.74-3.94 (8H, m), 3.94-4.11 (1H, m), 4.52 and 4.82 (2H, bs), 6.90-7.60 (8H, m), 7.60-9.10 (4H, m).
    • Example 41 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.73 (3H, s), 1.09 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.31 (3H, s), 2.88-3.94 (8H, m), 3.94-4.11 (1H, m), 4.35-5.05 (2H, m), 6.88-7.63 (7H, m), 7.63-9.10 (4H, m).
    • Example 42 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • Triethylamine (0.15 ml) was added to a acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-yl-ethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.35 g). The mixture was cooled with ice. Benzenesulphonyl chloride (0.13 ml) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. Water was added to the residue, followed by extraction by ethyl acetate.
  • The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=30:70). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-ether mixture to give the title compound (0.1 g) as a white powder.
  • mp: 143.2 to 146.4° C.
    • Example 43 Synthesis of 7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.72 (3H, s), 1.05 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.59-3.72 (8H, m), 3.72-3.94 (1H, m), 3.94-4.11 (1H, m), 4.33-4.65 (3H, m), 6.85-8.18 (10H, m), 8.30-8.77 (2H, m), 11.17 (1H, bs).
    • Example 44 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 160 to 161° C.
    • Example 45 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 171 to 174° C.
    • Example 46 Synthesis of 7-({N-(2,6-dimethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 148 to 149° C.
    • Example 47 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(6-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 123 to 125° C.
    • Example 48 Synthesis of N-[2-({[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-7-yl)methyl][2-(pyridin-3-yl)ethyl]amino}methyl)phenyl]methanesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.71 and 0.73 (3H, s), 0.90-1.20 (3H, m), 1.33 (3H, s), 2.69-2.80 (1H, bs), 2.85 (2H, bs), 2.92-3.10 (4H, m), 3.20-3.70 (3H, m), 3.70-3.96 (3H, m), 3.96-4.10 (1H, m), 4.46-4.73 (2H, m), 7.00-7.70 (7H, m), 7.70-8.30 (2H, m), 8.52-8.80 (2H, m), 9.30-9.59 (1H, m), 10.90 (1H, bs).
    • Example 49 Synthesis of 7-{[N-(2,4-dimethylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.73 (3H, s), 1.09 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.30 (3H, bs), 2.59 (3H, s), 2.65-5.20 (13H, m), 6.32-8.07 (4H, m), 8.16-8.40 (1H, m), 8.66-8.90 (2H, m), 11.91 (1H, bs).
    • Example 50 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-methyl-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.71 and 0.75 (3H, s), 1.00-1.12 (3H, m), 1.32 and 1.34 (3H, s), 2.03 and 2.04 (3H, s), 2.85-5.50 (8H, m), 3.26 and 3.34 (3H, s), 6.86 (0.4H, d, J=7.8 Hz), 7.05-7.98 (8.3H, m), 8.39 (0.9H, bs), 8.63 (0.4H, bs), 8.74 (0.5H, bs), 8.87 (0.5H, bs).
    • Example 51 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.72 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.68 (3H, br), 3.10 (2H, br), 3.34 (3H, s), 3.18-3.60 (4H, m), 3.74-3.90 (3H, m), 3.99-4.05 (1H, m), 7.49 (2H, br), 7.73 (1H, br), 7.87 (1H, br), 7.98-8.01 (1H, br), 8.45 (1H, br), 8.68-8.70 (2H, m), 8.81 (1H, d, J=5.5 Hz), 8.89 (1H, br).
    • Example 52 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 171 to 172° C.
    • Example 53 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1,5-dihydro benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 146 to 147° C.
    • Example 54 Synthesis of 7-{[N-(2,6-dimethylpyridin-3-ylmethyl)-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.68 (3H, s), 1.02 (3H, t, J=7.1 Hz), 1.32 (3H, s), 3.32 (9H, s), 3.32 (3H, s), 3.67 (2H, br), 3.60-3.82 (1H, m), 3.78 (2H, br), 3.82 (2H, br), 3.97-4.04 (1H, m), 7.28 (1H, br), 7.34 (1H, br), 7.39-7.41 (1H, m), 7.67 (1H, d, J=7.8 Hz), 7.82-7.85 (1H, m), 8.43 (1H, br), 8.56 (1H, br), 8.61 (1H, br).
    • Example 55 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 0.67 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.48 (3H, s), 2.70 (3H, s), 3.31 (3H, s), 3.63-3.75 (3H, m), 3.87 (4H, br), 3.95-4.08 (1H, m), 7.25 (1H, m), 7.34 (1H, m), 7.38-7.40 (1H, m), 7.81-7.86 (2H, m), 8.55 (1H, br), 8.62 (1H, d, J=5.2 Hz), 8.69 (1H, d, J=5.9 Hz), 8.86 (1H, br).
    • Example 56 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(4-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.
  • White powder
  • 1H NMR (DMSO-d6) δppm: 0.70 (3H, s), 1.03 (3H, br), 1.33 (3H, s), 2.33 (3H, br), 2.86 (2H, br), 3.10 (2H, br), 3.32 (3H, s), 3.31-3.41 (1H, m), 3.77 (4H, br), 4.00-4.06 (1H, m), 7.20 (1H, br), 7.43 (2H, br), 7.80 (1H, br), 7.97 (1H, br), 8.41 (1H, br), 8.70 (2H, br), 8.79-8.81 (2H, m).
    • Example 57 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylthiazol-5-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 161 to 162° C.
    • Example 58 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 188 to 189° C.
    • Example 59 Synthesis of 2-methyl-2H-pyrazole-3-sulfonic acid N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl) amide
  • The synthesis of the title compound was performed in the same manner as in Example 42 using appropriate starting materials.
  • White powder (ethyl acetate)
  • mp: 123 to 124° C.
    • Example 60 Synthesis of 7-{[N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 136 to 145° C.
    • Example 61 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-4-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.
  • 1H NMR (DMSO-d6) δppm: 0.71 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.71 (5H, br), 3.20-3.39 (3H, m), 3.37 (3H, s), 3.55 (2H, br), 3.77 (2H, br), 3.99-4.04 (1H, m), 7.31 (1H, br), 7.47 (2H, br), 7.85 (2H, br), 7.95 (2H, br), 8.68 (1H, br), 8.85 (2H, br).
    • Example 62 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 164 to 165° C.
    • Example 63 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 181 to 183° C.
    • Example 64 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 134 to 136° C.
    • Example 65 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(thiazol-2-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.74-3.84 (1H, m), 3.92 (2H, s), 4.09-4.18 (3H, m), 7.25-7.27 (3H, m), 7.30 (1H, d, J=3.3 Hz), 7.75 (1H, d, J=3.3 Hz).
    • Example 66 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.38 (3H, s), 3.42 (3H, s), 3.74-3.84 (1H, m), 3.83 (2H, s), 3.87 (2H, s), 4.09-4.18 (1H, m), 7.09 (1H, d, J=4.9 Hz), 7.24-7.27 (3H, m), 8.39 (1H, d, J=4.9 Hz), 8.46 (1H, s).
    • Example 67 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.40 (3H, s), 3.43 (3H, s), 3.75-3.84 (1H, m), 3.86 (2H, s), 3.97 (2H, s), 4.09-4.18 (1H, m), 7.22-7.28 (3H, m), 8.65 (1H, s).
    • Example 68 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 164-165° C.
    • Example 69 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 193-195° C.
    • Example 70 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 203-204° C.
    • Example 71 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 181-182° C.
    • Example 72 Synthesis of 7-({N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 157-159° C.
    • Example 73 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(4-m ethylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.68 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.30 (3H, s), 2.70 (3H, s), 3.32 (3H, s), 3.68 (2H, s), 3.67-3.76 (1H, m), 3.84 (4H, br), 3.97-4.06 (1H, m), 7.25-7.27 (1H, m), 7.34 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.84 (1H, dd, J=6.0, 7.7 Hz), 8.48-8.50 (1H, m), 8.62 (1H, d, J=5.5 Hz), 8.95-8.97 (1H, m).
    • Example 74 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{(N-[(1-methyl-1H-indazol-3-yl)methyl]-N-[2-(pyridin-3-yl)ethyl]amino)methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (D2O), δppm: 0.73 (3H, s), 1.11 (3H, t, J=7.0 Hz), 1.41 (3H, s), 3.15-3.29 (2H, m), 3.30 (3H, s), 3.38-3.58 (2H, m), 3.68-3.88 (1H, m), 4.00-4.20 (1H, m), 4.04 (3H, s), 4.37 (2H, bs), 4.44 (2H, bs), 7.08-7.21 (1H, m), 7.35 (1H, d, J=7.8 Hz), 7.39-7.60 (5H, m), 7.65 (1H, dd, J=6.0, 7.5 Hz), 8.10 (1H, d, J=7.8 Hz), 8.35-8.49 (2H, m).
    • Example 75 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methyloxazol-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (D2O), δppm: 0.79 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.43 (3H, s), 2.48 (3H, s), 3.21-3.33 (2H, m), 3.37-3.52 (2H, m), 3.40 (3H, s), 3.77-3.93 (1H, m), 4.07-4.21 (1H, m), 4.36 (2H, s), 4.47 (2H, dd, J=13.6, 22.0 Hz), 7.50 (1H, dd, J=1.4, 8.4 Hz), 7.54-7.60 (1H, m), 7.63 (1H, d, J=8.4 Hz), 7.73 (1H, dd, J=5.6, 7.9 Hz), 7.95 (1H, bs), 8.09 (1H, d, J=7.9 Hz), 8.54 (1H, bs), 8.58 (1H, d, J=5.6 Hz).
    • Example 76 Synthesis of 7-{[N-[2-(2,3-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-dd, δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.12 (3H, s), 2.31 (3H, s), 2.45 (3H, br), 2.77 (2H, br), 3.28 (3H, s), 3.71-3.83 (3H, m), 3.94-4.07 (3H, m), 4.08 (2H, br), 6.54 (1H, br), 7.24 (1H, br), 7.35 (2H, br), 7.42 (1H, br), 7.67 (1H, br), 8.26 (1H, br), 8.52 (1H, br).
    • Example 77 Synthesis of 7-{[N-[2-(2,3-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.70 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.11 (3H, s), 2.24 (3H, br), 2.31 (3H, s), 2.80 (2H, br), 3.28 (3H, s), 3.71-3.84 (3H, m), 3.94-4.11 (5H, m), 6.50 (1H, br), 7.24 (1H, br), 7.36 (2H, br), 7.40 (1H, br), 7.59 (1H, br), 8.59 (1H, br), 8.64 (1H, br).
    • Example 78 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methylpyridin-3-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.72 (3H, s), 1.05 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.70 (8H, br), 3.34 (3H, br), 3.78 (3H, br), 4.01-4.20 (5H, m), 7.47 (1H, br), 7.52 (1H, br), 7.85 (2H, br), 8.35 (2H, br), 8.65 (2H, br), 9.00 (1H, br).
    • Example 79 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.73 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.43 (3H, s), 2.46 (3H, s), 3.36 (5H, br), 3.45 (2H, br), 3.77-3.88 (1H, m), 4.00-4.12 (1H, m), 4.45 (2H, br), 4.65 (2H, br), 7.52-7.54 (1H, m), 7.60 (1H, br), 7.88 (1H, d, J=6.0 Hz), 7.90 (1H, br), 7.71 (1H, d, J=6.0 Hz), 8.77 (1H, s), 9.15 (1H, s).
    • Example 80 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.73 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.11 (3H, s), 2.45 (3H, s), 3.36 (5H, br), 3.50 (2H, br), 3.50-3.82 (4H, m), 3.95-4.08 (1H, m), 4.45 (2H, br), 4.53 (2H, br), 6.51 (1H, br), 7.56 (1H, br), 7.61 (1H, br), 7.87-7.89 (1H, m), 8.02 (1H, m), 8.71 (1H, d, J=5.8 Hz), 8.78 (1H, s).
    • Example 81 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-dd, δppm: 0.74 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.41 (3H, s), 2.65 (3H, s), 3.36 (7H, br), 3.70-3.79 (1H, m), 3.95-4.08 (1H, m), 4.47 (2H, br), 4.73 (2H, br), 7.54 (1H, br), 7.60 (1H, br), 7.87 (1H, dd, J=7.8, 5.7 Hz), 7.92 (1H, br), 8.33 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=5.7 Hz), 9.12 (1H, s).
    • Example 82 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-dd, δppm: 0.75 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.12 (3H, s), 2.67 (3H, s), 3.36 (5H, br), 3.43 (2H, br), 3.70-3.90 (4H, m), 4.00-4.08 (1H, m), 4.45 (2H, br), 4.50 (2H, br), 6.50 (1H, br), 7.55-7.57 (1H, m), 7.61 (1H, br), 7.85-7.88 (1H, m), 7.94 (1H, br), 8.36 (1H, br), 8.67 (1H, d, J=5.6 Hz).
    • Example 83 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 152-153° C.
    • Example 84 Synthesis of 1-ethyl-7-({N-(4-methoxypyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.43 (3H, s), 2.77-2.87 (2H, m), 3.29 (3H, s), 3.61 (1H, d, J=14.3 Hz), 3.68-3.74 (2H, m), 3.78 (1H, d, J=14.3 Hz), 3.86 (3H, s), 3.97-4.08 (1H, m), 4.09-4.19 (3H, m), 6.43-6.46 (2H, m), 6.78 (1H, d, J=5.8 Hz), 7.00 (2H, br), 7.05 (1H, s), 7.10 (1H, d, J=7.3 Hz), 8.39-8.40 (2H, m).
    • Example 85 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-trifluoromethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 162-164° C.
    • Example 86 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.423 g) and acetic acid (0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36 g) The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound (0.37 g) as a white powder.
  • mp: 118-120° C.
    • Example 87 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(5-trifluoromethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 138-140° C.
    • Example 88 Synthesis of 1-ethyl-7-({N-(5-fluoropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 144-146° C.
    • Example 89 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 153-154° C.
    • Example 90 Synthesis of 1-Ethyl-7-({N-(3-fluoropyridin-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diethyl ether)
  • mp: 149-151° C.
    • Example 91 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methyl-2H-pyrazol-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (D2O), δppm: 0.79 (3H, s), 1.11 (3H, t, J=7.0 Hz), 1.43 (3H, s), 3.09-3.70 (5H, m), 3.39 (3H, s), 3.45 (2H, s), 3.70-3.94 (1H, m), 3.94-4.59 (5H, m), 6.3-6.57 (1H, m), 7.30-7.65 (4H, m), 7.82-8.06 (1H, m), 8.15-8.47 (1H, m), 8.51 (1H, bs), 8.54-8.74 (1H, m).
    • Example 92 Synthesis of 1-ethyl-7-{[N-(1H-indol-7-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • White powder (ethanol)
  • mp: 155-167.8° C.
    • Example 93 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(4-methylpyridin-3-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.32 (3H, s), 2.94-2.96 (2H, m), 3.00 (2H, br), 3.42 (3H, s), 3.74-3.74 (1H, m), 3.96 (2H, br), 4.04-4.11 (1H, m), 7.07 (1H, d, J=4.9 Hz), 7.26-7.28 (2H, m), 7.34 (1H, br), 8.33 (1H, d, J=4.9 Hz), 8.38 (1H, s).
    • Example 94 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(2-methylpyridin-3-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.55 (3H, s), 2.85-2.93 (4H, m), 3.41 (3H, s), 3.75-3.83 (1H, m), 3.86 (2H, s), 4.11-4.17 (1H, m), 7.08 (1H, dd, J=7.6, 4.8 Hz), 7.19-7.21 (2H, m), 7.24-7.26 (1H, m), 7.44 (1H, dd, J=7.6, 1.6 Hz), 8.37 (1H, dd, 4.8, 1.6 Hz).
    • Example 95 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methyloxazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.69 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.395 (3H, s), 2.404 (3H, s), 3.32 (3H, s), 3.47 (2H, br), 3.74-3.81 (1H, m), 3.95-4.06 (1H, m), 4.23 (2H, br), 4.37 (4H, br), 6.55 (1H, s), 6.76 (1H, d, J=7.4 Hz), 7.48 (2H, br), 7.57 (1H, d, J=7.4 Hz), 7.67 (1H, br), 8.14 (1H, br).
    • Example 96 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(oxazol-5-ylmethyl)amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.66 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.39 (3H, s), 3.21 (3H, s), 3.28-3.49 (2H, m), 3.74 (1H, br), 3.91-3.97 (1H, m), 4.20 (6H, br), 6.69 (1H, s), 6.69-6.71 (1H, m), 7.11-7.31 (4H, m), 7.54 (1H, d, J=7.5 Hz), 8.33 (1H, br).
    • Example 97 Synthesis of 7-({N-(2,4-dimethylthiazol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Pale yellow powder
  • mp: 187-188° C.
    • Example 98 Synthesis of 7-{[N-(2-chloropyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • mp: 183-187° C.
    • Example 99 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(quinolin-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • mp: 136-141° C.
    • Example 100 Synthesis of 7-{[N-[2-(2,6-dimethylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-yl methyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 136-137° C.
    • Example 101 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 139-140° C.
    • Example 102 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 145-147° C.
    • Example 103 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 138-142° C.
    • Example 104 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 144-145° C.
    • Example 105 Synthesis of 7-{[N-[2-(2,3-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 148-150° C.
    • Example 106 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 125-127° C.
    • Example 107 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 193-195° C.
    • Example 108 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2,6-dimethylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.75 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.11 (3H, s), 2.65 (3H, br), 2.71 (3H, br), 3.36 (5H, br), 3.50 (3H, s), 3.60-3.82 (3H, m), 4.00-4.10 (1H, m), 4.44 (2H, br), 4.53 (2H, br), 6.50 (1H, br), 7.57-7.67 (2H, m), 7.69 (1H, d, J=7.9 Hz), 8.00 (1H, br), 8.23 (1H, br).
  • The following compounds shown in Examples 109 to 308 can be prepared by the same manner as mentioned above or a conventional manner using appropriate starting materials.
    • Example 109 1-Ethyl-3,3,5-trimethyl-7-{[oxazol-5-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 110 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-2-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 111 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-5-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 112 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-4-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 113 1-Ethyl-3,3,5-trimethyl-7-{[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 114 7-{[(4,5-Dimethyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 115 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 116 1-Ethyl-7-{[(3-fluoro-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 117 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 118 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 119 7-{[[2-(2,6-Dimethyl-pyridin-3-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b ][1,4]diazepine-2,4-dione Example 120 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 121 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 122 1-Ethyl-7-{[(2-methoxy-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 123 7-{[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 124 1-Ethyl-7-{[(3-hydroxy-benzyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 125 1-Ethyl-7-{[furan-2-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 126 1-Ethyl-7-{[furan-3-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 127 1-Ethyl-3,3,5-trimethyl-7-{[(5-methyl-furan-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 128 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-furan-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 129 7-{[(4,5-Dimethyl-furan-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 130 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 131 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-thiophen-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 132 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiophen-2-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 133 7-{[(4,5-Dimethyl-thiophen-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 134 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 135 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 136 1-Ethyl-3,3,5-trimethyl-7-{2-[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 137 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 138 1-Ethyl-3,3,5-trimethyl-7-{2-[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 139 7-{2-[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 140 N-(2-{[[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-(2-pyridin-3-yl-ethyl)-amino]-methyl}-phenyl)-methanesulfonamide Example 141 7-{2-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 142 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 143 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 144 1-Ethyl-3,3,5-trimethyl-7-{3-[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 145 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 146 1-Ethyl-3,3,5-trimethyl-7-{3-[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 147
  • N-(2-{[[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-(2-pyridin-3-yl-ethyl)-amino]-methyl}-phenyl)-methanesulfonamide
    • Example 148 7-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 149 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 150 1-Ethyl-3,3,5-trimethyl-7-({oxazol-5-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 151 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 152 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 153 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 154 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 155 7-({(2,4-Dimethyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 156 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 157 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 158 1-Ethyl-7-({(3-fluoro-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 159 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 160 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 161 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 162 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 163 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 164 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 165 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 166 1-Ethyl-7-({(3-hydroxy-benzyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 167 1-Ethyl-7-({furan-2-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl) ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 168 1-Ethyl-7-({furan-3-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl) ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 169 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 170 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 171 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 172 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 173 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 174 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 175 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-thiophen-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 176 7-({(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 177 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-oxazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 178 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-5-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 179 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 180 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 181 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 182 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-4-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 183 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 184 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 185 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 186 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 187 1-Ethyl-7-({(3-hydroxy-benzyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 188 1-Ethyl-7-({furan-2-ylmethyl-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 189 1-Ethyl-7-({furan-3-ylmethyl-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 190 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 191 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 192 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 193 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 194 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 195 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-thiophen-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 196 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 197 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 198 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 199 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 200 1-Ethyl-3,3,5-trimethyl-7-{[[2-(3-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 201 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 202 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 203 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 204
  • N-(2-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-amino]-methyl}-phenyl)-methanesulfonamide
    • Example 205 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 206 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 207 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 208 1-Ethyl-3,3,5-trimethyl-7-(2-{(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 209
  • N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide
    • Example 210 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 211 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 212 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 213 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 214 7-(2-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 215
  • N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide
    • Example 216 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 217 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 218 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 219 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 220 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 221 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 222
  • N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide
    • Example 223 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 224 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 225 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 226 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 227 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 228 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 229
  • N-[2-({[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-[2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide
    • Example 230 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 231 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 232 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 233 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 234 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 235 1-Ethyl-3,3,5-trimethyl-7-(3-{(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 236
  • N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide
    • Example 237 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 238 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 239 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 240 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 241 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 242 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 243 7-{3-[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 244 7-(3-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 245 N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 246 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 247 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 248 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 249 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 250 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 251 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 252 N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 253 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 254 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 255 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 256 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 257 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 258 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 259
  • N-[2-({[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-amino}-methyl)-phenyl]-methane sulfonamide
    • Example 260 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 261 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 262 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 263 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 264 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 265 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 266 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 267 1-Ethyl-3,3,5-trimethyl-7-({oxazol-5-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 268 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 269 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-5-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 270 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 271 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 272 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b ][1,4]diazepine-2,4-dione Example 273 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 274 7-({(2,4-Dimethyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 275 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-pyridin-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 276 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 277 1-Ethyl-7-({(3-fluoro-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 278 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 279 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 280 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 281 1-Ethyl-3,3,5-trimethyl-7-{[[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 282 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 283 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 284 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 285 1-Ethyl-7-({(3-hydroxybenzyl)-[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 286 1-Ethyl-7-({furan-2-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 287 1-Ethyl-7-({furan-3-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 288 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 289 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(2-oxo-3,4-divinyl-2H-pyridin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 290 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 291 1-Ethyl-3,3,5-trimethyl-7-{[[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 292 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 293 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-thiophen-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 294 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 295 7-({(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 296 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 297 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 298 1-Ethyl-3,3,5-trimethyl-7-(2-{(2-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 299 7-(2-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 300 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 301 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 302 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 303 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 304 7-(3-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 305 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 306 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 307 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 308 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 309 7-{[N-(4-Chloropyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • mp: 200-205° C. (dec.)
    • Example 310 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 161-165° C.
    • Example 311 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 144-146° C.
    • Example 312 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 127-128° C.
    • Example 313 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 197-199° C.
    • Example 314 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 190-193° C.
    • Example 315 1-Ethyl-3,3,5-trimethyl-7-{[N-(4-methylthiazol-2-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white amorphous
  • 1H NMR (D2O), δppm: 0.75 (3H, s), 1.10 (3H, t, J=7.2 Hz), 1.42 (3H, s), 2.39 (3H, s), 3.25-3.36 (4H, m), 3.37 (3H, s), 3.73-3.87 (1H, m), 4.07-4.22 (3H, m), 4.41 (2H, s), 7.18 (1H, d, J=1.0 Hz), 7.32-7.38 (1H, m), 7.38-7.43 (1H, m), 7.49 (1H, d, J=8.3 Hz), 7.99 (1H, dd, J=6.0, 8.0 Hz), 8.44 (1H, d, J=8.3 Hz), 8.66-8.73 (2H, m)
    • Example 316 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 123-125° C.
    • Example 317 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 127-129° C.
    • Example 318 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 104-111° C.
    • Example 319 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • 4 M HCl/AcOEt (90 μl) was added to an ethyl acetate solution (1 ml) of 1-ethyl-7-({(2-methoxymethylpyridin-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (26 mg) and stirred for 5 minutes at room temperature. The resulting precipitate was collected and washed with ether to give the title compound as a white powder (14 mg).
  • 1H NMR (DMSO-d6), 8 ppm: 0.75 (3H, s), 1.05 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.16 (3H, s), 3.27-3.33 (8H, m), 3.70-4.40 (6H, m), 4.52 (2H, br), 4.65 (2H, br), 6.93 (1H, s), 7.28-7.48 (4H, m), 7.72-7.84 (1H, m), 7.97 (1H, s), 8.35 (1H, br), 8.53-8.65 (1H, m).
    • Example 320 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-2-trifluoromethyl-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 132-134° C.
    • Example 321 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methyl-3H-imidazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 106-108° C.
    • Example 322 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methyl-3H-imidazol-4-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 100-105° C.
    • Example 323 1-Ethyl-7-({N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 123-126° C.
    • Example 324 1-Ethyl-7-({N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • pale yellow powder
  • 1H NMR (DMSO-d6), δppm: 0.69 (3H, s), 1.01 (3H, t, J=7.1 HZ), 1.33 (3H, s), 2.22 (3H, s), 2.80 (2H, s), 3.27 (3H, s), 3.30 (3H, s), 3.61-4.05 (6H, m), 4.12 (2H, br), 4.48 (2H, s), 6.63 (1H, d, J=7.4 Hz), 6.78 (1H, s), 7.22 (1H, br), 7.32-7.33 (2H, m), 7.54 (1H, d, J=7.0 Hz), 7.61 (1H, d, J=5.7 Hz), 8.61 (1H, d, J=5.7 Hz), 8.63 (1H, s).
    • Example 325 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • ivory powder
  • 1H NMR (DMSO-d6), δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.04 (3H, s), 2.71 (2H, br), 3.27 (3H, s), 3.30 (3H, br), 3.45-4.00 (6H, m), 3.85 (3H, s), 4.39-4.63 (4H, m), 6.44 (1H, br), 6.61-7.02 (2H, m), 7.05-7.95 (4H, m).
    • Example 326 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-phenyl-N-(2-pyridin-3-ylethyl)acetamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.
  • white amorphous
  • 1H NMR (DMSO-d6), δppm: 0.70 and 0.73 (3H, s), 0.95-1.13 (3H, m), 1.32 and 1.33 (3H, s), 2.91-3.03 (2H, m), 3.22 and 3.25 (3H, s), 3.50-3.82 (5H, m), 3.96-4.09 (1H, m), 4.56-4.74 (2H, m), 7.04-7.34 (7H, m), 7.42-7.52 (1H, m), 7.78 (1H, bs), 8.19 (1H, bs), 8.65-8.77 (2H, m)
    • Example 327
  • N-[2-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 161-163° C.
    • Example 328 7-({N-(2-Chloropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 158.7-160.8° C.
    • Example 329 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile
  • 2-Chloro-3-({(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine (0.3 g), zinc cyanide (120 mg), tris(dibenzylideneacetone)dipalladium (24 mg), 1,1′-bis(diphenylphosphino)ferrocene (14 mg), and zinc powder (3.4 mg) were added to DMF (3 ml), and the mixture was heated at 95° C. for 3 hours. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture and subjected to celite filtration. Extraction with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=93:7). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (1.35 g) as a white powder.
  • mp: 113.5-117.5° C.
    • Example 330 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride
  • To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dion e (0.5 g), 1-methyl-3-indoleacetic acid (0.27 g), and 1-hydroxybenzotriazole (HOBT)(0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.26 g) as a pale orange white amorphous.
  • 1H NMR (DMSO-d6), δppm: 0.65 and 0.69 (3H, s), 0.95-1.13 (3H, m), 1.31 and 1.32 (3H, s), 2.90-3.05 (2H, m), 3.06 and 3.14 (3H, s), 3.20-3.90 (5H, m), 3.70 and 3.73 (3H, s), 3.90-4.08 (1H, m), 4.55-4.79 (2H, m), 6.96 (1H, t, J=7.4 Hz), 7.05-7.24 (4H, m), 7.32-7.42 (2H, m), 7.43-7.55 (1H, m), 7.63-7.79 (1H, m), 8.13 (1H, bs), 8.57-8.72 (2H, m)
    • Example 331 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(1-pyridin-3-ylethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 128-132° C.
    • Example 332
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-phenyl-N-(2-pyridin-3-ylethyl)isobutyramide hydrochloride
  • To a solution of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), 2-Phenylisobutyric acid (0.24 g), and diisopropylethylamine (0.23 ml) in DMF (10 ml), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.50 g) was added and stirred at 40° C. for 10 hours. Water was added to the reaction mixture, and stirred for 1 hour, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.35 g) as a white amorphous.
  • 1H NMR (DMSO-d6), δppm: 0.67 and 0.72 (3H, s), 0.90-1.20 (3H, m), 1.20-1.40 (3H, m), 1.43 and 1.48 (6H, s), 2.30-2.50 (1H, m), 2.83-3.40 (5H, m), 3.40-4.30 (4H, m), 4.57-4.79 (1H, m), 6.76-7.03 (1H, m), 7.03-7.56 (8H, m), 7.56-8.80 (3H, m)
    • Example 333 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-3-phenyl-N-(2-pyridin-3-ylethyl)propionamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.
  • white amorphous
  • 1H NMR (DMSO-d6), δppm: 0.70 and 0.72 (3H, s), 0.95-1.12 (3H, m), 1.33 (3H, s), 2.53-2.69 (2H, m), 2.69-2.86 (2H, m), 2.90-3.03 (2H, m), 3.25 and 3.28 (3H, s), 3.45-3.68 (2H, m), 3.69-3.81 (1H, m), 3.96-4.10 (1H, m), 4.53-4.69 (2H, m), 7.04-7.29 (7H, m), 7.43 and 7.45 (1H, d, J=4.9 Hz), 7.78-7.86 (1H, m), 8.10-8.27 (1H, m), 8.57-8.77 (2H, m)
    • Example 334
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)-2-quinolin-6-ylacetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.
  • white amorphous
  • 1H NMR (DMSO-d6), δppm: 0.68 and 0.70 (3H, s), 1.00-1.08 (3H, m), 1.31 and 1.32 (3H, s), 3.03 (1H, t, J=7.0 Hz), 3.10-3.18 (1H, m), 3.23 and 3.26 (3H, s), 3.40-3.90 (2H, m), 3.95-4.13 (4H, m), 4.60-4.88 (2H, m), 7.18-7.29 (2H, m), 7.42-7.52 (1H, m), 7.66-8.04 (4H, m), 8.07-8.21 (1H, m), 8.28-8.45 (1H, m), 8.65-8.93 (3H, m), 9.06-9.16 (1H, m)
    • Example 335 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.71 and 0.76 (3H, s), 1.00-1.13 (3H, m), 1.33 and 1.34 (3H, s), 2.98 (1H, t, J=7.2 Hz), 3.10-3.17 (1H, m), 3.29 and 3.33 (3H, s), 3.50-3.68 (1H, m), 3.68-3.84 (2H, m), 3.97-4.13 (1H, m), 4.55-4.72 (2H, m), 4.76-4.87 (2H, m), 6.63-7.05 (4H, m), 7.15-7.38 (2H, m) 7.41-7.60 (1H, m), 7.75-7.88 (1H, m), 8.17-8.38 (1H, m), 8.56-8.86 (2H, m), 10.84 and 10.89 (1H, s)
    • Example 336 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]N-(pyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 124-127° C.
    • Example 337 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride (0.26 g), cesium carbonate (0.43 g), and methyl iodide (0.04 ml) were added to DMF (5 ml), and the mixture was stirred at room temperature for 1 days. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (0.44 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.20 g) as a white powder.
  • 1H NMR (DMSO-d6), δppm: 0.71 and 0.76 (3H, s), 1.00-1.13 (3H, m), 1.33 and 1.34 (3H, s), 2.92-3.03 (1H, m), 3.10-3.25 (1H, m), 3.30 and 3.30 (3H, s), 3.30-3.50 (3H, m), 3.50-3.81 (3H, m), 3.97-4.14 (1H, m), 4.57-4.91 (4H, m), 6.74-7.11 (3H, m), 7.11-7.40 (3H, m), 7.46 and 7.57 (1H, d, J=8.3 Hz), 7.72-7.85 (1H, m), 8.15-8.37 (1H, m), 8.63-8.86 (2H, m)
    • Example 338 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]benzamide
  • The synthesis of the title compound was performed in the same manner as in Example 42 using appropriate starting materials.
  • white powder
  • 1H NMR (CDCl3), δppm: 0.79 (3H, bs), 1.15-1.24 (3H, m), 1.52 and 1.54 (3H, s), 2.43 (3H, d, J=0.4 Hz), 3.33-3.42 (3H, m), 3.45-3.83 (3H, m), 3.83-5.04 (5H, m), 6.27-6.77 (2H, m), 6.80-7.14 (2H, m), 7.17-7.44 (7H, m)
    • Example 339 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(4-methylindol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.71 and 0.77 (3H, s), 0.90-1.15 (3H, m), 1.33 and 1.35 (3H, s), 2.44 and 2.46 (3H, s), 2.89-3.13 (2H, m), 3.29 and 3.30 (3H, s), 3.58-3.65 (1H, m), 3.66-3.86 (2H, m), 3.96-4.14 (1H, m), 4.56-4.89 (2H, m), 5.10 and 5.20 (2H, s), 6.38-6.50 (1H, m), 6.77-7.03 (3H, m), 7.15-7.36 (3H, m), 7.46 and 7.57 (1H, d, J=8.3 Hz), 7.66-7.78 (1H, m), 8.09-8.23 (1H, m), 8.60-8.79 (2H, m)
    • Example 340 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methoxymethylpyridin-3-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder (Ether)
  • mp: 103-104° C.
    • Example 341 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 119-122° C.
    • Example 342 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(5-methylthiazol-4-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 144-145° C.
    • Example 343 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]acetamide
  • The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.
  • white amorphous
  • 1H NMR (CDCl3), δppm: 0.74 and 0.78 (3H, s), 1.15-1.24 (3H, m), 1.49 and 1.51 (3H, s), 2.41 (3H, d, J=0.6 Hz), 3.11 and 3.24 (3H, s), 3.60-3.94 (9H, m), 3.94-4.26 (2H, m), 4.33-4.78 (2H, m), 6.09-6.59 (2H, m), 6.77-6.90 (1H, m), 6.90-6.98 (1H, m), 7.03-7.37 (5H, m), 7.57 (1H, d, J=8.0 Hz), 7.66 (1H, d, J=8.0 Hz)
    • Example 344 7-({N-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 138-139° C.
    • Example 345
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)-2-quinolin-3-ylacetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.
  • white powder
  • mp: 189-194° C.
    • Example 346 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid-N-benzyl-N-(2-pyridin-3-yl-ethyl)amide
  • The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.
  • white powder
  • mp: 181-182° C.
    • Example 347 1-Ethyl-3,3,5-trimethyl-7-({N-(5-methyloxazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 129.0-130.5° C.
    • Example 348 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid-N-(4-methoxybenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amide
  • The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.
  • white powder (Et2O-EtOH)
  • mp: 151.1-155.1° C.
    • Example 349 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 113-116° C.
    • Example 350
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-methylbenzoimidazol-1-yl)-N-(2-pyridin-3-yl-ethyl)acetamide
  • The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.
  • white amorphous
  • 1H NMR (CDCl3), δppm: 0.82 and 0.87 (3H, s), 1.15-1.30 (3H, m), 1.53 and 1.55 (3H, s), 2.41 and 2.47 (3H, s), 2.87-3.01 (2H, m), 3.33 and 3.39 (3H, s), 3.60-3.94 (3H, m), 4.05-4.26 (1H, m), 4.50-4.87 (4H, m), 6.89 (1H, t, J=8.0 Hz), 6.98-7.60 (7H, m), 7.68 (1H, t, J=9.1 Hz), 8.44 (1H, s), 8.52 and 8.61 (1H, d, J=3.5 Hz)
    • Example 351 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(3-methylpyridin-2-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder (AcOEt-Et2O)
  • mp: 139-143° C.
    • Example 352 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.69 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.31 (3H, s), 2.80-3.20 (2H, m), 3.29 (3H, s), 3.30 (3H, s), 3.39-3.45 (2H, m), 3.70-3.77 (1H, m), 3.92-4.04 (3H, m), 4.36 (2H, br), 4.74 (2H, br), 6.76 (1H, d, J=6.9 Hz), 7.30-7.40 (3H, m), 7.59 (1H, br), 7.83 (2H, br), 8.07 (1H, d, J=5.2 Hz), 8.65 (2H, br).
    • Example 353 7-({N-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.72 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.24 (3H, s), 3.30-3.43 (5H, m), 3.73 (3H, s), 3.66-3.86 (3H, m), 3.97-4.06 (1H, m), 4.27 (2H, br), 4.43 (2H, br), 6.32-6.35 (1H, m), 6.85 (1H, d, J=7.4 Hz), 6.97 (1H, s), 7.54-7.57 (1H, m), 7.61-7.72 (2H, m), 7.87 (1H, br), 7.94-7.95 (1H, m).
    • Example 354 1-Ethyl-7-({N-(6-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.67 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.40 (3H, s), 2.70-3.10 (2H, m), 3.27 (5H, br), 3.41 (3H, s), 3.65-4.10 (6H, m), 4.63 (2H, br), 6.51 (1H, br), 6.70 (1H, br), 7.57 (1H, d, J=7.2 Hz), 7.00-7.70 (4H, m), 8.23 (1H, br), 8.74 (1H, m).
    • Example 355 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)-N-(2-pyridin-3-ylethyl)isobutyramide
  • The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.
  • pale brown white amorphous
  • 1H NMR (CDCl3), δppm: 0.74 and 0.80 (3H, s), 1.08-1.23 (3H, m), 1.50 and 1.52 (3H, s), 1.95-2.07 (6H, m), 2.15-2.35 (1H, m), 2.87 (1H, t, J=7.5 Hz), 3.16 and 3.37 (3H, s), 3.42-3.63 (2H, m), 3.63-3.88 (1H, m), 3.95-4.18 (1H, m), 4.43-4.82 (2H, m), 6.52-6.62 (1H, m), 6.80-7.32 (7H, m), 7.48 (1H, d, J=7.8 Hz), 7.99 and 8.10 (1H, s), 8.30-8.63 (2H, m)
    • Example 356 1-Ethyl-3,3,5-trimethyl-7-({N-[1-(2-methylpyridin-3-yl)ethyl]-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder (Ether)
  • mp: 164-167° C.
    • Example 357 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-[1-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 163-164° C.
    • Example 358 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-[1-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 169-170° C.
    • Example 359 7-({N-(2-Ethoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 104-106° C.
    • Example 360 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(quinolin-5-yl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45 g), 5-bromoquinoline (0.25 g), tris(dibenzylideneacetone)dipalladium (5.4 mg), xantphos (10 mg), and cesium carbonate (0.46 g) were added to toluene (9 ml), and the mixture was heated at 130° C. for 3 days. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.20 g) as a yellow amorphous.
  • 1H NMR (DMSO-d6), δppm: 0.55 (3H, s), 0.99 (3H, t, J=7.0 Hz), 1.29 (3H, s), 3.03 (2H, t, J=7.1 Hz), 3.14 (3H, s), 3.30-3.80 (3H, m), 3.90-4.03 (1H, m), 4.49 (2H, s), 7.06-7.20 (2H, m), 7.33 (1H, d, J=8.1 Hz), 7.49 (1H, d, J=5.4 Hz), 7.73 (1H, dd, J=4.8 Hz, 8.8 Hz), 7.78-7.90 (3H, m), 8.23 (1H, d, J=8.1 Hz), 8.64 (1H, s), 8.69 (1H, d, J=4.8 Hz), 8.73 (1H, d, J=8.8 Hz), 9.07 (1H, d, J=3.6 Hz),
    • Example 361
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide
  • The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.
  • yellow amorphous
  • 1H NMR (CDCl3), δppm: 0.70 and 0.79 (3H, s), 1.08-1.23 (3H, m), 1.49 and 1.52 (3H, s), 2.77 (1H, t, J=7.7 Hz), 2.85 (1H, t, J=7.3 Hz), 3.06 and 3.21 (3H, s), 3.52-3.82 (3H, m), 4.01-4.16 (3H, m), 4.50-4.70 (2H, m), 6.75-7.32 (5H, m), 7.32-7.50 (3H, m), 7.82-7.92 (1H, m), 8.27-8.55 (2H, m), 10.1 and 10.1 (1H, bs)
    • Example 362 7-({N-(4-Chloropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 114-118° C.
    • Example 363 N-[3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl]formamide
  • 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile (0.40 g) and Raney nickel (1.2 g) were suspended in formic acid (8 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=75:25→80:20). The purified product was condensed under reduced pressure. Acetone and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (33 mg) as a pale brown white amorphous.
  • 1H NMR (CDCl3), δppm: 0.77 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.43 (3H, d, J=0.9 Hz), 2.85 (2H, t, J=5.8 Hz), 3.35 (3H, s), 3.58-3.84 (5H, m), 4.00-4.18 (3H, m), 4.54 (2H, d, J=4.4 Hz), 6.41 (1H, dd, J=0.4 Hz, 7.3 Hz), 6.47 (1H, t, J=0.8 Hz), 6.96 (1H, d, J=7.3 Hz), 7.06 (1H, dd, J=4.9, 7.7 Hz), 7.12-7.20 (3H, m), 7.38 (1H, bs), 7.55 (1H, dd, J=1.2, 7.7 Hz), 8.32 (1H, d, J=1.2 Hz), 8.36 (1H, dd, J=1.5, 4.9 Hz)
    • Example 364 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]N-(quinolin-5-yl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 166-168° C.
    • Example 365 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)propionamide
  • Sodium hydride (55% in oil) (52 mg) was suspended in DMF (7 ml), and cooled to 0° C. in an ice water bath.
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide (210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide (0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=90:10). The purified product was condensed to dryness to give the title compound (20 mg) as a pale yellow white amorphous.
  • 1H NMR (CDCl3), δppm: 0.75 and 0.86 (3H, s), 1.17 and 1.21 (3H, t, J=7.1 Hz), 1.51 (3H, s), 1.54 (3H, s), 2.94 (1H, t, J=7.7 Hz), 3.06 (1H, t, J=7.2 Hz), 3.40 and 3.48 (3H, s), 3.44-3.54 (2H, m), 3.68 (1H, t, J=6.7 Hz), 3.72-3.90 (1H, m), 3.95-4.22 (2H, m), 4.18 and 4.25 (3H, s), 4.70-4.84 (1H, m), 7.03-7.75 (8H, m), 8.27-8.35 (1H, m), 8.35-8.44 (1H, m), 8.51-8.64 (1H, m)
    • Example 366 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)formamide
  • Sodium hydride (55% in oil) (52 mg) was suspended in DMF (7 ml), and cooled to 0° C. in an ice water bath.
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide (210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide (0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed to dryness to give the title compound (17 mg) as a pale yellow white amorphous.
  • pale yellow white amorphous
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.19 and 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, bs), 2.85 (2H, t, J=7.7 Hz), 3.39 and 3.39 (3H, s), 3.44-3.54 (2H, m), 3.75-3.88 (1H, m), 4.06-4.20 (1H, m), 4.27-4.65 (2H, m), 6.98-7.10 (1H, m), 7.10-7.18 (1H, m), 7.21-7.35 (2H, m), 7.41 and 7.53 (1H, dt, J=7.9, 2.0 Hz), 8.05 and 8.30 (1H, s), 8.39 and 8.41 (1H, d, J=1.8 Hz), 8.50 and 8.62 (1H, dd, J=1.8, 4.8 Hz)
    • Example 367 1-Ethyl-7-({N-[1-(2-methoxymethylpyridin-3-yl)ethyl]-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • white powder
  • 1H NMR (DMSO-d6), δppm: 0.75 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.34 (3H, s), 1.41 (3H, s), 2.09 (3H, s), 2.57-2.84 (2H, m), 3.16 (2H, br), 3.35 (3H, s), 3.40 (3H, s), 3.62-3.70 (2H, m), 4.00-4.13 (1H, m), 4.18 (2H, br), 6.83 (1H, br), 7.09 (1H, br), 7.43-7.63 (3H, m), 7.83 (1H, br), 7.91-7.92 (1H, m), 8.40 (1H, br), 8.46 (1H, br).
    • Example 368 1-Ethyl-7-({N-(2-hydroxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 187-190° C.
    • Example 369 7-({N,N-Bis-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diaz epine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 160-165° C.
    • Example 370 1-Ethyl-7-({N-(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 169-170° C.
    • Example 371 1-Ethyl-7-({N-(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 113-115° C.
    • Example 372 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 184-186° C.
    • Example 373 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 207-210° C.
    • Example 374 1-Isobutyl-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 180-182° C.
    • Example 375 1-Isobutyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 229-231° C.
    • Example 376 1-(2-Methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 182-185° C.
    • Example 377 1-(2-Methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 188-189° C.
    • Example 378 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 149-151° C.
    • Example 379 1-(2-Methoxyethyl)-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 179-181° C.
    • Example 380 1-(2-Methoxyethyl)-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 205-206° C.
    • Example 381 1-Cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 189-191° C.
    • Example 382 1-Cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 192-194° C.
    • Example 383 1-Cyclopropylmethyl-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 138-143° C.
    • Example 384 1-Cyclopropylmethyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 220-221° C.
    • Example 385 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 130-131° C.
    • Example 386 1-Cyclopropyl-7-({N-(2-methoxymethyl-pyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 213-214° C.
    • Example 387 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 182-184° C.
    • Example 388 1-Cyclopropyl-3,3-dimethyl-7-({[2-N-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 172-173° C.
    • Example 389 1-Cyclopropyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 191-193° C.
    • Example 390 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 149-150° C.
    • Examples 391 to 582
  • The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.
  • Figure US20140343277A1-20141120-C00044
    Example No. R1 MS (M + 1)
    391
    Figure US20140343277A1-20141120-C00045
         		461
    392
    Figure US20140343277A1-20141120-C00046
         		472
    393
    Figure US20140343277A1-20141120-C00047
         		472
    394
    Figure US20140343277A1-20141120-C00048
         		475
    395
    Figure US20140343277A1-20141120-C00049
         		477
    396
    Figure US20140343277A1-20141120-C00050
         		491
    397
    Figure US20140343277A1-20141120-C00051
         		478
    398
    Figure US20140343277A1-20141120-C00052
         		489
    399
    Figure US20140343277A1-20141120-C00053
         		487
    400
    Figure US20140343277A1-20141120-C00054
         		461
    401
    Figure US20140343277A1-20141120-C00055
         		564
    402
    Figure US20140343277A1-20141120-C00056
         		540
    403
    Figure US20140343277A1-20141120-C00057
         		489
    404
    Figure US20140343277A1-20141120-C00058
         		492
    405
    Figure US20140343277A1-20141120-C00059
         		529
    406
    Figure US20140343277A1-20141120-C00060
         		506
    407
    Figure US20140343277A1-20141120-C00061
         		492
    408
    Figure US20140343277A1-20141120-C00062
         		505
    409
    Figure US20140343277A1-20141120-C00063
         		492
    410
    Figure US20140343277A1-20141120-C00064
         		486
    411
    Figure US20140343277A1-20141120-C00065
         		486
    412
    Figure US20140343277A1-20141120-C00066
         		486
    413
    Figure US20140343277A1-20141120-C00067
         		486
    414
    Figure US20140343277A1-20141120-C00068
         		486
    415
    Figure US20140343277A1-20141120-C00069
         		490
    416
    Figure US20140343277A1-20141120-C00070
         		475
    417
    Figure US20140343277A1-20141120-C00071
         		506
    418
    Figure US20140343277A1-20141120-C00072
         		489
    419
    Figure US20140343277A1-20141120-C00073
         		475
    420
    Figure US20140343277A1-20141120-C00074
         		486
    421
    Figure US20140343277A1-20141120-C00075
         		490
    422
    Figure US20140343277A1-20141120-C00076
         		540
    423
    Figure US20140343277A1-20141120-C00077
         		502
    424
    Figure US20140343277A1-20141120-C00078
         		478
    425
    Figure US20140343277A1-20141120-C00079
         		478
    426
    Figure US20140343277A1-20141120-C00080
         		473
    427
    Figure US20140343277A1-20141120-C00081
         		462
    428
    Figure US20140343277A1-20141120-C00082
         		473
    429
    Figure US20140343277A1-20141120-C00083
         		486
    430
    Figure US20140343277A1-20141120-C00084
         		502
    431
    Figure US20140343277A1-20141120-C00085
         		476
    432
    Figure US20140343277A1-20141120-C00086
         		486
    433
    Figure US20140343277A1-20141120-C00087
         		462
    434
    Figure US20140343277A1-20141120-C00088
         		462
    435
    Figure US20140343277A1-20141120-C00089
         		476
    436
    Figure US20140343277A1-20141120-C00090
         		560
    437
    Figure US20140343277A1-20141120-C00091
         		487
    438
    Figure US20140343277A1-20141120-C00092
         		500
  • Figure US20140343277A1-20141120-C00093
    Example No. R1 MS (M + 1)
    439
    Figure US20140343277A1-20141120-C00094
         		517
    440
    Figure US20140343277A1-20141120-C00095
         		528
    441
    Figure US20140343277A1-20141120-C00096
         		528
    442
    Figure US20140343277A1-20141120-C00097
         		531
    443
    Figure US20140343277A1-20141120-C00098
         		533
    444
    Figure US20140343277A1-20141120-C00099
         		547
    445
    Figure US20140343277A1-20141120-C00100
         		534
    446
    Figure US20140343277A1-20141120-C00101
         		545
    447
    Figure US20140343277A1-20141120-C00102
         		543
    448
    Figure US20140343277A1-20141120-C00103
         		517
    449
    Figure US20140343277A1-20141120-C00104
         		620
    450
    Figure US20140343277A1-20141120-C00105
         		596
    451
    Figure US20140343277A1-20141120-C00106
         		545
    452
    Figure US20140343277A1-20141120-C00107
         		548
    453
    Figure US20140343277A1-20141120-C00108
         		585
    454
    Figure US20140343277A1-20141120-C00109
         		562
    455
    Figure US20140343277A1-20141120-C00110
         		548
    456
    Figure US20140343277A1-20141120-C00111
         		561
    457
    Figure US20140343277A1-20141120-C00112
         		548
    458
    Figure US20140343277A1-20141120-C00113
         		542
    459
    Figure US20140343277A1-20141120-C00114
         		542
    460
    Figure US20140343277A1-20141120-C00115
         		542
    461
    Figure US20140343277A1-20141120-C00116
         		542
    462
    Figure US20140343277A1-20141120-C00117
         		542
    463
    Figure US20140343277A1-20141120-C00118
         		546
    464
    Figure US20140343277A1-20141120-C00119
         		531
    465
    Figure US20140343277A1-20141120-C00120
         		562
    466
    Figure US20140343277A1-20141120-C00121
         		545
    467
    Figure US20140343277A1-20141120-C00122
         		531
    468
    Figure US20140343277A1-20141120-C00123
         		542
    469
    Figure US20140343277A1-20141120-C00124
         		546
    470
    Figure US20140343277A1-20141120-C00125
         		596
    471
    Figure US20140343277A1-20141120-C00126
         		558
    472
    Figure US20140343277A1-20141120-C00127
         		534
    473
    Figure US20140343277A1-20141120-C00128
         		534
    474
    Figure US20140343277A1-20141120-C00129
         		529
    475
    Figure US20140343277A1-20141120-C00130
         		518
    476
    Figure US20140343277A1-20141120-C00131
         		529
    477
    Figure US20140343277A1-20141120-C00132
         		542
    478
    Figure US20140343277A1-20141120-C00133
         		558
    479
    Figure US20140343277A1-20141120-C00134
         		532
    480
    Figure US20140343277A1-20141120-C00135
         		542
    481
    Figure US20140343277A1-20141120-C00136
         		518
    482
    Figure US20140343277A1-20141120-C00137
         		518
    483
    Figure US20140343277A1-20141120-C00138
         		532
    484
    Figure US20140343277A1-20141120-C00139
         		616
    485
    Figure US20140343277A1-20141120-C00140
         		543
    486
    Figure US20140343277A1-20141120-C00141
         		556
  • Figure US20140343277A1-20141120-C00142
    Example No. R1 MS (M + 1)
    487
    Figure US20140343277A1-20141120-C00143
         		527
    488
    Figure US20140343277A1-20141120-C00144
         		538
    489
    Figure US20140343277A1-20141120-C00145
         		538
    490
    Figure US20140343277A1-20141120-C00146
         		541
    491
    Figure US20140343277A1-20141120-C00147
         		543
    492
    Figure US20140343277A1-20141120-C00148
         		557
    493
    Figure US20140343277A1-20141120-C00149
         		544
    494
    Figure US20140343277A1-20141120-C00150
         		555
    495
    Figure US20140343277A1-20141120-C00151
         		553
    496
    Figure US20140343277A1-20141120-C00152
         		527
    497
    Figure US20140343277A1-20141120-C00153
         		630
    498
    Figure US20140343277A1-20141120-C00154
         		606
    499
    Figure US20140343277A1-20141120-C00155
         		555
    500
    Figure US20140343277A1-20141120-C00156
         		558
    501
    Figure US20140343277A1-20141120-C00157
         		595
    502
    Figure US20140343277A1-20141120-C00158
         		572
    503
    Figure US20140343277A1-20141120-C00159
         		558
    504
    Figure US20140343277A1-20141120-C00160
         		571
    505
    Figure US20140343277A1-20141120-C00161
         		558
    506
    Figure US20140343277A1-20141120-C00162
         		552
    507
    Figure US20140343277A1-20141120-C00163
         		552
    508
    Figure US20140343277A1-20141120-C00164
         		552
    509
    Figure US20140343277A1-20141120-C00165
         		552
    510
    Figure US20140343277A1-20141120-C00166
         		552
    511
    Figure US20140343277A1-20141120-C00167
         		556
    512
    Figure US20140343277A1-20141120-C00168
         		541
    513
    Figure US20140343277A1-20141120-C00169
         		572
    514
    Figure US20140343277A1-20141120-C00170
         		555
    515
    Figure US20140343277A1-20141120-C00171
         		541
    516
    Figure US20140343277A1-20141120-C00172
         		552
    517
    Figure US20140343277A1-20141120-C00173
         		556
    518
    Figure US20140343277A1-20141120-C00174
         		606
    519
    Figure US20140343277A1-20141120-C00175
         		568
    520
    Figure US20140343277A1-20141120-C00176
         		544
    521
    Figure US20140343277A1-20141120-C00177
         		544
    522
    Figure US20140343277A1-20141120-C00178
         		539
    523
    Figure US20140343277A1-20141120-C00179
         		528
    524
    Figure US20140343277A1-20141120-C00180
         		539
    525
    Figure US20140343277A1-20141120-C00181
         		552
    526
    Figure US20140343277A1-20141120-C00182
         		568
    527
    Figure US20140343277A1-20141120-C00183
         		542
    528
    Figure US20140343277A1-20141120-C00184
         		552
    529
    Figure US20140343277A1-20141120-C00185
         		528
    530
    Figure US20140343277A1-20141120-C00186
         		528
    531
    Figure US20140343277A1-20141120-C00187
         		542
    532
    Figure US20140343277A1-20141120-C00188
         		626
    533
    Figure US20140343277A1-20141120-C00189
         		553
    534
    Figure US20140343277A1-20141120-C00190
         		566
  • Figure US20140343277A1-20141120-C00191
    Example No. R1 MS (M + 1)
    535
    Figure US20140343277A1-20141120-C00192
         		517
    536
    Figure US20140343277A1-20141120-C00193
         		528
    537
    Figure US20140343277A1-20141120-C00194
         		528
    538
    Figure US20140343277A1-20141120-C00195
         		531
    539
    Figure US20140343277A1-20141120-C00196
         		533
    540
    Figure US20140343277A1-20141120-C00197
         		547
    541
    Figure US20140343277A1-20141120-C00198
         		534
    542
    Figure US20140343277A1-20141120-C00199
         		545
    543
    Figure US20140343277A1-20141120-C00200
         		543
    544
    Figure US20140343277A1-20141120-C00201
         		517
    545
    Figure US20140343277A1-20141120-C00202
         		620
    546
    Figure US20140343277A1-20141120-C00203
         		596
    547
    Figure US20140343277A1-20141120-C00204
         		545
    548
    Figure US20140343277A1-20141120-C00205
         		548
    549
    Figure US20140343277A1-20141120-C00206
         		585
    550
    Figure US20140343277A1-20141120-C00207
         		562
    551
    Figure US20140343277A1-20141120-C00208
         		548
    552
    Figure US20140343277A1-20141120-C00209
         		561
    553
    Figure US20140343277A1-20141120-C00210
         		548
    554
    Figure US20140343277A1-20141120-C00211
         		542
    555
    Figure US20140343277A1-20141120-C00212
         		542
    556
    Figure US20140343277A1-20141120-C00213
         		542
    557
    Figure US20140343277A1-20141120-C00214
         		542
    558
    Figure US20140343277A1-20141120-C00215
         		542
    559
    Figure US20140343277A1-20141120-C00216
         		546
    560
    Figure US20140343277A1-20141120-C00217
         		531
    561
    Figure US20140343277A1-20141120-C00218
         		562
    562
    Figure US20140343277A1-20141120-C00219
         		545
    563
    Figure US20140343277A1-20141120-C00220
         		531
    564
    Figure US20140343277A1-20141120-C00221
         		542
    565
    Figure US20140343277A1-20141120-C00222
         		546
    566
    Figure US20140343277A1-20141120-C00223
         		596
    567
    Figure US20140343277A1-20141120-C00224
         		558
    568
    Figure US20140343277A1-20141120-C00225
         		534
    569
    Figure US20140343277A1-20141120-C00226
         		534
    570
    Figure US20140343277A1-20141120-C00227
         		529
    571
    Figure US20140343277A1-20141120-C00228
         		518
    572
    Figure US20140343277A1-20141120-C00229
         		529
    573
    Figure US20140343277A1-20141120-C00230
         		542
    574
    Figure US20140343277A1-20141120-C00231
         		558
    575
    Figure US20140343277A1-20141120-C00232
         		532
    576
    Figure US20140343277A1-20141120-C00233
         		542
    577
    Figure US20140343277A1-20141120-C00234
         		518
    578
    Figure US20140343277A1-20141120-C00235
         		518
    579
    Figure US20140343277A1-20141120-C00236
         		532
    580
    Figure US20140343277A1-20141120-C00237
         		616
    581
    Figure US20140343277A1-20141120-C00238
         		543
    582
    Figure US20140343277A1-20141120-C00239
         		556
    • Example 583 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyrimidin-5-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 146.2-148.2° C.
    • Example 584 1-Ethyl-3,3,5-trimethyl-7-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)piperidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.203 g) and acetic acid (0.063 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170 g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.235 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed to dryness to give the title compound (0.205 g) as pale yellow amorphous.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.54 (3H, s), 1.68-1.75 (2H, m), 2.13-2.21 (2H, m), 2.55-2.60 (2H, m), 2.64-2.76 (2H, m), 2.80-2.85 (2H, m), 2.95-3.03 (2H, m), 3.44 (3H, s), 3.57 (2H, s), 3.77-3.85 (1H, m), 4.10-4.19 (1H, m), 4.25-4.33 (1H, m), 7.01 (1H, dt, J=1.9, 7.4 Hz), 7.14-7.28 (6H, m)
    • Example 585 1-Ethyl-3,3,5-trimethyl-7-[4-(2-oxo-2H-quinolin-1-yl)-piperidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.85 (3H, s), 1.21 (3H, t, J=7.0 Hz), 1.54 (3H, s), 1.70-1.77 (2H, m), 2.28-2.34 (2H, m), 2.94 (2H, br), 3.05-3.13 (2H, m), 3.46 (3H, s), 3.64 (2H, s), 3.78-3.87 (1H, m), 4.11-4.19 (1H, m), 5.33 (1H, bs), 6.67 (1H, d, J=9.4 Hz), 7.21 (1H, t, J=8.0 Hz), 7.27-7.32 (3H, m), 7.50-7.57 (2H, m), 7.62 (1H, d, J=9.4 Hz), 7.78 (1H, br)
    • Example 586
  • N-[1-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)piperidin-4-yl]-N-phenylbenzamide
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.55-1.63 (2H, m), 1.88-1.95 (2H, m), 2.16-2.26 (2H, m), 2.88-2.94 (2H, m), 3.38 (3H, s), 3.45-3.53 (2H, m), 3.73-3.82 (1H, m), 4.10-4.16 (1H, m), 4.70-4.82 (1H, m), 6.98-7.02 (2H, m), 7.07-7.24 (11H, m)
    • Example 587 1-Ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-pyrrolidin-1-ylmethyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.73-0.82 (3H, m), 1.16-1.20 (3H, m), 1.51-1.53 (3H, m), 2.10-2.35 (2H, m), 2.55-3.20 (8H, m), 3.40-3.44 (3H, m), 3.61-4.16 (4H, m), 5.30-5.45 (1H, m), 6.98-7.04 (1H, m), 7.14-7.30 (5H, m), 7.65-7.68 (1H, m)
    • Example 588 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.48 (3H, s), 2.62-2.65 (2H, m), 2.94-2.98 (2H, m), 3.39 (3H, s), 3.46-3.59 (6H, m), 3.76-3.82 (1H, m), 4.09-4.13 (1H, m), 6.71 (1H, d, J=8.0 Hz), 7.09-7.17 (4H, m), 7.21-7.24 (2H, m), 7.68 (1H, dd, J=1.6, 7.7 Hz), 7.91 (1H, br), 8.38 (1H, dd, J=1.7, 4.9 Hz)
    • Example 589 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.50 (3H, s), 2.62-2.65 (2H, m), 2.94-2.97 (2H, m), 3.39 (3H, s), 3.49-3.61 (6H, m), 3.76-3.84 (1H, m), 4.09-4.13 (1H, m), 6.74 (1H, d, J=1.1 Hz), 6.97 (1H, dd, J=1.4, 7.7 Hz), 7.10-7.13 (2H, m), 7.16 (1H, d, J=1.1 Hz), 7.22-7.28 (2H, m), 7.70 (1H, dd, J=1.6, 7.7 Hz), 8.17 (1H, br), 8.38 (1H, dd, J=1.6, 4.9 Hz)
    • Example 590 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205 g) was added to a methanol solution (10 ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.213 g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (0.400 g) as a white amorphous.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.77-2.81 (2H, m), 2.96-3.00 (2H, m), 3.40 (3H, s), 3.73 (2H, s), 3.74-3.83 (1H, m), 3.81 (2H, s), 4.12-4.17 (1H, m), 5.17 (2H, s), 6.83 (1H, d, J=8.3 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.16 (1H, d, J=1.6 Hz), 7.19-7.25 (6H, m), 7.27-7.33 (2H, m)
    • Example 591 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 590 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.53 (3H, s), 2.77-2.80 (2H, m), 2.96-3.00 (2H, m), 3.38 (3H, s), 3.67 (2H, s), 3.68 (2H, s), 3.76-3.81 (1H, m), 4.12-4.18 (1H, m), 5.20 (2H, s), 6.90-6.95 (2H, m), 7.09 (1H, dd, J=1.8, 8.4 Hz), 7.12-7.14 (2H, m), 7.17-7.24 (4H, m), 7.25-7.30 (2H, m)
    • Example 592 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • ivory powder
  • mp: 146-148° C.
    • Example 593 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • white powder
  • mp: 127-130° C.
    • Example 594 1-Ethyl-3,3,5-trimethyl-7-(2-phenylpiperidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.78 and 0.81 (3H, s), 1.15-1.20 (3H, m), 1.33-1.47 (1H, m), 1.51-1.53 (3H, m), 1.55-1.84 (5H, m), 1.95-2.05 (1H, m), 2.83-2.97 (2H, m), 3.12-3.17 (1H, m), 3.38 and 3.41 (3H, s), 3.70-3.85 (2H, m), 4.07-4.18 (1H, m), 7.07-7.26 (4H, m), 7.30-7.36 (2H, m), 7.40-7.45 (2H, m)
    • Example 595 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • White powder
  • 1H NMR (DMSO-d6), δppm: −0.27-0.01 (1H, m), 0.43-0.46 (1H, m), 0.74 (3H, s), 0.73-0.79 (1H, m), 1.05-1.34 (1H, m), 1.34 (3H, s), 2.16 (3H, s), 2.81 (2H, br), 3.21-3.28 (1H, m), 3.28 (3H, s), 3.28 (3H, s), 3.84 (4H, br), 4.15 (2H, br), 4.55 (2H, br), 6.93 (1H, s), 7.36 (2H, br), 7.43 (2H, br), 7.77 (1H, br), 7.97 (1H, d, J=2.1 Hz), 8.38 (1H, s), 8.60 (1H, br).
    • Example 596 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • White powder
  • 1H NMR (DMSO-d6), δppm: 0.71 (3H, s), 1.35 (3H, s), 2.43 (3H, s), 2.51 (3H, s), 2.80 (2H, br), 3.12 (3H, s), 3.29 (3H, s), 3.41 (2H, t, J=5.2 Hz), 3.83 (2H, br), 3.85-3.88 (2H, m), 4.00-4.60 (4H, m), 6.46 (1H, s), 6.23 (1H, s), 7.10-7.49 (4H, m), 7.71 (1H, br), 8.28 (1H, br), 8.56 (1H, br).
    • Example 597 7-{N-(Benzo[1,3]dioxol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]aminomethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 135.9-137.5° C.
    • Example 598 1-Ethyl-3,3,5-trimethyl-7-{N-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.77-2.83 (2H, m), 2.97-3.02 (2H, m), 3.41 (3H, s), 3.76-3.83 (5H, m), 4.10-4.18 (1H, m), 5.17 (2H, s), 6.86 (1H, d, J=8.2 Hz), 6.97 (1H, dt, J=1.0 and 7.4 Hz), 7.07-7.14 (2H, m), 7.17-7.29 (7H, m)
    • Example 599 1-Ethyl-7-({N-(1H-indol-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • 1H NMR (CDCl3), δppm: 0.65 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.47 (3H, s), 2.48 (3H, d, J=1.0 Hz), 2.86 (2H, t, J=5.1 Hz), 3.13 (3H, s), 3.41 (2H, s), 3.61-3.72 (1H, m), 3.91-4.17 (3H, m), 4.22-4.35 (1H, m), 4.35-4.43 (1H, m), 6.24 (1H, dd, J=0.62, 7.4 Hz), 6.47 (1H, dd, J=2.0, 3.0 Hz), 6.67 (1H, d, J=0.84 Hz), 6.73-6.84 (3H, m), 6.89 (1H, d, J=1.4 Hz), 6.95-7.03 (2H, m), 7.17 (1H, t, J=2.8 Hz), 7.52-7.59 (1H, m), 10.51 (1H, s).
    • Example 600 7-{N-(Benzo[1,3]dioxol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]aminomethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 179.7-181.8° C.
    • Example 601 1-Ethyl-7-({N-(1H-indol-6-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.76 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.86 (2H, dt, J=2.4, 5.9 Hz), 3.31 (3H, s), 3.62-3.83 (5H, m), 3.98-4.18 (3H, m), 6.40 (1H, dd, J=0.70, 7.3 Hz), 6.48 (1H, t, J=0.88 Hz), 6.50-6.54 (1H, m), 6.95-7.11 (4H, m), 7.15 (1H, bs), 7.19 (1H, dd, J=2.5, 3.1 Hz), 7.53 (1H, d, J=8.1 Hz), 8.10 (1H, bs).
    • Example 602 7-({N-(1H-Benzoimidazol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.76 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.43 (3H, d, J=0.68 Hz), 2.80-2.92 (2H, m), 3.33 (3H, s), 3.62-3.88 (5.H, m), 3.92-4.25 (3H, m), 6.40 (1H, d, J=7.4 Hz), 6.47 (1H, s), 6.82-7.25 (5H, m), 7.26-7.92 (2H, m), 8.02 (1H, s), 9.38 (1H, bs).
    • Example 603 1-Isobutyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ethyl acetate-hexane-diisopropyl ether)
  • mp: 128-130° C.
    • Example 604 1-Isobutyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 206-208° C.
    • Example 605 1-Isobutyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Pale pink powder (ethyl acetate-hexane-diisopropyl ether)
  • mp: 155-159° C.
    • Example 606 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methylimidazo[1,5-a]pyridin-1-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 104.1-109.4° C.
    • Example 607 1-Cyclopropylmethyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Ivory powder (ethyl acetate-hexane-diisopropyl ether)
  • mp: 153-155° C.
    • Example 608 1-Cyclopropylmethyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Ivory powder (Ether)
  • mp: 207-210° C.
    • Example 609 1-Cyclopropylmethyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 139-141° C.
    • Example 610 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Ivory powder (Ether)
  • mp: 151-152° C.
    • Example 611 1-Ethyl-3,3,5-trimethyl-7-({N-[(1-methyl-1H-benzoimidazol-2-yl)methyl]-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 126.9-132.6° C.
    • Example 612 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-pyrazol-1-ylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.86 (2H, dt, J=1.8, 5.8 Hz), 3.30 (3H, s), 363-3.84 (5H, m), 3.98-4.23 (3H, m), 6.37 (1H, dd, J=0.68, 7.3 Hz), 6.49 (1H, t, J=0.88 Hz), 6.95 (1H, d, J=7.4 Hz), 7.03-7.15 (3H, m), 7.16-7.26 (4H, m), 7.32 (1H, d, J=7.7 Hz), 7.32-7.37 (1H, m), 7.83 (1H, t, J=1.1 Hz).
    • Example 613 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrazol-1-yl-benzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Pale yellow white powder
  • mp: 123-130° C.
    • Example 614 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyrazin-2-ylmethylamino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 128.7-130.7° C.
    • Example 615 1-Ethyl-7-({N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.76 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.43 (3H, d, J=0.72 Hz), 2.91 (2H, t, J=5.5 Hz), 3.32 (3H, s), 3.69-3.85 (3H, m), 3.85-3.95 (2H, m), 3.95-4.22 (3H, m), 6.43 (1H, dd, J=0.68, 7.3 Hz), 6.48 (1H, s), 6.76 (1H, dt, J=1.1, 6.8 Hz), 7.02-7.11 (2H, m), 7.12-7.23 (3H, m), 7.32 (1H, s), 7.53 (1H, q, J=3.2 Hz), 7.95 (1H, td, J=1.1, 6.8 Hz).
    • Example 616 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)-N-methylamino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl) amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (247 mg) was dissolved in DMF (2 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 13.56 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (73.5 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (169 mg) as a white amorphous.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.04 (3H, s), 2.75-2.8 (2H, m), 2.95-3.00 (2H, m), 3.38 (3H, s), 3.40-3.44 (4H, m), 3.75-3.85 (1H, m), 4.07-4.19 (1H, m), 5.20 (2H, s), 6.92-6.96 (2H, m), 7.07-7.14 (3H, m), 7.17-7.31 (6H, m)
    • Example 617 1-Ethyl-7-({N-(2-hydroxybenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 166-170° C.
    • Example 618 1-Isobutyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ethyl acetate-hexanes)
  • mp: 96-100° C.
    • Example 619 1-Cyclopropylmethyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ethyl acetate-hexane)
  • mp: 95-99° C.
    • Example 620 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzonitrile
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 156.7-158.6° C.
    • Example 621 4-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde
  • A 2N-hydrochloric acid (5 ml) was added to an THF solution (5 ml) of 7-({N-(4-diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.52 g), and the mixture was stirred at room temperature for 1 hour. 2N-Sodium hydroxide solution (5 ml) was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. The residue was recrystallized from ethyl acetate and ether, and dried to give the title compound (0.35 g) as a white powder.
  • mp: 153-155° C.
    • Example 622 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 152-153° C.
    • Example 623 1-Ethyl-7-({N-(6-methoxy-2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 143-144° C.
    • Example 624 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 112-114° C.
    • Example 625 1,3,3-Trimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-pyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Ivory powder (Ether)
  • mp: 117-122° C.
    • Example 626 1,3,3-Trimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 154-157° C.
    • Example 627 1-Ethyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 108-114° C.
    • Example 628 1-Ethyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 177-179° C.
    • Example 629 1-Ethyl-7-({N-(6-methoxy-2-methylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 155-156° C.
    • Example 630 1,3,3-Trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-pyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 176-178° C.
    • Example 631 1,3,3-Trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Pale pink powder (Ether)
  • mp: 142-144° C.
    • Example 632 1-Ethyl-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 213-215° C.
    • Example 633 1-Ethyl-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 197-199° C.
    • Example 634 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridazin-4-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 137-141° C.
    • Example 635 1-Ethyl-3,3,5-trimethyl-7-({[N-(1-methyl-1H-indazol-3-yl)methyl]-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 96-102° C.
    • Example 636 1-Ethyl-3,3,5-trimethyl-7-({N-(7-methyl-1H-indazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 111-118° C.
    • Example 637 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.62-4.68 (20H, m), 6.69-8.75 (12H, m),
    • Example 638 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 150.9-154.7° C.
    • Example 639 1-Ethyl-3,3,5-trimethyl-7-{3-[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.72 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.09-3.79 (18H, m), 4.65 (2H, br-s), 7.22 (1H, d, J=8.0 Hz), 7.33 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.83 (1H, t, J=6.6 Hz), 7.93-7.97 (1H, m), 8.44 (1H, d, J=7.5 Hz), 8.76-8.80 (3H, m), 8.90 (1H, s)
    • Example 640 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 106.4-114.6° C.
    • Example 641 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 128.2-130.9° C.
    • Example 642 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 171-173° C.
    • Example 643 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 168-170° C.
    • Example 644 8-({N-(2-Methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 179-182° C.
    • Example 645 8-({N-(2-Methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 123-134° C.
    • Example 646 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 159-160° C.
    • Example 647 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 131-135° C.
    • Example 648 7-[2-(4-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.65-1.98 (3H, m), 2.15-2.30 (2H, m), 3.05-3.17 (2H, m), 3.35-3.45 (4H, m), 3.70-3.83 (2H, m), 4.08-4.18 (1H, m), 7.06-7.23 (3H, m), 7.27-7.32 (2H, m), 7.34-7.38 (2H, m)
    • Example 649 7-(3-Benzylpiperidin-1-ylmethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.77 and 0.79 (3H, s), 0.97-2.10 (5H, m), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.45-2.55 (2H, m), 2.80-2.90 (2H, m), 3.35 and 3.40 (3H, s), 3.41-3.60 (4H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 7.08-7.26 (8H, m)
    • Example 650 1-Ethyl-3,3,5-trimethyl-7-(2-phenylazetidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.70 and 0.71 (3H, s), 1.10-1.15 (3H, m), 1.50 (3H, s), 2.10-2.20 (1H, m), 2.32-2.40 (1H, m), 2.90-3.01 (1H, m), 3.26 and 3.32 (3H, s), 3.41-3.46 (1H, m), 3.58-3.78 (3H, m), 4.07-4.17 (2H, m), 7.07-7.21 (4H, m), 7.22-7.28 (2H, m), 7.33-7.38 (2H, m)
    • Example 651 1-Ethyl-3,3,5-trimethyl-7-(6-methyl-3′,4′,5′,6′-tetrahydro-2′H-[2,3′]bipyridinyl-1′-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 and 0.82 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.54-1.83 (3H, m), 1.95-2.02 (1H, m), 2.03-2.14 (1H, m), 2.18-2.26 (1H, m), 2.51 (3H, s), 2.81-2.90 (1H, m), 2.95-3.10 (2H, m), 3.41 and 3.42 (3H, s), 3.50-3.60 (2H, m), 3.75-3.85 (1H, m), 4.08-4.17 (1H, m), 6.95-6.98 (2H, m), 7.21-7.24 (3H, m), 7.45-7.50 (1H, m)
    • Example 652 7-(2-Benzylpyrrolidin-1-ylmethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.53-1.83 (4H, m), 2.15-2.25 (1H, m), 2.53-2.63 (1H, m), 2.68-2.76 (1H, m), 2.88-3.06 (2H, m), 3.26-3.35 (1H, m), 3.42 and 3.43 (3H, s), 3.75-3.85 (1H, m), 4.03-4.20 (2H, m), 7.17-7.30 (8H, m)
    • Example 653 1-Ethyl-3,3,5-trimethyl-7-[(2-phenoxypyridin-3-ylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.39 (3H, s), 3.75-3.85 (1H, m), 4.09-4.19 (1H, m), 4.45 (2H, d, J=5.8 Hz), 4.89 (1H, t, J=5.8 Hz), 6.80 (1H, dd, J=1.7 and 7.8 Hz), 6.85 (1H, dd, J=4.8 and 7.8 Hz), 7.13-7.23 (3H, m), 7.24-7.34 (3H, m), 7.38-7.43 (2H, m), 7.51 (1H, dd, J=1.7 and 4.8 Hz)
    • Example 654 7-[(1-Benzyl-1H-pyrazol-4-ylamino)methyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • Pale brown amorphous
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.51 (3H, s), 3.36 (3H, s), 3.75-3.82 (1H, m), 4.08-4.15 (1H, m), 4.17 (2H, s), 5.18 (2H, s), 6.85 (1H, d, J=0.8 Hz), 7.15-7.20 (3H, m), 7.21-7.35 (6H, m)
    • Example 655 7-[(3-Benzyloxypyrazin-2-ylamino)methyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • Pale yellow amorphous
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.37 (3H, s), 3.75-3.83 (1H, m), 4.07-4.15 (1H, m), 4.68 (2H, d, J=6.1 Hz), 5.41 (2H, s), 5.46 (1H, t, J=6.1 Hz), 7.20-7.25 (3H, m), 7.35-7.43 (4H, m), 7.44-7.47 (2H, m), 7.61 (1H, d, J=3.2 Hz)
    • Example 656 1-Ethyl-3,3,5-trimethyl-7-(3-phenethylpiperidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 and 0.83 (3H, s), 0.90-1.00 (1H, m), 1.19 (3H, t, J=7.1 Hz), 1.50-1.75 (6H, m), 1.53 (3H, s), 1.80-1.88 (1H, m), 1.90-2.00 (1H, m), 2.50-2.60 (2H, m), 2.71-2.84 (2H, m), 3.40 and 3.41 (3H, s), 3.45-3.52 (2H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 7.10-7.30 (8H, m)
    • Example 657 1-Ethyl-3,3,5-trimethyl-7-[(4-phenoxymethylthiazol-2-ylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • White amorphous
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.39 (3H, s), 3.76-3.85 (1H, m), 4.09-4.19 (1H, m), 4.53 (2H, d, J=5.0 Hz), 5.04 (2H, s), 5.69 (1H, brs), 6.54 (1H, s), 6.95-7.00 (3H, m), 7.23-7.32 (5H, m)
    • Example 658 1-Ethyl-3,3,5-trimethyl-7-[2-(4-trifluoromethylphenyl)pyrrolidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.68-2.00 (3H, m), 2.20-2.32 (2H, m), 3.10-3.23 (2H, m), 3.39 (3H, s), 3.47-3.51 (1H, m), 3.70-3.82 (2H, m), 4.09-4.16 (1H, m), 7.07-7.23 (3H, m), 7.53-7.62 (4H, m)
    • Example 659 7-[2-(2-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.55-1.70 (1H, m), 1.75-1.95 (2H, m), 2.28-2.45 (2H, m), 3.12-3.18 (1H, m), 3.25-3.30 (1H, m), 3.39 and 3.40 (3H, s), 3.71-3.85 (2H, m), 3.92-4.00 (1H, m), 4.09-4.20 (1H, m), 7.11-7.22 (4H, m), 7.24-7.34 (2H, m), 7.73-7.78 (1H, m)
    • Example 660 7-[2-(3-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.14-1.19 (3H, m), 1.52 (3H, s), 1.65-2.00 (3H, m), 2.17-2.31 (2H, m), 3.06-3.22 (2H, m), 3.35-3.44 (4H, m), 3.73-3.81 (2H, m), 4.08-4.16 (1H, m), 7.06-7.30 (6H, m), 7.43-7.47 (1H, m)
    • Example 661 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (diisopropyl ether)
  • mp: 127-128° C.
    • Example 662 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 131° C.
    • Example 663 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (Ether)
  • mp: 146-148° C.
    • Example 664 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ether)
  • mp: 128-129° C.
    • Example 665 Acetic Acid 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.09 (3H, s), 2.43 (1H, d, J=0.96 Hz), 2.84 (2H, t, J=6.4 Hz), 3.35 (3H, s), 3.66-3.80 (5H m), 4.02-4.15 (3H, m), 5.16 (2H, s), 6.40 (1H, d, J=7.3 Hz), 6.50 (1H, br), 6.88 (1H, d, J=7.3 Hz), 7.07-7.19 (4H, m), 7.58 (1H, dd, J=7.8, 1.6 Hz), 8.46 (1H, dd, J=4.8, 1.6 Hz).
    • Example 666 1-Ethyl-7-({N-(2-hydroxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Potassium carbonate (2.0 g) was added to a methanol solution (30 mL) of (3-((((1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl)(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)pyridin-2-yl)methyl acetate (3.0 g) and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The residue was purified by column-chromatography (methanol:ethyl acetate=0:100→1:9) to give the titled compound as ivory powder (1.95 g).
  • mp: 186-188° C.
    • Example 667 5-Cyclopropyl-1-cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder (ethyl acetate-hexane)
  • mp: 121-122° C.
    • Example 668 1-Ethyl-3,3,5-trimethyl-7-{3-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 134.7-134.8° C.
    • Example 669 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbaldehyde
  • 2-iodoxybenzoic acid (IBX, 0.235 g) was added to the dimethyl sulfoxide suspension (10 mL) of 1-ethyl-7-((N-((2-(hydroxymethyl)pyridin-3-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.48 g) and the mixture was stirred overnight at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate twice. The combined organic layer was concentrated under reduced pressure, and then the residue was purified by column-chromatography (ethyl acetate:hexanes=50:50→100:0). The purified product was recrystallized from ether to afford the titled compound as ivory powder (0.29 g).
  • mp: 147-149° C.
    • Example 670 1-Ethyl-3,3,5-trimethyl-7-{[(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound (148 mg) as a white amorphous.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.62-2.67 (2H, m), 2.86-2.93 (2H, m), 3.37 (3H, s), 3.42 (3H, s), 3.75-3.86 (5H, m), 4.10-4.17 (1H, m), 6.97-7.02 (2H, m), 7.12-7.15 (1H, m), 7.22-7.29 (3H, m)
    • Example 671 1-Ethyl-3,3,5-trimethyl-7-{[(2-oxo-1-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.75-2.81 (2H, m), 2.95-3.02 (2H, m), 3.38 (3H, s), 3.69-3.73 (4H, m), 3.75-3.83 (1H, m), 4.09-4.16 (1H, m), 5.20 (2H, s), 6.78 (1H, brs), 6.96 (1H, dd, J=1.2 and 7.6 Hz), 7.08 (1H, dd, J=1.9 and 8.4 Hz), 7.11-7.18 (4H, m), 7.23 (1H, d, J=8.4 Hz), 8.50-8.53 (2H, m)
    • Example 672 7-({N-(3-Aminopyridin-2-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • Ivory powder
  • mp: 217-218° C.
    • Example 673 7-({N-(3-Aminopyridin-2-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 188-192° C.
    • Example 674 7-({N-(2-Diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • mp: 138-139° C.
    • Example 675 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde
  • The synthesis of the title compound was performed in the same manner as in Example 621 using appropriate starting materials.
  • mp: 157-158° C.
    • Example 676 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.00 (2H, br), 0.21-0.23 (2H, m), 0.61 (3H, s), 0.75 (1H, br), 1.26 (3H, s), 2.35 (3H, s), 2.68 (2H, br), 3.24 (3H, s), 3.12-3.80 (6H, m), 3.90-4.20 (6H, m), 4.50 (2H, s), 6.41 (1H, s), 6.55 (1H, br), 7.20 (1H, br), 7.25-7.50 (3H, m), 7.60 (1H, br), 8.20 (1H, br), 8.48 (1H, s).
    • Example 677 5-Cyclopropyl-1-cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: −0.09-0.05 (3H, m), 0.12-0.23 (2H, m), 0.35-0.46 (1H, m), 0.63-0.80 (2H, m), 0.72 (3H, s), 1.06-1.13 (1H, m), 1.33 (3H, s), 2.43 (3H, s), 2.81 (2H, br), 3.20 (1H, br), 3.34 (3H, s), 3.37-3.45 (2H, m), 3.80 (2H, br), 4.15-4.20 (3H, m), 4.67 (3H, br), 6.49 (1H, br), 6.66 (1H, br), 7.13-7.60 (4H, m), 7.77-7.80 (1H, m), 8.42 (1H, br), 8.63 (1H, br).
    • Example 678 7-({N-(3-Diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • mp: 112-114° C.
    • Example 679 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde
  • The synthesis of the title compound was performed in the same manner as in Example 621 using appropriate starting materials.
  • mp: 79-84° C.
    • Example 680 1-Ethyl-7-({N-(2-hydroxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium borohydride (47 mg) were added to a methanol solution (10 ml) of 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.59 g) and the mixture was stirred for 3 hours at 0° C. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from ethyl acetate-ether mixture to give the title compound (0.42 g) as a pale brown white powder.
  • mp: 159-161° C.
    • Example 681 1-Ethyl-3,3,5-trimethyl-7-{[4-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.76-2.81 (2H, m), 2.95-3.02 (2H, m), 3.41 (3H, s), 3.74-3.83 (5H, m), 4.10-4.18 (1H, m), 5.17 (2H, s), 6.85-6.90 (1H, m), 6.96-7.00 (1H, m), 7.07-7.13 (1H, m), 7.15-7.35 (8H, m)
    • Example 682 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.03-0.10 (2H, m), 0.25-0.29 (2H, m), 0.66 (3H, s), 0.77-0.85 (1H, m), 1.30 (3H, s), 2.38 (3H, s), 2.95-3.15 (2H, m), 3.07 (3H, s), 3.10-3.42 (4H, m), 3.30 (3H, s), 3.50-3.57 (1H, m), 3.87 (2H, br), 3.97-4.09 (1H, m), 4.33 (4H, br), 4.77 (2H, br), 6.48 (1H, s), 6.64 (1H, d, J=7.3 Hz), 7.47 (2H, br), 7.57-7.60 (1H, m), 7.79-7.82 (2H, m), 8.66-8.67 (2H, m).
    • Example 683 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: −0.09-0.03 (3H, m), 0.15-0.27 (2H, m), 0.37-0.44 (1H, m), 0.72 (3H, s), 0.65-0.76 (2H, m), 1.06-1.10 (1H, m), 1.33 (3H, s), 2.43 (3H, br), 2.49 (3H, br), 2.79 (2H, br), 3.17-3.22 (1H, m), 3.38-3.49 (1H, m), 3.77 (2H, br), 3.81 (2H, br), 4.14 (2H, br), 4.16-4.22 (1H, m), 6.45 (1H, s), 6.62 (1H, d, J=7.0 Hz), 7.26 (1H, br), 7.36 (1H, br), 7.45-7.48 (2H, m), 7.68-7.72 (1H, m), 8.29 (1H, br), 8.56 (1H, br).
    • Example 684 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-morpholin-4-ylmethylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Morpholine (0.06 ml) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (7 ml) of 2-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.35 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.20 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by dichloromethane. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure.
  • The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=3:2). The purified product was condensed under reduced pressure to give the title compound (0.30 g) as a white amorphous solid.
  • 1H NMR (CDCl3), d ppm: 0.78 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.28-2.38 (4H, m), 2.43 (3H, d, J=1.0 Hz), 2.83 (2H, t, J=6.1 Hz), 3.32 (3H, s), 3.43 (2H, s), 3.56-3.88 (9H, m), 3.96-4.07 (2H, m), 4.07-4.18 (1H, m), 6.40 (1H, dd, J=0.64, 7.4 Hz), 6.48 (1H, d, J=0.88 Hz), 6.89 (1H, d, J=7.3 Hz), 7.08 (2H, d, J=0.96 Hz), 7.12-7.20 (3H, m), 7.21-7.26 (1H, m), 7.37 (1H, dd, J=2.1, 7.0 Hz).
    • Example 685 1-Ethyl-7-({N-(3-hydroxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 680 using appropriate starting materials.
  • mp: 170-172° C.
    • Example 686 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-morpholin-4-ylmethylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1H NMR (CDCl3) 0.77 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.37-2.46 (4H, m), 2.43 (3H, d, J=0.96 Hz), 2.82 (2H, dt, J=2.3, 5.8 Hz), 3.31 (3H, s), 3.41 (2H, s), 3.59-3.82 (9H, m), 3.96-4.19 (3.H, m), 6.44 (1H, dd, J=0.70 7.4 Hz), 6.48 (1H, t, J=0.9 Hz), 6.97-7.09 (3H, m), 7.11-7.26 (5H, m).
    • Example 687 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-oxo-1-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.75-2.81 (2H, m), 2.95-3.01 (2H, m), 3.39 (3H, s), 3.70-3.73 (4H, m), 3.74-3.84 (1H, m), 4.08-4.14 (1H, m), 5.30 (2H, s), 6.95 (1H, dd, J=1.3 and 7.6 Hz), 7.05 (1H, brs), 7.11-7.25 (6H, m), 7.60 (1H, dt, J=1.8 and 7.7 Hz), 8.50-8.55 (1H, m)
    • Example 688 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-oxo-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.75-2.80 (2H, m), 2.94-2.99 (2H, m), 3.39 (3H, s), 3.70-3.73 (4H, m), 3.75-3.84 (1H, m), 4.08-4.18 (1H, m), 5.22 (2H, s), 6.91 (1H, brs), 6.96 (1H, dd, J=1.2 and 7.6 Hz), 7.10-7.18 (3H, m), 7.20-7.24 (2H, m), 7.55 (1H, dt, J=2.2 and 7.8 Hz), 8.47 (1H, dd, J=1.6 and 4.8 Hz), 8.56 (1H, d, J=1.8 Hz)
    • Example 689 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.15-1.21 (3H, m), 1.53 (3H, s), 2.16 (3H, s), 2.76-2.81 (2H, m), 2.95-3.01 (2H, m), 3.40 (3H, s), 3.47-3.54 (4H, m), 3.75-3.82 (1H, m), 4.08-4.16 (1H, m), 5.18 (2H, s), 6.86 (1H, dd, J=0.8 and 8.1 Hz), 6.95 (1H, dt, J=1.0 and 7.4 Hz), 7.04-7.12 (2H, m), 7.15-7.30 (7H, m)
    • Example 690 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-benzyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.18 (3H, s), 2.76-2.81 (2H, m), 2.95-3.01 (2H, m), 3.41 (3H, s), 3.48-3.52 (4H, m), 3.75-3.82 (1H, m), 4.08-4.17 (1H, m), 5.17 (2H, s), 6.85-6.90 (1H, m), 6.95-7.00 (1H, m), 7.06-7.13 (1H, m), 7.15-7.33 (8H, m)
    • Example 691 7-({N-(2-Dimethylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • To the 1,2-dichloroethan suspension (5 ml) of 3-((N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)picolinaldehyde (205 mg), dimethylammonium chloride (59 mg) and triethylamine (0.10 ml) was added sodium triacetoxyborohydride (114 mg) at room temperature, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and then the residue was purified by column-chromatography (methanol:ethyl acetate=1:9→50:50). The purified product was dissolved in ethyl acetate (ca. 5 mL) and then 4 M HCl/ethyl acetate was added to the mixture. The precipitate was collected and dried in vacuo to give the titled compound as light brown powder (114 mg).
  • 1H NMR (DMSO-d6), δppm: 0.70 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.40 (3H, br), 2.89 (6H, s), 3.15-3.44 (2H, m), 3.34 (3H, s), 3.70-4.05 (10H, m), 6.55 (1H, s), 6.73 (1H, d, J=7.4 Hz), 7.20-8.00 (5H, m), 8.26 (1H, br), 8.64 (1H, br).
    • Example 692 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • To a methanol solution (5 ml) of 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbaldehyde (243 mg) was added 9.8 M THF solution of methylamine (87 μl) and the mixture was stirred overnight at room temperature. NaBH4 (16 mg) was added to the mixture, and then the mixture was stirred overnight. The resulting mixture was evaporated and the residue was purified by column chromatography (methanol:ethyl acetate=1:9→50:50). The purified product was dissolved in ethyl acetate (ca. 5 ml) and then 4 M HCl/ethyl acetate was added to the mixture. The precipitate was collected and dried in vacuo to give the titled compound as light brown powder (18 mg).
  • 1H NMR (DMSO-d6), δppm: 0.70 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.40 (3H, br), 2.66 (3H, s), 3.05-3.45 (2H, m), 3.34 (3H, s), 3.70-4.05 (10H, m), 6.56 (1H, s), 6.74 (1H, d, J=7.4 Hz), 7.48 (3H, br), 7.64 (1H, d, J=6.5 Hz), 7.77 (1H, br), 8.23 (1H, br), 8.62 (1H, br), 9.32 (2H, br).
    • Example 693 7-({N-(2-Cyclopropylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 692 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.72 (3H, s), 0.70-0.74 (2H, m), 0.98 (2H, br), 1.08 (3H, t, J=7.0 Hz), 1.35 (3H, s), 2.41 (3H, br), 2.75 (2H, br), 3.33 (3H, s), 3.60-3.90 (5H, m), 3.91-4.05 (1H, m), 4.20-4.70 (5H, m), 6.55 (1H, s), 6.73 (1H, d, J=7.3 Hz), 7.45 (3H, br), 7.59-7.61 (2H, m), 8.15 (1H, br), 8.59 (1H, br), 9.54 (2H, br).
    • Example 694 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrrolidin-1-ylmethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 691 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.71 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.35 (3H, s), 2.00 (4H, br), 2.43 (3H, br), 2.76 (2H, br), 3.28 (7H, br), 3.75 (4H, br), 3.90-4.30 (2H, m), 4.55 (4H, br), 6.52 (1H, br), 6.70 (1H, br), 7.25 (2H, br), 7.32 (1H, br), 7.52 (2H, br), 7.69 (1H, br), 8.47 (1H, br), 10.3 (1H, br).
    • Example 695 1-Ethyl-7-({N-[2-(3-hydroxypyrrolidin-1-ylmethyl)pyridin-3-ylmethyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 691 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.71 (3H, s), 1.07 (3H, t, J=6.9 Hz), 1.35 (3H, s), 1.95 (1H, br), 2.19 (1H, br), 2.42 (3H, br), 2.75 (2H, br), 3.10-3.60 (9H, m), 3.75 (4H, br), 3.90-4.25 (3H, m), 4.47 (2H, br), 6.52 (1H, br), 6.70 (1H, br), 7.27 (3H, br), 7.53 (2H, br), 7.69 (1H, br), 8.49 (1H, br), 10.4 (1H, br).
    • Example 696 1-Ethyl-3,3,5-trimethyl-7-{[2-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.78-2.83 (2H, m), 2.99-3.04 (2H, m), 3.32 (3H, s), 3.74-3.81 (1H, m), 3.90-3.93 (4H, m), 4.08-4.14 (1H, m), 5.30-5.34 (2H, m), 6.82 (1H, dd, J=1.0 and 7.9 Hz), 6.91-7.03 (3H, m), 7.13-7.35 (7H, m)
    • Example 697 1-Ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 120-121° C.
    • Example 698 7-({N-(2,6-Dimethylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 159-160° C.
    • Example 699 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 174-175° C.
    • Example 700 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 163-165° C.
    • Example 701 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyrimidin-5-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 166-167° C.
    • Example 702 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 174-177° C.
    • Example 703 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzyl]amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.
  • White powder
  • mp: 125-127° C.
    • Example 704 1-Ethyl-7-({N-(6-hydroxymethylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using 6-((tert-butyldimethylsilyloxy)methyl)nicotinaldehyde and 1-ethyl-3,3,5-trimethyl-7-((2-(1-oxoisoquinolin-2(1H)-yl)ethylamino)methyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione, followed by deprotection of TBDMS group with tetrabutylammonium fluoride.
  • 1H NMR (CDCl3), δppm: 0.75 (3H, s), 1.13 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.85-2.88 (2H, m), 3.27 (3H, s), 3.62-3.75 (5H, m), 3.96-4.02 (1H, m), 4.13 (2H, t, J=7.2 Hz), 4.65 (2H, s), 6.46 (1H, d, J=7.3 Hz), 6.93 (1H, d, J=7.3 Hz), 6.96-6.99 (2H, m), 7.05 (1H, dd, J=1.8, 8.4 Hz), 7.13 (1H, d, J=1.6 Hz), 7.48-7.57 (3H, m), 7.66-7.71 (1H, m), 8.33 (1H, dd, J=0.6, 8.1 Hz), 8.41 (1H, d, J=1.5 Hz).
    • Example 705 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-dd, δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 1.65-2.34 (2H, m), 2.52-2.92 (6H, m), 3.25-4.82 (12H, m), 6.60-6.92 (1H, m), 7.03-7.19 (1H, m), 7.19-7.31 (1H, m), 7.31-7.41 (2H, m), 7.41-7.90 (2H, m), 8.00-8.11 (1H, m), 8.12-8.60 (2H, m).
    • Example 706 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.66-2.29 (2H, m), 2.55-2.71 (2H, m), 2.71-2.92 (4H, m), 2.96-4.81 (12H, m), 6.81-7.02 (2H, m), 7.02-7.41 (4H, m), 7.41-7.69 (1H, m), 7.41-7.90 (2H, m), 8.42-8.93 (1H, m),
    • Example 707 7-{[2-(2,6-Dimethylpyridin-3-yl)ethylamino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 590 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.49 (3H, s), 2.51 (3H, s), 2.78-2.83 (2H, m), 2.85-2.89 (2H, m), 3.40 (3H, s), 3.74-3.84 (1H, m), 3.84 (2H, s), 4.09-4.19 (1H, m), 6.93 (1H, d, J=7.7 Hz), 7.17-7.19 (2H, m), 7.24 (1H, s), 7.32 (1H, d, J=7.7 Hz).
    • Example 708 7-{[N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.23 (3H, s), 3.42 (3H, s), 3.75-3.83 (8H, m), 4.09-4.20 (1H, m), 5.94 (1H, s), 7.20-7.28 (3H, m).
    • Example 709 1-Ethyl-7-{[N-(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.41 (3H, s), 3.42 (3H, s), 3.74-3.85 (1H, s), 3.85 (2H, s), 3.91 (2H, s), 4.10-4.67 (1H, m), 4.67 (2H, s), 7.22-7.28 (4H, m), 7.72-7.74 (1H, m), 8.49-8.51 (1H, m).
    • Example 710 1-Ethyl-3,3,5-trimethyl-7-{[N-(3-methyl-3H-imidazol-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.69 (3H, s), 3.75-3.84 (1H, m), 3.80 (2H, s), 3.83 (2H, s), 4.11-4.18 (1H, m), 6.92 (1H, s), 7.20-7.23 (2H, m), 7.25-7.28 (1H, m), 7.42 (1H, s).
    • Example 711 1-Ethyl-3,3,5-trimethyl-7-[(1-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81-0.82 (3H, m), 1.17 (3H, t, J=7.1 Hz), 1.42-1.44 (3H, m), 1.53 (3H, s), 3.40-3.41 (3H, m), 3.62-3.70 (2H, m), 3.73-3.83 (1H, m), 3.85-3.91 (1H, m), 4.09-4.19 (1H, m), 7.14-7.19 (2H, m), 7.22-7.31 (2H, m), 7.70-7.74 (1H, m), 8.51-8.53 (1H, m), 8.58 (1H, d, J=2.0 Hz).
    • Example 712 7-{[(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.77 (6H, s), 2.26 (3H, s), 3.42 (3H, s), 3.74-3.85 (1H, m), 3.74 (3H, s), 3.77 (2H, s), 3.86 (2H, s), 5.96 (1H, s), 7.23-7.24 (3H, m).
    • Example 713 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-nitrobenzenesulfonamide
  • Triethylamine (0.6 ml) was added to a dichloromethane solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.0 g). The mixture was cooled with ice.
  • 2-Nitrobenzenesulphonyl chloride (0.80 g) was added, and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane.
  • The organic layer was washed with water and saturated saline, dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:4). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-hexane mixture to give the title compound (1.38 g) as a white solid.
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 3.35 (3H, s), 3.72-3.83 (1H, m), 4.06-4.17 (1H, m), 4.35 (2H, d, J=6.4 Hz), 5.78 (1H, d, J=6.4 Hz), 7.16-7.23 (3H, m), 7.73-7.79 (2H, m), 7.86-7.91 (1H, m), 8.12-8.15 (1H, m)
    • Example 714 1-Ethyl-3,3,5-trimethyl-7-{[(5-methyloxazol-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.29 (3H, s), 3.42 (3H, s), 3.68 (2H, s), 3.72-3.86 (3H, m), 4.09-4.23 (1H, m), 7.20-7.30 (3H, m), 7.74 (1H, s).
    • Example 715 1-Ethyl-7-{[(6-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.49 (3H, s), 3.74-3.85 (1H, m), 3.83 (2H, s), 3.85 (2H, s), 4.10-4.20 (1H, m), 4.58 (2H, s), 7.23-7.37 (3H, m), 7.40 (1H, d, J=8.0 Hz), 7.71 (1H, dd, J=8.0, 2.1 Hz), 8.53 (1H, d, J=1.9 Hz).
    • Example 716 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-1-oxypyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • To a dichloromethane solution (10 ml) of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.0 g) was added m-chloroperbenzoic acid (mCPBA, 0.89 g) at 0° C. and the mixture was stirred overnight. The resulting mixture was charged on silica gel and purified by column chromatography (methanol/ethyl acetate 1:9→1:1) to give the titled compound as white amorphous (0.46 g).
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.35 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.84 (2H, t, J=6.1 Hz), 3.35 (3H, s), 3.62 (2H, s), 3.69-3.83 (3H, m), 4.03-4.18 (3H, m), 6.41 (1H, dd, J=7.3, 0.7 Hz), 6.51 (1H, t, J=0.9 Hz), 6.85 (1H, d, J=7.3 Hz), 6.92-6.96 (1H, m), 7.09-7.11 (2H, m), 7.15-7.18 (1H, m), 7.21-7.22 (1H, m), 8.14 (1H, d, J=6.0 Hz).
    • Example 717 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-2-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.28 (3H, s), 3.42 (3H, s), 3.73-3.87 (1H, m), 3.91 (2H, s), 3.93 (2H, s), 4.08-4.23 (1H, m), 7.11 (1H, dd, J=4.8, 7.6 Hz), 7.22-7.34 (3H, m), 7.41-7.47 (1H, m), 8.41 (1H, dd, J=1.1, 4.8 Hz).
    • Example 718 1-Ethyl-3,3,5-trimethyl-7-{[1-(2-methylpyridin-3-yl)ethylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82-0.83 (3H, m), 1.15-1.89 (3H, m), 1.35-1.37 (3H, m), 1.53 (3H, s), 2.52 (3H, d, J=8.0 Hz), 3.39-3.40 (3H, m), 3.66 (2H, s), 3.73-3.82 (1H, m), 4.05-4.20 (2H, m), 7.18-7.20 (3H, m), 7.23-7.24 (1H, m), 7.85 (1H, dd, J=7.8, 1.6 Hz), 8.40 (1H, d, J=4.7 Hz).
    • Example 719 7-{[(2-Ethoxymethylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.17 (6H, t, J=7.0 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.57 (2H, q, J=7.0 Hz), 3.74-3.83 (1H, m), 3.84 (2H, s), 3.92 (2H, s), 4.09-4.20 (1H, m), 4.71 (2H, s), 7.22-7.28 (4H, m), 7.71 (1H, dd, J=7.7, 1.6 Hz), 8.49 (1H, dd, J=4.8, 1.6 Hz).
    • Example 720 1-Ethyl-7-{[1-(2-methoxymethylpyridin-3-yl)ethylamino]methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82-0.83 (3H, m), 1.16 (3H, t, J=6.9 Hz), 1.40 (3H, d, J=6.4 Hz), 1.52 (3H, s), 3.37-3.40 (6H, m), 3.60 (1H, d, J=13.6 Hz), 3.68 (1H, d, J=13.6 Hz), 3.72-3.82 (1H, m), 4.09-4.20 (1H, m), 4.23-4.30 (1H, m), 4.57-4.66 (2H, m), 7.15-7.19 (2H, m), 7.22-7.26 (1H, m), 7.27-7.32 (1H, m), 7.96-7.98 (1H, m), 8.49 (1H, dd, J=4.7, 1.7 Hz).
    • Example 721 1-Ethyl-3,3,5-trimethyl-7-{[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0 g) was added to a methanol solution (15 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.46 g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→8:2). The purified product was condensed under reduced pressure to give the title compound (1.92 g) as a white solid.
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 3.01-3.11 (2H, m), 3.31 (3H, s), 3.71-3.81 (1H, m), 3.84 (2H, s), 4.04-4.15 (1H, m), 4.16 (2H, t, J=6.0 Hz), 6.51 (1H, d, J=7.3 Hz), 7.12-7.18 (4H, m), 7.48-7.56 (2H, m), 7.63-7.70 (1H, m), 8.41 (1H, d, J=8.1 Hz)
    • Example 722 1-Ethyl-3,3,5-trimethyl-7-(quinolin-5-ylaminomethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.86 (3H, s), 1.21 (3H, t, J=7.1 Hz), 1.54 (3H, s), 3.38 (3H, s), 3.76-3.89 (1H, m), 4.09-4.22 (1H, m), 4.56 (2H, d, J=4.4 Hz), 4.70-4.88 (1H, m), 6.62 (1H, dd, J=2.6, 6.1 Hz), 7.28-7.35 (3H, m), 7.38 (1H, dd, J=4.2, 8.6 Hz), 7.50-7.58 (2H, m), 8.23 (1H, dd, J=1.4, 8.6 Hz), 8.92 (1H, dd, J=1.6, 4.2 Hz).
    • Example 723 7-{[(4-Chloro-pyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.72-3.90 (3H, m), 3.96 (2H, s), 4.08-4.22 (1H, m), 7.22-7.27 (3H, m), 7.33 (1H, d, J=5.3 Hz), 8.44 (1H, d, J=5.3 Hz), 8.60 (1H, s).
    • Example 724 7-{[(2-Chloropyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.74-3.86 (1H, m), 3.86 (2H, s), 3.93 (2H, s), 4.08-4.23 (1H, m), 7.21-7.31 (4H, m), 7.80 (1H, dd, J=1.9, 7.5 Hz), 8.32 (1H, dd, J=1.9, 4.8 Hz).
    • Example 725 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-pyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • To a THF solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-(((2-methylpyridin-3-yl)methylamino)methyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.92 g) was added di-tert-butyl dicarbonate (0.58 g) at room temperature, the mixture was stirred overnight. The resulting mixture was concentrated and then purified by column chromatography (ethyl acetate/hexanes 1:4→1:1→7:3) to give the titled compound as colorless oil (0.88 g).
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.49 (9H, s), 1.53 (3H, s), 2.45 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.09-4.18 (1H, s), 4.43 (4H, br), 6.99-7.12 (3H, m), 7.23-7.25 (1H, m), 7.35-7.38 (1H, m), 8.39-8.41 (1H, m).
    • Example 726 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(4-methylthiazol-5-ylmethyl)carbamic acid tert-butyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 725 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.45-1.55 (12H, m), 2.34 (3H, s), 3.36 (3H, s), 3.76-3.84 (1H, m), 4.09-4.16 (1H, m), 4.42 (2H, s), 4.54 (2H, s), 7.00-7.09 (2H, m), 7.24-7.27 (1H, m), 8.62 (1H, s).
    • Example 727 N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)carbamic acid tert-butyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 725 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.49 (9H, br), 1.54 (3H, s), 2.21 (3H, s), 3.38 (3H, s), 3.72 (3H, br), 3.75-3.85 (1H, m), 4.09-4.18 (1H, m), 4.35 (2H, br), 4.44 (2H, br), 5.88 (1H, s), 7.00-7.05 (2H, m), 7.24-7.27 (1H, m).
    • Example 728 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 716 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.20 (3H, t, J=7.0 Hz), 1.49 (9H, s), 1.54 (3H, s), 2.45 (3H, s), 3.38 (3H, s), 3.76-3.86 (1H, m), 4.08-4.16 (1H, m), 4.43 (4H, br), 6.99-7.12 (4H, m), 7.25-7.29 (1H, m), 8.21-8.23 (1H, m).
    • Example 729 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-hydroxymethylpyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 666 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.13 (3H, t, J=7.1 Hz), 1.49 (9H, br), 1.53 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.07-4.18 (1H, m), 4.40 (4H, br), 4.62 (2H, s), 7.00-7.08 (2H, m), 7.24-7.27 (2H, m), 7.47-7.49 (1H, m), 8.47-8.49 (1H, m).
    • Example 730 1-Ethyl-3,3,5-trimethyl-7-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.00-3.10 (2H, m), 3.34 (3H, s), 3.72-3.81 (1H, m), 3.84 (2H, s), 4.08-4.17 (1H, m), 4.21 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=7.0 Hz), 6.67 (1H, d, J=2.0 Hz), 7.13-7.22 (4H, m), 7.74 (1H, d, J=2.0 Hz)
    • Example 731 1-Ethyl-7-{[(2-hydroxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • To a ethanol solution (20 ml) of tert-butyl (1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl((2-(hydroxymethyl)pyridin-3-yl)methyl)carbamate (0.82 g) was added 5 M HCl and the mixture was stirred at 50° C. for 7 hours. The resulting mixture was concentrated and then 5 M NaOH was added thereto. Organic materials were extracted with ethyl acetate twice and then dried over MgSO4. After evaporation, the residue was purified by column chromatography (methanol/ethyl acetate 1:9→1:1) to give the titled compound as pale yellow oil (0.37 g).
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.74-3.90 (5H, m), 4.09-4.19 (1H, m), 4.80 (2H, s), 7.20-7.29 (4H, m), 7.64-7.67 (1H, m), 8.49-8.51 (1H, m).
    • Example 732 1-Ethyl-7-{[(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3, t, J=7.0 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.42 (3H, s), 3.77-3.87 (5H, m), 4.11-1.18 (1H, m), 4.41 (2H, s), 6.18 (1H, s), 7.21-7.28 (3H, m).
    • Example 733 1-Isobutyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.75 (3H, s), 0.77 (3H, s), 0.98 (3H, br), 1.53 (3H, br), 1.76-1.84 (1H, m), 2.56 (3H, s), 3.37-3.42 (1H, m), 3.82 (2H, s), 3.85 (2H, s), 4.34-4.40 (1H, m), 7.00-7.02 (1H, m), 7.10-7.14 (1H, m), 7.20-7.23 (1H, m), 7.24-7.27 (1H, m), 7.62 (1H, br), 7.62-7.64 (1H, m), 8.41 (1H, dd, J=4.9, 1.7 Hz).
    • Example 734 1-Isobutyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.74 (3H, s), 0.76 (3H, s), 0.98 (3H, br), 1.53 (3H, br), 1.74-1.85 (1H, m), 3.39-3.42 (1H, m), 3.40 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 4.34-4.39 (1H, m), 7.01-7.02 (1H, m), 7.18-7.21 (1H, m), 7.23-7.27 (2H, m), 7.68 (1H, br), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 735 1-(2-Methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.01 (3H, br), 1.53 (3H, br), 2.56 (3H, s), 3.34 (3H, s), 3.49 (1H, br), 3.60 (1H, br), 3.81 (2H, s), 3.84 (2H, s), 3.98 (1H, br), 4.11 (1H, br), 7.00 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.22 (1H, dd, J=8.4, 1.8 Hz), 7.58 (1H, d, J=8.4 Hz), 7.64 (1H, dd, J=7.6, 1.5 Hz), 7.92 (1H, br), 8.41 (1H, dd, J=4.9, 1.5 Hz).
    • Example 736 1-(2-Methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.01 (3H, br), 1.53 (3H, br), 3.34 (3H, s), 3.41 (3H, s), 3.59 (1H, br), 3.72 (1H, br), 3.81 (2H, s), 3.89 (2H, s), 3.98 (1H, br), 4.10 (1H, br), 4.67 (2H, s), 6.98-7.00 (1H, m), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.24-7.27 (1H, m), 7.57 (1H, d, J=8.4 Hz), 7.66 (1H, br), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 737 1-Cyclopropylmethyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.18 (2H, br), 0.41 (2H, d, J=8.0 Hz), 0.96-1.07 (4H, m), 1.54 (3H, br), 3.65 (1H, br), 3.82 (2H, s), 3.85 (2H, s), 4.11 (1H, br), 7.03 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.21 (1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 7.84 (1H, br), 8.41 (1H, dd. J=4.9, 1.6 Hz).
    • Example 738 1-Cyclopropylmethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.19 (2H, br), 0.40 (2H, d, J=8.1 Hz), 0.97-1.07 (4H, m), 1.54 (3H, br), 3.41 (3H, s), 3.66 (1H, br), 3.82 (2H, s), 3.90 (2H, s), 4.10 (1H, br), 4.67 (2H, s), 7.04 (1H, d, J=1.8 Hz), 7.20 (1H, dd, J=8.4, 1.8 Hz), 7.23-7.26 (1H, m), 7.32 (1H, d, J=8.4 Hz), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.07 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 739 1-Cyclopropyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.40 (2H, br), 1.00 (2H, br), 1.54 (6H, br), 2.56 (3H, s), 3.16-3.22 (1H, m), 3.82 (2H, s), 3.85 (2H, s), 6.99 (1H, br), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.23 (1H, dd, J=8.4, 1.9 Hz), 7.34 (1H, d, J=8.4 Hz), 7.64 (1H, dd, J=7.6, 1.6 Hz), 8.13 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 740 1-Cyclopropyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.40 (2H, br), 1.00 (2H, br), 1.54 (6H, br), 3.16-3.21 (1H, m), 3.41 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 4.67 (2H, s), 6.96 (1H, br), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.24-7.26 (1H, m), 7.34 (1H, d, J=8.4 Hz), 7.60 (1H, br), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 741 N-[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethy[l]benzenesulfonamide
  • Tributyl phosphine (1.2 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.17 g) were added to a toluene solution (100 ml) of 2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide (1.39 g), and 1-ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.94 g). The mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and saturated saline, dried with magnecium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was condensed under reduced pressure to produce the title compound (0.54 g) as a white amorphous.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.91-2.01 (2H, m), 2.61 (2H, t, J=7.7 Hz), 3.31-3.51 (2H, m), 3.40 (3H, s), 3.70 (2H, t, J=6.7 Hz), 3.72-3.81 (1H, m), 4.09-4.17 (1H, m), 4.22 (2H, t, J=6.7 Hz), 6.45 (1H, d, J=7.3 Hz), 6.94 (1H, dd, J=8.4 and 1.9 Hz), 7.02 (1H, d, J=1.9 Hz), 7.12-7.16 (2H, m), 7.46-7.66 (6H, m), 7.90-7.94 (1H, m), 8.34 (1H, d, J=7.5 Hz)
    • Example 742 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Lithium hydroxide (3.2 g), and thioglycolic acid (2.4 ml) were added to a DMF solution (27.4 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (4.56 g). The mixture was stirred at room temperature for 1 hour. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed under reduced pressure to produce the title compound (2.24 g) as a yellow oil.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.77-1.88 (2H, m), 2.64-2.72 (4H, m), 3.04 (2H, t, J=6.3 Hz), 3.38 (3H, s), 3.69-3.80 (1H, m), 4.08-4.17 (3H, m), 6.51 (1H, d, J=7.3 Hz), 7.00-7.03 (2H, m), 7.11-7.17 (2H, m), 7.46-7.53 (2H, m), 7.61-7.66 (1H, m), 8.42 (1H, dd, J=8.0 and 0.6 Hz)
    • Example 743 1-Cyclopropyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.12-0.19 (1H, m), 0.60-0.67 (1H, m), 0.75-0.83 (1H, m), 0.85 (3H, s), 1.24-1.28 (1H, m), 1.52 (3H, s), 3.15-3.21 (1H, m), 3.39 (3H, s), 3.40 (3H, s), 3.84 (2H, s), 3.91 (2H, s), 4.67 (2H, s), 7.19-7.20 (1H, m), 7.22-7.29 (2H, m), 7.33 (1H, d, J=4.3 Hz), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 744 1-Isobutyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.70 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.81 (3H, s), 1.53 (3H, s), 1.75-1.86 (1H, m), 3.31 (1H, dd, J=13.6, 6.4 Hz), 3.85 (2H, s), 3.91 (2H, s), 4.37 (1H, dd, J=13.6, 8.6 Hz), 4.67 (2H, s), 7.23-7.26 (4H, m), 7.72 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 745 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.85 (3H, s), 1.53 (3H, s), 2.56 (3H, s), 3.29 (3H, s), 3.41 (3H, s), 3.53-3.58 (1H, m), 3.69 (1H, ddd, J=10.3, 7.1, 4.4 Hz), 3.82 (2H, s), 3.87 (2H, s), 3.97 (1H, ddd, J=14.1, 5.2, 4.6 Hz), 4.07-4.15 (1H, m), 7.13 (1H, dd, J=7.6, 4.9 Hz), 7.23-7.26 (2H, m), 7.50 (1H, d, J=8.2 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.42 (1H, dd, J=4.8, 1.6 Hz).
    • Example 746 1-Isobutyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.76 (6H, d, J=6.7 Hz), 0.98 (3H, s), 1.53 (3H, s), 1.78-1.89 (1H, m), 2.55 (3H, s), 3.41 (1H, dd, J=13.8, 6.5 Hz), 3.80 (2H, s), 3.87 (2H, s), 4.37 (1H, dd, J=13.8, 8.3 Hz), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.7 Hz), 7.32 (1H, d, J=1.7 Hz), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.70 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 747 1-Isobutyl-8-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.76 (6H, d, J=6.7 Hz), 0.98 (3H, s), 1.53 (3H, s), 1.78-1.89 (1H, m), 3.39-3.46 (1H, m), 3.40 (3H, s), 3.83 (2H, s), 3.88 (2H, s), 4.33-4.42 (1H, m), 4.66 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.18 (1H, dd, J=8.1, 1.7 Hz), 7.23-7.26 (1H, m), 7.31 (1H, d, J=1.7 Hz), 7.72 (1H, dd, J=7.6, 1.6 Hz), 7.73 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 748 1-Cyclopropylmethyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.18 (2H, br), 0.41 (2H, d, J=7.9 Hz), 0.95-1.08 (4H, m), 1.54 (3H, br), 2.55 (3H, s), 3.70 (1H, br), 3.80 (2H, s), 3.87 (2H, s), 4.14 (1H, br), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.6 Hz), 7.39 (1H, d, J=1.6 Hz), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.74 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 749 1-Cyclopropylmethyl-8-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.18 (2H, br), 0.41 (2H, d, J=7.9 Hz), 0.95-1.08 (4H, m), 1.54 (3H, br), 3.40 (3H, s), 3.71 (1H, br), 3.84 (2H, s), 3.89 (2H, s), 4.10 (1H, br), 4.66 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.18 (1H, dd, J=8.1, 1.6 Hz), 7.23-7.26 (1H, m), 7.37 (1H, d, J=1.6 Hz), 7.72 (1H, dd, J=7.7, 1.6 Hz), 7.83 (1H, br), 8.41 (1H, dd, J=4.8, 1.6 Hz).
    • Example 750 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methoxymethylpyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl) carbamic acid tert-butyl ester (188 mg) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 19.7 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.028 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (162 mg) as a colorless oil.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.48 (9H, bs), 1.53 (3H, s), 3.33 (3H, s), 3.36 (3H, s), 3.74-3.84 (1H, m), 4.08-4.18 (1H, m), 4.30-4.50 (2H, m), 4.52-4.72 (4H, m), 7.02-7.15 (2H, m), 7.20-7.25 (2H, m), 7.46-7.57 (1H, m), 8.46 (1H, dd, J=1.5 and 4.8 Hz)
    • Example 751
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl)carbamic acid tert-butyl ester (2.35 g) was dissolved in acetic anhydride (20 ml). The reaction mixture was stirred at 100° C. for 2 h. The resulting mixture was evaporated, and dissolved in MeOH (15 ml). Potassium carbonate (6.8 g) was added to the mixture, and the reaction mixture was stirred 2 h at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (536 mg) as a pale yellow amorphous.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.49 (9H, s), 1.52 (3H, s), 2.37 (3H, s), 3.37 (3H, s), 3.77-3.83 (1H, m), 4.09-4.15 (1H, m), 4.30-4.52 (4H, m), 7.00-7.08 (2H, m), 7.09-7.15 (1H, m), 7.25-7.30 (1H, m), 8.07 (1H, d, J=2.6 Hz)
    • Example 752 1-Ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-yl-ethylamino)propyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.78-1.85 (2H, m), 2.63-2.72 (4H, m), 2.79-2.83 (2H, m), 2.86-2.92 (2H, m), 3.40 (3H, s), 3.73-3.81 (1H, m), 4.09-4.18 (1H, m), 7.01-7.06 (2H, m), 7.19-7.23 (2H, m), 7.52-7.55 (1H, m), 8.47-8.49 (2H, m)
    • Example 753 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.73-1.84 (2H, m), 2.60-2.71 (4H, m), 3.03 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.73-3.81 (1H, m), 4.09-4.18 (1H, m), 4.17 (2H, t, J=6.2 Hz), 6.47 (1H, d, J=7.0 Hz), 6.66 (1H, d, J=2.0 Hz), 6.98-7.05 (2H, m), 7.14-7.20 (2H, m), 7.74 (1H, d, J=2.0 Hz)
    • Example 754 Acetic acid 3-{[N-tert-butoxycarbonyl-N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)amino]methyl}pyridin-2-ylmethyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 751 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.48 (9H, br), 1.57 (3H, s), 2.08 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.09-4.18 (1H, m), 4.41 (2H, br), 4.57 (2H, br), 5.15 (2H, s), 7.03-7.12 (2H, m), 7.22-7.26 (2H, m), 7.47-7.50 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz).
    • Example 755 Acetic Acid 3-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)amino]methyl}pyridin-2-ylmethyl ester
  • The synthesis of the title compound was performed in the same manner as in Example 731 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.11 (3H, s), 3.41 (3H, s), 3.74-3.82 (1H, m), 3.86 (2H, s), 3.90 (2H, s), 4.09-4.20 (1H, m), 5.33 (2H, s), 7.23-7.27 (4H, m), 7.72 (1H, d, J=7.7 Hz), 8.52-8.54 (1H, m).
    • Example 756 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.76-1.83 (2H, m), 2.63-2.70 (4H, m), 3.01 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.72-3.81 (1H, m), 4.09-4.18 (3H, m), 6.54 (1H, dd, J=7.4 and 0.8 Hz), 6.96-7.04 (3H, m), 7.19 (1H, d, J=8.6 Hz), 7.23 (1H, d, J=7.4 Hz), 7.49 (1H, d, J=2.1 Hz),
    • Example 757 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(6-methoxy-2-methylpyridin-3-ylmethyl)carbamic acid tert-butyl ester
  • N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester (536 mg) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 56.1 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.081 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (550 mg) as a yellow oil.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.50 (9H, s), 1.53 (3H, s), 2.37 (3H, s), 3.36 (3H, s), 3.75-3.85 (4H, m), 4.09-4.20 (1H, m), 4.30-4.50 (4H, m), 6.85-6.98 (1H, m), 7.00-7.12 (2H, m), 7.23-7.28 (1H, m), 8.08 (1H, d, J=2.8 Hz)
    • Example 758 1-Ethyl-7-{[(6-methoxy-2-methyl-pyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.47 (3H, s), 3.42 (3H, s), 3.78-3.83 (3H, m), 3.85 (3H, s), 3.88 (2H, s), 4.10-4.17 (1H, m), 7.20-7.30 (4H, m), 8.10 (1H, d, J=2.9 Hz)
    • Example 759 1,3,3-Trimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.08 (3H, br), 1.63 (3H, br), 2.56 (3H, s), 3.47 (3H, s), 3.81 (2H, s), 3.87 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.7 Hz), 7.24-7.26 (1H, m), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.98 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 760 1-Ethyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.00 (3H, br), 1.26 (3H, t, J=7.1 Hz), 1.55 (3H, br), 2.56 (3H, s), 3.81 (2H, s), 3.87 (2H, s), 3.93 (1H, br), 4.09 (1H, br), 6.93-6.97 (1H, m), 7.12 (1H, dd, J=7.5, 4.9 Hz), 7.19 (1H, dd, J=8.2, 1.8 Hz), 7.24-7.26 (1H, m), 7.35 (1H, br), 7.63 (1H, dd, J=3.5, 1.5 Hz), 8.41 (1H, dd, J=4.8, 1.5 Hz).
    • Example 761 1,3,3-Trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.05 (3H, br), 1.55 (3H, br), 2.56 (3H, s), 3.46 (3H, s), 3.82 (2H, s), 3.85 (2H, s), 7.03 (1H, br), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.20-7.23 (2H, m), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.03 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 762 1-Ethyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.00 (3H, br), 1.22 (3H, t, J=7.1 Hz), 1.53 (3H, br), 2.56 (3H, s), 3.82 (2H, s), 3.85 (2H, s), 3.92 (1H, br), 4.12 (1H, br), 7.02 (1H, d, J=1.6 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.22 (1H, dd, J=8.4, 1.8 Hz), 7.29, (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.5 Hz), 7.85 (1H, br), 8.41 (1H, dd, J=4.9, 1.5 Hz).
    • Example 763 1-Ethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.00 (3H, br), 1.22 (3H, t, J=7.1 Hz), 1.53 (3H, br), 3.41 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 3.92 (1H, br), 4.08 (1H, br), 4.67 (2H, s), 7.01 (1H, d, J=1.5 Hz), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.23-7.29 (2H, m), 7.74 (1H, dd, J=7.7, 1.6 Hz), 7.79 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 764 8-{[(2-Methoxymethyl-pyridin-3-ylmethyl)amino]methyl}-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.02 (3H, br), 1.53 (3H, br), 3.40 (3H, s), 3.47 (3H, s), 3.84 (2H, s), 3.90 (2H, s), 4.67 (2H, s), 6.97 (1H, d, J=8.2 Hz), 7.18 (1H, dd, J=8.2, 1.7 Hz), 7.23-7.26 (2H, m), 7.72 (1H, dd, J=7.7, 1.6 Hz), 7.94 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 765 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.12-0.22 (2H, m), 0.34-0.50 (2H, m), 0.82 (3H, s), 0.94-1.03 (1H, m), 1.53 (3H, s), 2.56 (3H, s), 3.31 (3H, s), 3.49-3.60 (2H, m), 3.70 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.81 (2H, s), 3.87 (2H, s), 3.94 (1H, dt, J=13.9, 5.3 Hz), 4.12 (1H, dd, J=14.1, 7.4 Hz), 4.15-4.22 (1H, m), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.24-7.26 (2H, m), 7.33 (1H, br), 7.50 (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.41 (1H, dd, J=4.9, 1.6 Hz).
    • Example 766 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]-methyl}-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.12-0.23 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.96-1.03 (1H, m), 1.53 (3H, s), 3.30 (3H, s), 3.40 (3H, s), 3.49-3.60 (2H, m), 3.69 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.84 (2H, s), 3.89 (2H, s), 3.95 (1H, dt, J=13.9, 5.3 Hz), 4.11-4.22 (2H, m), 4.66 (2H, s), 7.23-7.26 (2H, m), 7.32 (1H, br), 7.49 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=7.6, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 767 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)-amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.11-0.22 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.94-1.03 (1H, m), 1.52 (3H, s), 2.56 (3H, s), 3.29 (3H, s), 3.49-3.57 (2H, m), 3.71 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.82 (2H, s), 3.87 (2H, s), 3.97 (1H, dt, J=13.9, 5.2 Hz), 4.11-4.22 (2H, m), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.23-7.27 (2H, m), 7.55 (1H, d, J=1.3 Hz), 7.64 (1H, dd, J=7.6, 1.6 Hz), 8.40 (1H, dd, J=4.9, 1.6 Hz).
    • Example 768 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]-methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.11-0.22 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.94-1.04 (1H, m), 1.52 (3H, s), 3.29 (3H, s), 3.40 (3H, s), 3.48-3.57 (2H, m), 3.70 (1H, ddd, J=10.0, 7.0, 5.6 Hz), 3.85 (2H, s), 3.90 (2H, s), 3.96 (1H, dt, J=13.9, 5.3 Hz), 4.14 (1H, dd, J=14.1, 7.4 Hz), 4.18-4.25 (1H, m), 4.67 (2H, s), 7.23-7.29 (3H, m), 7.52 (1H, br), 7.75 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 769 5-Cyclopropyl-1-cyclopropylmethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.00-0.06 (1H, m), 0.07-0.13 (1H, m), 0.18-0.35 (3H, m), 0.58-0.65 (1H, m), 0.75-0.90 (2H, m), 0.84 (3H, s), 1.14-1.22 (1H, m), 1.51 (3H, s), 3.20-3.25 (1H, m), 3.36 (1H, dd, J=14.1, 6.8 Hz), 3.40 (3H, s), 3.86 (2H, s), 3.90 (2H, s), 4.30 (1H, dd, J=14.1, 7.4 Hz), 4.67 (2H, s), 7.18-7.26 (3H, m), 7.36 (1H, br), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).
    • Example 770 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 165.3-166.5° C.
    • Example 771 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 155.1-155.8° C.
    • Example 772 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-2-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.23 (3H, d, J=0.9 Hz), 2.42 (3H, d, J=0.8 Hz), 2.76 (2H, t, J=7.4 Hz), 2.84-2.92 (2H, m), 2.95-3.04 (2H, m), 3.36 (3H, s), 3.71-3.79 (1H, m), 4.01 and 4.02 (2H, s), 4.03-4.16 (3H, m), 6.77 (1H, br), 6.93 (1H, br), 6.97-7.01 (m, 3H), 7.12 (1H, d, J=9.0 Hz), 7.52 (1H, d, J=2.1 Hz).
    • Example 773 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-2-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.41 (3H, s), 2.42 (3H, s), 2.75 (2H, t, J=7.4 Hz), 2.83-2.91 (2H, m), 2.99 (2H, t, J=6.4 Hz), 3.36 (3H, s), 3.72-3.79 (1H, m), 4.01 (2H, s), 4.07 (2H, t, J=6.4 Hz), 4.09-4.16 (1H, m), 6.43 (1H, d, J=7.3 Hz), 6.55 (1H, s), 6.77 (1H, br), 6.98-7.02 (m, 2H), 7.06 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=8.7 Hz).
    • Example 774 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.24 (3H, s), 2.41 (3H, d, J=0.9 Hz), 2.79-2.85 (2H, m), 2.88-2.93 (2H, m), 2.95 (2H, t, J=6.8 Hz), 3.37 (3H, s), 3.71-3.79 (1H, m), 3.89 (2H, s), 3.94-3.98 (2H, m), 4.10-4.17 (1H, m), 6.34 (1H, d, J=7.4 Hz), 6.53 (1H, br), 6.89 (1H, d, J=7.4 Hz), 7.01 (1H, d, J=1.8 Hz), 7.04 (1H, dd, J=1.8, 8.3 Hz), 7.12 (1H, dd, J=4.8, 7.6 Hz), 7.16 (1H, d, J=8.30 Hz), 7.37 (1H, dd, J=1.1, 7.6 Hz), 8.39 (1H, dd, J=1.1, 4.8 Hz).
    • Example 775 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.17 (3H, d, J=1.0 Hz), 2.22 (3H, s), 2.81-2.87 (2H, m), 2.89-2.97 (4H, m), 3.38 (3H, s), 3.71-3.80 (1H, m), 3.88 (2H, s), 3.93-4.00 (2H, m), 4.09-4.18 (1H, m), 6.70 (1H, br), 6.96 (1H, d, J=2.1 Hz), 7.03 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=1.8, 8.3 Hz), 7.11 (1H, dd, J=4.8, 7.6 Hz), 7.17 (1H, d, J=8.3 Hz), 7.34 (1H, dd, J=1.2, 7.6 Hz), 7.50 (1H, d, J=2.1 Hz), 8.39 (1H, dd, J=1.2, 4.8 Hz).
    • Example 776 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.14 (3H, d, J=1.0 Hz), 2.23 (3H, s), 2.42 (3H, d, J=1.0 Hz), 2.80-2.86 (2H, m), 2.88-2.96 (4H, m), 3.38 (3H, s), 3.71-3.79 (1H, m), 3.88 (2H, s), 3.91-3.99 (2H, m), 4.10-4.16 (1H, m), 6.54 (1H, br), 6.63 (1H, br), 7.02 (1H, d, J=1.9 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.12 (1H, dd, J=4.8, 7.6 Hz), 7.16 (1H, d, J=8.3 Hz), 7.36 (1H, dd, J=1.1, 7.6 Hz), 8.39 (1H, dd, J=1.1, 4.8 Hz).
    • Example 777 N-[2-({N′-[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.42 (3H, d, J=1.0 Hz), 2.78-2.98 (6H, m), 3.03 (3H, s), 3.36 (3H, s), 3.70-3.83 (1H, m), 3.88 (2H, s), 4.06-4.22 (3H, m), 6.43-6.45 (1H, m), 6.53 (1H, t, J=0.92 Hz), 6.97 (1H, d, J=1.8 Hz), 6.99-7.03 (1H, m), 7.04 (1H, d, J=7.4 Hz), 7.06-7.11 (1H, m), 7.14-7.18 (1H, m), 7.19 (1H, d, J=8.4 Hz), 7.30-7.35 (1H, m), 7.44 (1H, dd, J=0.96, 8.1 Hz), 9.88 (1H, bs).
    • Example 778 N-[2-({N′-[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N′-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.24 (3H, s), 2.79-2.97 (6H, m), 3.01 (3H, s), 3.36 (3H, s), 3.71-3.83 (1H, m), 3.87 (2H, s), 4.06-4.20 (3H, m), 6.87 (1H, d, J=1.0 Hz), 6.94-6.99 (2H, m), 7.02 (1H, dd, J=1.9, 8.3 Hz), 7.05-7.13 (1H, m), 7.13-7.18 (1H, m), 7.19 (1H, d, J=8.3 Hz), 7.29-7.36 (1H, m), 7.43 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=2.1 Hz), 9.84 (1H, bs).
    • Example 779 N-[2-({N′-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N′-[2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]amino}methyl)phenyl]methanesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.21 (3H, d, J=1.0 Hz), 2.43 (3H, d, J=1.0 Hz), 2.78-2.97 (6H, m), 3.02 (3H, s), 3.36 (3H, s), 3.72-3.85 (1H, m), 3.87 (2H, s), 4.04-4.19 (3H, m), 6.54 (1H, d, J=1.2 Hz), 6.81 (1H, d, J=1.1 Hz), 6.97 (1H, d, J=1.9 Hz), 7.01 (1H, dd, J=1.9, 8.3 Hz), 7.06-7.13 (1H, m), 7.13-7.17 (1H, m), 7.19 (1H, d, J=8.3 Hz), 7.29-7.36 (1H, m,), 7.44 (1H, dd, J=0.92, 8.1 Hz), 9.75 (1H, bs).
    • Example 780 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 168.5-170.5° C.
    • Example 781 7-(2-{N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 133.5-139.7° C.
    • Example 782 7-(2-{N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • White powder
  • mp: 171-172.9° C.
    • Example 783 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.39 (3H, s), 2.42 (3H, s), 2.70-2.85 (4H, m), 2.91 (2H, t, J=6.4 Hz), 3.36 (3H, s), 3.71-3.78 (1H, m), 3.83 (2H, s), 4.03 (2H, t, J=6.4 Hz), 4.06-4.16 (1H, m), 6.42 (1H, dd, J=0.8 and 7.4 Hz), 6.55 (1H, t, J=1.0 Hz), 6.95-7.02 (3H, m), 7.13 (1H, d, J=8.8 Hz), 8.58 (1H, s)
    • Example 784 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 2.70-2.85 (4H, m), 2.88-2.95 (2H, m), 3.36 (3H, s), 3.70-3.80 (1H, m), 3.82 (2H, s), 4.00-4.18 (3H, m), 6.86 (1H, d, J=1.0 Hz), 6.95-7.03 (3H, m), 7.12 (1H, d, J=8.2 Hz), 7.52 (1H, d, 2.1 Hz), 8.59 (1H, s)
    • Example 785 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.21 (3H, s), 2.39 (3H, s), 2.43 (3H, s), 2.70-2.85 (4H, m), 2.88-2.96 (2H, m), 3.36 (3H, s), 3.70-3.85 (3H, m), 3.96-4.18 (3H, m), 6.56 (1H, d, J=1.1 Hz), 6.79 (1H, d, J=1.1 Hz), 6.95-7.00 (2H, m), 7.12 (1H, d, J=8.6 Hz), 8.60 (1H, s)
  • The following compounds shown in Examples 786 to 791, Examples 793 and Example 795 to 802 can be prepared by the same manner as mentioned above or a conventional manner using appropriate starting materials.
    • Example 786 1-Ethyl-3,3,5-trimethyl-7-{2-[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 787 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 788 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 789 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyrimidin-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 790 N-[3-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]amino}methyl)pyridin-2-yl]methanesulfonamide Example 791 N-[3-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-yl]acetamide Example 792 Acetic acid 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H NMR (DMSO-dd, δppm: 0.69 (3H, s), 1.04 (3H, t, J=6.9 Hz), 1.34 (3H, s), 2.01-2.04 (3H, m), 2.42 (3H, s), 2.74 (2H, br), 3.26 (3H, s), 3.45-4.30 (8H, m), 5.10 (2H, br), 6.48 (1H, br), 6.64 (1H, br), 7.17 (1H, br), 7.31 (2H, br), 7.48 (2H, br), 7.79 (1H, br), 8.46 (1H, br).
    • Example 793 1-Ethyl-7-({N-(2-imidazol-1-ylmethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 794 1-Ethyl-7-({N-(3-imidazol-1-ylmethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.77 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.43 (3H, d, J=1.0 Hz), 2.79 (2H, dt, J=2.1, 5.9 Hz), 3.32 (3H, s), 3.55-3.68 (4H, m), 3.71-3.83 (1H, m), 3.99-4.17 (3H, m), 5.02 (2H, s), 6.43 (1H, dd, J=0.74, 7.3 Hz), 6.49 (1H, t, J=1.0 Hz), 6.88 (1H, t, J=1.3 Hz), 6.95 (1H, d, J=7.3 Hz), 6.98-7.07 (3H, m), 7.07-7.15 (3H, m), 7.15-7.25 (2H, m), 7.52 (1H, d, J=1.1 Hz).
    • Example 795 1-Ethyl-7-({N-(2-imidazol-1-ylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 796 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-morpholin-4-ylbenzyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 797 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-[1,2,4]triazol-1-yl-benzyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 798 1-Ethyl-7-(N-{imidazo[1,2-a]pyridin-8-ylmethyl-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 799 1-Ethyl-7-(N-{imidazo[1,2-a]pyridin-6-ylmethyl-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 800 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrazol-1-ylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 801 7-({N-(3H-Benzoimidazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 802 1-Ethyl-7-({N-(4-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 802-a 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.20 (3H, d, J=0.9 Hz), 2.42 (3H, d, J=0.9 Hz), 2.43 (3H, d, J=0.9 Hz), 2.76 (2H, t, J=7.4 Hz), 2.85-2.90 (2H, m), 2.95-3.02 (2H, m), 3.35 (3H, s), 3.71-3.77 (1H, m), 4.01 and 4.02 (2H, s), 4.02-4.16 (3H, m), 6.57 (1H, br), 6.77 (1H, br), 6.86 (1H, br), 6.97-7.01 (m, 2H), 7.12 (1H, d, J=8.9 Hz).
    • Examples 803 to 1038
  • The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.
  • Figure US20140343277A1-20141120-C00240
    Example No. R1 MS(M + 1)
    803
    Figure US20140343277A1-20141120-C00241
         		489
    804
    Figure US20140343277A1-20141120-C00242
         		500
    805
    Figure US20140343277A1-20141120-C00243
         		500
    806
    Figure US20140343277A1-20141120-C00244
         		503
    807
    Figure US20140343277A1-20141120-C00245
         		505
    808
    Figure US20140343277A1-20141120-C00246
         		519
    809
    Figure US20140343277A1-20141120-C00247
         		506
    810
    Figure US20140343277A1-20141120-C00248
         		517
    811
    Figure US20140343277A1-20141120-C00249
         		515
    812
    Figure US20140343277A1-20141120-C00250
         		489
    813
    Figure US20140343277A1-20141120-C00251
         		568
    814
    Figure US20140343277A1-20141120-C00252
         		517
    815
    Figure US20140343277A1-20141120-C00253
         		520
    816
    Figure US20140343277A1-20141120-C00254
         		557
    817
    Figure US20140343277A1-20141120-C00255
         		534
    818
    Figure US20140343277A1-20141120-C00256
         		520
    819
    Figure US20140343277A1-20141120-C00257
         		533
    820
    Figure US20140343277A1-20141120-C00258
         		520
    821
    Figure US20140343277A1-20141120-C00259
         		514
    822
    Figure US20140343277A1-20141120-C00260
         		514
    823
    Figure US20140343277A1-20141120-C00261
         		514
    824
    Figure US20140343277A1-20141120-C00262
         		514
    825
    Figure US20140343277A1-20141120-C00263
         		514
    826
    Figure US20140343277A1-20141120-C00264
         		503
    827
    Figure US20140343277A1-20141120-C00265
         		517
    828
    Figure US20140343277A1-20141120-C00266
         		503
    829
    Figure US20140343277A1-20141120-C00267
         		514
    830
    Figure US20140343277A1-20141120-C00268
         		518
    831
    Figure US20140343277A1-20141120-C00269
         		568
    832
    Figure US20140343277A1-20141120-C00270
         		530
    833
    Figure US20140343277A1-20141120-C00271
         		506
    834
    Figure US20140343277A1-20141120-C00272
         		506
    835
    Figure US20140343277A1-20141120-C00273
         		501
    836
    Figure US20140343277A1-20141120-C00274
         		490
    837
    Figure US20140343277A1-20141120-C00275
         		501
    838
    Figure US20140343277A1-20141120-C00276
         		514
    839
    Figure US20140343277A1-20141120-C00277
         		530
    840
    Figure US20140343277A1-20141120-C00278
         		504
    841
    Figure US20140343277A1-20141120-C00279
         		514
    842
    Figure US20140343277A1-20141120-C00280
         		490
    843
    Figure US20140343277A1-20141120-C00281
         		490
    844
    Figure US20140343277A1-20141120-C00282
         		504
    845
    Figure US20140343277A1-20141120-C00283
         		588
    846
    Figure US20140343277A1-20141120-C00284
         		515
    847
    Figure US20140343277A1-20141120-C00285
         		528
  • Figure US20140343277A1-20141120-C00286
    Example No. R1 MS(M + 1)
    848
    Figure US20140343277A1-20141120-C00287
         		545
    849
    Figure US20140343277A1-20141120-C00288
         		556
    850
    Figure US20140343277A1-20141120-C00289
         		556
    851
    Figure US20140343277A1-20141120-C00290
         		559
    852
    Figure US20140343277A1-20141120-C00291
         		561
    853
    Figure US20140343277A1-20141120-C00292
         		575
    854
    Figure US20140343277A1-20141120-C00293
         		562
    855
    Figure US20140343277A1-20141120-C00294
         		573
    856
    Figure US20140343277A1-20141120-C00295
         		571
    857
    Figure US20140343277A1-20141120-C00296
         		545
    858
    Figure US20140343277A1-20141120-C00297
         		624
    859
    Figure US20140343277A1-20141120-C00298
         		573
    860
    Figure US20140343277A1-20141120-C00299
         		576
    861
    Figure US20140343277A1-20141120-C00300
         		613
    862
    Figure US20140343277A1-20141120-C00301
         		590
    863
    Figure US20140343277A1-20141120-C00302
         		576
    864
    Figure US20140343277A1-20141120-C00303
         		589
    865
    Figure US20140343277A1-20141120-C00304
         		576
    866
    Figure US20140343277A1-20141120-C00305
         		570
    867
    Figure US20140343277A1-20141120-C00306
         		570
    868
    Figure US20140343277A1-20141120-C00307
         		570
    869
    Figure US20140343277A1-20141120-C00308
         		570
    870
    Figure US20140343277A1-20141120-C00309
         		570
    871
    Figure US20140343277A1-20141120-C00310
         		574
    872
    Figure US20140343277A1-20141120-C00311
         		559
    873
    Figure US20140343277A1-20141120-C00312
         		590
    874
    Figure US20140343277A1-20141120-C00313
         		573
    875
    Figure US20140343277A1-20141120-C00314
         		559
    876
    Figure US20140343277A1-20141120-C00315
         		570
    877
    Figure US20140343277A1-20141120-C00316
         		574
    878
    Figure US20140343277A1-20141120-C00317
         		624
    879
    Figure US20140343277A1-20141120-C00318
         		586
    880
    Figure US20140343277A1-20141120-C00319
         		562
    881
    Figure US20140343277A1-20141120-C00320
         		562
    882
    Figure US20140343277A1-20141120-C00321
         		557
    883
    Figure US20140343277A1-20141120-C00322
         		546
    884
    Figure US20140343277A1-20141120-C00323
         		557
    885
    Figure US20140343277A1-20141120-C00324
         		570
    886
    Figure US20140343277A1-20141120-C00325
         		586
    887
    Figure US20140343277A1-20141120-C00326
         		560
    888
    Figure US20140343277A1-20141120-C00327
         		570
    889
    Figure US20140343277A1-20141120-C00328
         		546
    890
    Figure US20140343277A1-20141120-C00329
         		546
    891
    Figure US20140343277A1-20141120-C00330
         		560
    892
    Figure US20140343277A1-20141120-C00331
         		644
    893
    Figure US20140343277A1-20141120-C00332
         		571
    894
    Figure US20140343277A1-20141120-C00333
         		584
  • Figure US20140343277A1-20141120-C00334
    Example No. R1 MS(M + 1)
    895
    Figure US20140343277A1-20141120-C00335
         		555
    896
    Figure US20140343277A1-20141120-C00336
         		566
    897
    Figure US20140343277A1-20141120-C00337
         		566
    898
    Figure US20140343277A1-20141120-C00338
         		569
    899
    Figure US20140343277A1-20141120-C00339
         		571
    900
    Figure US20140343277A1-20141120-C00340
         		585
    901
    Figure US20140343277A1-20141120-C00341
         		572
    902
    Figure US20140343277A1-20141120-C00342
         		583
    903
    Figure US20140343277A1-20141120-C00343
         		581
    904
    Figure US20140343277A1-20141120-C00344
         		555
    905
    Figure US20140343277A1-20141120-C00345
         		634
    906
    Figure US20140343277A1-20141120-C00346
         		583
    907
    Figure US20140343277A1-20141120-C00347
         		586
    908
    Figure US20140343277A1-20141120-C00348
         		623
    909
    Figure US20140343277A1-20141120-C00349
         		600
    910
    Figure US20140343277A1-20141120-C00350
         		586
    911
    Figure US20140343277A1-20141120-C00351
         		599
    912
    Figure US20140343277A1-20141120-C00352
         		586
    913
    Figure US20140343277A1-20141120-C00353
         		580
    914
    Figure US20140343277A1-20141120-C00354
         		580
    915
    Figure US20140343277A1-20141120-C00355
         		580
    916
    Figure US20140343277A1-20141120-C00356
         		580
    917
    Figure US20140343277A1-20141120-C00357
         		580
    918
    Figure US20140343277A1-20141120-C00358
         		584
    919
    Figure US20140343277A1-20141120-C00359
         		569
    920
    Figure US20140343277A1-20141120-C00360
         		600
    921
    Figure US20140343277A1-20141120-C00361
         		583
    922
    Figure US20140343277A1-20141120-C00362
         		569
    923
    Figure US20140343277A1-20141120-C00363
         		580
    924
    Figure US20140343277A1-20141120-C00364
         		584
    925
    Figure US20140343277A1-20141120-C00365
         		634
    926
    Figure US20140343277A1-20141120-C00366
         		596
    927
    Figure US20140343277A1-20141120-C00367
         		572
    928
    Figure US20140343277A1-20141120-C00368
         		572
    929
    Figure US20140343277A1-20141120-C00369
         		567
    930
    Figure US20140343277A1-20141120-C00370
         		556
    931
    Figure US20140343277A1-20141120-C00371
         		567
    932
    Figure US20140343277A1-20141120-C00372
         		580
    933
    Figure US20140343277A1-20141120-C00373
         		596
    934
    Figure US20140343277A1-20141120-C00374
         		570
    935
    Figure US20140343277A1-20141120-C00375
         		580
    936
    Figure US20140343277A1-20141120-C00376
         		556
    937
    Figure US20140343277A1-20141120-C00377
         		556
    938
    Figure US20140343277A1-20141120-C00378
         		570
    939
    Figure US20140343277A1-20141120-C00379
         		654
    940
    Figure US20140343277A1-20141120-C00380
         		581
    941
    Figure US20140343277A1-20141120-C00381
         		594
  • Figure US20140343277A1-20141120-C00382
    Example No. R1 MS(M + 1)
    942
    Figure US20140343277A1-20141120-C00383
         		545
    943
    Figure US20140343277A1-20141120-C00384
         		556
    944
    Figure US20140343277A1-20141120-C00385
         		556
    945
    Figure US20140343277A1-20141120-C00386
         		559
    946
    Figure US20140343277A1-20141120-C00387
         		561
    947
    Figure US20140343277A1-20141120-C00388
         		575
    948
    Figure US20140343277A1-20141120-C00389
         		562
    949
    Figure US20140343277A1-20141120-C00390
         		573
    950
    Figure US20140343277A1-20141120-C00391
         		571
    951
    Figure US20140343277A1-20141120-C00392
         		545
    952
    Figure US20140343277A1-20141120-C00393
         		624
    953
    Figure US20140343277A1-20141120-C00394
         		573
    954
    Figure US20140343277A1-20141120-C00395
         		576
    955
    Figure US20140343277A1-20141120-C00396
         		613
    956
    Figure US20140343277A1-20141120-C00397
         		590
    957
    Figure US20140343277A1-20141120-C00398
         		576
    958
    Figure US20140343277A1-20141120-C00399
         		589
    959
    Figure US20140343277A1-20141120-C00400
         		576
    960
    Figure US20140343277A1-20141120-C00401
         		570
    961
    Figure US20140343277A1-20141120-C00402
         		570
    962
    Figure US20140343277A1-20141120-C00403
         		570
    963
    Figure US20140343277A1-20141120-C00404
         		570
    964
    Figure US20140343277A1-20141120-C00405
         		570
    965
    Figure US20140343277A1-20141120-C00406
         		574
    966
    Figure US20140343277A1-20141120-C00407
         		559
    967
    Figure US20140343277A1-20141120-C00408
         		590
    968
    Figure US20140343277A1-20141120-C00409
         		573
    969
    Figure US20140343277A1-20141120-C00410
         		559
    970
    Figure US20140343277A1-20141120-C00411
         		570
    971
    Figure US20140343277A1-20141120-C00412
         		574
    972
    Figure US20140343277A1-20141120-C00413
         		624
    973
    Figure US20140343277A1-20141120-C00414
         		586
    974
    Figure US20140343277A1-20141120-C00415
         		562
    975
    Figure US20140343277A1-20141120-C00416
         		562
    976
    Figure US20140343277A1-20141120-C00417
         		557
    977
    Figure US20140343277A1-20141120-C00418
         		546
    978
    Figure US20140343277A1-20141120-C00419
         		557
    979
    Figure US20140343277A1-20141120-C00420
         		570
    980
    Figure US20140343277A1-20141120-C00421
         		586
    981
    Figure US20140343277A1-20141120-C00422
         		560
    982
    Figure US20140343277A1-20141120-C00423
         		570
    983
    Figure US20140343277A1-20141120-C00424
         		546
    984
    Figure US20140343277A1-20141120-C00425
         		546
    985
    Figure US20140343277A1-20141120-C00426
         		560
    986
    Figure US20140343277A1-20141120-C00427
         		644
    987
    Figure US20140343277A1-20141120-C00428
         		571
    988
    Figure US20140343277A1-20141120-C00429
         		584
  • Figure US20140343277A1-20141120-C00430
    Example No. R1 MS(M + 1)
    989
    Figure US20140343277A1-20141120-C00431
         		406
    990
    Figure US20140343277A1-20141120-C00432
         		421
    991
    Figure US20140343277A1-20141120-C00433
         		448
    992
    Figure US20140343277A1-20141120-C00434
         		434
    993
    Figure US20140343277A1-20141120-C00435
         		452
    994
    Figure US20140343277A1-20141120-C00436
         		436
    995
    Figure US20140343277A1-20141120-C00437
         		440
    996
    Figure US20140343277A1-20141120-C00438
         		392
    997
    Figure US20140343277A1-20141120-C00439
         		448
    998
    Figure US20140343277A1-20141120-C00440
         		438
    999
    Figure US20140343277A1-20141120-C00441
         		435
    1000
    Figure US20140343277A1-20141120-C00442
         		435
    1001
    Figure US20140343277A1-20141120-C00443
         		421
    1002
    Figure US20140343277A1-20141120-C00444
         		421
    1003
    Figure US20140343277A1-20141120-C00445
         		438
    1004
    Figure US20140343277A1-20141120-C00446
         		435
    1005
    Figure US20140343277A1-20141120-C00447
         		406
    1006
    Figure US20140343277A1-20141120-C00448
         		407
    1007
    Figure US20140343277A1-20141120-C00449
         		420
    1008
    Figure US20140343277A1-20141120-C00450
         		421
    1009
    Figure US20140343277A1-20141120-C00451
         		419
    1010
    Figure US20140343277A1-20141120-C00452
         		420
    1011
    Figure US20140343277A1-20141120-C00453
         		450
    1012
    Figure US20140343277A1-20141120-C00454
         		454
    1013
    Figure US20140343277A1-20141120-C00455
         		426
    1014
    Figure US20140343277A1-20141120-C00456
         		452
    1015
    Figure US20140343277A1-20141120-C00457
         		407
    1016
    Figure US20140343277A1-20141120-C00458
         		452
    1017
    Figure US20140343277A1-20141120-C00459
         		422
    1018
    Figure US20140343277A1-20141120-C00460
         		450
    1019
    Figure US20140343277A1-20141120-C00461
         		436
    1020
    Figure US20140343277A1-20141120-C00462
         		422
    1021
    Figure US20140343277A1-20141120-C00463
         		436
    1022
    Figure US20140343277A1-20141120-C00464
         		452
    1023
    Figure US20140343277A1-20141120-C00465
         		422
    1024
    Figure US20140343277A1-20141120-C00466
         		422
    1025
    Figure US20140343277A1-20141120-C00467
         		408
    1026
    Figure US20140343277A1-20141120-C00468
         		435
    1027
    Figure US20140343277A1-20141120-C00469
         		411
    1028
    Figure US20140343277A1-20141120-C00470
         		422
    1029
    Figure US20140343277A1-20141120-C00471
         		422
    1030
    Figure US20140343277A1-20141120-C00472
         		434
    1031
    Figure US20140343277A1-20141120-C00473
         		421
    1032
    Figure US20140343277A1-20141120-C00474
         		496
    1033
    Figure US20140343277A1-20141120-C00475
         		434
    1034
    Figure US20140343277A1-20141120-C00476
         		448
    1035
    Figure US20140343277A1-20141120-C00477
         		468
    1036
    Figure US20140343277A1-20141120-C00478
         		449
    1037
    Figure US20140343277A1-20141120-C00479
         		435
    1038
    Figure US20140343277A1-20141120-C00480
         		435
    • Examples 1039 to 1614
  • The following compounds can be obtained in the same manner as in Examples above using appropriate starting materials.
  •
    Figure US20140343277A1-20141120-C00481
    Example No. R1 MS (M + 1)
    1039
    Figure US20140343277A1-20141120-C00482
    1040
    Figure US20140343277A1-20141120-C00483
    1041
    Figure US20140343277A1-20141120-C00484
    1042
    Figure US20140343277A1-20141120-C00485
    1043
    Figure US20140343277A1-20141120-C00486
    1044
    Figure US20140343277A1-20141120-C00487
    1045
    Figure US20140343277A1-20141120-C00488
    1046
    Figure US20140343277A1-20141120-C00489
    1047
    Figure US20140343277A1-20141120-C00490
    1048
    Figure US20140343277A1-20141120-C00491
    1049
    Figure US20140343277A1-20141120-C00492
    1050
    Figure US20140343277A1-20141120-C00493
    1051
    Figure US20140343277A1-20141120-C00494
    1052
    Figure US20140343277A1-20141120-C00495
    1053
    Figure US20140343277A1-20141120-C00496
    1054
    Figure US20140343277A1-20141120-C00497
    1055
    Figure US20140343277A1-20141120-C00498
    1056
    Figure US20140343277A1-20141120-C00499
    1057
    Figure US20140343277A1-20141120-C00500
    1058
    Figure US20140343277A1-20141120-C00501
    1059
    Figure US20140343277A1-20141120-C00502
    1060
    Figure US20140343277A1-20141120-C00503
    1061
    Figure US20140343277A1-20141120-C00504
    1062
    Figure US20140343277A1-20141120-C00505
    1063
    Figure US20140343277A1-20141120-C00506
    1064
    Figure US20140343277A1-20141120-C00507
    1065
    Figure US20140343277A1-20141120-C00508
    1066
    Figure US20140343277A1-20141120-C00509
    1067
    Figure US20140343277A1-20141120-C00510
    1068
    Figure US20140343277A1-20141120-C00511
    1069
    Figure US20140343277A1-20141120-C00512
    1070
    Figure US20140343277A1-20141120-C00513
    1071
    Figure US20140343277A1-20141120-C00514
    1072
    Figure US20140343277A1-20141120-C00515
    1073
    Figure US20140343277A1-20141120-C00516
    1074
    Figure US20140343277A1-20141120-C00517
    1075
    Figure US20140343277A1-20141120-C00518
    1076
    Figure US20140343277A1-20141120-C00519
    1077
    Figure US20140343277A1-20141120-C00520
    1078
    Figure US20140343277A1-20141120-C00521
    1079
    Figure US20140343277A1-20141120-C00522
    1080
    Figure US20140343277A1-20141120-C00523
    1081
    Figure US20140343277A1-20141120-C00524
    1082
    Figure US20140343277A1-20141120-C00525
    1083
    Figure US20140343277A1-20141120-C00526
    1084
    Figure US20140343277A1-20141120-C00527
    1085
    Figure US20140343277A1-20141120-C00528
    1086
    Figure US20140343277A1-20141120-C00529
    Figure US20140343277A1-20141120-C00530
    Example No. R1 MS (M + 1)
    1087
    Figure US20140343277A1-20141120-C00531
    1088
    Figure US20140343277A1-20141120-C00532
    1089
    Figure US20140343277A1-20141120-C00533
    1090
    Figure US20140343277A1-20141120-C00534
    1091
    Figure US20140343277A1-20141120-C00535
    1092
    Figure US20140343277A1-20141120-C00536
    1093
    Figure US20140343277A1-20141120-C00537
    1094
    Figure US20140343277A1-20141120-C00538
    1095
    Figure US20140343277A1-20141120-C00539
    1096
    Figure US20140343277A1-20141120-C00540
    1097
    Figure US20140343277A1-20141120-C00541
    1098
    Figure US20140343277A1-20141120-C00542
    1099
    Figure US20140343277A1-20141120-C00543
    1100
    Figure US20140343277A1-20141120-C00544
    1101
    Figure US20140343277A1-20141120-C00545
    1102
    Figure US20140343277A1-20141120-C00546
    1103
    Figure US20140343277A1-20141120-C00547
    1104
    Figure US20140343277A1-20141120-C00548
    1105
    Figure US20140343277A1-20141120-C00549
    1106
    Figure US20140343277A1-20141120-C00550
    1107
    Figure US20140343277A1-20141120-C00551
    1108
    Figure US20140343277A1-20141120-C00552
    1109
    Figure US20140343277A1-20141120-C00553
    1110
    Figure US20140343277A1-20141120-C00554
    1111
    Figure US20140343277A1-20141120-C00555
    1112
    Figure US20140343277A1-20141120-C00556
    1113
    Figure US20140343277A1-20141120-C00557
    1114
    Figure US20140343277A1-20141120-C00558
    1115
    Figure US20140343277A1-20141120-C00559
    1116
    Figure US20140343277A1-20141120-C00560
    1117
    Figure US20140343277A1-20141120-C00561
    1118
    Figure US20140343277A1-20141120-C00562
    1119
    Figure US20140343277A1-20141120-C00563
    1120
    Figure US20140343277A1-20141120-C00564
    1121
    Figure US20140343277A1-20141120-C00565
    1122
    Figure US20140343277A1-20141120-C00566
    1123
    Figure US20140343277A1-20141120-C00567
    1124
    Figure US20140343277A1-20141120-C00568
    1125
    Figure US20140343277A1-20141120-C00569
    1126
    Figure US20140343277A1-20141120-C00570
    1127
    Figure US20140343277A1-20141120-C00571
    1128
    Figure US20140343277A1-20141120-C00572
    1129
    Figure US20140343277A1-20141120-C00573
    1130
    Figure US20140343277A1-20141120-C00574
    1131
    Figure US20140343277A1-20141120-C00575
    1132
    Figure US20140343277A1-20141120-C00576
    1133
    Figure US20140343277A1-20141120-C00577
    1134
    Figure US20140343277A1-20141120-C00578
    Figure US20140343277A1-20141120-C00579
    Example No. R1 MS (M + 1)
    1135
    Figure US20140343277A1-20141120-C00580
    1136
    Figure US20140343277A1-20141120-C00581
    1137
    Figure US20140343277A1-20141120-C00582
    1138
    Figure US20140343277A1-20141120-C00583
    1139
    Figure US20140343277A1-20141120-C00584
    1140
    Figure US20140343277A1-20141120-C00585
    1141
    Figure US20140343277A1-20141120-C00586
    1142
    Figure US20140343277A1-20141120-C00587
    1143
    Figure US20140343277A1-20141120-C00588
    1144
    Figure US20140343277A1-20141120-C00589
    1145
    Figure US20140343277A1-20141120-C00590
    1146
    Figure US20140343277A1-20141120-C00591
    1147
    Figure US20140343277A1-20141120-C00592
    1148
    Figure US20140343277A1-20141120-C00593
    1149
    Figure US20140343277A1-20141120-C00594
    1150
    Figure US20140343277A1-20141120-C00595
    1151
    Figure US20140343277A1-20141120-C00596
    1152
    Figure US20140343277A1-20141120-C00597
    1153
    Figure US20140343277A1-20141120-C00598
    1154
    Figure US20140343277A1-20141120-C00599
    1155
    Figure US20140343277A1-20141120-C00600
    1156
    Figure US20140343277A1-20141120-C00601
    1157
    Figure US20140343277A1-20141120-C00602
    1158
    Figure US20140343277A1-20141120-C00603
    1159
    Figure US20140343277A1-20141120-C00604
    1160
    Figure US20140343277A1-20141120-C00605
    1161
    Figure US20140343277A1-20141120-C00606
    1162
    Figure US20140343277A1-20141120-C00607
    1163
    Figure US20140343277A1-20141120-C00608
    1164
    Figure US20140343277A1-20141120-C00609
    1165
    Figure US20140343277A1-20141120-C00610
    1166
    Figure US20140343277A1-20141120-C00611
    1167
    Figure US20140343277A1-20141120-C00612
    1168
    Figure US20140343277A1-20141120-C00613
    1169
    Figure US20140343277A1-20141120-C00614
    1170
    Figure US20140343277A1-20141120-C00615
    1171
    Figure US20140343277A1-20141120-C00616
    1172
    Figure US20140343277A1-20141120-C00617
    1173
    Figure US20140343277A1-20141120-C00618
    1174
    Figure US20140343277A1-20141120-C00619
    1175
    Figure US20140343277A1-20141120-C00620
    1176
    Figure US20140343277A1-20141120-C00621
    1177
    Figure US20140343277A1-20141120-C00622
    1178
    Figure US20140343277A1-20141120-C00623
    1179
    Figure US20140343277A1-20141120-C00624
    1180
    Figure US20140343277A1-20141120-C00625
    1181
    Figure US20140343277A1-20141120-C00626
    1182
    Figure US20140343277A1-20141120-C00627
    Figure US20140343277A1-20141120-C00628
    Example No. R1 MS (M + 1)
    1183
    Figure US20140343277A1-20141120-C00629
    1184
    Figure US20140343277A1-20141120-C00630
    1185
    Figure US20140343277A1-20141120-C00631
    1186
    Figure US20140343277A1-20141120-C00632
    1187
    Figure US20140343277A1-20141120-C00633
    1188
    Figure US20140343277A1-20141120-C00634
    1189
    Figure US20140343277A1-20141120-C00635
    1190
    Figure US20140343277A1-20141120-C00636
    1191
    Figure US20140343277A1-20141120-C00637
    1192
    Figure US20140343277A1-20141120-C00638
    1193
    Figure US20140343277A1-20141120-C00639
    1194
    Figure US20140343277A1-20141120-C00640
    1195
    Figure US20140343277A1-20141120-C00641
    1196
    Figure US20140343277A1-20141120-C00642
    1197
    Figure US20140343277A1-20141120-C00643
    1198
    Figure US20140343277A1-20141120-C00644
    1199
    Figure US20140343277A1-20141120-C00645
    1200
    Figure US20140343277A1-20141120-C00646
    1201
    Figure US20140343277A1-20141120-C00647
    1202
    Figure US20140343277A1-20141120-C00648
    1203
    Figure US20140343277A1-20141120-C00649
    1204
    Figure US20140343277A1-20141120-C00650
    1205
    Figure US20140343277A1-20141120-C00651
    1206
    Figure US20140343277A1-20141120-C00652
    1207
    Figure US20140343277A1-20141120-C00653
    1208
    Figure US20140343277A1-20141120-C00654
    1209
    Figure US20140343277A1-20141120-C00655
    1210
    Figure US20140343277A1-20141120-C00656
    1211
    Figure US20140343277A1-20141120-C00657
    1212
    Figure US20140343277A1-20141120-C00658
    1213
    Figure US20140343277A1-20141120-C00659
    1214
    Figure US20140343277A1-20141120-C00660
    1215
    Figure US20140343277A1-20141120-C00661
    1216
    Figure US20140343277A1-20141120-C00662
    1217
    Figure US20140343277A1-20141120-C00663
    1218
    Figure US20140343277A1-20141120-C00664
    1219
    Figure US20140343277A1-20141120-C00665
    1220
    Figure US20140343277A1-20141120-C00666
    1221
    Figure US20140343277A1-20141120-C00667
    1222
    Figure US20140343277A1-20141120-C00668
    1223
    Figure US20140343277A1-20141120-C00669
    1224
    Figure US20140343277A1-20141120-C00670
    1225
    Figure US20140343277A1-20141120-C00671
    1226
    Figure US20140343277A1-20141120-C00672
    1227
    Figure US20140343277A1-20141120-C00673
    1228
    Figure US20140343277A1-20141120-C00674
    1229
    Figure US20140343277A1-20141120-C00675
    1230
    Figure US20140343277A1-20141120-C00676
    Figure US20140343277A1-20141120-C00677
    Example No. R1 MS (M + 1)
    1231
    Figure US20140343277A1-20141120-C00678
    1232
    Figure US20140343277A1-20141120-C00679
    1233
    Figure US20140343277A1-20141120-C00680
    1234
    Figure US20140343277A1-20141120-C00681
    1235
    Figure US20140343277A1-20141120-C00682
    1236
    Figure US20140343277A1-20141120-C00683
    1237
    Figure US20140343277A1-20141120-C00684
    1238
    Figure US20140343277A1-20141120-C00685
    1239
    Figure US20140343277A1-20141120-C00686
    1240
    Figure US20140343277A1-20141120-C00687
    1241
    Figure US20140343277A1-20141120-C00688
    1242
    Figure US20140343277A1-20141120-C00689
    1243
    Figure US20140343277A1-20141120-C00690
    1244
    Figure US20140343277A1-20141120-C00691
    1245
    Figure US20140343277A1-20141120-C00692
    1246
    Figure US20140343277A1-20141120-C00693
    1247
    Figure US20140343277A1-20141120-C00694
    1248
    Figure US20140343277A1-20141120-C00695
    1249
    Figure US20140343277A1-20141120-C00696
    1250
    Figure US20140343277A1-20141120-C00697
    1251
    Figure US20140343277A1-20141120-C00698
    1252
    Figure US20140343277A1-20141120-C00699
    1253
    Figure US20140343277A1-20141120-C00700
    1254
    Figure US20140343277A1-20141120-C00701
    1255
    Figure US20140343277A1-20141120-C00702
    1256
    Figure US20140343277A1-20141120-C00703
    1257
    Figure US20140343277A1-20141120-C00704
    1258
    Figure US20140343277A1-20141120-C00705
    1259
    Figure US20140343277A1-20141120-C00706
    1260
    Figure US20140343277A1-20141120-C00707
    1261
    Figure US20140343277A1-20141120-C00708
    1262
    Figure US20140343277A1-20141120-C00709
    1263
    Figure US20140343277A1-20141120-C00710
    1264
    Figure US20140343277A1-20141120-C00711
    1265
    Figure US20140343277A1-20141120-C00712
    1266
    Figure US20140343277A1-20141120-C00713
    1267
    Figure US20140343277A1-20141120-C00714
    1268
    Figure US20140343277A1-20141120-C00715
    1269
    Figure US20140343277A1-20141120-C00716
    1270
    Figure US20140343277A1-20141120-C00717
    1271
    Figure US20140343277A1-20141120-C00718
    1272
    Figure US20140343277A1-20141120-C00719
    1273
    Figure US20140343277A1-20141120-C00720
    1274
    Figure US20140343277A1-20141120-C00721
    1275
    Figure US20140343277A1-20141120-C00722
    1276
    Figure US20140343277A1-20141120-C00723
    1277
    Figure US20140343277A1-20141120-C00724
    1278
    Figure US20140343277A1-20141120-C00725
    Figure US20140343277A1-20141120-C00726
    Example No. R1 MS (M + 1)
    1279
    Figure US20140343277A1-20141120-C00727
    1280
    Figure US20140343277A1-20141120-C00728
    1281
    Figure US20140343277A1-20141120-C00729
    1282
    Figure US20140343277A1-20141120-C00730
    1283
    Figure US20140343277A1-20141120-C00731
    1284
    Figure US20140343277A1-20141120-C00732
    1285
    Figure US20140343277A1-20141120-C00733
    1286
    Figure US20140343277A1-20141120-C00734
    1287
    Figure US20140343277A1-20141120-C00735
    1288
    Figure US20140343277A1-20141120-C00736
    1289
    Figure US20140343277A1-20141120-C00737
    1290
    Figure US20140343277A1-20141120-C00738
    1291
    Figure US20140343277A1-20141120-C00739
    1292
    Figure US20140343277A1-20141120-C00740
    1293
    Figure US20140343277A1-20141120-C00741
    1294
    Figure US20140343277A1-20141120-C00742
    1295
    Figure US20140343277A1-20141120-C00743
    1296
    Figure US20140343277A1-20141120-C00744
    1297
    Figure US20140343277A1-20141120-C00745
    1298
    Figure US20140343277A1-20141120-C00746
    1299
    Figure US20140343277A1-20141120-C00747
    1300
    Figure US20140343277A1-20141120-C00748
    1301
    Figure US20140343277A1-20141120-C00749
    1302
    Figure US20140343277A1-20141120-C00750
    1303
    Figure US20140343277A1-20141120-C00751
    1304
    Figure US20140343277A1-20141120-C00752
    1305
    Figure US20140343277A1-20141120-C00753
    1306
    Figure US20140343277A1-20141120-C00754
    1307
    Figure US20140343277A1-20141120-C00755
    1308
    Figure US20140343277A1-20141120-C00756
    1309
    Figure US20140343277A1-20141120-C00757
    1310
    Figure US20140343277A1-20141120-C00758
    1311
    Figure US20140343277A1-20141120-C00759
    1312
    Figure US20140343277A1-20141120-C00760
    1313
    Figure US20140343277A1-20141120-C00761
    1314
    Figure US20140343277A1-20141120-C00762
    1315
    Figure US20140343277A1-20141120-C00763
    1316
    Figure US20140343277A1-20141120-C00764
    1317
    Figure US20140343277A1-20141120-C00765
    1318
    Figure US20140343277A1-20141120-C00766
    1319
    Figure US20140343277A1-20141120-C00767
    1320
    Figure US20140343277A1-20141120-C00768
    1321
    Figure US20140343277A1-20141120-C00769
    1322
    Figure US20140343277A1-20141120-C00770
    1323
    Figure US20140343277A1-20141120-C00771
    1324
    Figure US20140343277A1-20141120-C00772
    1325
    Figure US20140343277A1-20141120-C00773
    1326
    Figure US20140343277A1-20141120-C00774
    Figure US20140343277A1-20141120-C00775
    Example No. R1 MS (M + 1)
    1327
    Figure US20140343277A1-20141120-C00776
    1328
    Figure US20140343277A1-20141120-C00777
    1329
    Figure US20140343277A1-20141120-C00778
    1330
    Figure US20140343277A1-20141120-C00779
    1331
    Figure US20140343277A1-20141120-C00780
    1332
    Figure US20140343277A1-20141120-C00781
    1333
    Figure US20140343277A1-20141120-C00782
    1334
    Figure US20140343277A1-20141120-C00783
    1335
    Figure US20140343277A1-20141120-C00784
    1336
    Figure US20140343277A1-20141120-C00785
    1337
    Figure US20140343277A1-20141120-C00786
    1338
    Figure US20140343277A1-20141120-C00787
    1339
    Figure US20140343277A1-20141120-C00788
    1340
    Figure US20140343277A1-20141120-C00789
    1341
    Figure US20140343277A1-20141120-C00790
    1342
    Figure US20140343277A1-20141120-C00791
    1343
    Figure US20140343277A1-20141120-C00792
    1344
    Figure US20140343277A1-20141120-C00793
    1345
    Figure US20140343277A1-20141120-C00794
    1346
    Figure US20140343277A1-20141120-C00795
    1347
    Figure US20140343277A1-20141120-C00796
    1348
    Figure US20140343277A1-20141120-C00797
    1349
    Figure US20140343277A1-20141120-C00798
    1350
    Figure US20140343277A1-20141120-C00799
    1351
    Figure US20140343277A1-20141120-C00800
    1352
    Figure US20140343277A1-20141120-C00801
    1353
    Figure US20140343277A1-20141120-C00802
    1354
    Figure US20140343277A1-20141120-C00803
    1355
    Figure US20140343277A1-20141120-C00804
    1356
    Figure US20140343277A1-20141120-C00805
    1357
    Figure US20140343277A1-20141120-C00806
    1358
    Figure US20140343277A1-20141120-C00807
    1359
    Figure US20140343277A1-20141120-C00808
    1360
    Figure US20140343277A1-20141120-C00809
    1361
    Figure US20140343277A1-20141120-C00810
    1362
    Figure US20140343277A1-20141120-C00811
    1363
    Figure US20140343277A1-20141120-C00812
    1364
    Figure US20140343277A1-20141120-C00813
    1365
    Figure US20140343277A1-20141120-C00814
    1366
    Figure US20140343277A1-20141120-C00815
    1367
    Figure US20140343277A1-20141120-C00816
    1368
    Figure US20140343277A1-20141120-C00817
    1369
    Figure US20140343277A1-20141120-C00818
    1370
    Figure US20140343277A1-20141120-C00819
    1371
    Figure US20140343277A1-20141120-C00820
    1372
    Figure US20140343277A1-20141120-C00821
    1373
    Figure US20140343277A1-20141120-C00822
    1374
    Figure US20140343277A1-20141120-C00823
    Figure US20140343277A1-20141120-C00824
    Example No. R1 MS (M + 1)
    1375
    Figure US20140343277A1-20141120-C00825
    1376
    Figure US20140343277A1-20141120-C00826
    1377
    Figure US20140343277A1-20141120-C00827
    1378
    Figure US20140343277A1-20141120-C00828
    1379
    Figure US20140343277A1-20141120-C00829
    1380
    Figure US20140343277A1-20141120-C00830
    1381
    Figure US20140343277A1-20141120-C00831
    1382
    Figure US20140343277A1-20141120-C00832
    1383
    Figure US20140343277A1-20141120-C00833
    1384
    Figure US20140343277A1-20141120-C00834
    1385
    Figure US20140343277A1-20141120-C00835
    1386
    Figure US20140343277A1-20141120-C00836
    1387
    Figure US20140343277A1-20141120-C00837
    1388
    Figure US20140343277A1-20141120-C00838
    1389
    Figure US20140343277A1-20141120-C00839
    1390
    Figure US20140343277A1-20141120-C00840
    1391
    Figure US20140343277A1-20141120-C00841
    1392
    Figure US20140343277A1-20141120-C00842
    1393
    Figure US20140343277A1-20141120-C00843
    1394
    Figure US20140343277A1-20141120-C00844
    1395
    Figure US20140343277A1-20141120-C00845
    1396
    Figure US20140343277A1-20141120-C00846
    1397
    Figure US20140343277A1-20141120-C00847
    1398
    Figure US20140343277A1-20141120-C00848
    1399
    Figure US20140343277A1-20141120-C00849
    1400
    Figure US20140343277A1-20141120-C00850
    1401
    Figure US20140343277A1-20141120-C00851
    1402
    Figure US20140343277A1-20141120-C00852
    1403
    Figure US20140343277A1-20141120-C00853
    1404
    Figure US20140343277A1-20141120-C00854
    1405
    Figure US20140343277A1-20141120-C00855
    1406
    Figure US20140343277A1-20141120-C00856
    1407
    Figure US20140343277A1-20141120-C00857
    1408
    Figure US20140343277A1-20141120-C00858
    1409
    Figure US20140343277A1-20141120-C00859
    1410
    Figure US20140343277A1-20141120-C00860
    1411
    Figure US20140343277A1-20141120-C00861
    1412
    Figure US20140343277A1-20141120-C00862
    1413
    Figure US20140343277A1-20141120-C00863
    1414
    Figure US20140343277A1-20141120-C00864
    1415
    Figure US20140343277A1-20141120-C00865
    1416
    Figure US20140343277A1-20141120-C00866
    1417
    Figure US20140343277A1-20141120-C00867
    1418
    Figure US20140343277A1-20141120-C00868
    1419
    Figure US20140343277A1-20141120-C00869
    1420
    Figure US20140343277A1-20141120-C00870
    1421
    Figure US20140343277A1-20141120-C00871
    1422
    Figure US20140343277A1-20141120-C00872
    Figure US20140343277A1-20141120-C00873
    Example No. R1 MS (M + 1)
    1423
    Figure US20140343277A1-20141120-C00874
    1424
    Figure US20140343277A1-20141120-C00875
    1425
    Figure US20140343277A1-20141120-C00876
    1426
    Figure US20140343277A1-20141120-C00877
    1427
    Figure US20140343277A1-20141120-C00878
    1428
    Figure US20140343277A1-20141120-C00879
    1429
    Figure US20140343277A1-20141120-C00880
    1430
    Figure US20140343277A1-20141120-C00881
    1431
    Figure US20140343277A1-20141120-C00882
    1432
    Figure US20140343277A1-20141120-C00883
    1433
    Figure US20140343277A1-20141120-C00884
    1434
    Figure US20140343277A1-20141120-C00885
    1435
    Figure US20140343277A1-20141120-C00886
    1436
    Figure US20140343277A1-20141120-C00887
    1437
    Figure US20140343277A1-20141120-C00888
    1438
    Figure US20140343277A1-20141120-C00889
    1439
    Figure US20140343277A1-20141120-C00890
    1440
    Figure US20140343277A1-20141120-C00891
    1441
    Figure US20140343277A1-20141120-C00892
    1442
    Figure US20140343277A1-20141120-C00893
    1443
    Figure US20140343277A1-20141120-C00894
    1444
    Figure US20140343277A1-20141120-C00895
    1445
    Figure US20140343277A1-20141120-C00896
    1446
    Figure US20140343277A1-20141120-C00897
    1447
    Figure US20140343277A1-20141120-C00898
    1448
    Figure US20140343277A1-20141120-C00899
    1449
    Figure US20140343277A1-20141120-C00900
    1450
    Figure US20140343277A1-20141120-C00901
    1451
    Figure US20140343277A1-20141120-C00902
    1452
    Figure US20140343277A1-20141120-C00903
    1453
    Figure US20140343277A1-20141120-C00904
    1454
    Figure US20140343277A1-20141120-C00905
    1455
    Figure US20140343277A1-20141120-C00906
    1456
    Figure US20140343277A1-20141120-C00907
    1457
    Figure US20140343277A1-20141120-C00908
    1458
    Figure US20140343277A1-20141120-C00909
    1459
    Figure US20140343277A1-20141120-C00910
    1460
    Figure US20140343277A1-20141120-C00911
    1461
    Figure US20140343277A1-20141120-C00912
    1462
    Figure US20140343277A1-20141120-C00913
    1463
    Figure US20140343277A1-20141120-C00914
    1464
    Figure US20140343277A1-20141120-C00915
    1465
    Figure US20140343277A1-20141120-C00916
    1466
    Figure US20140343277A1-20141120-C00917
    1467
    Figure US20140343277A1-20141120-C00918
    1468
    Figure US20140343277A1-20141120-C00919
    1469
    Figure US20140343277A1-20141120-C00920
    1470
    Figure US20140343277A1-20141120-C00921
    Figure US20140343277A1-20141120-C00922
    Example No. R1 MS (M + 1)
    1471
    Figure US20140343277A1-20141120-C00923
    1472
    Figure US20140343277A1-20141120-C00924
    1473
    Figure US20140343277A1-20141120-C00925
    1474
    Figure US20140343277A1-20141120-C00926
    1475
    Figure US20140343277A1-20141120-C00927
    1476
    Figure US20140343277A1-20141120-C00928
    1477
    Figure US20140343277A1-20141120-C00929
    1478
    Figure US20140343277A1-20141120-C00930
    1479
    Figure US20140343277A1-20141120-C00931
    1480
    Figure US20140343277A1-20141120-C00932
    1481
    Figure US20140343277A1-20141120-C00933
    1482
    Figure US20140343277A1-20141120-C00934
    1483
    Figure US20140343277A1-20141120-C00935
    1484
    Figure US20140343277A1-20141120-C00936
    1485
    Figure US20140343277A1-20141120-C00937
    1486
    Figure US20140343277A1-20141120-C00938
    1487
    Figure US20140343277A1-20141120-C00939
    1488
    Figure US20140343277A1-20141120-C00940
    1489
    Figure US20140343277A1-20141120-C00941
    1490
    Figure US20140343277A1-20141120-C00942
    1491
    Figure US20140343277A1-20141120-C00943
    1492
    Figure US20140343277A1-20141120-C00944
    1493
    Figure US20140343277A1-20141120-C00945
    1494
    Figure US20140343277A1-20141120-C00946
    1495
    Figure US20140343277A1-20141120-C00947
    1496
    Figure US20140343277A1-20141120-C00948
    1497
    Figure US20140343277A1-20141120-C00949
    1498
    Figure US20140343277A1-20141120-C00950
    1499
    Figure US20140343277A1-20141120-C00951
    1500
    Figure US20140343277A1-20141120-C00952
    1501
    Figure US20140343277A1-20141120-C00953
    1502
    Figure US20140343277A1-20141120-C00954
    1503
    Figure US20140343277A1-20141120-C00955
    1504
    Figure US20140343277A1-20141120-C00956
    1505
    Figure US20140343277A1-20141120-C00957
    1506
    Figure US20140343277A1-20141120-C00958
    1507
    Figure US20140343277A1-20141120-C00959
    1508
    Figure US20140343277A1-20141120-C00960
    1509
    Figure US20140343277A1-20141120-C00961
    1510
    Figure US20140343277A1-20141120-C00962
    1511
    Figure US20140343277A1-20141120-C00963
    1512
    Figure US20140343277A1-20141120-C00964
    1513
    Figure US20140343277A1-20141120-C00965
    1514
    Figure US20140343277A1-20141120-C00966
    1515
    Figure US20140343277A1-20141120-C00967
    1516
    Figure US20140343277A1-20141120-C00968
    1517
    Figure US20140343277A1-20141120-C00969
    1518
    Figure US20140343277A1-20141120-C00970
    Figure US20140343277A1-20141120-C00971
    Example No. R1 MS (M + 1)
    1519
    Figure US20140343277A1-20141120-C00972
    1520
    Figure US20140343277A1-20141120-C00973
    1521
    Figure US20140343277A1-20141120-C00974
    1522
    Figure US20140343277A1-20141120-C00975
    1523
    Figure US20140343277A1-20141120-C00976
    1524
    Figure US20140343277A1-20141120-C00977
    1525
    Figure US20140343277A1-20141120-C00978
    1526
    Figure US20140343277A1-20141120-C00979
    1527
    Figure US20140343277A1-20141120-C00980
    1528
    Figure US20140343277A1-20141120-C00981
    1529
    Figure US20140343277A1-20141120-C00982
    1530
    Figure US20140343277A1-20141120-C00983
    1531
    Figure US20140343277A1-20141120-C00984
    1532
    Figure US20140343277A1-20141120-C00985
    1533
    Figure US20140343277A1-20141120-C00986
    1534
    Figure US20140343277A1-20141120-C00987
    1535
    Figure US20140343277A1-20141120-C00988
    1536
    Figure US20140343277A1-20141120-C00989
    1537
    Figure US20140343277A1-20141120-C00990
    1538
    Figure US20140343277A1-20141120-C00991
    1539
    Figure US20140343277A1-20141120-C00992
    1540
    Figure US20140343277A1-20141120-C00993
    1541
    Figure US20140343277A1-20141120-C00994
    1542
    Figure US20140343277A1-20141120-C00995
    1543
    Figure US20140343277A1-20141120-C00996
    1544
    Figure US20140343277A1-20141120-C00997
    1545
    Figure US20140343277A1-20141120-C00998
    1546
    Figure US20140343277A1-20141120-C00999
    1547
    Figure US20140343277A1-20141120-C01000
    1548
    Figure US20140343277A1-20141120-C01001
    1549
    Figure US20140343277A1-20141120-C01002
    1550
    Figure US20140343277A1-20141120-C01003
    1551
    Figure US20140343277A1-20141120-C01004
    1552
    Figure US20140343277A1-20141120-C01005
    1553
    Figure US20140343277A1-20141120-C01006
    1554
    Figure US20140343277A1-20141120-C01007
    1555
    Figure US20140343277A1-20141120-C01008
    1556
    Figure US20140343277A1-20141120-C01009
    1557
    Figure US20140343277A1-20141120-C01010
    1558
    Figure US20140343277A1-20141120-C01011
    1559
    Figure US20140343277A1-20141120-C01012
    1560
    Figure US20140343277A1-20141120-C01013
    1561
    Figure US20140343277A1-20141120-C01014
    1562
    Figure US20140343277A1-20141120-C01015
    1563
    Figure US20140343277A1-20141120-C01016
    1564
    Figure US20140343277A1-20141120-C01017
    1565
    Figure US20140343277A1-20141120-C01018
    1566
    Figure US20140343277A1-20141120-C01019
    Figure US20140343277A1-20141120-C01020
    Example No. R1 MS (M + 1)
    1567
    Figure US20140343277A1-20141120-C01021
    1568
    Figure US20140343277A1-20141120-C01022
    1569
    Figure US20140343277A1-20141120-C01023
    1570
    Figure US20140343277A1-20141120-C01024
    1571
    Figure US20140343277A1-20141120-C01025
    1572
    Figure US20140343277A1-20141120-C01026
    1573
    Figure US20140343277A1-20141120-C01027
    1574
    Figure US20140343277A1-20141120-C01028
    1575
    Figure US20140343277A1-20141120-C01029
    1576
    Figure US20140343277A1-20141120-C01030
    1577
    Figure US20140343277A1-20141120-C01031
    1578
    Figure US20140343277A1-20141120-C01032
    1579
    Figure US20140343277A1-20141120-C01033
    1580
    Figure US20140343277A1-20141120-C01034
    1581
    Figure US20140343277A1-20141120-C01035
    1582
    Figure US20140343277A1-20141120-C01036
    1583
    Figure US20140343277A1-20141120-C01037
    1584
    Figure US20140343277A1-20141120-C01038
    1585
    Figure US20140343277A1-20141120-C01039
    1586
    Figure US20140343277A1-20141120-C01040
    1587
    Figure US20140343277A1-20141120-C01041
    1588
    Figure US20140343277A1-20141120-C01042
    1589
    Figure US20140343277A1-20141120-C01043
    1590
    Figure US20140343277A1-20141120-C01044
    1591
    Figure US20140343277A1-20141120-C01045
    1592
    Figure US20140343277A1-20141120-C01046
    1593
    Figure US20140343277A1-20141120-C01047
    1594
    Figure US20140343277A1-20141120-C01048
    1595
    Figure US20140343277A1-20141120-C01049
    1596
    Figure US20140343277A1-20141120-C01050
    1597
    Figure US20140343277A1-20141120-C01051
    1598
    Figure US20140343277A1-20141120-C01052
    1599
    Figure US20140343277A1-20141120-C01053
    1600
    Figure US20140343277A1-20141120-C01054
    1601
    Figure US20140343277A1-20141120-C01055
    1602
    Figure US20140343277A1-20141120-C01056
    1603
    Figure US20140343277A1-20141120-C01057
    1604
    Figure US20140343277A1-20141120-C01058
    1065
    Figure US20140343277A1-20141120-C01059
    1606
    Figure US20140343277A1-20141120-C01060
    1607
    Figure US20140343277A1-20141120-C01061
    1608
    Figure US20140343277A1-20141120-C01062
    1609
    Figure US20140343277A1-20141120-C01063
    1610
    Figure US20140343277A1-20141120-C01064
    1611
    Figure US20140343277A1-20141120-C01065
    1612
    Figure US20140343277A1-20141120-C01066
    1613
    Figure US20140343277A1-20141120-C01067
    1614
    Figure US20140343277A1-20141120-C01068
    • Examples 1615 to 1625
  • The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.
  • Figure US20140343277A1-20141120-C01069
    Example No. R1 MS (M + 1)
    1615
    Figure US20140343277A1-20141120-C01070
         		450
    1616
    Figure US20140343277A1-20141120-C01071
         		450
    1617
    Figure US20140343277A1-20141120-C01072
         		465
    1618
    Figure US20140343277A1-20141120-C01073
         		438
    1619
    Figure US20140343277A1-20141120-C01074
         		432
    1620
    Figure US20140343277A1-20141120-C01075
         		445
    1621
    Figure US20140343277A1-20141120-C01076
         		432
    1622
    Figure US20140343277A1-20141120-C01077
         		460
    1623
    Figure US20140343277A1-20141120-C01078
         		463
    1624
    Figure US20140343277A1-20141120-C01079
         		459
    1625
    Figure US20140343277A1-20141120-C01080
         		432
    • Pharmacological Test 1 (1) Production of Human Kv1.5-Expressing CHO-K1 Cell Lines
  • CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.
  • Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).
  • The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.
    • (2) Production of CHO Cell Line Expressing Human GIRK1/4
  • CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.
  • Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).
  • TABLE 1
    Primer Sequence
    hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID
    GAAATTTG-3′ No. 1
    hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID
    AGTTC-3′ No. 2
    hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID
    ATTATGTCTGCACTCC-3′ No. 3
    hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID
    GA-3′ No. 4
    hGIRK1-A4  5′-CCGAGTGTAGGCGATCA SEQ ID
    CCC-3′ No. 5
    hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID
    GAATGCC-3′ No. 6
    hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID
    CCTCCC-3′ No. 7
    hGIRK4-S2  5′-AACCAGGACATGGAGAT SEQ ID
    TGG-3′ No. 8
    hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID
    CAC-3′ No. 9
  • The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM—002239) and GIRK4 (NM—000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.
    • (3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.
  • Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 40 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.
  • Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 4 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (5) Measurement of Human Kv1.5 Current
  • While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.
  • The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (6) Measurement of Human GIRK1/4 Current
  • While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.
  • The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current
  • The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC50 value) was calculated according to the following nonlinear regression equation:

  • Relative current=1/(1+[Concentration of the compound]/IC50)nH
  • wherein nH is the Hill coefficient.
  • Table 2 shows the test results.
  • TABLE 2
    Test Compound KV1.5 IC50 (μM)
    Compound of Example 10 0.62
    Compound of Example 15 0.81
    Compound of Example 16 0.51
    Compound of Example 18 0.60
    Compound of Example 35 0.94
    Compound of Example 41 6.30
    Compound of Example 42 1.70
    Compound of Example 43 0.32
    Compound of Example 48 0.30
    Compound of Example 104 1.4
    Compound of Example 317 0.63
    Compound of Example 318 2.9
    Compound of Example 330 0.86
    • 2. Second Invention Reference Example 1 Synthesis of 6-hydroxy-2H-isoquinolin-1-one
  • A 1.0 M boron tribromide/dichloromethane solution (8.5 ml) was added at 0° C. to a dichloromethane solution (50 ml) of 6-methoxy-2H-isoquinolin-1-one (1.0 g). The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction was carried out with a dichloromethane/methanol mixed solvent (dichloromethane:methanol=10:1). The organic layer was dried with anhydrous sodium sulfate, followed by condensation to dryness under reduced pressure, thereby obtaining the title compound (0.4 g) as a pale yellow solid.
  • 1H NMR (DMSO-d6), δppm: 6.37 (1H, d, J=7.1 Hz), 6.86-6.94 (2H, m), 7.03-7.08 (1H, m), 8.02 (1H, d, J=8.7 Hz), 10.22 (1H, br), 10.90 (1H, s).
    • Reference Example 2 Synthesis of 6-hydroxy-1,3-dimethyl-3,4-dihydro-1H-quinazolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 2.87 (3H, s), 3.13 (3H, s), 4.26 (2H, s), 6.57 (1H, d, J=2.7 Hz), 6.65 (1H, dd, J=2.7, 8.7 Hz), 6.73 (1H, d, J=8.7 Hz), 9.13 (1H, s).
    • Reference Example 3 Synthesis of 6-hydroxy-1,3-dimethyl-1H-quinazoline-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 3.29 (3H, s), 3.48 (3H, s), 7.20 (1H, dd, J=2.8, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 7.40 (1H, d, J=2.8 Hz), 9.76 (1H, s).
    • Reference Example 4 Synthesis of 6-hydroxy-2-methyl-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 3.44 (3H, s), 6.43 (1H, d, J=7.4 Hz), 6.86 (1H, d, J=2.2 Hz), 6.93 (1H, dd, J=8.7, 2.2 Hz), 7.35 (1H, d, J=7.4 Hz), 8.04 (1H, d, J=8.7 Hz).
    • Reference Example 5 Synthesis of 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (CDCl3), δppm: 2.95 (2H, t, J=6.7 Hz), 3.13 (3H, s), 3.57 (2H, t, J=6.7 Hz), 6.62 (1H, d, J=2.4 Hz), 6.76 (1H, dd, J=8.6, 2.4 Hz), 7.83 (1H, d, J=8.6 Hz).
    • Reference Example 6 Synthesis of 2-methyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-5-ol
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (CDCl3), δppm: 2.92 (3H, s), 4.24 (2H, s), 6.75 (1H, s), 6.92 (1H, d, J=8.5 Hz), 7.60 (1H, d, J=8.5 Hz).
    • Reference Example 7 Synthesis of 3-hydroxy-7,8-dihydro-6H-5-thia-8-azabenzocyclohepten-9-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (CD3OD), δppm: 3.15 (2H, t, J=6.0 Hz), 3.21-3.40 (2H, m), 6.84 (1H, dd, J=8.4, 2.4 Hz), 6.96 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=8.4 Hz).
    • Reference Example 8 Synthesis of 3-hydroxy-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (DMSO-d6), δppm: 3.70 (3H, s), 7.12 (1H, s), 7.17-7.28 (1H, m), 7.35-7.50 (2H, m), 7.56 (1H, d-d, J=1.3, 7.5 Hz), 9.46 (1H, br-s).
    • Reference Example 9 Synthesis of 7-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one
  • 7-(3-Chloropropoxy)-1-methyl-1H-quinolin-2-one (2.5 g) and sodium iodide (3.0 g) were added to 30 ml of acetonitrile. The mixture was stirred for 18 hours while heated under reflux. After cooled to room temperature, water was added to the reaction mixture, followed by extration using dichloromethane. The organic layer was dried with sodium sulfate and was condensed under reduced pressure to give the title compound (2.4 g) as a pale brown powder.
  • 1H-NMR (CDCl3), δppm: 2.29-2.37 (2H, m), 3.41 (2H, t, J=6.6 Hz), 3.69 (3H, s), 4.17 (2H, t, J=5.8 Hz), 6.56 (1H, d, J=9.4 Hz), 6.81-6.84 (2H, m), 7.45-7.58 (1H, m), 7.60 (1H, d, J=9.4 Hz).
    • Reference Example 10 Synthesis of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one
  • Sodium hydride (60% in oil, 440 mg) was suspended in DMF (20 ml), and was cooled to 0° C. in ice water bath.
  • 6-(5-Bromopentyloxy)-1H-quinolin-2-one (3.1 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Methyl iodide (1.9 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (2.68 g) as a yellow powder.
  • 1H-NMR (CDCl3), δppm: 1.53-1.70 (2H, m), 1.81-1.97 (4H, m), 3.45 (2H, t, J=6.7 Hz), 3.71 (3H, s), 4.00-4.04 (2H, m), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=3.0 Hz), 7.16-7.20 (1H, m), 7.27-7.31 (1H, m), 7.59 (1H, d, J=9.5 Hz).
    • Reference Example 11 Synthesis of 6-(8-bromooctyloxy)-2-methoxyquinoline
  • Sodium hydride (60% in oil, 40 mg) was suspended in DMF (2 ml), and was cooled to 0° C. in ice water bath.
  • 6-Hydroxy-2-methoxyquinoline (171 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. 1,8-Dibromooctane (0.37 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (225 mg) as a white powder.
  • 1H-NMR (CDCl3), δppm: 1.37-1.51 (8H, m), 1.81-1.89 (4H, m), 3.41 (2H, t, J=6.8 Hz), 4.04 (3H, s), 4.04 (2H, t, J=6.5 Hz), 6.87 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=2.8 Hz), 7.27 (1H, dd, J=9.1, 2.8 Hz), 7.75 (1H, d, J=9.1 Hz), 7.87 (1H, d J=8.8 Hz).
    • Reference Example 12 Synthesis of 6-(5-bromopentyloxy)-2-methoxyquinoline
  • The synthesis of the title compound was performed in the same manner as in Reference Example 11 using appropriate starting materials.
  • 1H-NMR (CDCl3), δppm: 1.61-1.66 (2H, m), 1.821-1.96 (4H, m), 3.45 (2H, t, J=6.7 Hz), 3.47 (3H, s), 4.00-4.04 (2H, m), 6.70 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Reference Example 13 Synthesis of 5-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.
  • 1H-NMR (CDCl3), δppm: 2.30-2.44 (2H, m), 3.42 (2H, t, J=6.7 Hz), 3.71 (3H, s), 4.19 (2H, t, J=5.8 Hz), 6.66 (1H, d, J=9.7 Hz), 6.70 (1H, d, J=8.1 Hz), 6.97 (1H, d, J=8.6 Hz), 7.48 (1H, dd, J=8.6, 8.1 Hz), 8.11 (1H, d, J=9.7 Hz).
    • Reference Example 14 Synthesis of 8-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.
  • 1H-NMR (CDCl3), δppm: 2.32-2.40 (2H, m), 3.39 (2H, t, J=6.6 Hz), 3.96 (3H, s), 4.15 (2H, t, J=5.9 Hz), 6.70 (1H, d, J=9.4 Hz), 7.08-7.17 (3H, m), 7.60 (1H, d, J=9.4 Hz).
    • Reference Example 15 Synthesis of (2-pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine
  • 4-Pyridine carbaldehyde (5.36 g) and 3-(2-aminoethyl)pyridine (6.5 ml) were added to 100 ml of methanol. The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (2.8 g) was added thereto. The mixture was further stirred at 0° C. for an hour. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5→85:5). The purified product was condensed under reduced pressure to give the title compound (10.03 g) as a colorless oily matter.
  • 1H-NMR (CDCl3), δppm: 2.79-2.98 (4H, m), 3.82 (2H, s), 7.21 (2H, d, J=5.8 Hz), 7.20-7.27 (1H, m), 7.50-7.56 (1H, m), 8.48 (1H, dd, J=6.7, 1.6 Hz), 8.49 (1H, s), 8.51-8.57 (2H, m).
    • Reference Example 16 Synthesis of (2-pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine
  • Sodium iodide (1.5 g) was added to a DMF solution (20 ml) of 2-(3-bromopropoxy)tetrahydropyran (0.85 ml). The mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature. (2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (1.28 g), and N-ethyldiisopropylamine (1.3 ml) were added thereto. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (236 mg) as a colorless oily matter.
  • 1H-NMR (CDCl3), δppm: 1.40-1.90 (7H, m), 2.51-2.83 (6H, m), 3.29-3.44 (1H, m), 3.44-3.54 (2H, m), 3.54-3.70 (2H, m), 3.69-3.90 (2H, m), 4.47-4.57 (1H, m), 7.12-7.23 (3H, m), 7.37-7.48 (1H, m), 8.38-8.53 (4H, m).
    • Reference Example 17 Synthesis of 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol
  • A 2N-hydrogen chloride methanol solution (1.2 ml) was added to a methanol solution (4 ml) of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine (236 mg). The mixture was stirred at room temperature overnight. A 2N-hydrogen chloride methanol solution (0.5 ml) was added thereto, and the mixture was further stirred at 50° C. for 3 hours. Triethylamine (0.64 ml) was added to the reaction mixture, and the mixture was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane). The purified product was condensed under reduced pressure to give the title compound (186.3 mg) as an orange oily matter.
  • 1H NMR (CDCl3), δppm: 1.66-1.88 (2H, m), 2.59-2.77 (4H, m), 2.77-2.88 (2H, m), 3.65 (2H, s), 3.68-3.84 (3H, m), 7.11-7.25 (3H, m), 7.42 (1H, d, J=7.8 Hz), 8.42 (1H, s), 8.43-8.47 (1H, m), 8.50-8.60 (2H, m).
    • Reference Example 18 Synthesis of (3-chloropropyl)-(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine
  • (2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (210 mg) and N-ethyldiisopropylamine (0.34 ml) were added to a DMF solution (2 ml) of 1-chloro-3-iodopropane (0.16 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (74 mg) as a colorless oily matter.
  • 1H-NMR (CDCl3), δppm: 1.82-1.99 (2H, m), 2.61-2.82 (6H, m), 3.52 (2H, t, J=6.3 Hz), 3.61 (2H, s), 7.14 (2H, d, J=5.9 Hz), 7.19 (1H, dd, J=7.7, 4.8 Hz), 7.36-7.49 (1H, m), 8.38-8.56 (4H, m).
    • Reference Example 19 Synthesis of 2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • 2-Nitrobenzene sulfonyl chloride (11.64 g) was added to a dichloromethane solution (100 ml) of 3-(2-aminoethyl)pyridine (6.11 g) and triethylamine (9 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (5.06 g) as a yellow powder.
  • 1H NMR (DMSO-d6), δppm: 2.76 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 7.26 (1H, dd, J=4.8 Hz, 7.8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.8-8.0 (4H, m), 8.19 (1H, brs), 8.3-8.4 (2H, m).
    • Reference Example 20 Synthesis of (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine
  • The synthesis of the title compound was performed in the same manner as in Reference Example 15 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.95-1.95 (1H, br-s), 2.30 (3H, s), 2.77-2.88 (2H, m), 2.91-3.02 (2H, m), 3.78 (2H, s), 7.06-7.30 (5H, m), 7.53 (1H, br-d, J=7.5 Hz), 8.41-8.53 (2H, m).
    • Reference Example 21 Synthesis of 6-(3-chloropropoxy)-1-methyl-1H-quinolin-2-one
  • Potassium carbonate (0.829 g) was dissolved in acetonitrile (10 ml) and water (10 ml), and 6-hydroxy-2-methoxyquinoline (0.875 g) and 1-chloro-3-bromopropane (1.48 ml) was added thereto, and the mixture was stirred while heating under reflux for 4 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.107 g) as a white powder.
  • 1H-NMR (CDCl3) δppm: 2.18-2.35 (2H, m), 3.71 (3H, s), 3.78 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=5.9 Hz), 6.72 (1H, d, J=9.5 Hz), 7.03 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).
    • Reference Example 22 Synthesis of 6-(3-aminopropoxy)-1-methyl-1H-quinolin-2-one
  • Hydrazine hydrate (6.54 ml) was added to a ethanol solution (250 ml) of 2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]isoindole-1,3-dione (16.28 g), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.04 g) as a colorless oil.
  • 1H-NMR (CDCl3) δppm: 1.89-2.06 (2H, m), 2.95 (2H, t, J=6.8 Hz), 3.71 (3H, s), 4.11 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).
    • Reference Example 23 Synthesis of 6-(2-iodoethoxy)-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.45 (2H, t, J=6.6 Hz), 3.71 (3H, s), 4.31 (2H, t, J=6.6 Hz), 6.73 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).
    • Reference Example 24 Synthesis of 6-(2-aminoethoxy)-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 22 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.13 (2H, t, J=5.1 Hz), 3.71 (3H, s), 4.05 (2H, t, J=5.1 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).
    • Reference Example 25 Synthesis of 2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzene sulfonamide
  • The synthesis of the title compound was performed in the same manner as in Reference Example 19 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.42-1.99 (4H, m), 2.13-2.35 (2H, m), 2.43-2.69 (4H, m), 3.21 (2H, t, J=6.0 Hz), 3.39-3.54 (1H, m), 4.52 (2H, s), 7.28 (1H, dd, J=7.9, 4.8 Hz), 7.63-7.70 (1H, m), 7.70-7.79 (2H, m), 7.83-7.89 (1H, m), 8.91-8.98 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.56 (1H, d, J=1.6 Hz).
    • Reference Example 26 Synthesis of 6-(4-aminobutoxy)-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 22 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.58-1.72 (2H, m), 1.81-1.98 (2H, m), 2.80 (2H, t, J=6.9 Hz), 3.71 (3H, s), 4.03 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Reference Example 27 Synthesis of 6-(3-iodopropoxy)-1-methyl-3,4-dihydro-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.16-2.32 (2H, m), 2.56-2.70 (2H, m), 2.87 (2H, t, J=6.7 Hz), 3.33 (3H, s), 3.31-3.45 (2H, m), 4.02 (2H, t, J=5.8 Hz), 6.75 (1H, d, J=2.8 Hz), 6.78 (1H, dd, J=8.7, 2.8 Hz), 6.89 (1H, d, J=8.7 Hz).
    • Reference Example 28 Synthesis of N-(3-imidazol-1-yl-propyl)-2-nitrobenzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Reference Example 19 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.71-1.95 (2H, m), 2.85 (2H, t, J=6.8 Hz), 3.97 (2H, t, J=6.9 Hz), 6.86 (1H, s), 7.10 (1H, s), 7.55 (1H, s), 7.83-7.92 (2H, m), 7.92-8.02 (2H, m), 8.16 (1H, s).
    • Reference Example 30 Synthesis of N-(3-Chloropropyl)-N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amine
  • The synthesis of the title compound was performed in the same manner as in Reference Example 18 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.78-1.95 (2H, m), 2.26 (3H, s), 2.60-2.79 (6H, m), 3.50 (2H, t, J=6.5 Hz), 3.58 (2H, s), 7.08-7.24 (5H, m), 7.33-7.39 (1H, m), 8.36 (1H, d, J=1.7 Hz), 8.41 (1H, dd, J=4.8, 1.7 Hz).
    • Reference Example 31 Synthesis of 6-(3-iodopropoxy)-3,4-dihydro-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.19-2.35 (2H, m), 2.97 (2H, t, J=6.6 Hz), 3.37 (2H, t, J=6.7 Hz), 3.50-3.62 (2H, m), 4.09 (2H, t, J=5.8 Hz), 5.98 (1H, s), 6.71 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.6, 2.4 Hz), 8.01 (1H, d, J=8.6 Hz).
    • Reference Example 32 Synthesis of 2-hydroxy-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one
  • The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.
  • 1H-NMR (CD3OD) δppm: 3.06 (2H, t, J=6.0 Hz), 3.26 (2H, t, J=6.0 Hz), 6.85 (1H, dd, J=8.3, 2.8 Hz), 7.01 (1H, d, J=2.8 Hz), 7.34 (1H, d, J=8.3 Hz).
    • Example 1 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)-(2-pyridin-3-ylethyl)amino]pentyl oxy}-1H-quinolin-2-one dihydrochloride
  • Potassium carbonate (360 mg) and (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine (591 mg) were added to a DMF solution (6.5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (650 mg). The mixture was stirred at 60° C. for 8 hours. Ice water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol:aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (270 mg) as a pale yellow amorphus solid.
  • 1H-NMR (DMSO-d6) δppm: 1.32-1.50 (2H, m), 1.65-1.99 (4H, m), 2.47 (3H, s), 2.92-3.21 (2H, m), 3.21-3.50 (4H, m), 3.59 (3H, s), 3.88-4.09 (2H, m), 4.30-4.52 (2H, m), 6.61 (1H, d, J=9.4 Hz), 7.05-7.35 (5H, m), 7.46 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.2 Hz), 7.84 (1H, d, J=9.6 Hz), 7.89-8.01 (1H, m), 8.40 (1H, br-d, J=7.8 Hz), 8.79 (1H, d, J=4.9 Hz), 8.89 (1H, s).
    • Example 2 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • 2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (308 mg), and potassium carbonate (276 mg) were added to a DMF solution (5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (348 mg). The mixture was stirred at room temperature for 2 hours. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give 5 the title compound (535 mg) as a yellow amorphus solid.
  • 1H-NMR (CDCl3) δppm: 1.4-1.9 (6H, m), 2.88 (2H, t, J=7.5 Hz), 3.40 (2H, t, J=7.5 Hz), 3.52 (2H, t, J=7.7 Hz), 3.71 (3H, s), 3.98 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.1-7.3 (2H, m), 7.29 (1H, d, J=9.2 Hz), 7.4-7.7 (5H, m), 7.9-8.1 (1H, m), 8.40 (1H, d, J=1.8 Hz), 8.45 (1H, dd, J=1.8 Hz, 4.8 Hz).
    • Example 3 Synthesis of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride
  • Lithium hydroxide (102 mg), and thioglycolic acid (0.141 ml) were added to a DMF solution (5 ml) of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (535 mg). The mixture was stirred at room temperature overnight. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml), and ethyl acetate were added to the residue. The mixture was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (108 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 1.4-1.6 (2H, m), 1.6-1.8 (4H, m), 2.8-3.0 (2H, m), 3.2-3.4 (4H, m), 3.60 (3H, s), 4.04 (2H, t, J=6.1 Hz), 4.0-4.8 (1H, br), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=5.6 Hz, 8.1 Hz), 8.57 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=5.6 Hz), 8.94 (1H, s), 9.36 (1H, brs).
    • Example 4 Synthesis of 1-methyl-6-[5-((2-methylbenzyl)-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino)pentyloxy]-1H-quinolin-2-one trihydrochloride
  • Methane sulfonyl chloride (0.59 ml) was added to a dichloromethane solution (30 ml) of 6-{5-[(2-hydroxyethyl)-(2-methylbenzyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one (2.83 g) and N-ethyldiisopropylamine (1.81 ml). The mixture was stirred at room temperature for an hour. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was dissolved in acetonitrile (50 ml). Sodium iodide (1.56 g), 3-(piperidin-4-yloxymethyl)pyridine (1.46 g) and N-ethyldiisopropylamine (3.61 ml) were added thereto, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol:aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.41 ml) was added to an isopropyl alcohol solution of the residue. The mixture was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (2.41 g) as a white amorphous solid.
  • 1H-NMR (DMSO-d6) δppm: 1.4-1.6 (2H, m), 1.7-2.3 (8H, m), 2.46 (3H, s), 3.0-3.9 (11H, m), 3.60 (3H, s), 4.02 (2H, t, J=6.2 Hz), 4.46 (2H, s), 4.75 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.2-7.4 (5H, m), 7.47 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=9.5 Hz), 8.04 (1H, dd, J=5.7 Hz, 8.0 Hz), 8.5-8.6 (1H, br), 8.85 (1H, d, J=5.7 Hz), 8.94 (1H, brs), 10.2-11.8 (2H, br).
    • Example 5 Synthesis of 6-{5-[cyclohexylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • Triethylamine (0.15 ml) was added to a 1,2-dichloroethane solution (2.5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride (219 mg). The mixture was stirred at room temperature for 30 minutes. Cyclohexane carboxaldehyde (0.073 ml) and sodium triacetoxyborohydrate (159 mg) were added thereto, and the mixture was stirred at room temperature overnight. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml) was added to an ethanol solution (20 ml) of the residue, which was stirred at room temperature. The reaction mixture was condensed under reduced pressure and ethyl acetate was added to the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (100 mg) as a pale yellow powder.
  • 1H-NMR (DMSO-d6) δppm: 0.8-1.4 (6H, m), 1.5-2.0 (11H, m), 2.9-3.6 (8H, m), 3.59 (3H, s), 4.0-4.5 (1H, br), 4.06 (2H, t, J=6.1 Hz), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=5.6 Hz, 8.1 Hz), 8.53 (1H, J=8.1 Hz), 8.83 (1H, d, J=5.6 Hz), 8.95 (1H, s), 10.4 (1H, brs).
    • Example 6 Synthesis of 6-{5-[(2,6-dichlorobenzyl)-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.6 (2H, m), 1.7-2.0 (4H, m), 3.0-3.7 (8H, m), 3.58 (3H, s), 4.02 (2H, t, J=6.0 Hz), 4.0-5.0 (1H, br), 6.59 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=2.8 Hz, 9.1 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.1 Hz), 7.4-7.7 (3H, m), 7.82 (1H, d, J=9.5 Hz), 7.8-8.0 (1H, m), 8.38 (1H, d, J=7.7 Hz), 8.76 (1H, d, J=5.3 Hz), 9.02 (1H, s), 9.9-10.2 (1H, br).
    • Example 7 Synthesis of 6-{5-[isobutyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
    • Example 8 Synthesis of 6-{5-[cyclohexyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
    • Example 9 Synthesis of 6-{5-[benzyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.5 (2H, m), 1.7-2.0 (4H, m), 3.0-3.2 (2H, m), 3.3-3.5 (4H, m), 3.59 (3H, s), 4.03 (2H, t, J=6.2 Hz), 4.3-4.6 (2H, m), 4.0-4.5 (1H, br), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=2.8 Hz, 9.1 Hz), 7.29 (1H, d, J=2.8 Hz), 7.4-7.5 (4H, m), 7.6-7.8 (2H, m), 7.83 (1H, d, J=9.5 Hz), 7.90 (1H, dd, J=5.3 Hz, 8.1 Hz), 8.35 (1H, d, J=8.1 Hz), 8.78 (1H, d, J=5.3 Hz), 8.85 (1H, s), 11.22 (1H, brs).
    • Example 10 Synthesis of 1-methyl-6-{5-[(2-pyridin-3-ylethyl)-o-tolylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • 1-Methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (183 mg), 2-bromotoluene (0.072 ml), palladium acetate (II)(5.6 mg), tri-tert-butylphosphine tetrafluoroborate (8 mg), and sodium t-butoxide (0.19 ml) were added to toluene (1 ml). The mixture was heated under reflux for 8 hours under nitrogen atmosphere. After the reaction, the precipitate was removed from the reaction mixture by celite filtration. Water was added thereto, followed by extraction using dichloromethane. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=20:1). The purified product was condensed under reduced pressure to give the title compound (93 mg) as a yellow oily matter.
  • 1H-NMR (DMSO-d6) δppm: 1.2-1.5 (2H, m), 1.6-1.9 (2H, m), 2.0-2.2 (2H, m), 2.50 (3H, s), 2.7-3.5 (6H, m), 3.59 (3H, s), 3.96 (2H, t, J=6.3 Hz), 4.0-5.0 (2H, br), 6.59 (1H, d, J=9.5 Hz), 7.0-7.4 (6H, m), 7.44 (1H, d, J=9.1 Hz), 7.82 (1H, d, J=9.5 Hz), 7.9-8.0 (1H, m), 8.3-8.4 (1H, m), 8.7-8.8 (2H, m).
    • Example 11 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)-(2-pyridin-3-ylethyl)amino]pentyl oxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 2.0-2.2 (2H, m), 2.63 (2H, t, J=7.7 Hz), 3.0-3.5 (8H, m), 3.59 (3H, s), 3.8-4.2 (3H, m), 6.60 (1H, d, J=9.5 Hz), 7.1-7.4 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.97 (1H, dd, J=5.3 Hz, 8.1 Hz), 8.48 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.3 Hz), 8.92 (1H, s), 11.04 (1H, brs).
    • Example 12 Synthesis of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 3.0-3.2 (2H, m), 3.2-3.5 (4H, m), 3.58 (3H, s), 3.85 (3H, s), 4.00 (2H, t, J=6.3 Hz), 4.3-4.6 (2H, m), 4.5-5.5 (1H, br), 6.59 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.86 (2H, d, J=8.3 Hz), 7.9-8.0 (1H, m), 7.99 (2H, d, J=8.3 Hz), 8.42 (1H, d, J=8.2 Hz), 8.79 (1H, d, J=5.5 Hz), 8.88 (1H, s), 11.50 (1H, brs).
    • Example 13 Synthesis of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid
  • A 1N-sodium hydroxide aqueous solution (0.72 ml) was added to a methanol solution (2 ml) of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (153 mg). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, and acetic acid was added for neutralization. The mixture was extracted using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. Diisopropyl ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (115 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 2.3-2.6 (2H, m), 2.6-2.8 (4H, m), 3.59 (3H, s), 3.67 (2H, s), 3.96 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=9.5 Hz), 7.1-7.3 (3H, m), 7.33 (2H, d, J=8.2 Hz), 7.44 (1H, d, J=9.1 Hz), 7.5-7.6 (1H, m), 7.7-7.9 (3H, m), 8.1-8.3 (2H, m), 12.5-13.0 (1H, br).
    • Example 14 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)pyridin-3-ylmethylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.5 (2H, m), 1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 2.35 (3H, s), 3.0-3.2 (2H, m), 3.60 (3H, s), 3.9-4.1 (2H, m), 4.2-5.7 (5H, m), 6.61 (1H, d, J=9.5 Hz), 7.1-7.4 (5H, m), 7.46 (1H, d, J=9.2 Hz), 7.75 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=5.4 Hz, 7.9 Hz), 8.85 (1H, d, J=7.9 Hz), 8.91 (1H, d, J=5.4 Hz), 9.21 (1H, s), 11.64 (1H, brs).
    • Example 15 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)pyridin-3-ylmethylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 1.9-2.2 (2H, m), 2.61 (2H, t, J=7.5 Hz), 2.9-3.2 (4H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.2 Hz), 4.0-5.0 (3H, m), 6.61 (1H, d, J=9.5 Hz), 7.1-7.4 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.9-8.1 (1H, m), 8.77 (1H, d, J=7.9 Hz), 8.92 (1H, d, J=5.0 Hz), 9.18 (1H, s), 11.71 (1H, brs).
    • Example 16 Synthesis of 6-[5-(bis{pyridin-3-ylmethyl}amino)pentyloxy]-1-methyl-1H-quinolin-2-one
  • Pyridine-3-carbaldehyde (0.076 ml) was added to a 1,2-dichloroethane solution (3 ml) of 1-methyl-6-{5-[(pyridin-3-ylmethyl)-amino]-pentyloxy}-1H-quinolin-2-one (237 mg). The mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature for 3 days. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1). The purified product was condensed under reduced pressure to give the title compound (247 mg) as a yellow oil.
  • 1H-NMR (CDCl3) δppm: 1.3-1.8 (6H, m), 2.47 (2H, t, J=6.8 Hz), 3.58 (4H, s), 3.71 (3H, s), 3.95 (2H, t, J=6.4 Hz), 6.70 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.2-7.4 (3H, m), 7.60 (1H, d, J=9.5 Hz), 7.6-7.7 (2H, m), 8.49 (2H, dd, J=1.6 Hz, 4.8 Hz), 8.57 (2H, d, J=1.7 Hz).
    • Example 17 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)pyridin-3-ylamino]pentyloxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.5-1.7 (2H, m), 1.8-1.9 (4H, m), 2.32 (3H, s), 3.45 (2H, t, J=7.6 Hz), 3.71 (3H, s), 4.01 (2H, t, J=6.3 Hz), 4.46 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.8-6.9 (1H, m), 6.98 (1H, d, J=2.8 Hz), 7.0-7.3 (6H, m), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz), 7.92 (1H, dd, J=1.2 Hz, 4.6 Hz), 8.09 (1H, d, J=3.0 Hz).
    • Example 18 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)pyridin-3-ylamino]pentyloxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.4-1.7 (4H, m), 1.8-2.1 (4H, m), 2.66 (2H, t, J=7.7 Hz), 3.2-3.4 (4H, m), 3.70 (3H, s), 4.00 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.8-6.9 (1H, m), 6.98 (1H, d, J=2.8 Hz), 7.05 (1H, dd, J=4.6 Hz, 8.6 Hz), 7.1-7.4 (7H, m), 7.58 (1H, d, J=9.5 Hz), 7.88 (1H, dd, J=1.2 Hz, 4.5 Hz), 8.04 (1H, d, J=3.0 Hz).
    • Example 19 Synthesis of 1-methyl-6-{5-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6)6 ppm: 0.80-2.02 (6H, m), 3.05-3.25 (2H, m), 3.36-3.52 (4H, m), 3.60 (3H, s), 3.97-4.10 (2H, m), 4.82 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.1, 2.8 Hz), 7.32 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=9.5 Hz), 8.06 (1H, dd, J=8.1, 5.7 Hz), 8.53 (2H, d, J=6.3 Hz), 8.59 (1H, d, J=8.1 Hz), 8.86 (1H, d, J=5.7 Hz), 8.88 (1H, s), 9.04 (2H, d, J=6.3 Hz).
    • Example 20 Synthesis of 1-Methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δ: 2.78-2.91 (4H, m), 3.00 (2H, t, J=5.6 Hz), 3.69 (3H, s), 3.79 (2H, s), 4.04 (2H, t, J=5.6 Hz), 6.70 (1H, d, J=9.5 Hz), 6.63 (1H, d, J=2.8 Hz), 7.15-7.30 (4H, m), 7.41-7.50 (1H, m), 7.57-7.60 (2H, m), 8.42-8.53 (4H, m).
    • Example 21 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]ethoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.79-2.91 (4H, m), 3.01 (2H, t, J=5.6 Hz), 3.70 (3H, s), 3.79 (2H, s), 4.05 (2H, t, J=5.6 Hz), 6.71 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.11-7.20 (4H, m), 7.27-7.30 (1H, m), 7.41-7.48 (1H, m), 7.58 (1H, d, J=9.5 Hz), 8.43-8.49 (4H, m).
    • Example 22 Synthesis of 1-methyl-6-[3-(pyridin-4-ylmethylpyridin-3-ylmethylamino)propoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.86-2.19 (2H, m), 3.61 (3H, s), 3.71-5.00 (8H, m), 6.62 (1H, d, J=9.5 Hz), 7.09 (1H, dd, J=9.2, 2.8 Hz), 7.20 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.80-7.94 (1H, m), 8.02-8.12 (2H, m), 8.52 (1H, d, J=7.3 Hz), 8.73-8.83 (3H, m), 8.93 (1H, s).
    • Example 23 Synthesis of 1-methyl-6-[4-(pyridin-4-ylmethylpyridin-3-ylmethylamino)butoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.61-1.98 (4H, m), 2.60-3.00 (2H, m), 3.60 (3H, s), 3.23-5.11 (6H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.9 Hz), 7.24 (1H, d, J=2.9 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.89-8.00 (1H, m), 8.11-8.26 (2H, m), 8.64 (1H, d, J=7.8 Hz), 8.84 (1H, d, J=4.5 Hz), 8.88 (2H, d, J=6.4 Hz), 9.02 (1H, s).
    • Example 24 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.88-1.96 (2H, m), 2.68-2.81 (6H, m), 3.66 (2H, s), 3.71 (3H, s), 3.93 (2H, t, J=6.0 Hz), 6.73 (1H, d, J=9.5 Hz), 6.92 (1H, d, J=2.8 Hz), 7.09-7.16 (4H, m), 7.28-7.31 (1H, m), 7.39-7.46 (1H, m), 7.62 (1H, d, J=9.5 Hz), 8.41-8.46 (4H, m).
    • Example 25 Synthesis of 1-Methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.85-1.91 (2H, m), 2.60-2.88 (10H, m), 3.33 (3H, s), 3.64 (2H, s), 3.88 (2H, t, J=6.0 Hz), 6.64-6.71 (2H, m), 6.89 (1H, d, J=8.7 Hz), 7.13-7.19 (2H, m), 7.30-7.33 (1H, m), 7.35-7.46 (1H, m), 8.40-8.52 (3H, m), 8.53 (1H, d, J=1.2 Hz).
    • Example 26 Synthesis of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(quinolin-6-yloxy)propyl]amine
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.93-2.02 (2H, m), 2.71-2.80 (6H, m), 3.66 (2H, s), 4.02 (2H, t, J=6.1 Hz), 6.989 (1H, d, J=2.8 Hz), 7.09-7.18 (3H, m), 7.28-7.39 (3H, m), 7.98-8.06 (2H, m), 8.43-8.45 (4H, m), 8.77-8.78 (1H, m).
    • Example 27 Synthesis of 1-methyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • (2-Pyridin-3-ylethyl)pyridin-4-ylmethylamine (128 mg), and N-ethyldiisopropylamine (0.13 ml) were added to a DMF solution (5 ml) of 5-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg). The mixture was stirred at 60° C. for 3.5 hours. The reaction mixture was added to ice water, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→1:1).
  • The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration and dried to give the title compound (21 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.26-2.54 (2H, m), 3.00-5.29 (10H, m), 3.60 (3H, s), 6.56 (1H, d, J=9.7 Hz), 6.83 (1H, d, J=8.2 Hz), 7.12 (1H, d, J=8.6 Hz), 7.51-7.60 (1H, m), 7.92 (1H, d, J=9.7 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.24-8.40 (2H, m), 8.54 (1H, d, J=8.0 Hz), 8.84 (1H, d, J=5.5 Hz), 8.92 (2H, d, J=5.6 Hz), 8.95 (1H, s).
    • Example 28 Synthesis of 1-methyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.14-2.43 (2H, m), 2.88-4.95 (10H, m), 3.59 (3H, s), 6.44 (1H, d, J=9.4 Hz), 6.85 (1H, d, J=8.6 Hz), 6.89 (1H, s), 7.65 (1H, d, J=8.6 Hz), 7.83 (1H, d, J=9.4 Hz), 7.97 (1H, dd, J=8.0, 5.6 Hz), 8.07-8.24 (2H, m), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.6 Hz), 8.86 (2H, d, J=5.6 Hz), 8.90 (1H, s).
    • Example 29 Synthesis of 1-methyl-8-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.30-2.55 (2H, m), 3.25-3.60 (6H, m), 3.77 (3H, s), 4.09-4.29 (2H, m), 4.54-5.00 (2H, m), 6.60 (1H, d, J=9.4 Hz), 7.16-7.28 (2H, m), 7.31 (1H, dd, J=6.8, 2.3 Hz), 7.84 (1H, d, J=9.4 Hz), 8.04 (1H, dd, J=8.1, 5.4 Hz), 8.32-8.46 (2H, m), 8.56 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.4 Hz), 8.91-9.02 (3H, m).
    • Example 30 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.18-2.40 (2H, m), 3.15-3.56 (6H, m), 3.95-4.16 (2H, m), 4.59-4.87 (2H, m), 6.51 (1H, d, J=9.5 Hz), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.20 (1H, d, J=2.7 Hz), 7.28 (1H, d, J=8.9 Hz), 7.86 (1H, d, J=9.5 Hz), 8.03 (1H, dd, J=8.1, 5.4 Hz), 8.31-8.44 (2H, m), 8.55 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=5.4 Hz), 8.93-9.03 (3H, m).
    • Example 31 Synthesis of 1-methyl-4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • Triphenyl phosphine (102 mg) and diethyl azodicarboxylate (68 mg) were added to a tetrahydrofuran (THF) solution (5 ml) of 4-hydroxy-1-methyl-1H-quinolin-2-one (63 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propane-1-ol (81.4 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.29 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and dried to give the title compound (126.8 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.29-2.56 (2H, m), 3.11-3.61 (6H, m), 3.56 (3H, s), 4.11-4.30 (2H, m), 4.50-4.94 (2H, m), 6.03 (1H, s), 7.32-7.41 (1H, m), 7.52 (1H, d, J=8.4 Hz), 7.62-7.76 (2H, m), 8.10 (1H, dd, J=8.0, 5.3 Hz), 8.21-8.34 (2H, m), 8.53 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.90 (2H, d, J=5.7 Hz), 8.94 (1H, s).
    • Example 32 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2H-isoquinolin-1-one trihydrochloride
  • Triphenyl phosphine (51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution (1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one (29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound (31.4 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.14-2.45 (2H, m), 2.91-3.78 (6H, m), 4.08-4.25 (2H, m), 4.37-4.81 (2H, m), 6.46 (1H, d, J=7.1 Hz), 6.99 (1H, dd, J=8.8, 2.2 Hz), 7.08 (1H, d, J=2.2 Hz), 7.10-7.18 (1H, m), 7.92 (1H, dd, J=8.0, 5.5 Hz), 7.99-8.14 (2H, m), 8.08 (1H, d, J=8.8 Hz), 8.41 (1H, d, J=8.0 Hz), 8.78 (1H, d, J=5.5 Hz), 8.83 (2H, d, J=5.8 Hz), 8.87 (1H, s), 10.98-11.17 (1H, m).
    • Example 33 Synthesis of 2-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.09-2.41 (2H, m), 2.85-3.44 (6H, m), 3.47 (3H, s), 4.08-4.26 (2H, m), 4.26-4.66 (2H, m), 6.52 (1H, d, J=7.3 Hz), 6.99 (1H, dd, J=8.9, 2.3 Hz), 7.07 (1H, d, J=2.3 Hz), 7.44 (1H, d, J=7.3 Hz), 7.72 (1H, dd, J=7.6, 5.3 Hz), 7.81-7.92 (2H, m), 8.11 (1H, d, J=8.9 Hz), 8.11-8.19 (1H, m), 8.67 (1H, dd, J=5.3, 1.2 Hz), 8.69-8.76 (3H, m).
    • Example 34 Synthesis of 1,3-dimethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinazolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.08-2.38 (2H, m), 2.88 (3H, s), 3.16 (3H, s), 3.08-3.56 (6H, m), 3.92-4.05 (2H, m), 4.32 (2H, s), 4.42-4.85 (2H, m), 6.73 (1H, br-s), 6.70-6.90 (2H, m), 7.98 (1H, d-d, J=5.5, 8.1 Hz), 8.04-8.28 (2H, m), 8.46 (1H, d, J=8.1 Hz), 8.81 (1H, d, J=5.5 Hz), 8.81-8.98 (3H, m).
    • Example 35 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.13-2.40 (2H, m), 2.86 (2H, t, J=6.5 Hz), 3.10-3.57 (8H, m), 4.00-4.15 (2H, m), 4.55-4.81 (2H, m), 6.74-6.88 (2H, m), 7.66-7.80 (2H, m), 8.01 (1H, d-d, J=5.0, 8.0 Hz), 8.19-8.40 (2H, m), 8.52 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.0 Hz), 8.85-9.00 (3H, m).
    • Example 36 Synthesis of 5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2,3-dihydro-isoindol-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.15-2.43 (2H, m), 3.00-3.58 (6H, m), 3.96-4.16 (2H, m), 4.32 (2H, s), 4.44-4.83 (2H, m), 6.96 (1H, d-d, J=1.9, 8.3 Hz), 7.07 (1H, s), 7.57 (1H, d, J=8.3 Hz), 7.92-8.05 (1H, m), 8.10-8.40 (3H, m), 8.41-8.55 (1H, m), 8.78-9.00 (4H, m).
    • Example 37 Synthesis of N-ethyl-4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}benzamide trihydrochloride
  • 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(95 mg), and 1-hydroxy benzotriazole (HOBt)(66 mg) were added to a DMF solution (4 ml) of 4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}benzoic acid (149 mg), ethyl amine hydrochloride (38 mg), and triethylamine (0.08 ml). The mixture was stirred at room temperature overnight. The reaction mixture was added to ice water. A 1N-sodium hydroxide aqueous solution was added thereto, followed by extraction using ethyl acetate. The organic layer was washed with water and then was dried with anhydrous sodium sulfate, followed by condensation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.16 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (80 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 1.11 (3H, t, J=7.2 Hz), 2.10-2.38 (2H, m), 2.89-3.57 (8H, m), 3.95-4.20 (2H, m), 4.28-4.69 (2H, m), 6.92 (2H, d, J=8.8 Hz), 7.75 (1H, dd, J=7.8, 5.2 Hz), 7.82 (2H, d, J=8.8 Hz), 7.83-7.94 (2H, m), 8.18 (1H, d, J=7.8 Hz), 8.35 (1H, t, J=5.4 Hz), 8.68 (1H, dd, J=5.2, 1.3 Hz), 8.71-8.79 (3H, m).
    • Example 38 Synthesis of 2-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.10-2.40 (2H, m), 2.74-3.62 (10H, m), 2.99 (3H, s), 3.74-4.20 (2H, m), 4.39-4.82 (2H, m), 6.77 (1H, s), 6.82 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.87-8.00 (1H, m), 8.05-8.22 (2H, m), 8.46 (1H, d, J=8.2 Hz), 8.71-8.92 (4H, m).
    • Example 39 Synthesis of [3-(2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yloxy)propyl]-(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.08-2.39 (2H, m), 2.79 (3H, s), 2.88-3.58 (6H, m), 4.00-4.20 (2H, m), 4.29-4.65 (2H, m), 4.35 (2H, s), 7.02-7.11 (2H, m), 7.70-7.81 (2H, m), 7.81-7.93 (2H, m), 8.18 (1H, d, J=8.1 Hz), 8.68 (1H, dd, J=5.2, 1.2 Hz), 8.70-8.79 (3H, m).
    • Example 40 Synthesis of 1-methyl-6-[3-(phenethylpyridin-4-ylmethylamino)propoxy]-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.10-2.40 (2H, m), 2.79-3.70 (6H, m), 3.60 (3H, s), 3.99-4.19 (2H, m), 4.30-4.61 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.15-7.36 (7H, m), 7.47 (1H, d, J=9.2 Hz), 7.68-7.80 (2H, m), 7.84 (1H, d, J=9.5 Hz), 8.67 (2H, d, J=4.9 Hz).
    • Example 41 Synthesis of 1-methyl-6-{3-[(2-pyridin-2-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.12-2.31 (2H, m), 3.07-3.29 (2H, m), 3.33-3.59 (4H, m), 3.60 (3H, s), 3.95-4.19 (2H, m), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.58-7.67 (1H, m), 7.72 (1H, d, J=7.9 Hz), 7.85 (1H, d, J=9.5 Hz), 8.04 (2H, d, J=6.2 Hz), 8.11-8.21 (1H, m), 8.67 (1H, d, J=4.7 Hz), 8.80 (2H, d, J=6.2 Hz).
    • Example 42 Synthesis of N-methyl-N-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.15-2.41 (2H, m), 2.95 (3H, s), 3.01-3.51 (4H, m), 3.60 (3H, s), 3.70-4.24 (4H, m), 4.33-4.72 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.33-7.54 (6H, m), 7.82 (1H, d, J=9.5 Hz), 7.92-8.08 (2H, m), 8.67-8.82 (2H, m).
    • Example 43 Synthesis of 1-ethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.19 (3H, t, J=7.0 Hz), 2.18-2.41 (2H, m), 2.94-3.59 (6H, m), 3.96-4.18 (2H, m), 4.25 (2H, q, J=7.0 Hz), 4.35-4.63 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.3, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.52 (1H, d, J=9.3 Hz), 7.61-7.76 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.85-8.00 (2H, m), 8.09-8.20 (1H, m), 8.67 (1H, dd, J=5.3, 1.4 Hz), 8.69-8.80 (3H, m).
    • Example 44 Synthesis of 1-benzyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.80-2.00 (2H, m), 2.52-2.82 (6H, m), 3.63 (2H, s), 3.78-3.98 (2H, m), 5.54 (2H, s), 6.82 (1H, d, J=9.5 Hz), 6.84-6.99 (2H, m), 7.05-7.44 (10H, m), 7.67 (1H, d, J=9.5 Hz), 8.30-8.52 (4H, m).
    • Example 45 Synthesis of N-methyl-N-(2-{[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide dihydrochloride
  • Benzoyl chloride (0.14 ml) was added to a dichloromethane solution (10 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride (382 mg), and triethylamine (0.56 ml) under ice cooling. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.28 ml) was added to an ethyl acetate solution (10 ml) of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (242 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.04-2.36 (2H, m), 2.78-2.92 (2H, m), 2.95 (3H, s), 3.00-3.46 (6H, m), 3.64-3.94 (2H, m), 3.94-4.21 (2H, m), 4.31-4.61 (2H, m), 6.77 (1H, s), 6.81 (1H, d, J=8.5 Hz), 7.29-7.59 (6H, m), 7.78 (1H, d, J=8.5 Hz), 7.91-8.18 (2H, m), 8.78 (2H, d, J=4.9 Hz).
    • Example 46 Synthesis of 2,3-dihydrobenzofuran-7-carboxylic acid methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)amide dihydrochloride
  • PS-Carbodiimide resin (1.3 g) and 1-hydroxy benzotriazole (HOBt)(230 mg) were added to acetonitrile and THF solution (4 ml+6 ml) of 1-methyl-6-{3-[(2-methylamino ethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one (304 mg) and 2,3-dihydrobenzofuran-7-carboxylic acid (164 mg). The mixture was stirred at room temperature overnight. After the reaction mixture was filtrated and condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.35 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (324.2 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.10-2.44 (2H, m), 2.88-3.45 (6H, m), 2.91 (3H, s), 3.59 (3H, s), 3.70-4.25 (4H, m), 4.31-4.72 (4H, m), 6.58 (1H, d, J=9.5 Hz), 6.75-6.91 (1H, m), 6.91-7.12 (1H, m), 7.12-7.32 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 7.98-8.30 (2H, m), 8.69-8.94 (2H, m).
    • Example 47 Synthesis of 3-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.10-2.41 (2H, m), 3.00-3.60 (10H, m), 3.99-4.19 (2H, m), 4.43-4.84 (2H, m), 6.89-7.01 (2H, m), 7.48 (1H, d, J=8.6 Hz), 7.98 (1H, dd, J=8.0, 5.3 Hz), 8.04-8.21 (2H, m), 8.27 (1H, t, J=6.5 Hz), 8.46 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.3 Hz), 8.81-8.98 (3H, m).
    • Example 48 Synthesis of 1-methyl-3-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 31 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.20-2.42 (2H, m), 3.10-3.33 (2H, m), 3.34-3.60 (4H, m), 3.67 (3H, s), 4.00-4.20 (2H, m), 4.55-4.82 (2H, m), 7.20-7.35 (2H, m), 7.40-7.53 (2H, m), 7.65 (1H, d, J=7.7 Hz), 7.93-8.08 (1H, m), 8.18-8.35 (2H, m), 8.53 (1H, d, J=8.1 Hz), 8.82 (1H, d, J=5.1 Hz), 8.90-9.05 (3H, m).
    • Example 49 Synthesis of 1-(6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-quinolin-1-yl)ethanone trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.71-1.92 (2H, m), 2.11 (3H, s), 2.01-2.39 (2H, m), 2.58-2.79 (2H, m), 3.00-3.48 (6H, m), 3.51-3.71 (2H, m), 3.89-4.10 (2H, m), 4.50 (2H, s), 6.59-6.79 (2H, m), 7.04-7.56 (1H, m), 7.78 (1H, dd, J=7.8, 5.3 Hz), 7.94 (2H, d, J=4.4 Hz), 8.23 (1H, d, J=7.8 Hz), 8.63-8.82 (4H, m).
    • Example 50 Synthesis of 2,3-dihydrobenzofuran-7-carboxylic acid methyl-(2-{[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)amide dihydrochloride
  • 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(144 mg), and 1-hydroxy benzotriazole (HOBt)(115 mg) were added to a DMF solution (5 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride (234 mg), and 2,3-dihydrobenzofuran-7-carboxylic acid (123 mg). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.19 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (164.6 mg) as a white powder.
  • 1H-NMR (DMSO-d6) δppm: 2.04-2.35 (2H, m), 2.65-3.41 (10H, m), 2.90 (3H, s), 3.69-4.66 (8H, m), 6.65-6.90 (3H, m), 6.90-7.14 (1H, m), 7.27 (1H, d, J=5.2 Hz), 7.35-7.61 (1H, m), 7.77 (1H, d, J=8.5 Hz), 7.86-8.19 (2H, m), 8.64-8.90 (2H, m).
    • Example 51 Synthesis of 1-methyl-6-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.90-2.09 (2H, m), 2.65-2.81 (4H, m), 2.91 (2H, t, J=6.6 Hz), 3.48 (2H, t, J=6.6 Hz), 3.62-3.78 (4H, m), 3.70 (3H, s), 4.01 (2H, t, J=6.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.88 (1H, d, J=2.8 Hz), 7.00-7.48 (7H, m), 7.54 (1H, d, J=9.5 Hz), 8.02-8.11 (1H, m), 8.39-8.50 (2H, m).
    • Example 52 Synthesis of 2-fluoro-N-methyl-N-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide tris(phosphate)
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • Colorless solid (ethanol)
  • mp: 190-191° C.
    • Example 53 Synthesis of 1,3-dimethyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,3-dihydrobenzoimidazol-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.06-2.42 (2H, brs), 2.97-3.73 (m, 12H), 4.04 (2H, t, J=7.0 Hz), 4.42-4.95 (2H, brs), 6.60 (1H, dd, J=2.0, 8.5 Hz), 6.78 (1H, d, J=2.0 Hz), 7.02 (1H, d, J=8.5 Hz), 8.00 (1H, dd, J=5.6, 7.9 Hz), 8.15-8.40 (2H, brs), 8.51 (1H, d, J=7.9 Hz), 8.83 (1H, d, J=5.6 Hz), 8.92 (3H, m), 12.45 (1H, Brs).
    • Example 54 Synthesis of 1,3-dimethyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]propoxy}-1,3-dihydrobenzoimidazol-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.17-2.43 (2H, brs), 3.09-3.64 (m, 12H), 3.95-4.18 (2H, m), 4.49-4.84 (2H, brs), 6.63 (1H, dd, J=2.2 and 8.5 Hz), 6.81 (1H, d, J=2.2 Hz), 7.03 (1H, d, J=8.5 Hz), 7.89 (1H, dd, J=7.9 and 5.6 Hz), 8.01 (1H, dd, J=7.9 and 5.6 Hz), 8.26 (1H, d, J=8.0 Hz), 8.71 (1H, d, J=8.0 Hz), 8.77-8.92 (2H, m), 8.96 (1H, s), 9.16 (1H, s), 12.18 (1H, brs).
    • Example 55 Synthesis of 2-[2-({3-[4-(2-oxopyrrolidin-1-yl)phenoxy]propyl}pyridin-4-ylmeth ylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • 2-(2-{[3-(4-Bromophenoxy)propyl]pyridin-4-ylmethylamino}ethyl)-2H-isoquinolin-1-one (500 mg), 2-pyrrolidone (0.228 ml), potassium carbonate (415 mg), copper iodide (I) (190 mg), and N,N′-dimethyl ethylenediamine (0.39 ml) were added to toluene (5 ml). The mixture was stirred at 100° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. After adding aqueous ammonia, extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, and dried with sodium sulfate. After the organic layer was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→70:30). The purified product was condensed under reduced pressure. A condensed hydrochloric acid (0.3 ml) was added to an ethanol solution of the residue, followed by condensation under reduced pressure. The residue was recrystallized from isopropyl alcohol/water to give the title compound (350 mg) as a white powder.
  • mp: 210 to 214° C. (dec.)
    • Example 56 Synthesis of N-methyl-N-[4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)phenyl]acetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.
  • 1H-NMR (CD3OD) δppm: 1.82 (3H, s), 2.35-2.54 (2H, m), 3.21 (3H, s), 3.56-3.73 (2H, m), 3.75-3.90 (2H, m), 4.16 (2H, t, J=5.7 Hz), 4.53-4.75 (2H, m), 5.05 (2H, brs), 6.71-6.92 (2H, m), 6.98 (2H, d, J=8.9 Hz), 7.20 (2H, d, J=8.9 Hz), 7.49 (1H, d, J=7.4 Hz), 7.57 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=7.4 Hz), 7.76 (1H, d, J=8.2 Hz), 8.31 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=6.7 Hz), 8.99 (1H, d, J=6.7 Hz).
    • Example 57 Synthesis of 2-[2-({3-[4-(2-oxopiperidin-1-yl)phenoxy]propyl}-pyridin-4-ylmeth ylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.
  • 1H-NMR (CD3OD) δppm: 1.94-2.11 (4H, m), 2.22-2.42 (2H, m), 2.56-2.77 (2H, m), 3.59 (2H, t, J=7.3 Hz), 3.64-3.77 (2H, m), 3.78-3.92 (2H, m), 4.08 (2H, t, J=5.5 Hz), 4.67 (2H, brs), 5.04 (2H, brs), 6.80 (1H, d, J=7.4 Hz), 6.90 (2H, d, J=8.9 Hz), 7.24 (2H, d, J=8.9 Hz), 7.51 (1H, d, J=7.4 Hz), 7.55-7.63 (1H, m), 7.68 (1H, d, J=7.5 Hz), 7.72-7.84 (1H, m), 8.32 (1H, d, J=7.8 Hz), 8.49 (2H, d, J=6.7 Hz), 8.88 (2H, d, J=6.7 Hz).
    • Example 58 Synthesis of 2-[2-({3-[4-(2-oxo-2H-pyridin-1-yl)phenoxy]propyl}-pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.
  • 1H-NMR (CD3OD) δppm: 2.25-2.54 (2H, m), 3.50-3.73 (2H, m), 3.76-3.93 (2H, m), 4.16 (2H, t, J=5.6 Hz), 4.67 (2H, brs), 4.84-5.21 (2H, m), 6.79 (1H, d, J=7.4 Hz), 6.86 (1H, dt, J=1.2 and 6.8 Hz), 6.96 (1H, d, J=8.9 Hz), 7.03 (2H, d, J=8.9 Hz), 7.39 (2H, d, J=8.9 Hz), 7.52 (1H, d, 7.4 Hz), 7.57 (1H, dt, J=1.2 and 8.2 Hz), 7.67 (1H, d, J=7.4 Hz), 7.75 (1H, dt, J=1.2 and 8.2 Hz), 7.82-7.99 (2H, m), 8.32 (1H, d, J=8.1 Hz), 8.53 (1H, d, J=6.6 Hz), 8.94 (1H, d, J=6.6 Hz).
    • Example 59 Synthesis of 2-[2-({3-[4-(morpholine-4-carbonyl)phenoxy]propyl}-pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • 2-(2-{[3-(4-Bromophenoxy)propyl]pyridin-4-ylmethylamino}ethyl)-2H-isoquinolin-1-one (500 mg), hexacarbonyl molybdenum (264 mg), trans-di-μ-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium (II) (Herrmann's palladacycle) (23 mg), sodium carbonate (318 mg), and morpholine (0.26 ml) were added to THF (5 ml). The mixture was heated at 170° C. for 10 minutes (microwave reactor). The reaction mixture was cooled to room temperature. Water and ethyl acetate were added thereto, followed by celite filtration. The organic layer was dried with sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→7:3). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (150 mg) as a white powder.
  • 1H-NMR (CD3OD) δppm: 2.17-2.41 (2H, m), 3.37-3.90 (10H, m), 3.99-4.15 2H, m), 4.50-4.64 (2H, m), 4.67-5.00 (2H, m), 6.81 (1H, d, J=7.4 Hz), 6.88 (2H, d, J=6.2 Hz), 7.38 (2H, d, J=8.5 Hz), 7.45 (1H, d, J=7.4 Hz), 7.60 (1H, t, J=8.2 Hz), 7.71 (1H, d, J=7.4 Hz), 7.79 (1H, t, J=8.2 Hz), 8.32 (1H, d, J=7.9 Hz), 8.38 (2H, brs), 8.83 (2H, brs).
    • Example 60 Synthesis of 1,3-dimethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinazoline-2,4-dione trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.11-2.39 (2H, m), 3.00-5.03 (16H, m), 7.25-7.37 (1H, m), 7.37-7.54 (2H, m), 7.94-8.05 (1H, m), 8.05-8.35 (2H, m), 8.49 (1H, d, J=8.2 Hz), 8.73-8.99 (4H, m), 12.24 (1H, brs).
    • Example 61 Synthesis of 2-[2-(pyridin-4-ylmethyl-{3-[4-(pyrrolidine-1-carbonyl)phenoxy]propyl}amino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.75-1.89 (4H, m), 1.92-2.08 (2H, m), 2.78-2.97 (2H, m), 2.99-3.16 (2H, m), 3.35-3.58 (4H, m), 3.91-4.00 (2H, m), 4.07-4.17 (2H, m), 4.17-4.30 (2H, m), 6.57 (1H, d, J=7.3 Hz), 6.79 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8 Hz), 7.34-7.54 (2H, m), 7.56-7.79 (4H, m), 8.20 (1H, d, J=8.7 Hz), 8.53 (2H, d, J=6.2 Hz).
    • Example 62 Synthesis of N-tert-butyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.38 (9H, s), 1.92-2.08 (2H, m), 2.83-3.00 (2H, m), 3.04-3.22 (2H, m), 3.96 (2H, d, J=6.2 Hz), 4.10-4.21 (2H, m), 4.21-4.31 (2H, m), 6.59 (1H, d, J=7.3 Hz), 6.77 (2H, d, J=8.8 Hz), 7.23 (1H, brs), 7.42 (1H, d, J=7.3 Hz), 7.49 (1H, m), 7.67 (2H, t, J=7.0 Hz), 7.71 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=6.3), 8.20 (1H, d, J=2.0), 8.56 (2H, d, J=6.3 Hz).
    • Example 63 Synthesis of N-isobutyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 0.90 (6H, d, J=6.5 Hz), 1.75-1.93 (1H, m), 1.93-2.14 (2H, m), 2.85-3.03 (2H, m), 3.03-3.26 (4H, m), 3.90-4.02 (2H, m), 4.15-4.35 (4H, m), 6.59 (1H, d, J=7.4 Hz), 6.80 (2H, d, J=8.8 Hz), 7.31-7.54 (2H, m), 7.61-7.74 (2H, m), 7.76 (2H, d, J=8.8 Hz), 7.86 (2H, d, J=6.3 Hz), 7.98 (1H, brs), 8.20 (1H, d, J=7.4 Hz), 8.59 (2H, d, J=6.3 Hz).
    • Example 64 Synthesis of N-cyclohexyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.00-1.45 (4H, m), 1.53-1.66 (1H, m), 1.66-1.88 (4H, m), 1.92-2.08 (2H, m), 2.82-3.01 (2H, m), 3.04-3.22 (2H, m), 3.65-3.84 (2H, m), 3.88-4.01 (2H, m), 4.21-4.30 (4H, m), 6.58 (1H, d, J=7.3 Hz), 6.79 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=7.3 Hz), 7.46-7.53 (1H, m), 7.57-7.84 (7H, m), 8.20 (1H, d, J=7.3 Hz), 8.56 (2H, d, J=6.4 Hz).
    • Example 65 1-methyl-6-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • Colorless solid (isopropyl alcohol/water)
  • mp: 171 to 174° C.
    • Example 66 Synthesis of 2-[2-({3-[4-(2-oxo-oxazolidin-3-yl)phenoxy]propyl}pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.87-2.08 (2H, m), 2.79-3.00 (2H, m), 3.01-3.21 (2H, m), 3.86-3.96 (2H, m), 3.96-4.05 (2H, m), 4.11-4.33 (4H, m), 4.34-4.49 (2H, m), 6.58 (1H, d, J=7.4 Hz), 6.79 (2H, d, J=9.1 Hz), 7.39 (2H, d, J=9.1 Hz), 7.33-7.44 (1H, m), 7.44-7.55 (2H, m), 7.57-7.73 (2H, m), 7.77-7.87 (2H, m), 8.20 (1H, d, J=8.0 Hz), 8.50-8.64 (2H, m).
    • Example 67 Synthesis of 2-[2-({3-[3-(2-oxopyrrolidin-1-yl)phenoxy]propyl}pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.85-2.16 (4H, m), 2.35-2.55 (2H, m), 2.79-3.01 (2H, m), 3.01-3.21 (2H, m), 3.73-4.26 (8H, m), 6.49-6.63 (2H, m), 7.04-7.14 (1H, m), 7.14-7.28 (2H, m), 7.35-7.54 (2H, m), 7.55-7.72 (2H, m), 7.72-7.92 (2H, m), 8.19 (1H, dd, J=8.1 and 0.6 Hz), 8.47-8.66 (2H, m).
    • Example 68 Synthesis of 2-[2-(pyridin-4-ylmethyl-{3-[3-(pyrrolidine-1-carbonyl)phenoxy]propyl}amino)ethyl]-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.
  • 1H-NMR (DMSO-d6, 80° C.) δppm: 1.72-1.90 (4H, m), 1.94-2.14 (2H, m), 2.86-3.05 (2H, m), 3.05-3.22 (2H, m), 3.25-3.50 (4H, m), 3.70-4.36 (6H, m), 6.58 (1H, d, J=7.4 Hz), 6.78-6.95 (2H, m), 7.01 (1H, d, J=7.7 Hz), 7.28 (1H, t, J=7.9 Hz), 7.42 (1H, d, J=7.4 Hz), 7.44-7.51 (1H, m), 7.55-7.74 (2H, m), 7.83 (2H, d, J=4.9 Hz), 8.20 (1H, d, J=8.1 Hz), 8.58 (2H, d, J=5.6 Hz).
    • Example 69 Synthesis of 5-{2-[[3-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yloxy) propyl]-(2-methylpyridin-3-ylmethyl)amino]ethyl}-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-1.95 (2H, m), 2.40 (3H, s), 2.48 (3H, s), 2.76 (2H, t, J=6.9 Hz), 2.86 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.40 (3H, s), 3.63 (2H, s), 3.90 (2H, t, J=6.0 Hz), 4.01 (2H, t, J=6.2 Hz), 6.31 (1H, dd, J=7.3, 0.6 Hz), 6.49-6.51 (2H, m), 6.54 (1H, dd, J=8.5, 2.3 Hz), 6.83 (1H, d, J=8.4 Hz), 6.86 (1H, dd, J=7.7, 4.9 Hz), 6.93 (1H, d, J=7.3 Hz), 7.42-7.44 (1H, m), 8.28-8.30 (1H, m).
    • Example 70 Synthesis of 2-{2-[[3-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yloxy) propyl]-(2-methylpyridin-3-ylmethyl)amino]ethyl}-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 1.92-1.96 (2H, m), 2.48 (3H, s), 2.76 (2H, t, J=6.9 Hz), 2.88 (2H, t, J=6.2 Hz), 3.38 (3H, s), 3.39 (3H, s), 3.63 (2H, s), 3.91 (2H, t, J=6.0 Hz), 4.01 (2H, t, J=6.2 Hz), 6.35 (1H, d, J=7.3 Hz), 6.47 (1H, d, J=2.3 Hz), 6.50 (1H, dd, J=8.4, 2.3 Hz), 6.72 (1H, dd, J=7.6, 4.8 Hz), 6.81 (1H, d, J=8.4 Hz), 6.90 (1H, d, J=7.3 Hz), 7.41 (1H, dd, J=7.6, 1.5 Hz), 7.44-7.49 (2H, m), 7.60-7.65 (1H, m), 8.20-8.22 (1H, m), 8.34-8.36 (1H, m).
    • Example 71 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • A 1N-hydrogen chloride ethanol solution (1.7 ml) was added to an ethanol solution (10 ml) of 1-Methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one (195 mg), which was stirred at room temperature. The reaction mixture was condensed under reduced pressure and ethyl acetate was added to the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (199 mg) as a pale yellow powder.
  • 1H-NMR (DMSO-d6), δppm: 3.08-5.02 (10H, m), 3.61 (3H, s), 6.64 (1H, d, J=9.5 Hz), 7.26-7.38 (2H, m), 7.49 (1H, d, J=9.3 Hz), 7.75-7.83 (1H, m), 7.86 (1H, d, J=9.5 Hz), 7.92 (1H, dd, J=8.0, 5.6 Hz), 8.41 (1H, d, J=8.0 Hz), 8.42-8.53 (1H, m), 8.73-8.81 (2H, m), 8.87 (1H, s), 8.92-9.05 (1H, m).
    • Example 72 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 3.02-5.62 (10H, m), 3.61 (3H, s), 6.63 (1H, d, J=9.5 Hz), 7.21-7.34 (2H, m), 7.47 (1H, d, J=9.1 Hz), 7.85 (1H, d, J=9.5 Hz), 7.92-8.01 (1H, m), 8.02-8.21 (2H, m), 8.49 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.3 Hz), 8.82-8.92 (3H, m).
    • Example 73 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.18-2.43 (2H, m), 3.07-3.49 (4H, m), 3.60 (3H, s), 4.05-4.18 (2H, m), 4.50-4.88 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.7 Hz), 7.27 (1H, d, J=2.7 Hz), 7.47 (1H, d, J=9.1 Hz), 7.84 (1H, d, J=9.5 Hz), 7.94-8.05 (1H, m), 8.08-8.36 (2H, m), 8.49 (1H, d, J=7.6 Hz), 8.82 (1H, d, J=4.9 Hz), 8.83-8.99 (3H, m).
    • Example 74 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.14-2.38 (2H, m), 2.77-4.95 (14H, m), 3.22 (3H, s), 6.73-6.82 (2H, m), 6.99 (1H, d, J=9.2 Hz), 7.99 (1H, d, J=5.7 Hz), 8.22-8.34 (2H, m), 8.52 (1H, d, J=8.1 Hz), 8.81-8.98 (4H, m).
    • Example 75 Synthesis of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(quinolin-6-yloxy)propyl]amine tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 2.22-4.78 (12H, m), 7.51-7.61 (2H, m), 7.73-7.97 (4H, m), 8.15 (1H, d, J=9.1 Hz), 8.20-8.33 (1H, m), 8.62-8.81 (5H, m), 8.98 (1H, d, J=4.9 Hz).
    • Example 76 Synthesis of 6-{5-[benzo[1,3]dioxol-5-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.31-1.50 (2H, m), 1.68-1.93 (4H, m), 2.95-3.12 (2H, m), 3.12-3.40 (4H, m), 3.58 (3H, s), 3.91-4.38 (4H, m), 6.05 (2H, s), 6.59 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=8.0 Hz), 7.10 (1H, dd, J=8.0, 1.5 Hz), 7.23 (1H, dd, J=9.1, 2.9 Hz), 7.27 (1H, d, J=2.9 Hz), 7.30 (1H, d, J=1.5 Hz), 7.44 (1H, d, J=9.1 Hz), 7.78-7.87 (2H, m), 8.26 (1H, d, J=8.0 Hz), 8.73 (1H, d, J=5.4 Hz), 8.79 (1H, s).
    • Example 77 Synthesis of 6-{5-[benzofuran-2-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.40-1.59 (2H, m), 1.68-1.83 (2H, m), 1.83-2.00 (2H, m), 3.04-3.24 (2H, m), 3.24-3.50 (4H, m), 3.58 (3H, s), 3.92-4.11 (2H, m), 4.70 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.19-7.41 (5H, m), 7.44 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=7.3 Hz), 7.82 (1H, d, J=9.5 Hz), 7.96 (1H, dd, J=8.0, 5.2 Hz), 8.46 (1H, d, J=8.0 Hz), 8.79 (1H, d, J=5.2 Hz), 8.90 (1H, s).
    • Example 78 Synthesis of 6-{5-[benzo[b]thiophen-3-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.30-1.49 (2H, m), 1.60-1.98 (4H, m), 3.08-3.28 (2H, m), 3.28-3.51 (4H, m), 3.58 (3H, s), 3.90-4.08 (2H, m), 4.72 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.39-7.52 (3H, m), 7.82 (1H, d, J=9.5 Hz), 7.90 (1H, dd, J=7.9, 5.4 Hz), 8.06 (1H, d, J=8.7 Hz), 8.14 (1H, d, J=7.3 Hz), 8.30-8.40 (2H, m), 8.76 (1H, d, J=5.4 Hz), 8.85 (1H, s).
    • Example 79 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(pyridin-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.39-1.55 (2H, m), 1.69-1.82 (2H, m), 1.69-2.01 (2H, m), 3.11-3.31 (2H, m), 3.39-3.57 (4H, m), 3.60 (3H, s), 3.96-4.11 (2H, m), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.59 (1H, dd, J=6.8, 5.4 Hz), 7.86 (1H, d, J=9.5 Hz), 7.94 (1H, d, J=7.8 Hz), 8.02-8.12 (2H, m), 8.60 (1H, d, J=8.1 Hz), 8.73 (1H, d, J=4.7 Hz), 8.87 (1H, d, J=5.4 Hz), 8.87 (1H, s).
    • Example 80 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.40-1.58 (2H, m), 1.71-1.88 (2H, m), 1.88-2.09 (2H, m), 3.08-3.32 (2H, m), 3.32-3.56 (4H, m), 3.60 (3H, s), 3.96-4.10 (2H, m), 4.79 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.8 Hz), 7.33 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.5 Hz), 8.08 (1H, dd, J=8.1, 5.7 Hz), 8.16 (1H, dd, J=8.1, 5.8 Hz), 8.65 (1H, d, J=8.1 Hz), 8.87 (1H, d, J=5.7 Hz), 9.02 (1H, d, J=5.8 Hz), 9.04 (1H, s), 9.08 (1H, d, J=8.1 Hz), 9.39 (1H, s).
    • Example 81 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • Triethylamine (0.35 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (219 mg) and ice-cooled. Benzenesulfonyl chloride (0.096 ml) was added to the resulting mixture, and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (68 mg) as a yellow powder.
  • 1H-NMR (DMSO-D6) δppm: 1.19-1.39 (2H, m), 1.39-1.55 (2H, m), 1.55-1.78 (2H, m), 2.92-3.20 (4H, m), 3.31-3.50 (2H, m), 3.58 (3H, s), 3.86-4.07 (2H, m), 6.59 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.51-7.71 (3H, m), 7.71-7.89 (3H, m), 7.99 (1H, dd, J=8.0, 5.7 Hz), 8.49 (1H, d, J=8.0 Hz), 8.79 (1H, d, J=5.7 Hz), 8.87 (1H, s).
    • Example 82 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.00-2.19 (2H, m), 2.92 (2H, t, J=7.6 Hz), 3.50-3.66 (4H, m), 3.71 (3H, s), 4.01 (2H, t, J=5.8 Hz), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.13 (1H, dd, J=9.2, 2.8 Hz), 7.19 (1H, dd, J=7.8, 5.4 Hz), 7.29 (1H, d, J=9.2 Hz), 7.50-7.64 (5H, m), 7.96-8.02 (1H, m), 8.42 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=4.8, 1.7 Hz).
    • Example 83 Synthesis of N-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)butyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.70-1.89 (4H, m), 2.89 (2H, t, J=7.5 Hz), 3.40-3.60 (4H, m), 3.68 (3H, s), 4.01 (2H, t, J=5.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.13-7.22 (2H, m), 7.29 (1H, d, J=9.2 Hz), 7.49-7.72 (5H, m), 7.95-8.01 (1H, m), 8.40 (1H, d, J=1.7 Hz), 8.44 (1H, dd, J=4.9, 1.7 Hz).
    • Example 84 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 2.48 (3H, s), 3.60 (3H, s), 3.10-4.65 (10H, m), 6.63 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.41 (4H, m), 7.48 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.96 (1H, dd, J=7.8, 5.5 Hz), 8.43 (1H, d, J=7.8 Hz), 8.80 (1H, d, J=5.5 Hz), 8.90 (1H, s).
    • Example 85 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.61-1.86 (2H, m), 1.86-2.14 (2H, m), 2.48 (3H, s), 3.10-3.33 (2H, m), 3.33-3.58 (4H, m), 3.60 (3H, s), 3.90-4.80 (4H, m), 6.61 (1H, d, J=9.5 Hz), 7.18-7.37 (5H, m), 7.47 (1H, d, J=9.2 Hz), 7.75 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=8.0, 5.5 Hz), 8.56 (1H, d, J=8.0 Hz), 8.85 (1H, d, J=5.5 Hz), 8.98 (1H, s).
    • Example 86 Synthesis of 1-methyl-6-{3-[N-(3-phenylpropyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.91-2.12 (2H, m), 2.12-2.31 (2H, m), 2.59-2.78 (2H, m), 3.58 (3H, s), 3.05-4.39 (10H, m), 6.60 (1H, d, J=9.5 Hz), 7.13-7.34 (7H, m), 7.45 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.98 (1H, dd, J=7.9, 5.5 Hz), 8.51 (1H, d, J=7.9 Hz), 8.80 (1H, d, J=5.5 Hz), 8.92 (1H, s).
    • Example 87 Synthesis of 1-methyl-6-{4-[N-(3-phenylpropyl)-N-(2-pyridin-3-ylethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.71-2.15 (6H, m), 2.55-2.75 (2H, m), 3.57 (3H, s), 3.00-4.34 (10H, m), 6.59 (1H, d, J=9.5 Hz), 7.14-7.32 (7H, m), 7.44 (1H, d, J=9.2 Hz), 7.81 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=7.9, 5.5 Hz), 8.53 (1H, d, J=7.9 Hz), 8.81 (1H, d, J=5.5 Hz), 8.93 (1H, s).
    • Example 88 Synthesis of 1-methyl-6-{5-[N-((E)-3-phenylallyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.40-1.60 (2H, m), 1.71-2.00 (4H, m), 3.59 (3H, s), 2.97-4.20 (10H, m), 6.51 (1H, dt, J=15.9, 7.0 Hz), 6.61 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=15.9 Hz), 7.20-7.54 (8H, m), 7.83 (1H, d, J=9.5 Hz), 8.00 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.96 (1H, s).
    • Example 89 Synthesis of N-methyl-4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride
  • Diethyl phosphorocyanidate (39.1 mg) was added to a DMF solution (1 ml) of 4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid (0.10 g), methylamine hydrochloride (27 mg), and triethylamine (0.07 ml), and the mixture was stirred at room temperature overnight. Ice water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (81.3 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm: 1.40-1.89 (6H, m), 2.54 (2H, t, J=6.2 Hz), 2.71-2.76 (4H, m), 3.03 (3H, d, J=4.9 Hz), 3.66 (2H, s), 3.73 (3H, s), 3.98 (2H, t, J=6.4 Hz), 6.22-6.31 (1H, m), 6.74 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.16-7.20 (2H, m), 7.28-7.33 (3H, m), 7.42-7.68 (4H, m), 8.41-7.46 (2H, m).
    • Example 90 Synthesis of N-ethyl-4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 89 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.11 (3H, t, J=7.2 Hz), 1.34-1.50 (2H, m), 1.70-1.96 (4H, m), 3.60 (3H, s), 3.00-4.60 (12H, m), 6.62 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.78 (2H, d, J=8.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.86-7.96 (3H, m), 8.31 (1H, d, J=8.0 Hz), 8.55-8.64 (1H, m), 8.76 (1H, d, J=5.2 Hz), 8.80-8.85 (1H, m).
    • Example 91 Synthesis of N,N-dimethyl-4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl](2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 89 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.35-1.51 (2H, m), 1.68-1.92 (4H, m), 2.89 (3H, s), 3.00 (3H, s), 3.60 (3H, s), 3.04-4.59 (10H, m), 6.62 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.43-7.52 (3H, m), 7.75 (2H, d, J=8.1 Hz), 7.85 (1H, d, J=9.5 Hz), 7.81-7.89 (1H, m), 8.29 (1H, d, J=8.0 Hz), 8.75 (1H, d, J=5.4 Hz), 8.81 (1H, s).
    • Example 92 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.41-1.60 (2H, m), 1.69-1.88 (2H, m), 1.88-2.06 (2H, m), 3.60 (3H, s), 3.21-4.26 (8H, m), 4.85 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.65-7.74 (1H, m), 7.79-7.91 (3H, m), 8.02-8.13 (3H, m), 8.53 (1H, d, J=8.5 Hz), 8.59 (1H, d, J=8.2 Hz), 8.86 (1H, d, J=5.4 Hz), 9.00 (1H, s).
    • Example 93 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.42-1.60 (2H, m), 1.72-1.90 (2H, m), 1.90-2.10 (2H, m), 3.60 (3H, s), 3.14-4.36 (8H, m), 4.76 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.79-7.90 (2H, m), 7.97-8.08 (2H, m), 8.17 (1H, d, J=7.9 Hz), 8.27 (1H, d, J=8.6 Hz), 8.57 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.3 Hz), 8.99 (1H, s), 9.13 (1H, s), 9.45 (1H, d, J=1.7 Hz).
    • Example 94 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.33-1.52 (2H, m), 1.63-1.82 (2H, m), 1.82-2.04 (2H, m), 3.60 (3H, s), 2.99-4.26 (8H, m), 5.00-5.30 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.7 Hz), 7.28 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.87-7.96 (1H, m), 7.96-8.12 (2H, m), 8.37 (1H, d, J=8.5 Hz), 8.42-8.66 (3H, m), 8.83 (1H, d, J=5.5 Hz), 8.94 (1H, s), 9.25 (1H, d, J=5.1 Hz).
    • Example 95 Synthesis of 1-methyl-6-{5-[N-(naphthalen-2-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.31-1.56 (2H, m), 1.67-1.82 (2H, m), 1.82-2.05 (2H, m), 3.05-3.25 (2H, m), 3.60 (3H, s), 3.36-4.20 (6H, m), 4.49-4.75 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.7 Hz), 7.28 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.53-7.65 (2H, m), 7.81-8.08 (6H, m), 8.24 (1H, s), 8.55 (1H, d, J=8.2 Hz), 8.83 (1H, d, J=5.4 Hz), 8.98 (1H, s).
    • Example 96 Synthesis of 1-methyl-6-{5-[N-(pyridin-2-yl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (182 mg), 2-bromopyridine (0.060 ml), palladium acetate (II) (11.2 mg), xantphos (32 mg), and sodium t-butoxide (68 mg) were added to toluene (2 ml). The mixture was heated at 80° C. for 10 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (0.58 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and diethyl ether were added to the residue. The precipitated insoluble matter was separated, washed with diethyl ether, and dried to give the title compound (72 mg) as a yellow powder.
  • 1H-NMR (DMSO-D6) δppm: 1.42-1.91 (6H, m), 3.60 (3H, s), 3.09-4.36 (8H, m), 6.62 (1H, d, J=9.5 Hz), 6.98 (1H, t, J=6.6 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.38 (1H, d, J=9.1 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.98-8.11 (3H, m), 8.76-8.88 (2H, m), 9.16 (1H, s).
    • Example 97 Synthesis of N-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)butyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.50-1.76 (4H, m), 3.00-3.15 (2H, m), 3.15-3.29 (2H, m), 3.40-3.55 (2H, m), 3.60 (3H, s), 3.91-4.01 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.54-7.73 (3H, m), 7.77-7.89 (3H, m), 8.02 (1H, dd, J=8.0, 5.6 Hz), 8.52 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.6 Hz), 8.90 (1H, s).
    • Example 98 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.21-1.41 (2H, m), 1.41-1.59 (2H, m), 1.59-1.79 (2H, m), 2.91-3.18 (4H, m), 3.30-3.48 (2H, m), 3.59 (3H, s), 3.90-4.08 (2H, m), 4.44 (2H, s), 6.60 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.32-7.43 (5H, m), 7.45 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.5 Hz), 8.87 (1H, s).
    • Example 99 Synthesis of 2,4,6-trimethyl-N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.21-1.41 (2H, m), 1.41-1.75 (4H, m), 2.22 (3H, s), 2.37 (6H, s), 2.93-3.08 (2H, m), 3.26-3.38 (2H, m), 3.45-3.59 (2H, m), 3.60 (3H, s), 3.89-4.02 (2H, m), 6.61 (1H, d, J=9.5 Hz), 6.87 (2H, s), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.88 (2H, m), 8.32 (1H, d, J=8.0 Hz), 8.71-8.79 (2H, m).
    • Example 100 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)biphenyl-4-sulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.25-1.45 (2H, m), 1.45-1.63 (2H, m), 1.62-1.81 (2H, m), 3.00-3.18 (2H, m), 3.18-3.30 (2H, m), 3.41-3.57 (2H, m), 3.58 (3H, s), 3.90-4.10 (2H, m), 6.60 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.41-7.51 (4H, m), 7.69-7.72 (2H, m), 7.81 (1H, d, J=9.5 Hz), 7.85-7.90 (4H, m), 8.00-8.05 (1H, m), 8.53 (1H, d, J=5.5 Hz), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).
    • Example 101 Synthesis of 6-[3-[N,N-bis(pyridin-3-ylmethyl)amino]propoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.05-2.36 (2H, m), 2.84-3.19 (2H, m), 3.60 (3H, s), 3.94-4.12 (2H, m), 4.40-4.71 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.6 Hz), 7.24 (1H, d, J=2.6 Hz), 7.45 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.00 (2H, dd, J=7.7, 5.4 Hz), 8.77 (2H, d, J=7.7 Hz), 8.90 (2H, dd, J=5.4 Hz), 9.14 (2H, s).
    • Example 102 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.21-1.44 (2H, m), 1.51-1.75 (4H, m), 2.98-3.19 (2H, m), 3.19-3.40 (2H, m), 3.59 (3H, s), 3.59-3.78 (2H, m), 3.89-4.08 (2H, m), 6.58 (1H, d, J=9.5 Hz), 7.14-7.28 (4H, m), 7.33-7.47 (4H, m), 7.79 (1H, d, J=9.5 Hz), 7.87-7.99 (1H, m), 8.25-8.45 (1H, m), 8.74 (1H, d, J=5.4 Hz), 8.69-8.85 (1H, m).
    • Example 103 Synthesis of 2-methyl-N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.21-1.49 (2H, m), 1.49-1.80 (4H, m), 2.13 (3H, s), 2.89-3.77 (6H, m), 3.58 (3H, s), 3.86-4.10 (2H, m), 6.55 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=7.4 Hz), 7.10-7.28 (5H, m), 7.35-7.43 (1H, m), 7.59-7.73 (1H, m), 7.74 (1H, d, J=9.5 Hz), 7.89-8.23 (1H, m), 8.46-8.69 (1H, m), 8.59 (1H, d, J=5.9 Hz).
    • Example 104 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)-nicotinamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.28-1.48 (2H, m), 1.52-1.79 (4H, m), 2.78-3.00 (2H, m), 3.22-3.51 (2H, m), 3.58 (3H, s), 3.51-3.67 (2H, m), 3.91-4.06 (2H, m), 6.55 (1H, d, J=9.5 Hz), 7.15-7.28 (3H, m), 7.33-7.42 (2H, m), 7.47-7.55 (1H, m), 7.55-7.63 (1H, m), 7.74 (1H, d, J=9.5 Hz), 8.32-8.44 (3H, m), 8.57 (1H, dd, J=4.8, 1.7 Hz).
    • Example 105 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(thiophen-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.38-1.56 (2H, m), 1.68-2.00 (4H, m), 3.00-3.19 (2H, m), 3.27-3.49 (4H, m), 3.60 (3H, s), 3.92-4.10 (2H, m), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.14 (1H, dd, J=5.1, 3.5 Hz), 7.25 (1H, dd, J=9.1, 2.8 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.49-7.54 (1H, m), 7.72 (1H, dd, J=5.1, 1.1 Hz), 7.85 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.6 Hz), 8.50 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).
    • Example 106 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(thiophen-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.35-1.55 (2H, m), 1.69-2.00 (4H, m), 2.95-3.14 (2H, m), 3.29-3.51 (4H, m), 3.60 (3H, s), 3.97-4.10 (2H, m), 4.43 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.1, 2.7 Hz), 7.31 (1H, d, J=2.7 Hz), 7.44-7.52 (2H, m), 7.63-7.69 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.95 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=8.1, 5.6 Hz), 8.54 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.6 Hz), 8.96 (1H, s).
    • Example 107 Synthesis of 1-methyl-6-{5-[N-(pyridin-3-yl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.40-1.55 (4H, m), 1.66-1.87 (2H, m), 2.98-3.15 (2H, m), 3.32-4.10 (6H, m), 3.59 (3H, s), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.1, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.1 Hz), 7.77 (1H, dd, J=9.0, 5.0 Hz), 7.83 (1H, d, J=9.5 Hz), 7.88-8.09 (3H, m), 8.35 (1H, d, J=2.6 Hz), 8.61 (1H, d, J=8.1 Hz), 8.81 (1H, d, J=5.5 Hz), 9.01 (1H, s).
    • Example 108 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.95-2.10 (2H, m), 3.50 (2H, t, J=7.2 Hz), 3.58 (3H, s), 3.75-4.18 (2H, m), 4.77 (2H, s), 6.57 (1H, d, J=9.5 Hz), 7.08 (1H, dd, J=9.1, 2.7 Hz), 7.12 (1H, d, J=2.7 Hz), 7.35-7.45 (6H, m), 7.70-7.79 (1H, m), 7.75 (1H, d, J=9.5 Hz), 8.18 (1H, d, J=6.9 Hz), 8.67 (1H, d, J=5.2 Hz), 8.71 (1H, s).
    • Example 109 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.82-2.00 (2H, m), 3.02-3.15 (2H, m), 3.29-3.39 (2H, m), 3.45-3.54 (2H, m), 3.60 (3H, s), 3.97 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=9.5 Hz), 7.19-7.27 (2H, m), 7.47 (1H, d, J=9.1 Hz), 7.53-7.71 (3H, m), 7.77-7.83 (2H, m), 7.85 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.91 (1H, s).
    • Example 110 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 3.18-3.35 (2H, m), 3.35-3.53 (4H, m), 3.60 (3H, s), 4.01-4.20 (2H, m), 4.50-4.78 (2H, m), 6.63 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=9.1 Hz), 7.82-7.93 (1H, m), 7.85 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.2, 5.8 Hz), 8.52 (1H, d, J=8.2 Hz), 8.67 (1H, d, J=7.0 Hz), 8.80-8.90 (2H, m), 8.95 (1H, s), 9.14 (1H, s).
    • Example 111 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)ethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.15 (3H, t, J=7.4 Hz), 1.30-1.49 (2H, m), 1.49-1.65 (2H, m), 1.65-1.82 (2H, m), 2.80-2.93 (2H, m), 3.14-3.50 (6H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.4 Hz), 6.60 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.39-7.48 (1H, m), 7.83 (1H, d, J=9.5 Hz), 7.78-7.85 (1H, m), 8.48 (1H, d, J=5.2 Hz), 8.54 (1H, s).
    • Example 112 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)cyclohexylmethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.90-1.89 (17H, m), 2.75-2.95 (4H, m), 3.08-3.49 (4H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.5 Hz), 6.60 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.0, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.42 (1H, dd, J=7.9, 4.9 Hz), 7.45 (1H, d, J=9.0 Hz), 7.77-7.82 (1H, m), 7.83 (1H, d, J=9.5 Hz), 8.48 (1H, dd, J=4.9, 1.6 Hz), 8.53 (1H, d, J=1.6 Hz).
    • Example 113 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.70-1.91 (2H, m), 3.36 (2H, t, J=7.7 Hz), 3.60 (3H, s), 3.89 (2H, t, J=6.0 Hz), 4.60 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.11-7.19 (2H, m), 7.44 (1H, d, J=8.8 Hz), 7.60-7.77 (3H, m), 7.83 (1H, d, J=9.5 Hz), 7.92 (2H, d, J=7.2 Hz), 8.03 (1H, dd, J=8.0, 5.6 Hz), 8.55 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.89 (1H, s).
    • Example 114 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 3.10-3.25 (2H, m), 3.60 (3H, s), 3.70-3.90 (4H, m), 4.11-4.28 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.10 (1H, dd, J=9.2, 2.9 Hz), 7.23 (1H, d, J=2.9 Hz), 7.44 (1H, d, J=9.2 Hz), 7.74-7.91 (3H, m), 7.93-8.09 (3H, m), 8.53 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.5 Hz), 8.93 (1H, s).
    • Example 115 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.88-2.04 (2H, m), 3.00-3.14 (2H, m), 3.23-3.39 (2H, m), 3.39-3.51 (2H, m), 3.60 (3H, s), 3.89-4.09 (2H, m), 4.47 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21-7.30 (2H, m), 7.33-7.44 (5H, m), 7.48 (1H, d, J=9.0 Hz), 7.86 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.5 Hz), 8.87 (1H, s).
    • Example 116 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)phenylmethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.71-1.89 (2H, m), 3.24-3.41 (2H, m), 3.59 (3H, s), 3.88 (2H, t, J=6.0 Hz), 4.55 (2H, s), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.09-7.21 (2H, m), 7.34-7.51 (6H, m), 7.83 (1H, d, J=9.5 Hz), 7.94-8.06 (1H, m), 8.50 (1H, d, J=7.9 Hz), 8.81 (1H, d, J=5.1 Hz), 8.85 (1H, s).
    • Example 117 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 3.01-3.19 (2H, m), 3.40-3.61 (4H, m), 3.60 (3H, s), 4.00-4.15 (2H, m), 4.54 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.0, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.32-7.44 (5H, m), 7.48 (1H, d, J=9.0 Hz), 7.86 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.1, 5.6 Hz), 8.49 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.6 Hz), 8.87 (1H, s).
    • Example 118 Synthesis of 1-methyl-6-{2-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]ethoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.48 (3H, s), 3.35-3.84 (6H, m), 3.61 (3H, s), 4.59 (4H, s), 6.64 (1H, d, J=9.5 Hz), 7.23-7.41 (5H, m), 7.50 (1H, d, J=9.2 Hz), 7.80 (1H, d, J=7.4 Hz), 7.86 (1H, d, J=9.5 Hz), 8.03 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.85 (1H, d, J=5.5 Hz), 8.96 (1H, s).
    • Example 119 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.80-2.06 (2H, m), 2.17 (3H, s), 3.26-3.49 (2H, m), 3.59 (3H, s), 3.78-4.00 (2H, m), 4.80-5.01 (2H, m), 6.58 (1H, d, J=9.5 Hz), 6.91-7.51 (7H, m), 7.77 (1H, d, J=9.5 Hz), 7.89-8.11 (1H, m), 8.44-8.65 (1H, m), 8.73-8.90 (1H, m), 8.90-9.03 (1H, m).
    • Example 120 Synthesis of 6-[2-[N,N-bis-(pyridin-3-ylmethyl)amino]ethoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.85-3.15 (2H, m), 3.61 (3H, s), 3.89-4.41 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.25-7.34 (2H, m), 7.46 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=9.5 Hz), 7.89-8.01 (2H, m), 8.50-8.60 (2H, m), 8.80 (2H, d, J=5.2 Hz), 8.95 (2H, s).
    • Example 121 Synthesis of 6-[2-[N,N-bis-(pyridin-4-ylmethyl)amino]ethoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.91-3.05 (2H, m), 3.60 (3H, s), 4.14 (4H, s), 4.12-4.29 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.21-7.27 (2H, m), 7.41-7.48 (1H, m), 7.80 (1H, d, J=9.5 Hz), 8.09 (4H, d, J=6.5 Hz), 8.84 (4H, d, J=6.5 Hz).
    • Example 122 Synthesis of 6-[3-[N,N-bis-(pyridin-4-ylmethyl)amino]propoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.96-2.19 (2H, m), 2.70-2.98 (2H, m), 3.60 (3H, s), 3.92-4.10 (2H, m), 4.10-4.43 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.08 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.23 (4H, d, J=6.0 Hz), 8.88 (4H, d, J=6.0 Hz).
    • Example 123 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 3.07-3.21 (2H, m), 3.49-3.69 (4H, m), 3.60 (3H, s), 4.05-4.23 (2H, m), 6.63 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.9 Hz), 7.25 (1H, d, J=2.9 Hz), 7.46 (1H, d, J=9.1 Hz), 7.53-7.72 (3H, m), 7.79-7.89 (3H, m), 8.01 (1H, dd, J=8.1, 5.6 Hz), 8.53 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.6 Hz), 8.89 (1H, s).
    • Example 124 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.82-2.00 (2H, m), 2.12 (3H, s), 2.88-3.50 (6H, m), 3.59 (3H, s), 4.04-4.30 (2H, m), 6.59 (1H, d, J=9.5 Hz), 6.96-7.33 (6H, m), 7.33-7.50 (1H, m), 7.69-7.97 (2H, m), 8.41-8.52 (1H, m), 8.62-8.78 (1H, m), 8.85-8.93 (1H, m).
    • Example 125 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide
  • Sodium iodide (2.93 g) was added to a acetonitrile solution (20 ml) of methanesulfonic acid
  • 2-[[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)propyl]-(2-nitro-benzenesulfonyl)amino]-ethyl ester (4.37 g), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. 4-(pyridin-3-ylmethoxy)piperidine (1.87 g) and N-ethyl diisopropylamine (4.23 ml) were then added to the reaction mixture and stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to give the title compound (3.48 g) as a yellow solid.
  • 1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.82-1.99 (2H, m), 2.04-2.29 (4H, m), 2.50-2.61 (2H, m), 2.69-2.82 (2H, m), 3.35-3.52 (3H, m), 3.52-3.68 (2H, m), 3.70 (3H, s), 4.01 (2H, t, J=5.9 Hz), 4.54 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.32 (2H, m), 7.55-7.70 (5H, m), 8.04-8.13 (1H, m), 8.53 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz).
    • Example 126 Synthesis of 1-methyl-6-{5-[N-(3-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.33-1.51 (2H, m), 1.69-1.99 (4H, m), 2.32 (3H, s), 2.96-3.15 (2H, m), 3.29-3.50 (4H, m), 3.60 (3H, s), 3.95-4.10 (2H, m), 4.26-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.21-7.38 (4H, m), 7.43-7.55 (3H, m), 7.85 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.0, 5.6 Hz), 8.48 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).
    • Example 127 Synthesis of 1-methyl-6-{5-[N-(4-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.35-1.54 (2H, m), 1.66-2.00 (4H, m), 2.32 (3H, s), 2.94-3.11 (2H, m), 3.28-3.51 (4H, m), 3.60 (3H, s), 4.03 (2H, t, J=6.3 Hz), 4.24-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.19-7.34 (4H, m), 7.46 (1H, d, J=9.1 Hz), 7.59 (2H, d, J=8.0 Hz), 7.85 (1H, d, J=9.5 Hz), 8.04 (1H, dd, J=8.1, 5.5 Hz), 8.53 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.5 Hz), 8.95 (1H, s).
    • Example 128 Synthesis of 6-{5-[N-(2-methoxybenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.33-1.51 (2H, m), 1.68-1.97 (4H, m), 2.96-3.20 (2H, m), 3.28-3.49 (2H, m), 3.59 (3H, s), 3.85 (3H, s), 3.95-4.09 (2H, m), 4.25-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 6.98-7.06 (1H, m), 7.09-7.16 (1H, m), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.42-7.50 (2H, m), 7.61-7.69 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.97-8.06 (1H, m), 8.42 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.3 Hz), 8.93 (1H, s).
    • Example 129 Synthesis of 6-{5-[N-(2-chlorobenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.36-1.55 (2H, m), 1.69-2.00 (4H, m), 3.05-3.22 (2H, m), 3.34-3.64 (4H, m), 3.59 (3H, s), 4.03 (2H, t, J=6.3 Hz), 4.46-4.72 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.40-7.55 (3H, m), 7.55-7.64 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.96-8.09 (2H, m), 8.49 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).
    • Example 130 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.84-2.00 (2H, m), 2.79 (2H, t, J=6.7 Hz), 2.84-2.96 (4H, m), 3.71 (3H, s), 3.85 (2H, t, J=6.0 Hz), 4.10 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.77 (1H, d, J=2.8 Hz), 6.98 (1H, dd, J=9.2, 2.8 Hz), 7.09-7.16 (1H, m), 7.24 (1H, d, J=9.2 Hz), 7.33 (1H, d, J=4.4 Hz), 7.35-7.45 (2H, m), 7.57 (1H, d, J=9.5 Hz), 7.57-7.66 (1H, m), 8.00-8.11 (2H, m), 8.41-8.47 (2H, m), 8.74 (1H, d, J=4.4 Hz).
    • Example 131 Synthesis of 1-methyl-6-{2-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.72-2.86 (2H, m), 2.86-3.01 (2H, m), 3.01-3.15 (2H, m), 3.69 (3H, s), 4.00-4.14 (2H, m), 4.22 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.89 (1H, d, J=2.8 Hz), 7.03-7.13 (2H, m), 7.26 (1H, d, J=9.2 Hz), 7.33-7.48 (3H, m), 7.55 (1H, d, J=9.5 Hz), 7.64-7.72 (1H, m), 8.05-8.15 (2H, m), 8.38 (1H, dd, J=4.7, 1.8 Hz), 8.43 (1H, d, J=1.8 Hz), 8.79 (1H, d, J=4.4 Hz).
    • Example 132 Synthesis of 1-methyl-6-[3-N-(pyridin-3-ylmethyl)-N-(quinolin-4-ylmethyl)amino]propoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.93-2.25 (2H, m), 2.63-3.08 (2H, m), 3.62 (3H, s), 3.85-4.79 (6H, m), 6.61 (1H, d, J=9.5 Hz), 6.99 (1H, dd, J=9.2, 2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 7.40 (1H, d, J=9.2 Hz), 7.79 (1H, d, J=9.5 Hz), 7.85-8.08 (3H, m), 8.19-8.36 (1H, m), 8.33 (1H, d, J=8.4 Hz), 8.41-8.52 (1H, m), 8.58-8.71 (1H, m), 8.83 (1H, d, J=5.4 Hz), 8.95-9.07 (1H, m), 9.16 (1H, d, J=5.4 Hz).
    • Example 133 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.52-1.79 (2H, m), 1.79-1.98 (2H, m), 2.11-2.29 (2H, m), 2.59 (2H, t, J=6.8 Hz), 2.67-2.81 (2H, m), 3.35-3.49 (1H, m), 3.57 (2H, t, J=6.8 Hz), 3.70 (3H, s), 3.81 (2H, t, J=5.5 Hz), 4.21 (2H, t, J=5.5 Hz), 4.53 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.09 (1H, dd, J=9.1, 2.8 Hz), 7.25-7.32 (2H, m), 7.58 (1H, d, J=9.5 Hz), 7.62-7.72 (4H, m), 8.10-8.16 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.57 (1H, d, J=1.6 Hz).
    • Example 134 Synthesis of 1-methyl-6-[3-[N-(2-methylbenzyl)-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino]propoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.70-2.40 (6H, m), 2.45 (3H, s), 2.78-3.95 (11H, m), 3.60 (3H, s), 4.01-4.19 (2H, m), 4.38-4.60 (2H, m), 4.71 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.3, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.21-7.39 (3H, m), 7.47 (1H, d, J=9.3 Hz), 7.61-7.78 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.85-7.99 (1H, m), 8.30-8.48 (1H, m), 8.80 (1H, d, J=4.7 Hz), 8.76-8.94 (1H, m).
    • Example 135 Synthesis of 1-methyl-6-[3-[N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino]propoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.79-2.47 (6H, m), 3.01-3.98 (11H, m), 3.60 (3H, s), 3.98-4.21 (2H, m), 4.73 (2H, s), 4.78 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.9 Hz), 7.32 (1H, d, J=2.9 Hz), 7.48 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.5 Hz), 8.04-8.14 (2H, m), 8.55-8.70 (1H, m), 8.87-9.04 (4H, m), 9.30 (1H, s).
    • Example 136 Synthesis of 1-methyl-6-[3-[N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino]propoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.79-2.35 (6H, m), 2.90-3.95 (11H, m), 3.60 (3H, s), 3.95-4.15 (2H, m), 4.40-4.69 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.5 Hz), 7.28 (1H, d, J=2.5 Hz), 7.46 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=9.5 Hz), 7.96-8.12 (1H, m), 8.33 (2H, s), 8.60 (1H, d, J=7.1 Hz), 8.83-9.01 (4H, m).
    • Example 137 Synthesis of 1-methyl-6-[2-(N-(2-methylbenzyl)-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino)ethoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.75-2.29 (4H, m), 2.46 (3H, s), 2.92-3.95 (11H, m), 3.61 (3H, s), 4.38-4.69 (4H, m), 4.75 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.23-7.42 (5H, m), 7.50 (1H, d, J=9.0 Hz), 7.73-7.85 (1H, m), 7.84 (1H, d, J=9.5 Hz), 8.06 (1H, dd, J=7.5, 5.6 Hz), 8.56 (1H, d, J=7.5 Hz), 8.87 (1H, d, J=5.6 Hz), 8.94 (1H, s).
    • Example 138 Synthesis of 1-methyl-6-[2-(N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino)ethoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.59-1.74 (2H, m), 1.83-1.99 (2H, m), 2.09-2.25 (2H, m), 2.46-2.60 (2H, m), 2.70-2.85 (4H, m), 2.94-3.06 (2H, m), 3.39-3.50 (1H, m), 3.69 (3H, s), 3.78 (2H, s), 4.08 (2H, t, J=5.7 Hz), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.20-7.31 (3H, m), 7.58 (1H, d, J=9.5 Hz), 7.65-7.76 (2H, m), 8.49 (1H, dd, J=4.8, 1.7 Hz), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz), 8.60 (1H, d, J=1.7 Hz).
    • Example 139 Synthesis of 1-methyl-6-[2-(N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino)ethoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.82-1.96 (2H, m), 2.08-2.22 (2H, m), 2.45-2.57 (2H, m), 2.65-2.89 (4H, m), 2.98 (2H, t, J=5.7 Hz), 3.35-3.49 (1H, m), 3.69 (3H, s), 3.79 (2H, s), 4.09 (2H, t, J=5.7 Hz), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.36 (4H, m), 7.58 (1H, d, J=9.5 Hz), 7.68 (1H, dt, J=7.8, 1.7 Hz), 8.48-8.55 (3H, m), 8.57 (1H, d, J=1.7 Hz).
    • Example 140 Synthesis of 6-[4-(N,N-bis-(pyridin-3-ylmethyl)amino)butoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.60-1.80 (2H, m), 1.80-2.05 (2H, m), 2.80-3.18 (2H, m), 3.60 (3H, s), 3.69-4.71 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.91 (2H, m), 7.85 (1H, d, J=9.5 Hz), 8.58 (2H, d, J=8.0 Hz), 8.82 (2H, d, J=4.4 Hz), 9.03 (2H, s).
    • Example 141 Synthesis of 6-[4-(N,N-bis-(pyridin-4-ylmethyl)amino)butoxy]-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.64-1.88 (4H, m), 2.58-2.82 (2H, m), 3.60 (3H, s), 3.88-4.05 (2H, m), 4.19 (4H, s), 6.61 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.24 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.19 (4H, d, J=5.6 Hz), 8.90 (4H, d, J=5.6 Hz).
    • Example 142 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(pyridin-3-ylmethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.62-1.80 (2H, m), 1.92-2.14 (2H, m), 2.33 (3H, s), 3.00-3.25 (2H, m), 3.60 (3H, s), 3.90-4.78 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.13-7.35 (5H, m), 7.48 (1H, d, J=9.2 Hz), 7.63-7.79 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.79-7.92 (1H, m), 8.59-8.75 (1H, m), 8.83 (1H, s), 9.02-9.20 (1H, m).
    • Example 143 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(pyridin-4-ylmethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.60-1.80 (2H, m), 1.89-2.15 (2H, m), 2.36 (3H, s), 3.00-3.30 (2H, m), 3.60 (3H, s), 3.82-4.82 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.06-7.31 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.61-7.79 (1H, m), 7.84 (1H, d, J=9.5 Hz), 8.11-8.40 (2H, m), 8.86 (2H, d, J=3.5 Hz).
    • Example 144 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.55-1.78 (2H, m), 1.78-1.95 (2H, m), 1.95-2.25 (4H, m), 2.55 (2H, t, J=6.8 Hz), 2.65-2.81 (2H, m), 3.32-3.51 (3H, m), 3.58 (2H, t, J=7.2 Hz), 3.71 (3H, s), 4.01 (2H, t, J=5.8 Hz), 4.53 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.30 (3H, m), 7.54-7.64 (4H, m), 8.50-8.61 (1H, m), 8.56 (2H, d, J=6.0 Hz).
    • Example 145 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.51-1.74 (2H, m), 1.74-1.97 (2H, m), 2.05-2.29 (4H, m), 2.52 (2H, t, J=6.9 Hz), 2.64-2.78 (2H, m), 3.28 (2H, t, J=7.1 Hz), 3.36-3.50 (3H, m), 3.70 (3H, s), 4.06 (2H, t, J=6.0 Hz), 4.53 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.31 (2H, m), 7.45-7.62 (4H, m), 7.62-7.70 (1H, m), 7.81-7.88 (2H, m), 8.52 (1H, dd, J=4.8, 1.6 Hz), 8.57 (1H, d, J=1.6 Hz).
    • Example 146 Synthesis of N-[3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}phenylmethanesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.85-2.08 (2H, m), 2.08-2.29 (4H, m), 2.46 (2H, t, J=6.5 Hz), 2.69-2.83 (2H, m), 3.19 (2H, t, J=7.3 Hz), 3.27 (2H, t, J=6.5 Hz), 3.38-3.52 (1H, m), 3.69 (3H, s), 3.97 (2H, t, J=6.1 Hz), 4.39 (2H, s), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.31 (2H, m), 7.34-7.46 (5H, m), 7.58 (1H, d, J=9.5 Hz), 7.67 (1H, dt, J=7.8, 1.8 Hz), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz).
    • Example 147 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzamide
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.31-2.81 (10H, m), 2.21 (3H, s), 3.04-4.16 (9H, m), 3.58 (3H, s), 4.40-4.60 (2H, m), 6.57 (1H, d, J=9.5 Hz), 6.95-7.50 (8H, m), 7.61-7.88 (2H, m), 8.47 (1H, d, J=3.5 Hz), 8.51 (1H, s).
    • Example 148 Synthesis of N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.00-2.14 (2H, m), 2.55-2.68 (2H, m), 2.80-3.00 (4H, m), 3.33 (3H, s), 3.50-3.65 (4H, m), 3.94 (2H, t, J=5.8 Hz), 6.66-6.75 (2H, m), 6.87 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J=7.8, 4.8 Hz), 7.50-7.68 (4H, m), 7.97-8.02 (1H, m), 8.41 (1H, d, J=1.6 Hz), 8.46 (1H, dd, J=4.8, 1.6 Hz).
    • Example 149 Synthesis of 1-methyl-6-[3-(N-(2-methylbenzyl)-N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}amino)propoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.81-2.39 (6H, m), 2.46 (3H, s), 3.01-3.51 (7H, m), 3.60 (3H, s), 3.63-3.91 (4H, m), 4.01-4.18 (2H, m), 4.30-4.52 (2H, m), 4.84 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.21-7.38 (4H, m), 7.47 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=6.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.92 (2H, d, J=5.7 Hz), 8.84 (2H, d, J=5.7 Hz).
    • Example 150 Synthesis of 1-methyl-6-[3-(N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino)propoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.95-2.33 (6H, m), 3.00-3.90 (13H, m), 3.60 (3H, s), 4.00-4.12 (2H, m), 4.87 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.1, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.89 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.96-8.05 (2H, m), 8.56 (1H, d, J=7.9 Hz), 8.82 (1H, d, J=4.0 Hz), 8.89 (2H, d, J=6.6 Hz), 9.05 (1H, s).
    • Example 151 Synthesis of 1-methyl-6-[3-(N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino)propoxy]-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.82-2.30 (6H, m), 2.78-3.90 (13H, m), 3.60 (3H, s), 4.00-4.18 (2H, m), 4.87 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.9 Hz), 7.27 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.02 (2H, d, J=6.4 Hz), 8.15 (2H, d, J=5.3 Hz), 8.86 (2H, d, J=5.3 Hz), 8.89 (2H, d, J=6.4 Hz).
    • Example 152 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.14-2.41 (2H, m), 2.41-2.57 (2H, m), 2.70-2.85 (2H, m), 2.47 (3H, s), 3.21 (3H, s), 3.20-3.39 (2H, m), 3.39-3.62 (4H, m), 3.92-4.08 (2H, m), 4.48 (2H, s), 6.75-6.82 (2H, m), 6.99 (1H, d, J=9.4 Hz), 7.09-7.40 (3H, m), 7.76 (1H, d, J=7.3 Hz), 8.00 (1H, dd, J=8.0, 5.3 Hz), 8.50 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.95 (1H, s).
    • Example 153 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 2.40-2.61 (2H, m), 2.83 (2H, t, J=6.8 Hz), 3.22 (3H, s), 3.19-3.38 (2H, m), 3.38-3.60 (4H, m), 3.98-4.10 (2H, m), 4.67 (2H, s), 6.76-6.86 (2H, m), 7.00 (1H, d, J=8.8 Hz), 7.92 (1H, dd, J=8.0, 4.9 Hz), 8.02 (1H, dd, J=8.1, 5.4 Hz), 8.54 (1H, d, J=8.1 Hz), 8.74 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.4 Hz), 8.88 (1H, d, J=4.9 Hz), 8.96 (1H, s), 9.18 (1H, s).
    • Example 154 Synthesis of N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.76-1.95 (2H, m), 2.41-2.58 (2H, m), 2.83 (2H, t, J=7.8 Hz), 3.07 (2H, t, J=7.2 Hz), 3.22 (3H, s), 3.32 (2H, t, J=7.5 Hz), 3.49 (2H, t, J=7.2 Hz), 3.87 (2H, t, J=6.0 Hz), 6.73-6.82 (2H, m), 6.99 (1H, d, J=8.4 Hz), 7.52-7.87 (5H, m), 7.97 (1H, dd, J=8.1, 5.5 Hz), 8.46 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.5 Hz), 8.86 (1H, s).
    • Example 155 Synthesis of 3-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.30-1.52 (2H, m), 1.66-2.00 (4H, m), 2.98-3.19 (2H, m), 3.30-3.50 (4H, m), 3.60 (3H, s), 3.87 (3H, s), 3.95-4.11 (2H, m), 4.43-4.66 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.61 (1H, dd, J=7.8, 7.7 Hz), 7.84 (1H, d, J=9.5 Hz), 7.95-8.05 (2H, m), 8.08 (1H, d, J=7.8 Hz), 8.27 (1H, s), 8.48 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.2 Hz), 8.94 (1H, s).
    • Example 156 Synthesis of 3-{[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 3.28 (2H, t, J=6.9 Hz), 3.37-3.58 (4H, m), 3.60 (3H, s), 3.87 (3H, s), 4.11 (2H, t, J=6.0 Hz), 4.48-4.72 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.62 (1H, dd, J=8.0, 7.7 Hz), 7.83 (1H, d, J=9.5 Hz), 8.02 (1H, d, J=8.0 Hz), 8.05 (1H, dd, J=8.1, 5.5 Hz), 8.13 (1H, d, J=7.7 Hz), 8.29 (1H, s), 8.57 (1H, d, J=8.1 Hz), 8.86 (1H, d, J=5.5 Hz), 8.99 (1H, s).
    • Example 157 Synthesis of 6-{3-[N-(1H-imidazol-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.21-2.49 (2H, m), 3.20-3.55 (6H, m), 3.60 (3H, s), 4.15 (2H, t, J=6.0 Hz), 4.64 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.9 Hz), 7.32 (1H, d, J=2.9 Hz), 7.48 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.00 (1H, dd, J=8.0, 5.3 Hz), 8.01 (1H, s), 8.56 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.99 (1H, s), 9.19 (1H, s).
    • Example 158 Synthesis of 1-methyl-6-{3-[N-(3-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.40 (2H, m), 2.32 (3H, s), 3.12-3.30 (2H, m), 3.30-3.50 (4H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.29-4.57 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.9 Hz), 7.23-7.30 (2H, m), 7.34 (1H, dd, J=7.8, 7.6 Hz), 7.47 (1H, d, J=9.2 Hz), 7.49-7.56 (2H, m), 7.84 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).
    • Example 159 Synthesis of N-(3-imidazol-1-ylpropyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitrobenzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.98-2.20 (4H, m), 3.35 (2H, t, J=6.4 Hz), 3.52 (2H, t, J=7.1 Hz), 3.71 (3H, s), 3.91-4.08 (4H, m), 6.73 (1H, d, J=9.5 Hz), 6.88-6.93 (2H, m), 7.05-7.09 (1H, m), 7.10 (1H, dd, J=9.1, 2.8 Hz), 7.24-7.31 (1H, m), 7.47 (1H, s), 7.55-7.65 (4H, m), 7.93-7.99 (1H, m).
    • Example 160 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-4-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.14-2.40 (2H, m), 2.48 (3H, s), 3.14-3.40 (2H, m), 3.40-4.30 (6H, m), 3.60 (3H, s), 4.30-4.60 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.06-7.39 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.74 (1H, d, J=8.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.98 (2H, d, J=5.6 Hz), 8.87 (2H, d, J=5.6 Hz).
    • Example 161 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-4-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.21-2.42 (2H, m), 3.19-3.39 (2H, m), 3.39-3.60 (4H, m), 3.60 (3H, s), 4.01-4.19 (2H, m), 4.50-4.79 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.23 (1H, d, J=9.0 Hz), 7.28 (1H, s), 7.48 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=9.5 Hz), 7.85-7.95 (1H, m), 8.05 (2H, d, J=5.5 Hz), 8.69 (1H, d, J=6.7 Hz), 8.82-8.93 (3H, m), 9.15 (1H, s).
    • Example 162 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-4-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.16-2.40 (2H, m), 3.13-3.40 (2H, m), 3.40-3.61 (4H, m), 3.60 (3H, s), 4.00-4.18 (2H, m), 4.58-4.88 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (2H, d, J=6.5 Hz), 8.34 (2H, d, J=5.5 Hz), 8.89 (2H, d, J=6.5 Hz), 8.95 (2H, d, J=5.5 Hz).
    • Example 163 Synthesis of N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)-N-[3-(quinolin-6-yloxy)propyl]amine trihydrochloride
  • Sodium iodide (113 mg) was added to a DMF solution (5 ml) of N-(3-chloropropyl)-N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amine (151 mg), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. Potassium carbonate (104 mg) and 6-hydroxyquinoline (87 mg) were then added to the reaction mixture and stirred at 60° C. for 24 hours. The reaction mixture was added to ice water, and the extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.014 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble product was separated, washed with ether, and dried to give the title compound (7.6 mg) as a brown powder.
  • 1H-NMR (DMSO-D6) δppm: 2.28-2.60 (2H, m), 2.49 (3H, s), 3.20-4.11 (6H, m), 4.27 (2H, t, J=5.6 Hz), 4.36-4.61 (2H, m), 7.22-7.38 (3H, m), 7.63 (1H, dd, J=9.2, 2.5 Hz), 7.68 (1H, d, J=2.5 Hz), 7.74 (1H, d, J=7.9 Hz), 7.87-7.96 (2H, m), 8.26 (1H, d, J=9.2 Hz), 8.39 (1H, d, J=7.9 Hz), 8.78 (1H, d, J=4.3 Hz), 8.84 (1H, d, J=8.8 Hz), 8.88 (1H, s), 9.05 (1H, d, J=5.0 Hz).
    • Example 164 Synthesis of N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)-N-[3-(pyridin-3-yloxy)propyl]amine trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 163 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.24-2.45 (2H, m), 2.49 (3H, s), 3.18-3.41 (2H, m), 3.41-3.68 (4H, m), 4.32 (2H, t, J=5.8 Hz), 4.37-4.62 (2H, m), 7.20-7.38 (3H, m), 7.78 (1H, d, J=7.4 Hz), 7.94 (1H, dd, J=8.7, 5.4 Hz), 8.04 (1H, dd, J=8.2, 5.7 Hz), 8.07 (1H, dd, J=8.7, 2.3 Hz), 8.52 (1H, d, J=5.4 Hz), 8.55 (1H, d, J=8.2 Hz), 8.62 (1H, d, J=2.3 Hz), 8.85 (1H, d, J=5.5 Hz), 8.97 (1H, s).
    • Example 165 Synthesis of 1-methyl-6-{3-[N-(3-methylpyridin-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.46 (2H, m), 2.58 (3H, s), 3.20-3.62 (6H, m), 3.61 (3H, s), 4.05-4.20 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=8.0, 5.6 Hz), 8.60 (1H, d, J=8.0 Hz), 8.51-8.67 (1H, m), 8.86 (1H, d, J=5.6 Hz), 8.82-8.92 (2H, m), 9.00 (1H, s).
    • Example 166 Synthesis of 1-methyl-6-{3-[N-(3-methylpyridin-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.04-2.36 (2H, m), 2.52 (3H, s), 2.83 (2H, t, J=7.9 Hz), 3.10-3.60 (6H, m), 3.22 (3H, s), 3.64-4.85 (6H, m), 6.72-6.81 (2H, m), 6.99 (1H, d, J=9.2 Hz), 8.00 (1H, dd, J=8.1, 5.5 Hz), 8.51 (1H, d, J=8.1 Hz), 8.69-8.84 (3H, m), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).
    • Example 167 Synthesis of 6-{3-[N-(3-imidazol-1-ylpropyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.17-2.60 (4H, m), 2.98-3.35 (4H, m), 3.60 (3H, s), 4.09 (2H, t, J=6.4 Hz), 4.32 (2H, t, J=7.2 Hz), 4.59 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.71 (1H, s), 7.78-7.89 (2H, m), 8.15 (2H, d, J=5.9 Hz), 8.86 (2H, d, J=5.9 Hz), 9.23 (1H, s).
    • Example 169 Synthesis of N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)-N-[3-(pyridin-3-yloxy)propyl]amine tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 163 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 3.06-4.10 (6H, m), 4.28 (2H, t, J=5.8 Hz), 4.74 (2H, s), 7.89 (1H, dd, J=8.7, 5.2 Hz), 7.96-8.06 (2H, m), 8.17 (2H, d, J=5.4 Hz), 8.46-8.52 (2H, m), 8.60 (1H, d, J=2.6 Hz), 8.82 (1H, d, J=5.6 Hz), 8.88 (2H, d, J=5.4 Hz), 8.91 (1H, s).
    • Example 170 Synthesis of 6-{3-[N-(3-hydroxybenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.41 (2H, m), 3.18-3.50 (6H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.24-4.51 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.88 (1H, dd, J=8.3, 1.1 Hz), 7.07-7.15 (2H, m), 7.19-7.25 (2H, m), 7.28 (1H, d, J=2.9 Hz), 7.47 (1H, d, J=9.2 Hz), 7.80-7.89 (2H, m), 8.30 (1H, d, J=8.0 Hz), 8.74 (1H, dd, J=5.4, 1.4 Hz), 8.83 (1H, d, J=1.4 Hz).
    • Example 171 Synthesis of 6-{3-[N-(3-hydroxymethylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • Sodium borohydride (16.5 mg) was added to a THF solution (4 ml) of 3-{[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (192 mg). Methanol (1 ml) was added to the mixture and stirred for 1.5 hour while heated under reflux. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.082 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (53.4 mg) as a white powder.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.41 (2H, m), 3.14-3.47 (6H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.30-4.60 (2H, m), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.38-7.45 (2H, m), 7.47 (1H, d, J=9.2 Hz), 7.56-7.66 (2H, m), 7.71 (1H, dd, J=8.0, 5.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.13 (1H, d, J=8.0 Hz), 8.67 (1H, dd, J=5.2, 1.5 Hz), 8.73 (1H, d, J=1.5 Hz).
    • Example 172 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-piperidin-1-ylethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.33-1.50 (2H, m), 1.50-1.61 (4H, m), 2.08-2.19 (2H, m), 2.30-2.46 (4H, m), 2.52 (2H, t, J=6.9 Hz), 3.50 (2H, t, J=6.9 Hz), 3.59 (2H, t, J=7.0 Hz), 3.70 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.71 (1H, d, J=9.5 Hz), 6.94 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.55-7.66 (4H, m), 8.06-8.14 (1H, m).
    • Example 173 Synthesis of N-(2-diethylaminoethyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitrobenzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.99 (6H, t, J=7.1 Hz), 2.00-2.19 (2H, m), 2.53 (4H, q, J=7.1 Hz), 2.65 (2H, t, J=7.1 Hz), 3.44 (2H, t, J=7.1 Hz), 3.60 (2H, t, J=7.0 Hz), 3.69 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.70 (1H, d, J=9.5 Hz), 6.94 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=9.2 Hz), 7.54-7.66 (4H, m), 8.02-8.09 (1H, m).
    • Example 174 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-nitrobenzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.01-2.19 (2H, m), 2.47 (3H, s), 2.28-2.56 (8H, m), 2.55 (2H, t, J=6.8 Hz), 3.48 (2H, t, J=6.8 Hz), 3.58 (2H, t, J=7.1 Hz), 3.69 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.69 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.7 Hz), 7.11 (1H, dd, J=9.2, 2.7 Hz), 7.27 (1H, d, J=9.2 Hz), 7.54-7.66 (4H, m), 8.04-8.12 (1H, m).
    • Example 175 Synthesis of 1-methyl-6-{3-[N-(2-piperidin-1-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.67-2.26 (8H, m), 2.71-3.60 (10H, m), 3.60 (3H, s), 3.98-4.14 (2H, m), 4.19-5.00 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.13 (2H, d, J=5.4 Hz), 8.86 (2H, d, J=5.4 Hz).
    • Example 176 Synthesis of 6-{3-[N-(2-diethylaminoethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.19 (6H, t, J=7.2 Hz), 1.90-2.10 (2H, m), 2.58-2.82 (2H, m), 2.90-3.30 (4H, m), 3.10 (4H, q, J=7.2 Hz), 3.60 (3H, s), 3.79-4.14 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.9 Hz), 7.26 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.2 Hz), 7.67 (2H, d, J=5.8 Hz), 7.84 (1H, d, J=9.5 Hz), 8.62 (2H, d, J=5.8 Hz).
    • Example 177 Synthesis of 1-methyl-6-(3-{N-[2-(4-methylpiperazin-1-yl)ethyl]N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one tetrahydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.01-2.21 (2H, m), 2.79 (3H, s), 2.87-3.02 (2H, m), 3.11-3.42 (8H, m), 3.42-3.70 (4H, m), 3.60 (3H, s), 4.00-4.14 (2H, m), 4.31 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.3, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.3 Hz), 7.85 (1H, d, J=9.5 Hz), 8.14 (2H, d, J=6.3 Hz), 8.83 (2H, d, J=6.3 Hz).
    • Example 178 Synthesis of 1-methyl-5-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.40 (2H, m), 2.40-2.68 (4H, m), 2.95-4.82 (10H, m), 3.23 (3H, s), 6.66-6.77 (2H, m), 7.21 (1H, dd, J=8.3, 8.2 Hz), 7.91 (1H, dd, J=8.0, 5.5 Hz), 7.97-8.08 (2H, m), 8.38 (1H, d, J=8.0 Hz), 8.73-8.82 (3H, m), 8.85 (1H, s).
    • Example 179 Synthesis of 1-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.08-2.36 (2H, m), 2.78 (2H, t, J=7.9 Hz), 2.97-4.81 (12H, m), 3.22 (3H, s), 6.50-6.58 (2H, m), 7.11 (1H, d, J=8.9 Hz), 7.88 (1H, dd, J=7.9, 5.4 Hz), 7.92-8.04 (2H, m), 8.35 (1H, d, J=7.9 Hz), 8.72-8.86 (4H, m).
    • Example 180 Synthesis of N-(4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}phenyl)acetamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 31 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.01 (3H, s), 2.13-2.40 (2H, m), 3.08-3.52 (6H, m), 3.90-4.10 (2H, m), 4.70 (2H, s), 6.83 (2H, d, J=9.0 Hz), 7.49 (2H, d, J=9.0 Hz), 8.01 (1H, dd, J=8.1, 2.6 Hz), 8.24-8.34 (2H, m), 8.52 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=2.6 Hz), 8.89-8.98 (3H, m).
    • Example 181 Synthesis of N-[4-(1,7-naphthyridin-2-yloxy)butyl]-N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amine dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.70-2.06 (4H, m), 2.99-3.20 (2H, m), 3.20-3.43 (4H, m), 4.33-4.71 (4H, m), 7.29 (1H, d, J=9.0 Hz), 7.64-7.72 (1H, m), 7.89 (2H, d, J=5.8 Hz), 7.94 (1H, d, J=5.5 Hz), 8.10 (1H, d, J=8.0 Hz), 8.36 (1H, d, J=9.0 Hz), 8.51 (1H, d, J=5.5 Hz), 8.63 (1H, d, J=5.1 Hz), 8.68 (2H, d, J=5.8 Hz), 8.70 (1H, s), 9.16 (1H, s).
    • Example 182 Synthesis of 7-{4-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]butoxy}-3,4-dihydro-1H-1,8-naphthyridin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.59-1.80 (2H, m), 1.80-2.04 (2H, m), 2.39-2.58 (2H, m), 2.78 (2H, t, J=8.0 Hz), 2.95-3.20 (2H, m), 3.20-3.45 (4H, m), 4.16 (2H, t, J=6.1 Hz), 4.51 (2H, s), 6.33 (1H, d, J=8.0 Hz), 7.50 (1H, d, J=8.0 Hz), 7.80 (1H, dd, J=7.9, 5.0 Hz), 7.96 (2H, d, J=5.8 Hz), 8.24 (1H, d, J=7.9 Hz), 8.71 (1H, d, J=5.0 Hz), 8.75 (2H, d, J=5.8 Hz), 8.78 (1H, s), 10.24 (1H, s).
    • Example 183 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.21-2.42 (2H, m), 3.14-3.45 (4H, m), 3.60 (3H, s), 3.58-4.20 (4H, m), 4.58-4.75 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, d, J=9.4 Hz), 7.24 (1H, s), 7.41-7.59 (4H, m), 7.82 (1H, d, J=9.5 Hz), 7.85-7.94 (2H, m), 8.04 (2H, d, J=5.5 Hz), 8.80 (2H, d, J=5.5 Hz), 8.93 (1H, s).
    • Example 184 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)isobutyramide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.98 (6H, d, J=6.9 Hz), 1.94-2.20 (2H, m), 2.29-2.41 (1H, m), 2.59-3.09 (4H, m), 3.09-3.54 (4H, m), 3.60 (3H, s), 3.92-4.19 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.56 (2H, d, J=4.2 Hz), 7.83 (1H, d, J=9.5 Hz), 7.92 (1H, s), 8.57 (2H, d, J=4.2 Hz).
    • Example 185 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)nicotinamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.16-2.43 (2H, m), 3.20-3.51 (4H, m), 3.60 (3H, s), 3.69-3.94 (2H, m), 3.94-4.21 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.0, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.0 Hz), 7.77-7.89 (2H, m), 8.31 (2H, d, J=5.5 Hz), 8.65 (1H, d, J=8.0 Hz), 8.83-8.98 (3H, m), 9.25 (1H, s), 9.56 (1H, s).
    • Example 186 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)carbamoyloxy}acetic acid ethyl ester
  • Potassium carbonate (1.66 g) was added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g). The mixture was cooled to 0° C., and ethyl bromoacetate (1.16 ml) was added to the mixture and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→10:1). The purified product was condensed under reduced pressure. The residue was recrystallized from ether, and dried to give the title compound (0.55 g) as a white powder.
  • 1H-NMR (CDCl3) δppm: 1.29 (3H, t, J=7.2 Hz), 2.00-2.19 (2H, m), 3.53 (2H, t, J=5.9 Hz), 3.71 (3H, s), 3.95-4.11 (2H, m), 4.23 (2H, q, J=7.2 Hz), 4.46-4.59 (2H, m), 4.63 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.99 (1H, s), 7.10-7.35 (4H, m), 7.59 (1H, d, J=9.5 Hz), 8.58 (2H, s).
    • Example 187 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid ethyl ester
  • Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.
  • 1H-NMR (CDCl3) δppm: 1.27 (3H, t, J=7.1 Hz), 1.89-2.04 (2H, m), 2.86 (2H, t, J=6.8 Hz), 3.38 (2H, s), 3.71 (3H, s), 3.84 (2H, s), 4.07 (2H, t, J=6.2 Hz), 4.17 (2H, q, J=7.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.25-7.35 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.48 (2H, d, J=6.0 Hz).
    • Example 188 Synthesis of 2-methyl-N-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 2.33 (3H, s), 3.07-3.45 (4H, m), 3.60 (3H, s), 3.63-3.84 (2H, m), 4.12 (2H, t, J=5.9 Hz), 4.58 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.16-7.29 (4H, m), 7.29-7.41 (2H, m), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.99 (2H, d, J=6.0 Hz), 8.57 (1H, s), 8.78 (2H, d, J=6.0 Hz).
    • Example 189 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.81-1.98 (2H, m), 2.51-2.66 (4H, m), 2.98-3.10 (2H, m), 3.50 (2H, s), 3.72 (3H, s), 4.01 (2H, t, J=5.9 Hz), 5.03 (1H, t, J=5.4 Hz), 6.73 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.10-7.18 (3H, m), 7.30 (1H, d, J=9.2 Hz), 7.42-7.47 (2H, m), 7.48-7.55 (1H, m), 7.62 (1H, d, J=9.5 Hz), 7.74-7.94 (2H, m), 8.47 (2H, d, J=5.9 Hz).
    • Example 190 Synthesis of N-ethyl-2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.00 (3H, t, J=7.2 Hz), 2.09-2.40 (2H, m), 3.00-3.17 (2H, m), 3.17-3.35 (2H, m), 3.60 (3H, s), 3.73 (2H, s), 4.10 (2H, t, J=5.9 Hz), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.07 (2H, d, J=6.2 Hz), 8.53 (1H, s), 8.85 (2H, d, J=6.2 Hz).
    • Example 191 Synthesis of N,N-diethyl-2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}acetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.97 (3H, t, J=7.1 Hz), 1.06 (3H, t, J=7.1 Hz), 2.17-2.35 (2H, m), 3.12-3.30 (4H, m), 3.30-3.45 (2H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.8 Hz), 4.29 (2H, s), 4.61 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.06 (2H, d, J=5.9 Hz), 8.87 (2H, d, J=5.9 Hz).
    • Example 192 Synthesis of 2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-phenylacetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.07-2.32 (2H, m), 3.12-3.40 (2H, m), 3.61 (3H, s), 3.90-4.08 (2H, m), 4.08-4.21 (2H, m), 4.60 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.09 (1H, t, J=7.4 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.28-7.37 (2H, m), 7.44 (1H, d, J=9.2 Hz), 7.59 (2H, d, J=7.7 Hz), 7.82 (1H, d, J=9.5 Hz), 8.16 (2H, d, J=6.2 Hz), 8.88 (2H, d, J=6.2 Hz).
    • Example 193 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)phenylmethanesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.02-2.38 (2H, m), 2.79-3.56 (6H, m), 3.60 (3H, s), 3.96-4.16 (2H, m), 4.40-4.72 (2H, m), 4.41 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.7 Hz), 7.27 (1H, d, J=2.7 Hz), 7.31-7.41 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.01 (2H, d, J=5.8 Hz), 8.81 (2H, d, J=5.8 Hz).
    • Example 194 Synthesis of 1-methyl-6-{3-[N-(pyridin-4-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.40 (4H, m), 2.75-2.92 (2H, m), 3.00-3.16 (2H, m), 3.16-3.31 (2H, m), 3.60 (3H, s), 4.10 (2H, t, J=5.8 Hz), 4.50 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.84 (1H, d, J=9.5 Hz), 7.83-8.09 (3H, m), 8.34 (1H, d, J=7.9 Hz), 8.64-9.02 (4H, m).
    • Example 195 Synthesis of 2-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2,3-dihydroisoindol-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 3.07 (3H, s), 3.13-3.33 (2H, m), 3.33-3.53 (4H, m), 4.12 (2H, t, J=5.8 Hz), 4.39 (2H, s), 4.66 (2H, s), 7.09 (1H, dd, J=8.2, 2.3 Hz), 7.14 (1H, d, J=2.3 Hz), 7.48 (1H, d, J=8.2 Hz), 7.99 (1H, dd, J=8.1, 5.2 Hz), 8.22 (2H, d, J=5.0 Hz), 8.50 (1H, d, J=8.1 Hz), 8.82 (1H, d, J=5.2 Hz), 8.89 (2H, d, J=5.0 Hz), 8.92 (1H, s).
    • Example 196 Synthesis of 7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.80-2.04 (2H, m), 2.63-2.86 (6H, m), 3.66 (2H, s), 4.08 (2H, t, J=6.0 Hz), 6.54 (1H, d, J=7.1 Hz), 7.07 (1H, d, J=6.5 Hz), 7.15 (2H, d, J=5.9 Hz), 7.15-7.24 (2H, m), 7.39-7.46 (1H, m), 7.49 (1H, d, J=8.7 Hz), 7.77 (1H, d, J=2.6 Hz), 8.39-8.45 (3H, m), 8.47 (1H, dd, J=4.8, 1.6 Hz), 10.96 (1H, s).
    • Example 197 Synthesis of 2-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.13-2.40 (2H, m), 3.00-3.40 (6H, m), 3.51 (3H, s), 4.13 (2H, t, J=5.6 Hz), 4.48 (2H, s), 6.58 (1H, d, J=7.3 Hz), 7.25 (1H, dd, J=8.7, 2.6 Hz), 7.35 (1H, d, J=7.3 Hz), 7.56-7.65 (2H, m), 7.75 (1H, dd, J=7.9, 5.3 Hz), 7.90 (2H, d, J=5.2 Hz), 8.20 (1H, d, J=7.9 Hz), 8.68 (1H, d, J=5.3 Hz), 8.70-8.78 (3H, m).
    • Example 198 Synthesis of 3-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3H-quinazolin-4-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.43 (2H, m), 3.05-3.60 (6H, m), 3.52 (3H, s), 4.10-4.30 (2H, m), 4.65 (2H, s), 7.40 (1H, dd, J=8.9, 2.8 Hz), 7.52 (1H, d, J=2.8 Hz), 7.67 (1H, d, J=8.9 Hz), 7.99 (1H, dd, J=8.0, 5.3 Hz), 8.21 (2H, d, J=5.8 Hz), 8.43 (1H, s), 8.49 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.3 Hz), 8.89 (2H, d, J=5.8 Hz), 8.92 (1H, s).
    • Example 199 Synthesis of 2-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.16-2.39 (2H, m), 2.90 (2H, t, J=6.6 Hz), 3.02 (3H, s), 3.10-3.46 (6H, m), 3.52 (2H, t, J=6.6 Hz), 3.97-4.12 (2H, m), 4.59 (2H, s), 6.98 (1H, dd, J=8.3, 2.7 Hz), 7.21 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.7 Hz), 7.92 (1H, dd, J=8.0, 5.5 Hz), 8.07 (2H, d, J=6.1 Hz), 8.40 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=6.1 Hz), 8.86 (1H, s).
    • Example 200 Synthesis of 7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.18-2.41 (2H, m), 2.82 (2H, t, J=6.6 Hz), 3.12-3.60 (8H, m), 4.00-4.18 (2H, m), 4.72 (2H, s), 7.00 (1H, dd, J=8.4, 2.7 Hz), 7.23 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=2.7 Hz), 7.96 (1H, s), 8.02 (1H, dd, J=8.0, 5.7 Hz), 8.23-8.38 (2H, m), 8.53 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.7 Hz), 8.89-8.99 (3H, m).
    • Example 201 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.23 (3H, t, J=7.1 Hz), 2.05-2.39 (2H, m), 2.91-3.52 (6H, m), 3.97-4.21 (2H, m), 4.17 (2H, q, J=7.1 Hz), 4.46 (2H, s), 6.99-7.07 (1H, m), 7.11 (1H, d, J=8.4 Hz), 7.49-7.58 (1H, m), 7.65 (1H, dd, J=7.7, 1.7 Hz), 7.71 (1H, dd, J=7.5, 5.6 Hz), 7.79-7.93 (2H, m), 8.14 (1H, d, J=7.5 Hz), 8.62-8.76 (4H, m).
    • Example 202 Synthesis of 3-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.32 (3H, t, J=7.1 Hz), 2.10-2.40 (2H, m), 2.94-3.60 (6H, m), 4.00-4.18 (2H, m), 4.32 (2H, q, J=7.1 Hz), 4.50 (2H, s), 7.11-7.24 (1H, m), 7.40 (1H, s), 7.37-7.49 (1H, m), 7.56 (1H, d, J=7.7 Hz), 7.81 (1H, dd, J=7.8, 5.4 Hz), 7.83-8.00 (2H, m), 8.25 (1H, d, J=7.8 Hz), 8.64-8.84 (4H, m).
    • Example 203 Synthesis of 4-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.31 (3H, t, J=7.1 Hz), 2.12-2.41 (2H, m), 3.02-3.60 (6H, m), 4.00-4.20 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.41-4.74 (2H, m), 6.99 (2H, d, J=8.8 Hz), 7.89 (1H, dd, J=7.7, 5.8 Hz), 7.91 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=5.8 Hz), 8.36 (1H, d, J=7.7 Hz), 8.76 (1H, d, J=5.8 Hz), 8.79 (2H, d, J=5.8 Hz), 8.84 (1H, s).
    • Example 204 Synthesis of N-ethyl-2-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.05 (3H, t, J=7.2 Hz), 2.20-2.42 (2H, m), 3.08-3.60 (8H, m), 4.07-4.26 (2H, m), 4.52-4.82 (2H, m), 7.02 (1H, dd, J=7.6, 7.5 Hz), 7.09 (1H, d, J=8.2 Hz), 7.39-7.48 (1H, m), 7.59 (1H, dd, J=7.6, 1.7 Hz), 7.99 (1H, dd, J=8.0, 5.2 Hz), 8.07 (1H, s), 8.22 (2H, d, J=5.0 Hz), 8.49 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.2 Hz), 8.88 (2H, d, J=5.0 Hz), 8.92 (1H, s).
    • Example 205 Synthesis of N,N-diethyl-2-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.91 (3H, t, J=7.1 Hz), 1.06 (3H, t, J=7.1 Hz), 2.01-2.41 (2H, m), 3.01 (4H, q, J=7.1 Hz), 2.97-3.59 (6H, m), 3.94-4.19 (2H, m), 4.38-4.74 (2H, m), 6.99 (1H, dd, J=7.4, 7.3 Hz), 7.05 (1H, d, J=8.3 Hz), 7.12 (1H, dd, J=7.4, 1.7 Hz), 7.31-7.40 (1H, m), 7.91 (1H, dd, J=8.0, 5.5 Hz), 8.05 (2H, d, J=5.9 Hz), 8.37 (1H, d, J=8.0 Hz), 8.78 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=5.9 Hz), 8.84 (1H, s).
    • Example 206 Synthesis of N-ethyl-3-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.12 (3H, t, J=7.2 Hz), 2.10-2.38 (2H, m), 3.00-3.41 (8H, m), 3.99-4.20 (2H, m), 4.42 (2H, s), 7.01 (1H, dd, J=8.0, 2.3 Hz), 7.31-7.49 (3H, m), 7.58 (1H, dd, J=7.7, 5.1 Hz), 7.79 (2H, d, J=5.8 Hz), 7.98 (1H, d, J=7.7 Hz), 8.51 (1H, t, J=5.2 Hz), 8.59 (1H, dd, J=5.1, 1.6 Hz), 8.63 (1H, d, J=1.6 Hz), 8.69 (2H, d, J=5.8 Hz).
    • Example 207 Synthesis of N,N-diethyl-3-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.90-1.25 (6H, m), 2.09-2.38 (2H, m), 2.92-3.59 (10H, m), 3.98-4.16 (2H, m), 4.52 (2H, s), 6.82 (1H, d, J=1.7 Hz), 6.89 (1H, d, J=7.5 Hz), 6.94 (1H, dd, J=8.2, 1.7 Hz), 7.34 (1H, dd, J=8.2, 7.5 Hz), 7.85 (1H, dd, J=8.0, 5.2 Hz), 7.99 (2H, d, J=5.4 Hz), 8.31 (1H, d, J=8.0 Hz), 8.74 (1H, dd, J=5.2, 1.5 Hz), 8.78 (2H, d, J=5.4 Hz), 8.82 (1H, d, J=1.5 Hz).
    • Example 208 Synthesis of N,N-diethyl-4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.09 (6H, t, J=6.8 Hz), 2.12-2.40 (2H, m), 2.95-3.59 (10H, m), 3.95-4.15 (2H, m), 4.56 (2H, s), 6.92 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.91 (1H, dd, J=8.0, 5.3 Hz), 8.06 (2H, d, J=6.0 Hz), 8.38 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.3 Hz), 8.82 (2H, d, J=6.0 Hz), 8.86 (1H, s).
    • Example 209 Synthesis of 2-methyl-8-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-2.10 (2H, m), 2.67-3.00 (6H, m), 2.91 (2H, t, J=6.4 Hz), 3.09 (3H, s), 3.46 (2H, t, J=6.4 Hz), 3.69 (2H, s), 4.00 (2H, t, J=5.9 Hz), 6.75 (1H, d, J=7.3 Hz), 6.79 (1H, d, J=8.5 Hz), 7.09-7.19 (3H, m), 7.31 (1H, dd, J=8.5, 7.3 Hz), 7.44 (1H, d, J=7.6 Hz), 8.35-8.46 (4H, m).
    • Example 210 Synthesis of N,N-dimethyl-2-(4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}phenyl)propionamide trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.23 (3H, d, J=6.8 Hz), 2.12-2.35 (2H, m), 2.80 (3H, s), 2.87 (3H, s), 3.00-3.49 (6H, m), 3.90-4.10 (3H, m), 4.56 (2H, s), 6.82 (2H, d, J=8.6 Hz), 7.16 (2H, d, J=8.6 Hz), 7.90 (1H, dd, J=8.0, 5.5 Hz), 8.05 (2H, d, J=5.5 Hz), 8.37 (1H, d, J=8.0 Hz), 8.76 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=5.5 Hz), 8.85 (1H, s).
    • Example 211 Synthesis of 2-methyl-5-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.06-2.40 (2H, m), 2.67 (2H, t, J=6.7 Hz), 3.00 (3H, s), 3.06-3.42 (6H, m), 3.47 (2H, t, J=6.7 Hz), 3.92-4.16 (2H, m), 4.16-4.78 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.29 (1H, dd, J=8.2, 8.0 Hz), 7.48 (1H, d, J=8.2 Hz), 7.68 (1H, dd, J=7.7, 5.2 Hz), 7.77-7.89 (2H, m), 8.10 (1H, d, J=7.7 Hz), 8.65 (1H, dd, J=5.2, 1.3 Hz), 8.66-8.75 (3H, m).
    • Example 212 Synthesis of 1,4-dimethyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.14-2.41 (2H, m), 2.42 (3H, s), 2.96-3.50 (6H, m), 3.58 (3H, s), 4.01-4.22 (2H, m), 4.52 (2H, s), 6.54 (1H, s), 7.16 (1H, d, J=2.5 Hz), 7.21 (1H, dd, J=9.2, 2.5 Hz), 7.47 (1H, d, J=9.2 Hz), 7.82 (1H, dd, J=7.9, 5.6 Hz), 7.96 (2H, d, J=4.8 Hz), 8.29 (1H, d, J=7.9 Hz), 8.72 (1H, d, J=5.6 Hz), 8.76 (2H, d, J=4.8 Hz), 8.81 (1H, s).
    • Example 213 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-2-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.22-2.40 (2H, m), 3.20-3.38 (2H, m), 3.46-3.62 (4H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.62 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.60-7.69 (1H, m), 7.74 (1H, d, J=7.9 Hz), 7.81 (1H, dd, J=7.9, 5.0 Hz), 7.85 (1H, d, J=9.5 Hz), 8.14-8.23 (1H, m), 8.58 (1H, d, J=7.9 Hz), 8.69 (1H, d, J=5.0 Hz), 8.82 (1H, dd, J=5.2, 1.3 Hz), 9.08 (1H, d, J=1.3 Hz).
    • Example 214 Synthesis of N-benzyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)acetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.99 (3H, s), 2.02-2.31 (2H, m), 2.90-3.45 (4H, m), 3.60 (3H, s), 3.50-3.89 (2H, m), 3.98-4.15 (2H, m), 4.25-4.65 (2H, m), 4.60 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.12-7.42 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 7.87 (2H, d, J=5.8 Hz), 8.75 (2H, d, J=5.8 Hz).
    • Example 215 Synthesis of 1-methyl-6-[3-[N-(pyridin-4-ylmethyl)-N-(quinolin-6-yl)amino]propoxy]-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.27 (2H, m), 3.60 (3H, s), 3.87 (2H, t, J=7.4 Hz), 4.16 (2H, t, J=5.8 Hz), 5.07 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.24-7.32 (3H, m), 7.47 (1H, d, J=10.1 Hz), 7.69-7.79 (4H, m), 7.81 (1H, d, J=9.5 Hz), 8.11 (1H, d, J=9.5 Hz), 8.61 (1H, d, J=8.4 Hz), 8.75 (2H, d, J=6.4 Hz), 8.82 (1H, d, J=5.1 Hz).
    • Example 216 Synthesis of 6-(3-{N-[2-(7-bromo-1-oxo-1H-isoquinolin-2-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.93-2.38 (2H, m), 2.74-3.54 (6H, m), 3.61 (3H, s), 3.79-4.15 (2H, m), 4.39 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.70 (1H, d, J=7.4 Hz), 6.98-7.25 (2H, m), 7.42 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=7.4 Hz), 7.65 (1H, d, J=8.5 Hz), 7.80 (1H, d, J=9.5 Hz), 7.87 (1H, dd, J=8.5, 1.8 Hz), 8.00-8.23 (2H, m), 8.27 (1H, d, J=1.8 Hz), 8.65-8.98 (2H, m).
    • Example 217 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)phenylmethanesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.82-2.02 (2H, m), 2.54 (2H, t, J=6.7 Hz), 2.62 (2H, t, J=6.7 Hz), 2.67 (3H, s), 2.99 (2H, t, J=6.7 Hz), 3.58 (2H, s), 3.71 (3H, s), 4.04 (2H, t, J=6.2 Hz), 4.22 (2H, s), 6.72 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.22 (2H, d, J=5.9 Hz), 7.23-7.40 (6H, m), 7.61 (1H, d, J=9.5 Hz), 8.46 (2H, d, J=5.9 Hz).
    • Example 218 Synthesis of 2,4,6,N-tetramethyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.82-2.01 (2H, m), 2.28 (3H, s), 2.56 (6H, s), 2.65 (3H, s), 2.61-2.79 (4H, m), 3.29 (2H, t, J=7.2 Hz), 3.60 (2H, s), 3.71 (3H, s), 4.04 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.92 (2H, s), 6.99 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.19-7.35 (3H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (2H, d, J=5.9 Hz).
    • Example 219 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-2.08 (2H, m), 2.67 (3H, s), 2.61-2.80 (4H, m), 3.12 (2H, t, J=6.5 Hz), 3.66 (2H, s), 3.71 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.04 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.35 (3H, m), 7.43-7.61 (3H, m), 7.63 (1H, d, J=9.5 Hz), 7.74 (2H, d, J=6.0 Hz), 8.48 (2H, d, J=6.0 Hz).
    • Example 220 Synthesis of 4-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.85-2.08 (2H, m), 2.64 (3H, s), 2.60-2.79 (4H, m), 3.09 (2H, t, J=6.6 Hz), 3.66 (2H, s), 3.71 (3H, s), 3.85 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.94 (2H, d, J=8.9 Hz), 7.04 (1H, d, J=2.8 Hz), 7.13 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.32 (3H, m), 7.56-7.73 (3H, m), 8.47 (2H, d, J=6.0 Hz).
    • Example 221 Synthesis of 2-nitro-N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.96-2.20 (2H, m), 2.82-3.04 (4H, m), 3.47-3.69 (6H, m), 3.99 (2H, t, J=5.8 Hz), 5.97 (1H, s), 6.62 (1H, d, J=2.4 Hz), 6.74 (1H, dd, J=8.6, 2.4 Hz), 7.20 (1H, dd, J=7.8, 4.8 Hz), 7.49-7.64 (4H, m), 7.94-8.01 (2H, m), 8.42 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=7.8, 1.7 Hz).
    • Example 222 Synthesis of 6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.15-2.42 (2H, m), 2.51 (3H, s), 2.86 (2H, t, J=6.5 Hz), 3.19-3.65 (8H, m), 4.11 (2H, t, J=6.0 Hz), 4.33-4.62 (2H, m), 6.78-6.91 (2H, m), 7.22-7.40 (3H, m), 7.70-7.82 (3H, m), 8.04 (1H, dd, J=8.0, 5.3 Hz), 8.54 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.3 Hz), 8.97 (1H, s).
    • Example 223 Synthesis of 6-{3-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.45 (2H, m), 2.84 (2H, t, J=6.4 Hz), 3.10-3.73 (8H, m), 3.95-4.10 (2H, m), 4.91-5.41 (2H, m), 6.70 (1H, s), 6.74 (1H, d, J=8.4 Hz), 7.64-7.80 (2H, m), 7.86-7.98 (1H, m), 7.98-8.12 (2H, m), 8.38 (1H, d, J=8.4 Hz), 8.43-8.69 (2H, m), 8.53 (1H, d, J=8.2 Hz), 8.82 (1H, d, J=5.2 Hz), 8.94 (1H, s), 9.23 (1H, d, J=1.7 Hz).
    • Example 224 Synthesis of 2-methyl-N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.82-2.24 (2H, m), 2.08 (3H, s), 2.85 (2H, t, J=6.1 Hz), 2.90-3.51 (6H, m), 3.36 (2H, t, J=6.6 Hz), 3.51-4.04 (2H, m), 6.46-7.30 (7H, m), 7.60-8.08 (2H, s), 8.35-9.00 (2H, m).
    • Example 225 Synthesis of N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.89-2.09 (2H, m), 2.80-3.04 (4H, m), 3.24-3.45 (4H, m), 3.45-3.60 (2H, m), 3.98 (2H, t, J=5.9 Hz), 5.92 (1H, s), 6.66 (1H, d, J=2.4 Hz), 6.82 (1H, dd, J=8.6, 2.4 Hz), 7.12-7.39 (1H, m), 7.43-7.63 (4H, m), 7.74-7.89 (2H, m), 8.00 (1H, d, J=8.6 Hz), 8.40 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=7.8, 1.7 Hz).
    • Example 226 Synthesis of 4-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.46 (2H, m), 2.99 (3H, s), 3.08-3.49 (4H, m), 3.60 (3H, s), 3.78 (3H, s), 3.74-3.98 (2H, m), 3.98-4.20 (2H, m), 4.62 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.96 (2H, d, J=8.9 Hz), 7.18 (1H, dd, J=8.9, 2.6 Hz), 7.25 (1H, d, J=2.6 Hz), 7.31-7.54 (3H, m), 7.82 (1H, d, J=9.5 Hz), 8.14 (2H, d, J=5.7 Hz), 8.85 (2H, d, J=5.7 Hz).
    • Example 227 Synthesis of thiophene-3-carboxylic acid methyl-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.11-2.38 (2H, m), 3.05 (3H, s), 3.02-3.47 (4H, m), 3.60 (3H, s), 3.47-4.21 (4H, m), 4.56 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.6 Hz), 7.25 (1H, d, J=2.6 Hz), 7.20-7.36 (1H, m), 7.46 (1H, d, J=9.1 Hz), 7.60 (1H, dd, J=4.9, 2.9 Hz), 7.82 (1H, d, J=9.5 Hz), 7.80-7.96 (1H, m), 8.03 (2H, d, J=5.2 Hz), 8.80 (2H, d, J=5.2 Hz).
    • Example 228 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)isobutyramide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 0.99 (6H, d, J=6.7 Hz), 2.11-2.41 (2H, m), 2.75-2.89 (1H, m), 3.05 (3H, s), 3.05-3.41 (4H, m), 3.60 (3H, s), 3.68-3.84 (2H, m), 4.00-4.21 (2H, m), 4.63 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.6 Hz), 7.27 (1H, d, J=2.6 Hz), 7.47 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.19 (2H, d, J=5.4 Hz), 8.90 (2H, d, J=5.4 Hz).
    • Example 229 Synthesis of 2-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.12-2.40 (2H, m), 2.79 (3H, s), 2.71-3.02 (2H, m), 3.10-3.33 (2H, m), 3.59 (3H, s), 3.76 (3H, s), 3.81-4.25 (4H, m), 4.55 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.90-7.27 (5H, m), 7.27-7.50 (2H, m), 7.78 (1H, d, J=9.5 Hz), 8.12 (2H, d, J=5.0 Hz), 8.81 (2H, d, J=5.0 Hz).
    • Example 230 Synthesis of 2-fluoro-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.13-2.41 (2H, m), 2.88 (3H, s), 2.76-3.10 (2H, m), 3.10-3.48 (2H, m), 3.59 (3H, s), 3.80-4.05 (2H, m), 4.05-4.21 (2H, m), 4.62 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.08-7.58 (7H, m), 7.79 (1H, d, J=9.5 Hz), 8.25 (2H, s), 8.86 (2H, s).
    • Example 231 Synthesis of 3,N-dimethyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.31 (3H, s), 2.21-2.45 (2H, m), 2.95 (3H, s), 3.12-3.49 (4H, m), 3.60 (3H, s), 3.79-4.21 (4H, m), 4.65 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.11-7.40 (6H, m), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.18 (2H, s), 8.86 (2H, s).
    • Example 232 Synthesis of benzo[1,3]dioxole-5-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.19-2.46 (2H, m), 2.97 (3H, s), 3.05-3.49 (4H, m), 3.60 (3H, s), 3.71-3.94 (2H, m), 3.94-4.20 (2H, m), 4.66 (2H, s), 6.06 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.87-7.12 (3H, m), 7.19 (1H, dd, J=9.1, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.1 Hz), 7.82 (1H, d, J=9.5 Hz), 8.21 (2H, d, J=5.6 Hz), 8.89 (2H, d, J=5.6 Hz).
    • Example 233 Synthesis of 2-(3-methoxyphenyl)-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)acetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.09-2.31 (2H, m), 2.78-3.30 (4H, m), 3.03 (3H, s), 3.59 (3H, s), 3.68 (2H, s), 3.72 (3H, s), 3.53-3.89 (2H, m), 3.96-4.19 (2H, m), 4.44 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.70-6.90 (3H, m), 7.10-7.29 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 8.00 (2H, d, J=5.3 Hz), 8.76 (2H, d, J=5.3 Hz).
    • Example 234 Synthesis of 4,5-dimethylfuran-2-carboxylic acid N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.91 (3H, s), 2.23 (3H, s), 2.13-2.42 (2H, m), 3.04-3.46 (4H, m), 3.17 (3H, s), 3.60 (3H, s), 3.81-4.21 (4H, m), 4.68 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.89 (1H, s), 7.18 (1H, dd, J=9.1, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.26 (2H, d, J=5.1 Hz), 8.92 (2H, d, J=5.1 Hz).
    • Example 235 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.40 (2H, m), 2.93-3.57 (10H, m), 3.95-4.15 (2H, m), 4.61 (2H, s), 6.97 (1H, dd, J=8.4, 2.7 Hz), 7.03 (1H, d, J=2.7 Hz), 7.40 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.1, 5.4 Hz), 8.11 (2H, s), 8.36 (1H, t, J=6.7 Hz), 8.44 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.4 Hz), 8.81-8.96 (3H, m).
    • Example 236 Synthesis of 1-ethyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.10 (3H, t, J=7.0 Hz), 2.08-2.30 (2H, m), 2.40-2.54 (2H, m), 2.80 (2H, t, J=7.9 Hz), 3.00-3.45 (6H, m), 3.87 (2H, q, J=7.0 Hz), 3.94-4.11 (2H, m), 4.49 (2H, s), 6.69-6.80 (2H, m), 7.03 (1H, d, J=9.0 Hz), 7.79 (1H, dd, J=8.0, 5.4 Hz), 7.93 (2H, d, J=4.9 Hz), 8.24 (1H, d, J=8.0 Hz), 8.70 (1H, d, J=5.4 Hz), 8.70-8.82 (3H, m).
    • Example 237 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-4-ylallyl)-N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.00 (2H, t, J=5.6 Hz), 3.43 (2H, d, J=2.1 Hz), 3.70 (3H, s), 3.81 (2H, s), 4.13 (2H, t, J=5.6 Hz), 6.46-6.55 (1H, m), 6.53 (1H, d, J=2.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.10-7.35 (5H, m), 7.57 (1H, d, J=9.5 Hz), 7.73 (1H, d, J=5.3 Hz), 8.42-8.58 (3H, m), 8.63 (1H, s).
    • Example 238 Synthesis of 1-methyl-6-{2-[N-(pyridin-3-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.07-2.31 (2H, m), 2.70-2.95 (2H, m), 3.03-3.25 (2H, m), 3.40-3.69 (2H, m), 3.61 (3H, s), 4.37-4.68 (4H, m), 6.64 (1H, d, J=9.5 Hz), 7.20-7.42 (2H, m), 7.51 (1H, d, J=9.2 Hz), 7.58-7.72 (1H, m), 7.78-7.99 (2H, m), 8.30-8.50 (2H, m), 8.68-8.80 (2H, m), 8.85 (1H, s), 8.98 (1H, s).
    • Example 239 Synthesis of 1-methyl-6-{2-[N-(pyridin-4-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.01-2.31 (2H, m), 2.69-2.90 (2H, m), 2.90-3.22 (2H, m), 3.22-3.55 (2H, m), 3.61 (3H, s), 4.30-4.66 (4H, m), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.7 Hz), 7.33 (1H, d, J=2.7 Hz), 7.50 (1H, d, J=9.2 Hz), 7.76-7.92 (2H, m), 7.98 (2H, d, J=6.1 Hz), 8.33 (1H, d, J=7.9 Hz), 8.72 (1H, d, J=6.5 Hz), 8.73-8.88 (3H, m).
    • Example 240 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-3-ylallyl)-N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 3.47-3.68 (2H, m), 3.60 (3H, s), 3.94-4.12 (2H, m), 4.46-4.70 (2H, m), 4.70 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.87-7.08 (2H, m), 7.29-7.54 (3H, m), 7.78-7.94 (3H, m), 8.49 (1H, d, J=8.0 Hz), 8.66 (1H, d, J=8.0 Hz), 8.75 (1H, d, J=5.4 Hz), 8.82 (1H, d, J=5.4 Hz), 9.01 (1H, s), 9.12 (1H, s).
    • Example 241 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-3-ylallyl)-N-(pyridin-4-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 3.21-3.48 (2H, m), 3.59 (3H, s), 3.70-3.98 (2H, m), 4.28-4.59 (4H, m), 6.62 (1H, d, J=9.5 Hz), 6.68-6.94 (2H, m), 7.18-7.38 (2H, m), 7.46 (1H, d, J=9.0 Hz), 7.57-7.71 (1H, m), 7.82 (1H, d, J=9.5 Hz), 8.02 (2H, d, J=5.1 Hz), 8.23 (1H, d, J=7.1 Hz), 8.62 (1H, d, J=5.1 Hz), 8.66-8.91 (3H, m).
    • Example 242 Synthesis of N-methyl-3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-phenylpropionamide
  • Sodium ethoxide (34 mg) and 3-chloro-N-methyl-N-phenylpropionamide (148 mg) were added to to a ethanol solution (5 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (161 mg), and stirred at 60° C. for 8.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (5.6 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δppm: 1.80-1.98 (2H, m), 2.26 (2H, t, J=7.3 Hz), 2.53 (2H, t, J=6.5 Hz), 2.81 (2H, t, J=7.3 Hz), 3.24 (3H, s), 3.44 (2H, s), 3.72 (3H, s), 3.98 (2H, t, J=6.0 Hz), 6.73 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.7 Hz), 7.00-7.19 (5H, m), 7.24-7.41 (4H, m), 7.60 (1H, d, J=9.5 Hz), 8.42 (2H, d, J=5.4 Hz).
    • Example 243 Synthesis of 3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-o-tolylpropionamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.30 (3H, s), 2.20-2.40 (2H, m), 2.91-3.18 (2H, m), 3.18-3.37 (2H, m), 3.37-3.55 (2H, m), 3.60 (3H, s), 3.93-4.20 (2H, m), 4.66 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.00-7.31 (5H, m), 7.36 (1H, d, J=7.3 Hz), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.20 (2H, d, J=5.2 Hz), 8.90 (2H, d, J=5.2 Hz), 9.72 (1H, s).
    • Example 244 Synthesis of N-methyl-3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-o-tolylpropionamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.18 (3H, s), 2.08-2.42 (2H, m), 2.95-3.19 (2H, m), 3.06 (3H, s), 3.19-3.49 (4H, m), 3.60 (3H, s), 3.93-4.13 (2H, m), 4.48 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.19-7.41 (5H, m), 7.48 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.97 (2H, d, J=6.0 Hz), 8.80 (2H, d, J=6.0 Hz).
    • Example 245 Synthesis of furan-3-carboxylic acid methyl-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.13-2.41 (2H, m), 2.98-3.48 (4H, m), 3.15 (3H, s), 3.60 (3H, s), 3.78-3.98 (2H, m), 3.98-4.20 (2H, m), 4.65 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.74 (1H, s), 7.18 (1H, dd, J=9.1, 2.6 Hz), 7.26 (1H, d, J=2.6 Hz), 7.46 (1H, d, J=9.1 Hz), 7.75 (1H, s), 7.83 (1H, d, J=9.5 Hz), 8.15 (1H, s), 8.20 (2H, d, J=5.2 Hz), 8.89 (2H, d, J=5.2 Hz).
    • Example 246 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)-2-thiophen-2-ylacetamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.12-2.49 (2H, m), 3.08 (3H, s), 3.12-3.41 (4H, m), 3.60 (3H, s), 3.65-3.88 (2H, m), 3.97 (2H, s), 4.00-4.16 (2H, m), 4.44-4.93 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.87-7.02 (2H, m), 7.19 (1H, dd, J=9.2, 2.7 Hz), 7.26 (1H, d, J=2.7 Hz), 7.37 (1H, dd, J=5.0, 1.3 Hz), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.24 (2H, d, J=5.4 Hz), 8.91 (2H, d, J=5.4 Hz).
    • Example 247 Synthesis of cyclohexanecarboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.03-1.45 (6H, m), 1.45-1.80 (4H, m), 2.17-2.41 (2H, m), 2.41-2.65 (1H, m), 3.05 (3H, s), 3.08-3.40 (4H, m), 3.60 (3H, s), 3.66-3.82 (2H, m), 4.00-4.20 (2H, m), 4.68 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.26 (2H, d, J=5.5 Hz), 8.94 (2H, d, J=5.5 Hz).
    • Example 248 Synthesis of 3-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.20-2.48 (2H, m), 2.95 (3H, s), 3.13-3.51 (4H, m), 3.60 (3H, s), 3.77 (3H, s), 3.82-4.01 (2H, m), 4.01-4.22 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.82-7.09 (3H, m), 7.09-7.40 (3H, m), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.32 (2H, s), 8.94 (2H, s).
    • Example 249 Synthesis of 5-methylisoxazole-3-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.85-2.09 (2H, m), 2.66 (3H, s), 2.59-2.82 (4H, m), 2.98-3.30 (2H, m), 3.20 (3H, s), 3.64 (2H, s), 3.71 (3H, s), 3.98-4.15 (2H, m), 6.25 (1H, s), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=7.4 Hz), 7.03-7.16 (1H, m), 7.16-7.35 (3H, m), 7.62 (1H, d, J=9.5 Hz), 8.36-8.51 (2H, m).
    • Example 250 Synthesis of benzo[b]thiophene-3-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.15-2.41 (2H, m), 3.03 (3H, s), 3.11-3.51 (4H, m), 3.59 (3H, s), 3.75-4.88 (6H, m), 6.61 (1H, d, J=9.5 Hz), 7.09-7.35 (2H, m), 7.35-7.54 (3H, m), 7.67-7.87 (2H, m), 7.87-8.32 (4H, m), 8.88 (2H, s).
    • Example 251 Synthesis of 2,4-dimethoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.08-2.32 (2H, m), 2.68-3.00 (2H, m), 2.84 (3H, s), 3.00-3.34 (2H, m), 3.59 (3H, s), 3.75 (3H, s), 3.77 (3H, s), 3.65-4.58 (6H, m), 6.45-6.62 (3H, m), 6.98-7.22 (3H, m), 7.41 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 7.94 (2H, s), 8.71 (2H, s).
    • Example 252 Synthesis of 2,3-dimethoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.16-2.40 (2H, m), 2.80 (3H, s), 2.80-3.11 (2H, m), 3.11-3.40 (2H, m), 3.59 (3H, s), 3.70 (3H, s), 3.82 (3H, s), 3.85-4.05 (2H, m), 4.05-4.21 (2H, m), 4.59 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.64-6.87 (2H, m), 7.00-7.29 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 8.20 (2H, s), 8.82 (2H, s).
    • Example 253 Synthesis of 6-{3-[N-(1-benzoylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.78-2.02 (2H, m), 2.02-2.42 (4H, m), 2.63-3.50 (5H, m), 3.59 (3H, s), 3.50-4.90 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.0, 2.6 Hz), 7.22 (1H, d, J=2.6 Hz), 7.35-7.56 (6H, m), 7.82 (1H, d, J=9.5 Hz), 8.27 (2H, s), 8.89 (2H, s).
    • Example 254 Synthesis of 6-(3-{N-[1-(2,3-dihydrobenzofuran-7-carbonyl)piperidin-4-yl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1-methyl-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.68-1.93 (2H, m), 2.03-2.41 (4H, m), 2.60-3.36 (5H, m), 3.59 (3H, s), 3.62-4.79 (6H, m), 4.04 (2H, t, J=7.1 Hz), 4.56 (2H, t, J=8.6 Hz), 6.62 (1H, d, J=9.5 Hz), 6.89 (1H, dd, J=7.2, 7.1 Hz), 7.09 (1H, d, J=7.2 Hz), 7.16 (1H, dd, J=9.2, 2.7 Hz), 7.22 (1H, d, J=2.7 Hz), 7.31 (1H, d, J=7.1 Hz), 7.45 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.28 (2H, s), 8.89 (2H, s).
    • Example 255 Synthesis of 1-methyl-6-{3-[N-(1-phenylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.91-2.43 (6H, m), 2.63-4.31 (9H, m), 3.60 (3H, s), 4.31-4.83 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.79-7.39 (7H, m), 7.45 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.09 (2H, d, J=5.0 Hz), 8.79 (2H, d, J=5.0 Hz).
    • Example 256 Synthesis of 1-Methyl-6-(3-{N-[2-(N′-methyl-N′-phenylamino)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one trihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.12-2.33 (2H, m), 2.90 (3H, s), 3.07-3.34 (4H, m), 3.60 (3H, s), 3.34-4.00 (2H, m), 4.00-4.16 (2H, m), 4.57 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.68 (1H, t, J=7.3 Hz), 6.79 (2H, d, J=7.3 Hz), 7.11-7.23 (3H, m), 7.24 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.0 Hz), 7.83 (1H, d, J=9.5 Hz), 8.04 (2H, d, J=4.9 Hz), 8.81 (2H, d, J=4.9 Hz).
    • Example 257 Synthesis of 6-{3-[N-(1-methoxyisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-2.17 (2H, m), 3.34 (2H, t, J=6.9 Hz), 3.70 (3H, s), 3.99 (2H, t, J=5.9 Hz), 4.09 (3H, s), 4.26 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.85 (1H, d, J=2.8 Hz), 7.04 (1H, dd, J=9.1, 2.8 Hz), 7.19-7.35 (3H, m), 7.52 (1H, d, J=9.5 Hz), 7.51-7.62 (1H, m), 7.62-7.74 (1H, m), 7.80 (1H, s), 8.18 (1H, d, J=8.2 Hz), 8.26 (1H, d, J=7.6 Hz), 8.48 (2H, d, J=5.9 Hz).
    • Example 258 Synthesis of 1-methyl-6-{3-[N-(1-oxo-1,2-dihydroisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one
  • 6-{3-[N-(1-Methoxyisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one (55 mg) was added to a 1N-hydrogen chloride in ethanol solution (5 ml), and stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature. 1N-Sodium hydroxide aqueous solution (5 ml) was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (20.6 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δppm: 1.92-2.14 (2H, m), 3.22 (2H, t, J=6.8 Hz), 3.70 (3H, s), 4.02 (2H, t, J=5.9 Hz), 4.16 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.89 (1H, d, J=2.8 Hz), 7.01 (1H, s), 7.09 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.33 (3H, m), 7.54 (1H, d, J=9.5 Hz), 7.52-7.67 (1H, m), 7.67-7.80 (1H, m), 8.08 (1H, d, J=8.2 Hz), 8.46 (1H, d, J=7.2 Hz), 8.51 (2H, d, J=5.9 Hz).
    • Example 259 Synthesis of 1-Methyl-6-(3-{N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 1.79-2.09 (2H, m), 2.60-4.15 (8H, m), 3.61 (3H, s), 4.76 (2H, s), 6.58 (1H, d, J=7.0 Hz), 6.63 (1H, d, J=9.5 Hz), 6.90 (1H, d, J=1.8 Hz), 6.99-7.19 (2H, m), 7.44 (1H, d, J=9.1 Hz), 7.51 (1H, d, J=7.0 Hz), 7.68 (2H, d, J=4.6 Hz), 7.83 (1H, d, J=9.5 Hz), 8.13 (1H, d, J=1.8 Hz), 8.53 (2H, d, J=4.6 Hz).
    • Example 260 Synthesis of 1-methyl-6-[3-(2-pyridin-3-ylethylamino)propoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.90-2.06 (2H, m), 2.76-3.00 (6H, m), 3.72 (3H, s), 4.08 (2H, t, J=6.1 Hz), 6.73 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.21 (1H, ddd, J=7.7, 4.8, 0.6 Hz), 7.29 (1H, d, J=9.2 Hz), 7.51-7.57 (1H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (1H, dd, J=4.8, 1.7 Hz), 8.51 (1H, d, J=1.7 Hz).
    • Example 261 Synthesis of 1-methyl-6-[4-(2-pyridin-3-ylethylamino)butoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.58-1.76 (2H, m), 1.76-1.92 (2H, m), 2.71 (2H, t, J=7.2 Hz), 2.78-3.00 (4H, m), 3.70 (3H, s), 4.00 (2H, t, J=6.2 Hz), 6.70 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.22 (1H, dd, J=7.7, 4.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.49-7.56 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.48 (1H, d, J=1.8 Hz).
    • Example 262 Synthesis of 1-methyl-6-{3-[(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one
  • 3N-Hydrochloric acid (5 ml) was added to a ethanol solution (5 ml) of N-[3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide (250.1 mg), and stirred for 60 hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, washed with ethyl acetate. A saturated sodium hydrogencarbonate aqueous solution was added to the aqueous layer, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure to give the title compound (168 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δppm: 1.93-2.10 (2H, m), 2.86 (2H, t, J=6.8 Hz), 3.71 (3H, s), 3.84 (2H, s), 4.11 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.65-7.72 (1H, m), 8.50 (1H, dd, J=4.8, 1.7 Hz), 8.58 (1H, d, J=1.7 Hz).
    • Example 263 Synthesis of 1-methyl-6-[2-(2-pyridin-3-ylethylamino)ethoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 2.76-2.90 (2H, m), 2.90-3.04 (2H, m), 3.07 (2H, t, J=5.2 Hz), 3.71 (3H, s), 4.12 (2H, t, J=5.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, dd, J=7.7, 4.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.52-7.59 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.48 (1H, dd, J=4.8, 1.7 Hz), 8.51 (1H, d, J=1.7 Hz).
    • Example 264 Synthesis of 1-methyl-6-{2-[N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one
  • 3-Pyridine carbaldehyde (0.99 ml) and 6-(2-Aminoethoxy)-1-methyl-1H-quinolin-2-one (2.18 g) were added to methanol (50 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (0.757 g) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound (3.063 g) as a yellow oil.
  • 1H-NMR (CDCl3) δppm: 3.06 (2H, t, J=5.0 Hz), 3.71 (3H, s), 3.91 (2H, s), 4.14 (2H, t, J=5.0 Hz), 6.72 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.68-7.75 (1H, m), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.61 (1H, d, J=1.7 Hz).
    • Example 265 Synthesis of methanesulfonic acid 2-[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-nitro-benzenesulfonyl)amino]ethyl ester
  • Methane sulfonyl chloride (1.14 ml) was added to a dichloromethane solution (50 ml) of N-(2-hydroxy-thyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-benzenesulfonamide (4.52 g) and triethylamine (2.73 ml). The mixture was stirred at room temperature overnight. 1N-Sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with saturated saline, and dried with sodium sulfate. After the organic layer was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound (4.37 g) as a yellow solid.
  • 1H-NMR (CDCl3) δppm: 2.00-2.21 (2H, m), 3.03 (3H, s), 3.63 (2H, t, J=7.6 Hz), 3.71 (3H, s), 3.75 (2H, t, J=5.5 Hz), 4.01 (2H, t, J=6.0 Hz), 4.40 (2H, t, J=5.5 Hz), 6.72 (1H, d, J=9.5 Hz), 6.92 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.56-7.67 (4H, m), 8.02-8.08 (1H, m).
    • Example 266 Synthesis of 1-methyl-6-(3-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethylamino}propoxy)-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.54-2.24 (8H, m), 2.49 (2H, t, J=6.1 Hz), 2.66-2.90 (6H, m), 3.33-3.50 (1H, m), 3.70 (3H, s), 4.00-4.18 (2H, m), 4.54 (2H, s), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.32 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.63-7.71 (1H, m), 8.53 (1H, dd, J=4.7, 1.5 Hz), 8.57 (1H, d, J=1.5 Hz).
    • Example 267 Synthesis of 1-methyl-6-(2-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethylamino}ethoxy)-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.58-1.85 (2H, m), 1.85-2.02 (2H, m), 2.10-2.25 (2H, m), 2.51 (2H, t, J=6.1 Hz), 2.70-2.85 (4H, m), 3.05 (2H, t, J=5.5 Hz), 3.36-3.50 (1H, m), 3.71 (3H, s), 4.13 (2H, t, J=5.5 Hz), 4.56 (2H, s), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.25-7.33 (2H, m), 7.60 (1H, d, J=9.5 Hz), 7.65-7.72 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.58 (1H, d, J=1.6 Hz).
    • Example 268 Synthesis of 1-methyl-6-{4-[(pyridin-4-ylmethyl)amino]butoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.62-1.80 (2H, m), 1.80-2.00 (2H, m), 2.72 (2H, t, J=7.0 Hz), 3.71 (3H, s), 3.83 (2H, s), 4.03 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.54 (2H, d, J=5.9 Hz).
    • Example 269 Synthesis of 1-methyl-6-{4-[(pyridin-3-ylmethyl)amino]butoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.60-1.80 (2H, m), 1.80-1.98 (2H, m), 2.72 (2H, t, J=7.0 Hz), 3.71 (3H, s), 3.83 (2H, s), 4.02 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.63-7.71 (1H, m), 8.51 (1H, dd, J=4.7, 1.5 Hz), 8.57 (1H, d, J=1.5 Hz).
    • Example 270 Synthesis of 1-methyl-6-(3-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethylamino}propoxy)-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.54-2.24 (8H, m), 2.49 (2H, t, J=6.0 Hz), 2.62-2.90 (6H, m), 3.30-3.49 (1H, m), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 4.54 (2H, s), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.7 Hz), 7.19 (1H, dd, J=9.2, 2.7 Hz), 7.20-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.56 (2H, d, J=5.9 Hz).
    • Example 272 Synthesis of 1-methyl-6-[3-(2-pyridin-3-ylethylamino)propoxy]-3,4-dihydro-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.82-2.02 (2H, m), 2.55-2.68 (2H, m), 2.78-2.99 (8H, m), 3.33 (3H, s), 3.99 (2H, t, J=6.1 Hz), 6.70 (1H, d, J=2.7 Hz), 6.74 (1H, dd, J=8.6, 2.7 Hz), 6.88 (1H, d, J=8.6 Hz), 7.21 (1H, dd, J=7.8, 4.8 Hz), 7.50-7.57 (1H, m), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).
    • Example 273 Synthesis of 1-methyl-6-[3-(2-pyridin-4-ylethylamino)propoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-2.08 (2H, m), 2.77-2.90 (4H, m), 2.90-3.01 (2H, m), 3.71 (3H, s), 4.07 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.09-7.19 (3H, m), 7.29 (1H, d, J=9.3 Hz), 7.59 (1H, d, J=9.5 Hz), 8.50 (2H, d, J=6.0 Hz).
    • Example 274 Synthesis of 6-[3-(3-imidazol-1-yl-propylamino)propoxy]-1-methyl-1H-quinolin-2-one
  • 3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propionaldehyde (127.5 mg) prepared from 6-hydroxy-1-methylquinolin-2(1H)-one and N-(3-aminopropyl)imidazole (82.9 mg) were added to methanol (10 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (31.4 mg) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (21 mg) as a yellow oil.
  • 1H-NMR (CDCl3) δppm: 1.81-2.02 (4H, m), 2.49-2.58 (2H, m), 2.80 (2H, t, J=6.9 Hz), 3.70 (3H, s), 3.93-4.15 (4H, m), 6.71 (1H, d, J=9.5 Hz), 6.91 (1H, s), 7.01 (1H, d, J=2.8 Hz), 7.05 (1H, s), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.47 (1H, s), 7.60 (1H, d, J=9.5 Hz).
    • Example 275 Synthesis of 1-methyl-6-[3-(2-piperidin-1-ylethylamino)propoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.32-1.49 (2H, m), 1.49-1.63 (4H, m), 1.94-2.08 (2H, m), 2.28-2.41 (4H, m), 2.45 (2H, t, J=6.2 Hz), 2.73 (2H, t, J=6.2 Hz), 2.83 (2H, t, J=6.9 Hz), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 6.70 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Example 276 Synthesis of 6-[3-(2-diethylaminoethylamino)propoxy]-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.00 (6H, t, J=7.1 Hz), 1.90-2.08 (2H, m), 2.41-2.60 (6H, m), 2.69 (2H, t, J=5.7 Hz), 2.83 (2H, t, J=6.9 Hz), 3.71 (3H, s), 4.10 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Example 277 Synthesis of 1-methyl-6-{3-[2-(4-methylpiperazin-1-yl)ethylamino]propoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.91-2.08 (2H, m), 2.26 (3H, s), 2.31-2.63 (10H, m), 2.73 (2H, t, J=6.1 Hz), 2.83 (2H, t, J=6.8 Hz), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.6 Hz), 7.19 (1H, dd, J=9.2, 2.6 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Example 278 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}benzamide
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.92-2.10 (2H, m), 2.82-3.00 (4H, m), 3.49-3.61 (2H, m), 3.68 (3H, s), 4.11 (2H, t, J=6.1 Hz), 6.70 (1H, d, J=9.5 Hz), 6.81 (1H, s), 6.97 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, d, J=9.2 Hz), 7.31-7.39 (2H, m), 7.41-7.48 (1H, m), 7.54 (1H, d, J=9.5 Hz), 7.70-7.77 (2H, m).
    • Example 279 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}isobutyramide
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.13 (6H, d, J=6.9 Hz), 1.90-2.08 (2H, m), 2.25-2.41 (1H, m), 2.75-2.90 (4H, m), 3.30-3.42 (2H, m), 3.70 (3H, s), 4.09 (2H, t, J=6.1 Hz), 6.09 (1H, s), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).
    • Example 280 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}nicotinamide
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.90-2.10 (2H, m), 2.80-3.00 (4H, m), 3.49-3.62 (2H, m), 3.68 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.69 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.7 Hz), 7.02 (1H, s), 7.14 (1H, dd, J=9.1, 2.7 Hz), 7.24 (1H, d, J=9.1 Hz), 7.31 (1H, dd, J=7.9, 4.8 Hz), 7.56 (1H, d, J=9.5 Hz), 8.03-8.11 (1H, m), 8.67 (1H, dd, J=4.8, 1.9 Hz), 8.95 (1H, d, J=1.9 Hz).
    • Example 281 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}benzenesulfonamide
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.80-1.99 (2H, m), 2.65-2.81 (4H, m), 2.99-3.12 (2H, m), 3.70 (3H, s), 4.05 (2H, t, J=6.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.7 Hz), 7.16 (1H, dd, J=9.1, 2.7 Hz), 7.28 (1H, d, J=9.1 Hz), 7.45-7.63 (4H, m), 7.82-7.90 (2H, m).
    • Example 282 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid
  • A 1N-sodium hydroxide aqueous solution (3 ml) was added to a methanol solution (15 ml) of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid ethyl ester (614 mg). The mixture was stirred at room temperature overnight. 1N-Hydrochloric acid (3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (468 mg) as a white amorphous solid.
  • 1H-NMR (DMSO-D6) δppm: 1.75-1.94 (2H, m), 2.73 (2H, t, J=6.8 Hz), 3.03 (2H, s), 3.59 (3H, s), 3.82 (2H, s), 4.04 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.9 Hz), 7.23 (1H, d, J=2.9 Hz), 7.32 (2H, d, J=5.9 Hz), 7.44 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.40 (2H, d, J=5.9 Hz).
    • Example 283 Synthesis of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.86-2.10 (2H, m), 2.70-2.92 (2H, m), 3.71 (3H, s), 3.85 (2H, s), 4.12 (2H, t, J=6.0 Hz), 6.72 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.08-7.38 (4H, m), 7.59 (1H, d, J=9.5 Hz), 8.53 (2H, d, J=5.9 Hz).
    • Example 284 Synthesis of 6-{3-[(2-aminoethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one
  • A 4N-hydrogen chloride ethyl acetate solution (0.22 ml) was added to an ethyl acetate solution (3 ml) of (2-{[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (137 mg), and the mixture was stirred at room temperature overnight. 5N-Ammoia methanol solution (1 ml) was added to the reaction mixture, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (85.7 mg) as an colorless oil.
  • 1H-NMR (CDCl3) δppm: 1.88-2.08 (2H, m), 2.57 (2H, t, J=6.0 Hz), 2.67 (2H, t, J=6.9 Hz), 2.80 (2H, t, J=6.0 Hz), 3.62 (2H, s), 3.71 (3H, s), 4.05 (2H, t, J=6.0 Hz), 6.71 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.49 (2H, d, J=6.0 Hz).
    • Example 285 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid
  • A 1N-sodium hydroxide aqueous solution (1.8 ml) was added to a methanol solution (3 ml) of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester (372 mg). The mixture was stirred at room temperature overnight. 6N-Hydrochloric acid (0.3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (458 mg) as a colorless oil.
  • 1H-NMR (DMSO-D6) δppm: 2.12-2.38 (2H, m), 3.09-3.48 (6H, m), 4.01-4.19 (2H, m), 4.46 (2H, s), 6.92-7.08 (1H, m), 7.10 (1H, d, J=6.9 Hz), 7.41-7.56 (1H, m), 7.64-7.77 (2H, m), 7.85 (2H, s), 8.13 (1H, d, J=7.6 Hz), 8.65 (1H, dd, J=5.2, 1.2 Hz), 8.68-8.80 (3H, m).
    • Example 286 Synthesis of 3-{3-[N-(2-pyridin-3-yl-ethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid
  • The synthesis of the title compound was performed in the same manner as in Example 285 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.10-2.41 (2H, m), 3.02-3.59 (6H, m), 3.98-4.22 (2H, m), 4.43-4.72 (2H, m), 7.19 (1H, d, J=8.3 Hz), 7.31-7.46 (2H, m), 7.54 (1H, d, J=7.7 Hz), 7.63-7.77 (1H, m), 7.83 (2H, s), 8.04-8.20 (1H, m), 8.65 (1H, d, J=5.3 Hz), 8.66-8.79 (3H, m).
    • Example 287 Synthesis of 4-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid
  • The synthesis of the title compound was performed in the same manner as in Example 285 using appropriate starting materials.
  • 1H-NMR (DMSO-D6) δppm: 2.16-2.38 (2H, m), 3.00-3.99 (6H, m), 3.99-4.16 (2H, m), 4.35-4.69 (2H, m), 6.96 (2H, d, J=8.8 Hz), 7.62-7.80 (1H, m), 7.80-7.99 (4H, m), 8.19 (1H, d, J=6.7 Hz), 8.60-8.80 (4H, m).
    • Example 288 Synthesis of 1-methyl-6-[3-(2-pyridin-2-ylethylamino)propoxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.91-2.12 (2H, m), 2.86 (2H, t, J=6.8 Hz), 2.92-3.14 (4H, m), 3.71 (3H, s), 4.07 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.07-7.25 (3H, m), 7.28 (1H, d, J=9.5 Hz), 7.51-7.68 (2H, m), 8.51 (1H, dd, J=4.8, 0.8 Hz).
    • Example 289 Synthesis of 1-methyl-6-[3-(quinolin-6-ylamino)propoxy]-1H-quinolin-2-one
  • 6-Aminoquinoline (360 mg) was added to the methanol solution (10 ml) of 6-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg) and stirred at 60° C. for 17 hours. The reaction mixture was added to ice water, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (86.4 mg) as a yellow amorphous solid.
  • 1H-NMR (CDCl3) δppm: 2.13-2.29 (2H, m), 3.50 (2H, t, J=6.6 Hz), 3.70 (3H, s), 4.18 (2H, t, J=5.8 Hz), 6.67-6.77 (2H, m), 7.01 (1H, d, J=2.7 Hz), 7.11 (1H, dd, J=9.1, 2.7 Hz), 7.18-7.27 (2H, m), 7.29 (1H, d, J=9.1 Hz), 7.56 (1H, d, J=9.5 Hz), 7.86 (1H, s), 7.89 (1H, s), 8.61 (1H, dd, J=4.2, 1.6 Hz).
    • Example 290 Synthesis of N-benzyl-N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}acetamide
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.87-2.06 (2H, m), 2.12 (3H, s), 2.70-2.90 (4H, m), 3.51 (2H, t, J=6.5 Hz), 3.71 (3H, s), 3.98-4.15 (2H, m), 4.58 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.98-7.03 (1H, m), 7.13-7.21 (2H, m), 7.21-7.40 (5H, m), 7.59 (1H, d, J=9.5 Hz).
    • Example 291 Synthesis of 6-{3-[2-(7-bromo-1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1-methyl-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.88-2.05 (2H, m), 2.87 (2H, t, J=6.6 Hz), 3.06 (2H, t, J=6.1 Hz), 3.70 (3H, s), 4.04 (2H, t, J=6.1 Hz), 4.12 (2H, t, J=6.1 Hz), 6.37 (1H, d, J=7.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.09 (1H, dd, J=9.2, 2.8 Hz), 7.12 (1H, d, J=7.3 Hz), 7.23 (1H, d, J=9.2 Hz), 7.32 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.67 (1H, dd, J=8.5, 2.1 Hz), 8.52 (1H, d, J=2.1 Hz).
    • Example 292 Synthesis of 1-Methyl-6-{3-[(2-methylamino-ethyl)-pyridin-4-ylmethyl-amino]-propoxy}-1H-quinolin-2-one trihydrochloride
  • A 4N-hydrogen chloride ethyl acetate solution (4.2 ml) was added to an ethyl acetate solution (30 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was condensed under reduced pressure to give the title compound (1.0 g) as a white powder.
  • 1H-NMR (DMSO-D6) δppm: 1.95-2.22 (2H, m), 2.52 (3H, s), 2.56 (2H, t, J=5.4 Hz), 2.77-3.40 (4H, m), 3.61 (3H, s), 3.99-4.16 (2H, m), 4.16-5.10 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.17 (2H, d, J=5.0 Hz), 8.83 (2H, d, J=5.0 Hz).
    • Example 293 Synthesis of 1-Methyl-6-{3-[(2-methylamino-ethyl)-pyridin-4-ylmethyl-amino]-propoxy}-1H-quinolin-2-one
  • A 4N-hydrogen chloride ethyl acetate solution (48 ml) was added to an ethyl acetate solution (300 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (11.5 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the methanol solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure to give the title compound (9.96 g) as a brown oil.
  • 1H-NMR (CDCl3) δppm: 1.88-2.07 (2H, m), 2.43 (3H, s), 2.68 (2H, t, J=6.9 Hz), 2.70-2.88 (4H, m), 3.64 (2H, s), 3.70 (3H, s), 4.04 (2H, t, J=5.9 Hz), 6.71 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.36 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.49 (2H, d, J=6.0 Hz).
    • Example 294 Synthesis of 6-[3-(2-Pyridin-3-yl-ethylamino)-propoxy]-3,4-dihydro-2H-isoquinolin-1-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.84-2.02 (2H, m), 2.74-2.87 (4H, m), 2.87-3.02 (4H, m), 3.48-3.61 (2H, m), 4.06 (2H, t, J=6.1 Hz), 5.88 (1H, s), 6.66 (1H, d, J=2.4 Hz), 6.81 (1H, dd, J=8.6, 2.4 Hz), 7.20 (1H, dd, J=7.7, 4.8 Hz), 7.47-7.60 (1H, m), 8.00 (1H, d, J=8.6 Hz), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).
    • Example 295 Synthesis of 1-Methyl-6-{2-[(pyridin-4-ylmethyl)-amino]-ethoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 3.05 (2H, t, J=5.2 Hz), 3.71 (3H, s), 3.92 (2H, s), 4.15 (2H, t, J=5.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.46 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.56 (2H, d, J=6.0 Hz).
    • Example 296 Synthesis of 3-[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propylamino]-N-o-tolyl-propionamide
  • Sodium ethoxide (34 mg) was added to an ethanol solution (5 ml) of 6-(3-amino-propoxy)-1-methyl-1H-quinolin-2-one (116 mg) and 3-chloro-N-o-tolyl-propionamide (148 mg). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (115 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm: 2.15-2.36 (2H, m), 2.26 (3H, s), 2.99-3.56 (6H, m), 3.63 (3H, s), 4.11 (2H, t, J=5.6 Hz), 6.66 (1H, d, J=9.5 Hz), 6.92-7.29 (6H, m), 7.47 (1H, d, J=9.5 Hz), 7.59 (1H, d, J=6.9 Hz), 9.25 (1H, s).
    • Example 297 Synthesis of N-Methyl-3-[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propylamino]-N-o-tolyl-propionamide
  • 6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (194 mg) was added to an ethanol solution (5 ml) of N-methyl-N-o-tolyl-acrylamide (146 mg). The mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (172.6 mg) as a colorless oil.
  • 1H-NMR (CDCl3) δppm: 2.06-2.25 (2H, m), 2.24 (3H, s), 2.25-2.50 (2H, m), 2.86-3.03 (4H, m), 3.20 (3H, s), 3.70 (3H, s), 4.12 (2H, t, J=6.0 Hz), 6.71 (1H, d, J=9.5 Hz), 7.07 (1H, d, J=2.3 Hz), 7.13 (1H, dd, J=8.3, 2.3 Hz), 7.19-7.38 (5H, m), 7.60 (1H, d, J=9.5 Hz).
    • Example 298 Synthesis of 1-Methyl-6-[3-(piperidin-4-yl-pyridin-4-ylmethyl-amino)-propoxy]-1H-quinolin-2-one
  • Trifluoroacetic acid (30 ml) was added to a dichloromethane solution (10 ml) of 4-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.08 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the dichloromethane solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=4:1). The purified product was condensed under reduced pressure to give the title compound (758 mg) as an orange oil.
  • 1H-NMR (CDCl3) δppm: 1.45-1.65 (2H, m), 1.70-1.99 (4H, m), 2.50-2.69 (3H, m), 2.74 (2H, t, J=6.7 Hz), 3.11-3.25 (2H, m), 3.68 (2H, s), 3.71 (3H, s), 4.00 (2H, t, J=6.0 Hz), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.35 (3H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (2H, d, J=6.0 Hz).
    • Example 299 Synthesis of 6-[3-(1-Methoxy-isoquinolin-4-ylamino)-propoxy]-1-methyl-1H-quinolin-2-one
  • 6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (232 mg), 4-bromo-1-methoxy-isoquinoline (286 mg), palladium acetate (II)(22 mg), xantphos (558 mg), and sodium t-butoxide (192 mg) were added to dioxane (10 ml). The mixture was heated at 80° C. for overnight under argon atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and followed by celite filtration. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→1:0). The purified product was condensed under reduced pressure to give the title compound (99 mg) as a brown amorphous solid.
  • 1H-NMR (CDCl3) δppm: 2.20-2.37 (2H, m), 3.48 (2H, t, J=6.5 Hz), 3.68 (3H, s), 4.06 (3H, s), 4.22 (2H, t, J=5.9 Hz), 6.69 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.7 Hz), 7.13-7.31 (2H, m), 7.39 (1H, s), 7.51-7.62 (2H, m), 7.62-7.73 (1H, m), 7.79 (1H, d, J=8.3 Hz), 8.25 (1H, dd, J=8.3, 0.5 Hz).
    • Example 300 Synthesis of 1-Methyl-6-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)-ethylamino]-propoxy}-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.87-2.03 (2H, m), 2.86 (2H, t, J=6.7 Hz), 3.06 (2H, t, J=6.2 Hz), 3.70 (3H, s), 4.06 (2H, t, J=6.1 Hz), 4.18 (2H, t, J=6.2 Hz), 6.39 (1H, d, J=7.0 Hz), 6.61 (1H, d, J=2.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.08-7.19 (2H, m), 7.21-7.32 (1H, m), 7.59 (1H, d, J=9.5 Hz), 7.71 (1H, d, J=2.1 Hz).
    • Example 301 Synthesis of 1-Methyl-6-[5-(2-pyridin-3-yl-ethylamino)-pentyloxy]-1H-quinolin-2-one
  • The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 1.44-1.72 (4H, m), 1.72-1.90 (2H, m), 2.67 (2H, t, J=6.9 Hz), 2.74-2.97 (4H, m), 3.71 (3H, s), 4.00 (2H, t, J=6.4 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.22 (1H, dd, J=7.8, 4.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.50-7.56 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.47 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).
    • Example 302 N-(2-Methyl-benzyl)-4-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-N-{2-[4-(pyridin-3-ylmethoxy)-piperidin-1-yl]-ethyl}-butyramide dihydrochloride
  • To a DMF solution (3 ml) of 4-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-butyric acid (100 mg) were sequentially added (2-methyl-benzyl)-{2-[4-(pyridin-3-ylmethoxy)-piperidin-1-yl]-ethyl}-amine (143 mg), triethylamine (47 mg), diethylphosphorocyanidate (DEPC, 84 mg) while ice-cooling, followed by stirring at room temperature overnight. Water was added to the reaction mixture and then subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate:methanol:28% ammonia solution=70:20:10:1). The purified product was concentrated under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution was added to a ethyl acetate solution of the residue. The mixture was condensed under reduced pressure to give the title compound (165 mg) as a pale yellow amorphous solid.
  • 1H-NMR (DMSO-d6) δppm: 1.79-2.60 (8H, m), 2.24, 2.28 (total 3H, each-s), 2.68-4.28 (11H, m), 3.58 (3H, s), 4.45-4.76 (4H, m), 6.59, 6.60 (total 1H, each-d, J=9.5 Hz), 6.82-7.50 (7H, m), 7.75-7.88 (1H, m), 7.88-8.00 (1H, m), 8.35-8.50 (1H, m), 8.72-8.95 (2H, m).
    • Example 303 N-(2-Methyl-benzyl)-4-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-N-(2-pyridin-3-yl-ethyl)-butyramide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 302 using appropriate starting materials.
  • 1H-NMR (DMSO-d6) δppm: 1.80-2.08 (2H, m), 2.23, 2.27 (total 3H, each-s), 2.29-2.63 (2H, m), 2.96-3.14 (2H, m), 3.59 (3H, s), 3.48-3.70 (2H, m), 3.93, 4.04 (total 2H, each-t, J=6.3 Hz), 4.57, 4.61 (total 2H, each-s), 6.60, 6.61 (total 1H, each-d, J=9.5 Hz), 6.85-7.33 (6H, m), 7.38-7.50 (1H, m), 7.78-7.89 (1H, m), 7.89-8.00 (1H, m), 8.82-8.47 (1H, m), 8.70-8.80 (1H, m), 8.80-8.92 (1H, m).
    • Example 304 1-[5-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-pentyl]-3-phenyl-1-(2-pyridin-3-yl-ethyl)-urea hydrochloride
  • N-Ethyldiisopropylamine (0.192 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride (219 mg). The mixture was stirred at room temperature for 5 minutes. The reaction mixture was condensed under reduced pressure. Phenylisocyanate (0.065 ml) and toluene (2 ml) were added to the residue. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (147 mg) as a pale yellow flakes.
  • 1H-NMR (DMSO-d6) δppm: 1.38-1.83 (6H, m), 3.04 (2H, t, J=7.0 Hz), 3.36 (2H, t, J=7.1 Hz), 3.59 (3H, s), 3.65 (2H, t, J=7.1 Hz), 4.03 (2H, t, J=6.4 Hz), 6.60 (1H, d, J=9.5 Hz), 6.93 (1H, t, J=7.3 Hz), 7.18-7.28 (4H, m), 7.38-7.45 (3H, m), 7.81 (1H, d, J=9.5 Hz), 7.89-7.94 (1H, m), 8.26 (1H, s), 8.42 (1H, d, J=8.1 Hz), 8.73 (1H, d, J=5.5 Hz), 8.86 (1H, s)
    • Example 305 2-Methyl-N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6, 100° C.) δppm: 1.81-2.08 (2H, m), 2.14 (3H, s), 2.40-2.60 (2H, m), 2.70-2.84 (2H, m), 2.85-3.03 (2H, m), 3.21 (3H, s), 3.38-3.73 (4H, m), 3.78-4.00 (2H, m), 6.56-6.82 (2H, m), 6.85-7.04 (2H, m), 7.08-7.31 (3H, m), 7.32-7.48 (1H, m), 7.54-7.84 (1H, m), 8.28-8.60 (2H, m).
    • Example 306 4-Methyl-N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-benzamide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6, 100° C.) δppm: 1.86-2.02 (2H, m), 2.32 (3H, s), 2.40-2.60 (2H, m), 2.73-2.88 (2H, m), 2.89-3.02 (2H, m), 3.21 (3H, s), 3.40-3.52 (2H, m), 3.56-3.69 (2H, m), 3.87-3.96 (2H, m), 6.70 (1H, s), 6.62-6.78 (1H, m), 6.93 (1H, d, J=9.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.41-7.58 (1H, m), 7.73-7.93 (1H, m), 8.38-8.58 (2H, m).
    • Example 307 N-[3-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-isobutyramide hydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6, 100° C.) δppm: 0.94 (6H, d, J=6.6 Hz), 1.86-2.00 (2H, m), 2.43-2.53 (2H, m), 2.65-2.89 (3H, m), 2.89-3.02 (2H, m), 3.21 (3H, s), 3.34-3.50 (2H, m), 3.52-3.66 (2H, m), 3.90-4.04 (2H, m), 6.70-6.84 (2H, m), 6.89-7.01 (1H, m), 7.56-7.70 (1H, m), 7.98-8.12 (1H, m), 8.50-8.67 (2H, m).
    • Example 308 N-[3-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-isonicotinamide dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.
  • 1H-NMR (DMSO-D6, 100° C.) δppm: 1.90-2.05 (2H, m), 2.49-2.53 (2H, m), 2.74-2.88 (2H, m), 2.91-3.12 (2H, m), 3.21 (3H, s), 3.32-3.54 (2H, m), 3.54-3.75 (2H, m), 3.81-4.02 (2H, m), 6.60-6.81 (2H, m), 6.94 (1H, d, J=8.7 Hz), 7.23 (2H, d, J=5.1 Hz), 7.43-7.68 (1H, m), 7.76-8.09 (1H, m), 8.42-8.70 (4H, m).
    • Examples 310 to 986
  • The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.
  • TABLE A
    Figure US20140343277A1-20141120-C01081
    Example No. R1 MS (M + 1)
    310 —OCH3 492
    311 —O(CH2)2C6H5 582
    312 —N(CH3)(CH2)2N(CH3)C6H5 624
    313 —OCH(C6H5)2 644
    314 —N(CH3)(CH2)2C6H5 595
    315 —N(CH3)(CH2)2N(C2H5)2 590
    316 —OC6H5 554
    317 —C6H5 538
    318 —CH2CONHC2H5 547
  • TABLE B
    Figure US20140343277A1-20141120-C01082
    Example MS
    No. R1 (M + 1)
    319
    Figure US20140343277A1-20141120-C01083
         		602
    320
    Figure US20140343277A1-20141120-C01084
         		636
    321
    Figure US20140343277A1-20141120-C01085
         		569
    322
    Figure US20140343277A1-20141120-C01086
         		609
    323
    Figure US20140343277A1-20141120-C01087
         		623
    324
    Figure US20140343277A1-20141120-C01088
         		637
    325
    Figure US20140343277A1-20141120-C01089
         		604
    326
    Figure US20140343277A1-20141120-C01090
         		601
    327
    Figure US20140343277A1-20141120-C01091
         		542
    328
    Figure US20140343277A1-20141120-C01092
         		545
    329
    Figure US20140343277A1-20141120-C01093
         		547
    330
    Figure US20140343277A1-20141120-C01094
         		586
    331
    Figure US20140343277A1-20141120-C01095
         		653
    332
    Figure US20140343277A1-20141120-C01096
         		592
    333
    Figure US20140343277A1-20141120-C01097
         		587
    334
    Figure US20140343277A1-20141120-C01098
         		636
    335
    Figure US20140343277A1-20141120-C01099
         		652
    336
    Figure US20140343277A1-20141120-C01100
         		609
    337
    Figure US20140343277A1-20141120-C01101
         		586
    338
    Figure US20140343277A1-20141120-C01102
         		566
    339
    Figure US20140343277A1-20141120-C01103
         		581
    340
    Figure US20140343277A1-20141120-C01104
         		544
    341
    Figure US20140343277A1-20141120-C01105
         		625
    342
    Figure US20140343277A1-20141120-C01106
         		596
    343
    Figure US20140343277A1-20141120-C01107
         		572
    344
    Figure US20140343277A1-20141120-C01108
         		638
    345
    Figure US20140343277A1-20141120-C01109
         		637
    346
    Figure US20140343277A1-20141120-C01110
         		581
    347
    Figure US20140343277A1-20141120-C01111
         		596
    348
    Figure US20140343277A1-20141120-C01112
         		600
    349
    Figure US20140343277A1-20141120-C01113
         		601
    350
    Figure US20140343277A1-20141120-C01114
         		621
    351
    Figure US20140343277A1-20141120-C01115
         		585
  • TABLE C
    Figure US20140343277A1-20141120-C01116
    MS
    Example No. R1 R2 (M + 1)
    352 —(CH2)3CH3 —(CH2)3CH3 373
    353 —CH2C6H5 —(CH2)3N(CH3)2 436
    354 —CH3 —(CH2)3N(CH3)CH2C6H5 436
    355 —H —(CH2)3N(CH3)2 346
    356 —CH3 —CH3 289
  • TABLE D
    Figure US20140343277A1-20141120-C01117
    Example MS
    No. R1 R2 (M + 1)
    357 —CH3
    Figure US20140343277A1-20141120-C01118
         		357
    358 —CH3
    Figure US20140343277A1-20141120-C01119
         		380
    359 —C2H5
    Figure US20140343277A1-20141120-C01120
         		455
    360 —CH3
    Figure US20140343277A1-20141120-C01121
         		468
    361 —CH3
    Figure US20140343277A1-20141120-C01122
         		399
    362 —H
    Figure US20140343277A1-20141120-C01123
         		351
    363 —H
    Figure US20140343277A1-20141120-C01124
         		338
    364 —C2H5
    Figure US20140343277A1-20141120-C01125
         		455
    365 —H
    Figure US20140343277A1-20141120-C01126
         		383
    366 —H
    Figure US20140343277A1-20141120-C01127
         		358
    367 —CH3
    Figure US20140343277A1-20141120-C01128
         		448
    368 —CH3
    Figure US20140343277A1-20141120-C01129
         		496
    369 —H
    Figure US20140343277A1-20141120-C01130
         		374
  • TABLE E
    Figure US20140343277A1-20141120-C01131
    Exam-
    ple MS
    No. R1 (M + 1)
    370
    Figure US20140343277A1-20141120-C01132
         		596
    371
    Figure US20140343277A1-20141120-C01133
         		553
    372
    Figure US20140343277A1-20141120-C01134
         		635
    373
    Figure US20140343277A1-20141120-C01135
         		580
    374
    Figure US20140343277A1-20141120-C01136
         		488
    375
    Figure US20140343277A1-20141120-C01137
         		530
    376
    Figure US20140343277A1-20141120-C01138
         		510
    377
    Figure US20140343277A1-20141120-C01139
         		549
    378
    Figure US20140343277A1-20141120-C01140
         		516
    379
    Figure US20140343277A1-20141120-C01141
         		516
    380
    Figure US20140343277A1-20141120-C01142
         		491
    381
    Figure US20140343277A1-20141120-C01143
         		554
    382
    Figure US20140343277A1-20141120-C01144
         		604
    383
    Figure US20140343277A1-20141120-C01145
         		604
    384
    Figure US20140343277A1-20141120-C01146
         		495
    385
    Figure US20140343277A1-20141120-C01147
         		496
    386
    Figure US20140343277A1-20141120-C01148
         		521
    387
    Figure US20140343277A1-20141120-C01149
         		523
    388
    Figure US20140343277A1-20141120-C01150
         		523
    389
    Figure US20140343277A1-20141120-C01151
         		527
    390
    Figure US20140343277A1-20141120-C01152
         		597
    391
    Figure US20140343277A1-20141120-C01153
         		496
    392
    Figure US20140343277A1-20141120-C01154
         		523
    393
    Figure US20140343277A1-20141120-C01155
         		496
  • TABLE F
    Figure US20140343277A1-20141120-C01156
    Example MS
    No. R1 R2 (M + 1)
    394 —(CH2)2CH3 —(CH2)3C6H5 554
    395 —(CH2)2N(CH3)2 —CH2C6H5 555
    396 —H —CH2C(CH3)3 464
    397 —CH3 —(CH2)2N(C2H5)2 507
    398 —H —(CH2)2SCH3 468
  • TABLE G
    Figure US20140343277A1-20141120-C01157
    Exam-
    ple MS
    No. R1 R2 (M + 1)
    399 —C2H5
    Figure US20140343277A1-20141120-C01158
         		572
    400 —CH3
    Figure US20140343277A1-20141120-C01159
         		490
    401 —H
    Figure US20140343277A1-20141120-C01160
         		607
    402 —CH3
    Figure US20140343277A1-20141120-C01161
         		518
    403 —CH3
    Figure US20140343277A1-20141120-C01162
         		513
    404 —CH3
    Figure US20140343277A1-20141120-C01163
         		505
    405 —H
    Figure US20140343277A1-20141120-C01164
         		504
    406 —H
    Figure US20140343277A1-20141120-C01165
         		485
    407 —H
    Figure US20140343277A1-20141120-C01166
         		485
    408 —H
    Figure US20140343277A1-20141120-C01167
         		485
    409 —H
    Figure US20140343277A1-20141120-C01168
         		474
    410 —CH3
    Figure US20140343277A1-20141120-C01169
         		559
    411 —CH3
    Figure US20140343277A1-20141120-C01170
         		533
    412 —C2H5
    Figure US20140343277A1-20141120-C01171
         		556
    413 —C2H5
    Figure US20140343277A1-20141120-C01172
         		518
    414 —CH3
    Figure US20140343277A1-20141120-C01173
         		601
    415 —H
    Figure US20140343277A1-20141120-C01174
         		528
    416 —H
    Figure US20140343277A1-20141120-C01175
         		462
    417 —H
    Figure US20140343277A1-20141120-C01176
         		502
    418 —H
    Figure US20140343277A1-20141120-C01177
         		521
    419 —H
    Figure US20140343277A1-20141120-C01178
         		562
    420 —H
    Figure US20140343277A1-20141120-C01179
         		521
    421 —CH2C6H5
    Figure US20140343277A1-20141120-C01180
         		657
    422 —CH3
    Figure US20140343277A1-20141120-C01181
         		591
    423 —H
    Figure US20140343277A1-20141120-C01182
         		490
    424 —H
    Figure US20140343277A1-20141120-C01183
         		478
    425 —H
    Figure US20140343277A1-20141120-C01184
         		499
    426 —H
    Figure US20140343277A1-20141120-C01185
         		494
    427 —H
    Figure US20140343277A1-20141120-C01186
         		474
    428 —H
    Figure US20140343277A1-20141120-C01187
         		491
    429 —H
    Figure US20140343277A1-20141120-C01188
         		487
  • TABLE H
    Figure US20140343277A1-20141120-C01189
    Example No. R1 MS (M + 1)
    432 —(CH2)3CH3 519
    433 —(CH2)2N(CH3)2 534
    434 —(CH2)3OCH3 535
    435 —(CH2)5CH3 547
    436 —CO2C(CH3)3 563
  • TABLE I
    Figure US20140343277A1-20141120-C01190
    Exam-
    ple MS
    No. R1 (M + 1)
    437
    Figure US20140343277A1-20141120-C01191
         		554
    438
    Figure US20140343277A1-20141120-C01192
         		554
    439
    Figure US20140343277A1-20141120-C01193
         		554
    440
    Figure US20140343277A1-20141120-C01194
         		540
    441
    Figure US20140343277A1-20141120-C01195
         		541
    442
    Figure US20140343277A1-20141120-C01196
         		597
    443
    Figure US20140343277A1-20141120-C01197
         		540
    444
    Figure US20140343277A1-20141120-C01198
         		659
    445
    Figure US20140343277A1-20141120-C01199
         		665
    446
    Figure US20140343277A1-20141120-C01200
         		630
    447
    Figure US20140343277A1-20141120-C01201
         		579
    448
    Figure US20140343277A1-20141120-C01202
         		596
    449
    Figure US20140343277A1-20141120-C01203
         		613
    450
    Figure US20140343277A1-20141120-C01204
         		579
    451
    Figure US20140343277A1-20141120-C01205
         		580
    452
    Figure US20140343277A1-20141120-C01206
         		567
    453
    Figure US20140343277A1-20141120-C01207
         		553
    454
    Figure US20140343277A1-20141120-C01208
         		531
    455
    Figure US20140343277A1-20141120-C01209
         		559
    456
    Figure US20140343277A1-20141120-C01210
         		560
    457
    Figure US20140343277A1-20141120-C01211
         		569
    458
    Figure US20140343277A1-20141120-C01212
         		637
    459
    Figure US20140343277A1-20141120-C01213
         		604
    460
    Figure US20140343277A1-20141120-C01214
         		635
    461
    Figure US20140343277A1-20141120-C01215
         		573
    462
    Figure US20140343277A1-20141120-C01216
         		649
    463
    Figure US20140343277A1-20141120-C01217
         		636
    464
    Figure US20140343277A1-20141120-C01218
         		593
    465
    Figure US20140343277A1-20141120-C01219
         		623
    466
    Figure US20140343277A1-20141120-C01220
         		607
    467
    Figure US20140343277A1-20141120-C01221
         		606
    468
    Figure US20140343277A1-20141120-C01222
         		596
    469
    Figure US20140343277A1-20141120-C01223
         		597
    470
    Figure US20140343277A1-20141120-C01224
         		596
    471
    Figure US20140343277A1-20141120-C01225
         		611
    472
    Figure US20140343277A1-20141120-C01226
         		549
    473
    Figure US20140343277A1-20141120-C01227
         		574
    474
    Figure US20140343277A1-20141120-C01228
         		543
    475
    Figure US20140343277A1-20141120-C01229
         		540
    476
    Figure US20140343277A1-20141120-C01230
         		557
    477
    Figure US20140343277A1-20141120-C01231
         		554
    478
    Figure US20140343277A1-20141120-C01232
         		597
    479
    Figure US20140343277A1-20141120-C01233
         		568
    480
    Figure US20140343277A1-20141120-C01234
         		622
    481
    Figure US20140343277A1-20141120-C01235
         		579
    482
    Figure US20140343277A1-20141120-C01236
         		639
    483
    Figure US20140343277A1-20141120-C01237
         		597
  • TABLE J
    Figure US20140343277A1-20141120-C01238
    Example No. R1 MS(M + 1)
    484 —CH2OC6H5 515
    485 —(CH2)2C6H5 513
    486 —CH═CHC6H5 511
    487 —(CH2)2OC6H5 529
    488 —(CH2)3C6H5 527
    489 —CH(CH3)2 451
    490 —(CH2)2N(COCH3)C6H5 570
  • TABLE K
    Figure US20140343277A1-20141120-C01239
    Example No. R1 MS(M + 1)
    491
    Figure US20140343277A1-20141120-C01240
         		514
    492
    Figure US20140343277A1-20141120-C01241
         		486
    493
    Figure US20140343277A1-20141120-C01242
         		486
    494
    Figure US20140343277A1-20141120-C01243
         		486
    495
    Figure US20140343277A1-20141120-C01244
         		500
    496
    Figure US20140343277A1-20141120-C01245
         		475
    497
    Figure US20140343277A1-20141120-C01246
         		491
    498
    Figure US20140343277A1-20141120-C01247
         		475
    499
    Figure US20140343277A1-20141120-C01248
         		491
    500
    Figure US20140343277A1-20141120-C01249
         		505
    501
    Figure US20140343277A1-20141120-C01250
         		505
    502
    Figure US20140343277A1-20141120-C01251
         		491
    503
    Figure US20140343277A1-20141120-C01252
         		505
    504
    Figure US20140343277A1-20141120-C01253
         		596
    505
    Figure US20140343277A1-20141120-C01254
         		541
    506
    Figure US20140343277A1-20141120-C01255
         		535
    507
    Figure US20140343277A1-20141120-C01256
         		535
    508
    Figure US20140343277A1-20141120-C01257
         		529
    509
    Figure US20140343277A1-20141120-C01258
         		513
    510
    Figure US20140343277A1-20141120-C01259
         		529
    511
    Figure US20140343277A1-20141120-C01260
         		541
    512
    Figure US20140343277A1-20141120-C01261
         		512
    513
    Figure US20140343277A1-20141120-C01262
         		512
    514
    Figure US20140343277A1-20141120-C01263
         		525
    515
    Figure US20140343277A1-20141120-C01264
         		524
    516
    Figure US20140343277A1-20141120-C01265
         		524
    517
    Figure US20140343277A1-20141120-C01266
         		474
    518
    Figure US20140343277A1-20141120-C01267
         		525
    519
    Figure US20140343277A1-20141120-C01268
         		513
    520
    Figure US20140343277A1-20141120-C01269
         		531
    521
    Figure US20140343277A1-20141120-C01270
         		538
    522
    Figure US20140343277A1-20141120-C01271
         		538
    523
    Figure US20140343277A1-20141120-C01272
         		541
    524
    Figure US20140343277A1-20141120-C01273
         		512
    525
    Figure US20140343277A1-20141120-C01274
         		554
    526
    Figure US20140343277A1-20141120-C01275
         		552
    527
    Figure US20140343277A1-20141120-C01276
         		514
    528
    Figure US20140343277A1-20141120-C01277
         		491
    529
    Figure US20140343277A1-20141120-C01278
         		525
    530
    Figure US20140343277A1-20141120-C01279
         		479
    531
    Figure US20140343277A1-20141120-C01280
         		493
    532
    Figure US20140343277A1-20141120-C01281
         		507
    533
    Figure US20140343277A1-20141120-C01282
         		492
    534
    Figure US20140343277A1-20141120-C01283
         		503
    535
    Figure US20140343277A1-20141120-C01284
         		501
    536
    Figure US20140343277A1-20141120-C01285
         		545
    537
    Figure US20140343277A1-20141120-C01286
         		527
    538
    Figure US20140343277A1-20141120-C01287
         		527
    539
    Figure US20140343277A1-20141120-C01288
         		539
    540
    Figure US20140343277A1-20141120-C01289
         		543
    541
    Figure US20140343277A1-20141120-C01290
         		540
    542
    Figure US20140343277A1-20141120-C01291
         		490
    543
    Figure US20140343277A1-20141120-C01292
         		492
    544
    Figure US20140343277A1-20141120-C01293
         		504
    545
    Figure US20140343277A1-20141120-C01294
         		543
    546
    Figure US20140343277A1-20141120-C01295
         		556
    547
    Figure US20140343277A1-20141120-C01296
         		562
    548
    Figure US20140343277A1-20141120-C01297
         		528
    549
    Figure US20140343277A1-20141120-C01298
         		543
    550
    Figure US20140343277A1-20141120-C01299
         		539
    551
    Figure US20140343277A1-20141120-C01300
         		518
    552
    Figure US20140343277A1-20141120-C01301
         		476
    553
    Figure US20140343277A1-20141120-C01302
         		489
    554
    Figure US20140343277A1-20141120-C01303
         		489
    555
    Figure US20140343277A1-20141120-C01304
         		489
    556
    Figure US20140343277A1-20141120-C01305
         		490
  • TABLE L
    Figure US20140343277A1-20141120-C01306
    Example No. R1 MS(M + 1)
    557
    Figure US20140343277A1-20141120-C01307
         		472
    558
    Figure US20140343277A1-20141120-C01308
         		468
    559
    Figure US20140343277A1-20141120-C01309
         		468
    560
    Figure US20140343277A1-20141120-C01310
         		470
    561
    Figure US20140343277A1-20141120-C01311
         		470
    562
    Figure US20140343277A1-20141120-C01312
         		468
    563
    Figure US20140343277A1-20141120-C01313
         		467
    564
    Figure US20140343277A1-20141120-C01314
         		483
    565
    Figure US20140343277A1-20141120-C01315
         		480
    566
    Figure US20140343277A1-20141120-C01316
         		508
    567
    Figure US20140343277A1-20141120-C01317
         		486
    568
    Figure US20140343277A1-20141120-C01318
         		499
    569
    Figure US20140343277A1-20141120-C01319
         		499
    570
    Figure US20140343277A1-20141120-C01320
         		482
    571
    Figure US20140343277A1-20141120-C01321
         		482
    572
    Figure US20140343277A1-20141120-C01322
         		484
    573
    Figure US20140343277A1-20141120-C01323
         		481
  • TABLE M
    Figure US20140343277A1-20141120-C01324
    Example
    No. R2 R3 R4 R5 R6 MS(M + 1)
    574 —H —H —OCH3 —H —H 515
    575 —H —H —NHCOCH3 —H —H 542
    576 —H —H —H —NHCOCH3 —H 542
    577 —H —H —CF3 —H —H 553
    578 —H —H —H —H —OCH3 515
    579 —H —H —H —H —CH3 499
    580 —H —H —H —H —F 503
    581 —H —H —H —H —N(CH3)2 528
    582 —H —H —H —OCH3 —H 515
    583 —H —H —H —CH3 —H 499
    584 —H —H —COCH3 —H —H 527
    585 —H —H —C6H5 —H —H 561
    586 —H —H —SO2NH2 —H —H 564
    587 —H —H
    Figure US20140343277A1-20141120-C01325
         		—H —H 550
    588 —H —H
    Figure US20140343277A1-20141120-C01326
         		—H —H 562
  • TABLE N
    Figure US20140343277A1-20141120-C01327
    Example
    No. R2 R3 R4 R5 R6 MS(M + 1)
    589 —H —H —H —H —OCH3 378
    590 —H —H —H —OCH3 —H 378
    591 —H —H —OCH3 —H —H 378
    592 —H —H —H —H —H 348
    593 —H —H —H —H —CN 373
    594 —H —H —H —CN —H 373
    595 —H —H —CN —H —H 373
    596 —H —H —H —H —CF3 416
    597 —H —H —H —CF3 —H 416
    598 —H —H —CF3 —H —H 416
    599 —H —H —H —H —OCF3 432
    600 —H —H —H —OCF3 —H 432
    601 —H —H —OCF3 —H —H 432
    602 —H —H —H —C6H5 —H 424
    603 —H —H —H —N(C2H5)2 —H 419
    604 —H —H —(CH2)2COCH3 —H —H 418
    605 —H —H —COC2H5 —H —H 404
    606 —H —OH —COCH3 —H —H 406
    607 —H —H —SCH3 —H —H 394
    608 —H —H —C6H5 —H —H 424
    609 —H —H —H —H —C6H5 424
    610 —H —H —H —OC6H5 —H 440
    611 —H —H —COCH3 —H —H 390
    612 —H —H
    Figure US20140343277A1-20141120-C01328
         		—H —H 415
    613 —H —H —H —H
    Figure US20140343277A1-20141120-C01329
         		415
    614 —H —H
    Figure US20140343277A1-20141120-C01330
         		—H —H 414
    615 —H —H
    Figure US20140343277A1-20141120-C01331
         		—H —H 413
    616 —H —H
    Figure US20140343277A1-20141120-C01332
         		—H —H 556
  • TABLE O
    Figure US20140343277A1-20141120-C01333
    Example No. R1 MS(M + 1)
    617
    Figure US20140343277A1-20141120-C01334
         		392
    618
    Figure US20140343277A1-20141120-C01335
         		398
    619
    Figure US20140343277A1-20141120-C01336
         		398
    620
    Figure US20140343277A1-20141120-C01337
         		405
    621
    Figure US20140343277A1-20141120-C01338
         		419
    622
    Figure US20140343277A1-20141120-C01339
         		416
    623
    Figure US20140343277A1-20141120-C01340
         		422
    624
    Figure US20140343277A1-20141120-C01341
         		399
    625
    Figure US20140343277A1-20141120-C01342
         		349
    626
    Figure US20140343277A1-20141120-C01343
         		399
    627
    Figure US20140343277A1-20141120-C01344
         		349
    628
    Figure US20140343277A1-20141120-C01345
         		416
    629
    Figure US20140343277A1-20141120-C01346
         		399
    630
    Figure US20140343277A1-20141120-C01347
         		413
    631
    Figure US20140343277A1-20141120-C01348
         		400
    632
    Figure US20140343277A1-20141120-C01349
         		402
    633
    Figure US20140343277A1-20141120-C01350
         		363
    634
    Figure US20140343277A1-20141120-C01351
         		380
    635
    Figure US20140343277A1-20141120-C01352
         		399
    636
    Figure US20140343277A1-20141120-C01353
         		402
    637
    Figure US20140343277A1-20141120-C01354
         		416
    638
    Figure US20140343277A1-20141120-C01355
         		416
    639
    Figure US20140343277A1-20141120-C01356
         		430
    640
    Figure US20140343277A1-20141120-C01357
         		430
    641
    Figure US20140343277A1-20141120-C01358
         		446
    642
    Figure US20140343277A1-20141120-C01359
         		445
    643
    Figure US20140343277A1-20141120-C01360
         		419
    644
    Figure US20140343277A1-20141120-C01361
         		432
    645
    Figure US20140343277A1-20141120-C01362
         		435
    646
    Figure US20140343277A1-20141120-C01363
         		460
    647
    Figure US20140343277A1-20141120-C01364
         		460
    648
    Figure US20140343277A1-20141120-C01365
         		460
    649
    Figure US20140343277A1-20141120-C01366
         		474
    650
    Figure US20140343277A1-20141120-C01367
         		445
    651
    Figure US20140343277A1-20141120-C01368
         		431
    652
    Figure US20140343277A1-20141120-C01369
         		417
    653
    Figure US20140343277A1-20141120-C01370
         		421
    654
    Figure US20140343277A1-20141120-C01371
         		431
    655
    Figure US20140343277A1-20141120-C01372
         		417
    656
    Figure US20140343277A1-20141120-C01373
         		431
    657
    Figure US20140343277A1-20141120-C01374
         		445
    658
    Figure US20140343277A1-20141120-C01375
         		431
    659
    Figure US20140343277A1-20141120-C01376
         		431
    660
    Figure US20140343277A1-20141120-C01377
         		405
    661
    Figure US20140343277A1-20141120-C01378
         		419
    662
    Figure US20140343277A1-20141120-C01379
         		446
    663
    Figure US20140343277A1-20141120-C01380
         		432
    664
    Figure US20140343277A1-20141120-C01381
         		417
    665
    Figure US20140343277A1-20141120-C01382
         		431
    666
    Figure US20140343277A1-20141120-C01383
         		403
    667
    Figure US20140343277A1-20141120-C01384
         		449
    668
    Figure US20140343277A1-20141120-C01385
         		449
    669
    Figure US20140343277A1-20141120-C01386
         		435
    670
    Figure US20140343277A1-20141120-C01387
         		445
    671
    Figure US20140343277A1-20141120-C01388
         		465
  • TABLE P
    Figure US20140343277A1-20141120-C01389
    Exam- MS
    ple No. R1 (M + 1)
    672
    Figure US20140343277A1-20141120-C01390
         		557
    673
    Figure US20140343277A1-20141120-C01391
         		545
    674
    Figure US20140343277A1-20141120-C01392
         		571
    675
    Figure US20140343277A1-20141120-C01393
         		647
    676
    Figure US20140343277A1-20141120-C01394
         		555
    677
    Figure US20140343277A1-20141120-C01395
         		555
    678
    Figure US20140343277A1-20141120-C01396
         		556
    679
    Figure US20140343277A1-20141120-C01397
         		578
    680
    Figure US20140343277A1-20141120-C01398
         		538
    681
    Figure US20140343277A1-20141120-C01399
         		577
    682
    Figure US20140343277A1-20141120-C01400
         		530
    683
    Figure US20140343277A1-20141120-C01401
         		571
    684
    Figure US20140343277A1-20141120-C01402
         		531
    685
    Figure US20140343277A1-20141120-C01403
         		571
    686
    Figure US20140343277A1-20141120-C01404
         		585
    687
    Figure US20140343277A1-20141120-C01405
         		583
    688
    Figure US20140343277A1-20141120-C01406
         		575
    689
    Figure US20140343277A1-20141120-C01407
         		575
    690
    Figure US20140343277A1-20141120-C01408
         		557
    691
    Figure US20140343277A1-20141120-C01409
         		556
    692
    Figure US20140343277A1-20141120-C01410
         		621
    693
    Figure US20140343277A1-20141120-C01411
         		605
  • TABLE Q
    Figure US20140343277A1-20141120-C01412
    Example
    No. R2 R3 R4 R5 R6 MS(M + 1)
    694 —H —H —OCH3 —H —H 532
    695 —H —OCH3 —OCH3 —H —H 562
    696 —Cl —H —H —H —H 536
    697 —H —Cl —H —H —H 536
    698 —H —H —Cl —H —H 536
    699 —H —Cl —Cl —H —H 570
    700 —H —H —CH3 —H —H 516
    701 —H —CH3 —CH3 —H —H 530
    702 —H —H —CO2C2H5 —H —H 574
    703 —H —H —CN —H —H 527
    704 —H —H —CF3 —H —H 570
    705 —H —H —OCF3 —H —H 586
    706 —H —H —(CH2)2CH3 —H —H 544
    707 —H —F —Cl —H —H 554
    708 —OCH3 —H —CH2CH═CH2 —H —H 572
    709 —H —N(C2H5)2 —H —H —H 573
    710 —H —H —CH(CH3)2 —H —H 544
    711 —H —H —(CH2)2COCH3 —H —H 572
    712 —H —NHC6H5 —H —H —H 593
    713 —H —H —SCH3 —H —H 548
    714
    Figure US20140343277A1-20141120-C01413
         		—H —H —H —H 635
    715 —H —H —C6H5 —H —H 578
    716 —H —H —OCH2C6H5 —H —H 608
    717 —H —H —CH2C6H5 —H —H 592
    718 —H —H —O(CH2)7CH3 —H —H 630
    719 —H —OC6H5 —H —H —H 594
    720 —H —H —(CH2)5CH3 —H —H 586
    721 —H —H —NO2 —H —H 547
    722 —H —H —COCH3 —H —H 544
    723 —H —H —H —H —H 502
    724 —H —H —NHCOCH3 —H —H 559
    725 —H —H
    Figure US20140343277A1-20141120-C01414
         		—H —H 569
    726 —H —H
    Figure US20140343277A1-20141120-C01415
         		—H —H 568
    727 —H —H
    Figure US20140343277A1-20141120-C01416
         		—H —H 567
    728 —H —H
    Figure US20140343277A1-20141120-C01417
         		—H —H 724
    729 —H —H
    Figure US20140343277A1-20141120-C01418
         		—H —H 584
    730 —H —H
    Figure US20140343277A1-20141120-C01419
         		—H —H 724
    731 —H —H
    Figure US20140343277A1-20141120-C01420
         		—H —H 585
  • TABLE R
    Figure US20140343277A1-20141120-C01421
    Example No. R1 MS(M + 1)
    732
    Figure US20140343277A1-20141120-C01422
         		546
    733
    Figure US20140343277A1-20141120-C01423
         		552
    734
    Figure US20140343277A1-20141120-C01424
         		552
    735
    Figure US20140343277A1-20141120-C01425
         		559
    736
    Figure US20140343277A1-20141120-C01426
         		570
    737
    Figure US20140343277A1-20141120-C01427
         		576
    738
    Figure US20140343277A1-20141120-C01428
         		553
    739
    Figure US20140343277A1-20141120-C01429
         		503
    740
    Figure US20140343277A1-20141120-C01430
         		553
    741
    Figure US20140343277A1-20141120-C01431
         		503
    742
    Figure US20140343277A1-20141120-C01432
         		570
    743
    Figure US20140343277A1-20141120-C01433
         		553
    744
    Figure US20140343277A1-20141120-C01434
         		543
    745
    Figure US20140343277A1-20141120-C01435
         		544
    746
    Figure US20140343277A1-20141120-C01436
         		554
    747
    Figure US20140343277A1-20141120-C01437
         		542
    748
    Figure US20140343277A1-20141120-C01438
         		517
    749
    Figure US20140343277A1-20141120-C01439
         		534
    750
    Figure US20140343277A1-20141120-C01440
         		553
    751
    Figure US20140343277A1-20141120-C01441
         		556
    752
    Figure US20140343277A1-20141120-C01442
         		577
    753
    Figure US20140343277A1-20141120-C01443
         		584
    754
    Figure US20140343277A1-20141120-C01444
         		584
    755
    Figure US20140343277A1-20141120-C01445
         		585
    756
    Figure US20140343277A1-20141120-C01446
         		599
    757
    Figure US20140343277A1-20141120-C01447
         		599
    758
    Figure US20140343277A1-20141120-C01448
         		586
    759
    Figure US20140343277A1-20141120-C01449
         		614
    760
    Figure US20140343277A1-20141120-C01450
         		571
    761
    Figure US20140343277A1-20141120-C01451
         		573
    762
    Figure US20140343277A1-20141120-C01452
         		575
    763
    Figure US20140343277A1-20141120-C01453
         		585
    764
    Figure US20140343277A1-20141120-C01454
         		571
    765
    Figure US20140343277A1-20141120-C01455
         		585
    766
    Figure US20140343277A1-20141120-C01456
         		599
    767
    Figure US20140343277A1-20141120-C01457
         		585
    768
    Figure US20140343277A1-20141120-C01458
         		587
    769
    Figure US20140343277A1-20141120-C01459
         		587
    770
    Figure US20140343277A1-20141120-C01460
         		587
    771
    Figure US20140343277A1-20141120-C01461
         		601
    772
    Figure US20140343277A1-20141120-C01462
         		571
    773
    Figure US20140343277A1-20141120-C01463
         		599
    774
    Figure US20140343277A1-20141120-C01464
         		599
    775
    Figure US20140343277A1-20141120-C01465
         		603
    776
    Figure US20140343277A1-20141120-C01466
         		597
  • TABLE S
    Figure US20140343277A1-20141120-C01467
    Example No. R1 MS(M + 1)
    777 —CH2C6H5 659
    778 —CH2CH═CH2 609
    779 —CH2CH═CHC6H5 685
    780 —(CH2)3C6H5 687
    781 —CH2COC6H5 687
    782 —CH3 583
    783 —C2H5 597
    784 —(CH2)2CH3 611
    785 —CH2CH(CH3)2 625
    786 —(CH2)2N(CH3)2 640
    787 —(CH2)3CH2CH═CH2 651
    788 —(CH2)3OH 627
  • TABLE T
    Figure US20140343277A1-20141120-C01468
    Example No. R1 MS(M + 1)
    789
    Figure US20140343277A1-20141120-C01469
         		693
    790
    Figure US20140343277A1-20141120-C01470
         		727
    791
    Figure US20140343277A1-20141120-C01471
         		673
    792
    Figure US20140343277A1-20141120-C01472
         		735
    793
    Figure US20140343277A1-20141120-C01473
         		665
    794
    Figure US20140343277A1-20141120-C01474
         		660
    795
    Figure US20140343277A1-20141120-C01475
         		660
    796
    Figure US20140343277A1-20141120-C01476
         		660
    797
    Figure US20140343277A1-20141120-C01477
         		664
  • TABLE U
    Figure US20140343277A1-20141120-C01478
    Example No. R1 MS(M + 1)
    798
    Figure US20140343277A1-20141120-C01479
         		448
    799
    Figure US20140343277A1-20141120-C01480
         		478
    800
    Figure US20140343277A1-20141120-C01481
         		455
    801
    Figure US20140343277A1-20141120-C01482
         		455
    802
    Figure US20140343277A1-20141120-C01483
         		474
    803
    Figure US20140343277A1-20141120-C01484
         		405
    804
    Figure US20140343277A1-20141120-C01485
         		472
    805
    Figure US20140343277A1-20141120-C01486
         		455
    806
    Figure US20140343277A1-20141120-C01487
         		469
    807
    Figure US20140343277A1-20141120-C01488
         		456
    808
    Figure US20140343277A1-20141120-C01489
         		455
    809
    Figure US20140343277A1-20141120-C01490
         		483
    810
    Figure US20140343277A1-20141120-C01491
         		501
    811
    Figure US20140343277A1-20141120-C01492
         		475
    812
    Figure US20140343277A1-20141120-C01493
         		488
    813
    Figure US20140343277A1-20141120-C01494
         		516
    814
    Figure US20140343277A1-20141120-C01495
         		516
    815
    Figure US20140343277A1-20141120-C01496
         		487
    816
    Figure US20140343277A1-20141120-C01497
         		477
    817
    Figure US20140343277A1-20141120-C01498
         		487
    818
    Figure US20140343277A1-20141120-C01499
         		487
    819
    Figure US20140343277A1-20141120-C01500
         		501
    820
    Figure US20140343277A1-20141120-C01501
         		487
    821
    Figure US20140343277A1-20141120-C01502
         		489
    822
    Figure US20140343277A1-20141120-C01503
         		503
    823
    Figure US20140343277A1-20141120-C01504
         		487
    824
    Figure US20140343277A1-20141120-C01505
         		461
    825
    Figure US20140343277A1-20141120-C01506
         		475
    826
    Figure US20140343277A1-20141120-C01507
         		475
    827
    Figure US20140343277A1-20141120-C01508
         		489
    828
    Figure US20140343277A1-20141120-C01509
         		502
    829
    Figure US20140343277A1-20141120-C01510
         		488
    830
    Figure US20140343277A1-20141120-C01511
         		473
    831
    Figure US20140343277A1-20141120-C01512
         		487
    832
    Figure US20140343277A1-20141120-C01513
         		459
    833
    Figure US20140343277A1-20141120-C01514
         		505
    834
    Figure US20140343277A1-20141120-C01515
         		475
    835
    Figure US20140343277A1-20141120-C01516
         		489
    836
    Figure US20140343277A1-20141120-C01517
         		501
    837
    Figure US20140343277A1-20141120-C01518
         		473
    838
    Figure US20140343277A1-20141120-C01519
         		473
    839
    Figure US20140343277A1-20141120-C01520
         		474
    840
    Figure US20140343277A1-20141120-C01521
         		455
    841
    Figure US20140343277A1-20141120-C01522
         		469
    842
    Figure US20140343277A1-20141120-C01523
         		443
    843
    Figure US20140343277A1-20141120-C01524
         		485
    844
    Figure US20140343277A1-20141120-C01525
         		499
    845
    Figure US20140343277A1-20141120-C01526
         		487
    846
    Figure US20140343277A1-20141120-C01527
         		458
    847
    Figure US20140343277A1-20141120-C01528
         		484
    848
    Figure US20140343277A1-20141120-C01529
         		455
    849
    Figure US20140343277A1-20141120-C01530
         		485
    850
    Figure US20140343277A1-20141120-C01531
         		469
    851
    Figure US20140343277A1-20141120-C01532
         		473
    852
    Figure US20140343277A1-20141120-C01533
         		473
    853
    Figure US20140343277A1-20141120-C01534
         		456
    854
    Figure US20140343277A1-20141120-C01535
         		461
    855
    Figure US20140343277A1-20141120-C01536
         		455
    856
    Figure US20140343277A1-20141120-C01537
         		455
    857
    Figure US20140343277A1-20141120-C01538
         		455
    858
    Figure US20140343277A1-20141120-C01539
         		444
    859
    Figure US20140343277A1-20141120-C01540
         		487
    860
    Figure US20140343277A1-20141120-C01541
         		473
    861
    Figure US20140343277A1-20141120-C01542
         		487
    862
    Figure US20140343277A1-20141120-C01543
         		487
    863
    Figure US20140343277A1-20141120-C01544
         		487
  • TABLE V
    Figure US20140343277A1-20141120-C01545
    Example No. R2 R3 R4 R5 R6 MS(M + 1)
    864 —H —H —H —H —H 428
    865 —H —H —OCH3 —H —H 458
    866 —H —N(CH3)2 —H —H —H 471
    867 —H —H —N(CH3)2 —H —H 471
    868 —H —H —CN —H —H 453
    869 —COCH3 —H —H —H —H 470
    870 —H —H —COCH3 —H —H 470
    871 —OC6H5 —H —H —H —H 520
    872 —H —H —OC6H5 —H —H 520
    873 —CN —H —H —H —H 453
    874 —H —H —C6H5 —H —H 504
    875 —H —H —SO2CH3 —H —H 506
    876 —H —H —N(C2H5)2 —H —H 499
    877 —H —C6H5 —H —H —H 504
    878 —H —H
    Figure US20140343277A1-20141120-C01546
         		—H —H 511
    879 —H —H
    Figure US20140343277A1-20141120-C01547
         		—H —H 493
    880 —H —H
    Figure US20140343277A1-20141120-C01548
         		—H —H 494
    881 —H
    Figure US20140343277A1-20141120-C01549
         		—H —H —H 509
    882 —H
    Figure US20140343277A1-20141120-C01550
         		—H —H —H 495
  • TABLE W
    Figure US20140343277A1-20141120-C01551
    Example
    No. R2 R3 R4 R5 R6 MS(M + 1)
    883 —H —H —CH3 —H —H 456
    884 —H —H —F —H —H 460
    885 —H —H —OCH3 —H —H 472
    886 —H —H —H —H —CH3 456
    887 —H —H —H —OCH3 —H 472
    888 —H —H —H —H —OCH3 472
    889 —H —H —OCH3 —OH —H 488
  • TABLE X
    Figure US20140343277A1-20141120-C01552
    Example No. R1 MS(M + 1)
    890 —CH2OC6H5 458
    891 —(CH2)2C6H5 456
    892 —CH═CHC6H5 454
    893 —(CH2)2OC6H5 472
    894 —(CH2)3C6H5 470
    895 —(CH2)4C6H5 484
    896 —CH2SC6H5 474
    897 —(CH2)2COC6H5 484
  • TABLE Y
    Figure US20140343277A1-20141120-C01553
    Example No. R1 MS(M + 1)
    898
    Figure US20140343277A1-20141120-C01554
         		457
    899
    Figure US20140343277A1-20141120-C01555
         		476
    900
    Figure US20140343277A1-20141120-C01556
         		488
    901
    Figure US20140343277A1-20141120-C01557
         		429
    902
    Figure US20140343277A1-20141120-C01558
         		429
    903
    Figure US20140343277A1-20141120-C01559
         		429
    904
    Figure US20140343277A1-20141120-C01560
         		418
    905
    Figure US20140343277A1-20141120-C01561
         		434
    906
    Figure US20140343277A1-20141120-C01562
         		418
    907
    Figure US20140343277A1-20141120-C01563
         		434
    908
    Figure US20140343277A1-20141120-C01564
         		448
    909
    Figure US20140343277A1-20141120-C01565
         		448
    910
    Figure US20140343277A1-20141120-C01566
         		434
    911
    Figure US20140343277A1-20141120-C01567
         		484
    912
    Figure US20140343277A1-20141120-C01568
         		484
    913
    Figure US20140343277A1-20141120-C01569
         		472
    914
    Figure US20140343277A1-20141120-C01570
         		497
    915
    Figure US20140343277A1-20141120-C01571
         		514
    916
    Figure US20140343277A1-20141120-C01572
         		498
    917
    Figure US20140343277A1-20141120-C01573
         		468
    918
    Figure US20140343277A1-20141120-C01574
         		455
    919
    Figure US20140343277A1-20141120-C01575
         		455
    920
    Figure US20140343277A1-20141120-C01576
         		468
    921
    Figure US20140343277A1-20141120-C01577
         		475
    922
    Figure US20140343277A1-20141120-C01578
         		467
    923
    Figure US20140343277A1-20141120-C01579
         		467
    924
    Figure US20140343277A1-20141120-C01580
         		469
    925
    Figure US20140343277A1-20141120-C01581
         		502
    926
    Figure US20140343277A1-20141120-C01582
         		486
    927
    Figure US20140343277A1-20141120-C01583
         		481
    928
    Figure US20140343277A1-20141120-C01584
         		495
    929
    Figure US20140343277A1-20141120-C01585
         		481
    930
    Figure US20140343277A1-20141120-C01586
         		500
    931
    Figure US20140343277A1-20141120-C01587
         		514
    932
    Figure US20140343277A1-20141120-C01588
         		455
    933
    Figure US20140343277A1-20141120-C01589
         		527
    934
    Figure US20140343277A1-20141120-C01590
         		527
    935
    Figure US20140343277A1-20141120-C01591
         		527
    936
    Figure US20140343277A1-20141120-C01592
         		539
    937
    Figure US20140343277A1-20141120-C01593
         		523
    938
    Figure US20140343277A1-20141120-C01594
         		511
    939
    Figure US20140343277A1-20141120-C01595
         		495
    940
    Figure US20140343277A1-20141120-C01596
         		457
    941
    Figure US20140343277A1-20141120-C01597
         		431
    942
    Figure US20140343277A1-20141120-C01598
         		444
    943
    Figure US20140343277A1-20141120-C01599
         		480
    944
    Figure US20140343277A1-20141120-C01600
         		468
    945
    Figure US20140343277A1-20141120-C01601
         		436
    946
    Figure US20140343277A1-20141120-C01602
         		450
    947
    Figure US20140343277A1-20141120-C01603
         		435
    948
    Figure US20140343277A1-20141120-C01604
         		446
    949
    Figure US20140343277A1-20141120-C01605
         		468
    950
    Figure US20140343277A1-20141120-C01606
         		444
    951
    Figure US20140343277A1-20141120-C01607
         		486
    952
    Figure US20140343277A1-20141120-C01608
         		482
    953
    Figure US20140343277A1-20141120-C01609
         		510
    954
    Figure US20140343277A1-20141120-C01610
         		433
    955
    Figure US20140343277A1-20141120-C01611
         		435
    956
    Figure US20140343277A1-20141120-C01612
         		495
    957
    Figure US20140343277A1-20141120-C01613
         		447
    958
    Figure US20140343277A1-20141120-C01614
         		495
    959
    Figure US20140343277A1-20141120-C01615
         		489
    960
    Figure US20140343277A1-20141120-C01616
         		517
    961
    Figure US20140343277A1-20141120-C01617
         		501
    962
    Figure US20140343277A1-20141120-C01618
         		468
    963
    Figure US20140343277A1-20141120-C01619
         		513
    964
    Figure US20140343277A1-20141120-C01620
         		505
    965
    Figure US20140343277A1-20141120-C01621
         		505
    966
    Figure US20140343277A1-20141120-C01622
         		505
    967
    Figure US20140343277A1-20141120-C01623
         		486
    968
    Figure US20140343277A1-20141120-C01624
         		490
    969
    Figure US20140343277A1-20141120-C01625
         		419
    970
    Figure US20140343277A1-20141120-C01626
         		500
    971
    Figure US20140343277A1-20141120-C01627
         		508
    972
    Figure US20140343277A1-20141120-C01628
         		508
    973
    Figure US20140343277A1-20141120-C01629
         		433
    974
    Figure US20140343277A1-20141120-C01630
         		468
    975
    Figure US20140343277A1-20141120-C01631
         		484
    976
    Figure US20140343277A1-20141120-C01632
         		514
    977
    Figure US20140343277A1-20141120-C01633
         		509
    978
    Figure US20140343277A1-20141120-C01634
         		482
    979
    Figure US20140343277A1-20141120-C01635
         		498
  • TABLE Z
    Example No . structure MS(M + 1)
    981
    Figure US20140343277A1-20141120-C01636
         		628
    982
    Figure US20140343277A1-20141120-C01637
         		446
    983
    Figure US20140343277A1-20141120-C01638
         		502
    984
    Figure US20140343277A1-20141120-C01639
         		474
    985
    Figure US20140343277A1-20141120-C01640
         		530
    986
    Figure US20140343277A1-20141120-C01641
         		544
    • Pharmacological Test 1
  • (1) Production of human Kv1.5-expressing CHO-K1 Cell Lines
  • CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.
  • Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).
  • The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.
    • (2) Production of CHO Cell Line Expressing Human GIRK1/4
  • CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.
  • Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).
  • TABLE 1
    Primer Sequence
    hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID
    GAAATTTG-3′ No. 1
    hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID
    AGTTC-3′ No. 2
    hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID
    ATTATGTCTGCACTCC-3′ No. 3
    hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID
    GA-3′ No. 4
    hGIRK1-A4 5′-CCGAGTGTAGGCGATCA SEQ ID
    CCC-3′ No. 5
    hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID
    GAATGCC-3′ No. 6
    hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID
    CCTCCC-3′ No. 7
    hGIRK4-S2 5′-AACCAGGACATGGAGAT SEQ ID
    TGG-3′ No. 8
    hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID
    CAC-3′ No. 9
  • The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM—002239) and GIRK4 (NM—000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.
    • (3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.
  • Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 40 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.
  • Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 4 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (5) Measurement of Human Kv1.5 Current
  • While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.
  • The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (6) Measurement of Human GIRK1/4 Current
  • While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.
  • The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current
  • The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC50 value) was calculated according to the following nonlinear regression equation:

  • Relative current=1/(1+[Concentration of the compound]/IC50)nH
  • wherein nH is the Hill coefficient.
  • Table 2 shows the test results.
  • TABLE 2
    Test Compound KV1.5 IC50 (μM)
    Compound of Example 14 0.23
    Compound of Example 18 0.39
    Compound of Example 24 0.32
    Compound of Example 26 0.30
    Compound of Example 34 0.33
    Compound of Example 38 0.38
    Compound of Example 40 0.86
    Compound of Example 42 0.77
    Compound of Example 46 0.42
    Compound of Example 62 0.12
    • 3. Third Invention Reference Example 1 Synthesis of ethyl N-(5-methoxy-2-nitrophenyl)-N-methyl malonamate
  • Sodium hydride (60% in oil, 96 mg) was suspended in 10 ml of dimethylformamide (DMF). N-Methyl-5-methoxy-2-nitroaniline (364 mg) was added thereto at 0° C., and stirring was conducted at room temperature for 30 minutes. Ethyl malonyl chloride (0.38 ml) was added at 0° C. to the stirred mixture, and the reaction mixture was stirred at room temperature overnight. Water was added thereto, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:2). The purified product was concentrated under reduced pressure to give the title compound (554 mg) as a yellow oil.
  • 1H-NMR (CDCl3) δppm:
  • 1.24 (3H, t, J=7.1 Hz), 3.15-3.17 (2H, m), 3.25 (3H, s), 3.92 (3H, s), 4.13 (2H, q, J=7.1 Hz), 6.93 (1H, d, J=2.8 Hz), 7.02 (1H, dd, J=2.8 and 9.2 Hz), 8.15 (1H, d, J=9.2 Hz).
    • Reference Example 2 Synthesis of ethyl N-(2-amino-5-methoxyphenyl)-N-methyl malonamate
  • Palladium on carbon (10%, 0.5 g) was added to an ethanol solution (150 ml) of ethyl N-(5-methoxy-2-nitrophenyl)-N-methyl malonamate (3.0 g), and catalytic reduction was conducted at room temperature and normal pressure. The reaction mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give the title compound (2.68 g) as a yellow oil.
  • 1H-NMR (CDCl3) δppm:
  • 1.22 (3H, t, J=7.1 Hz), 3.19-3.27 (5H, m), 3.52-3.68 (2H, br), 3.74 (3H, s), 4.11 (2H, q, J=7.1 Hz), 6.62 (1H, d, J=2.7 Hz), 6.73 (1H, d, J=8.7 Hz), 6.79 (1H, dd, J=2.7 and 8.7 Hz).
    • Reference Example 3 Synthesis of 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of ethyl N-(2-amino-5-methoxyphenyl)-N-methyl malonamate (266 mg), and stirred at 65° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→10:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm:
  • 3.36 (2H, s), 3.43 (3H, s), 3.84 (3H, s), 6.79-6.83 (1H, m), 7.06-7.09 (1H, m), 8.72 (1H, br-s).
    • Reference Example 4 Synthesis of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium hydride (60% in oil, 44 mg) was suspended in dimethylformamide (DMF) (8 ml), and cooled in an ice water bath to 0° C.
  • 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (190.2 mg) as a yellow solid.
  • 1H-NMR (CDCl3) δppm:
  • 1.11 (3H, t, J=7.1 Hz), 3.31-3.32 (2H, m), 3.40 (3H, s), 3.59-3.68 (1H, m), 3.85 (3H, s), 4.18-4.30 (1H, m), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H, dd, J=9.0 and 2.8 Hz), 7.26 (1H, d, J=9.0 Hz).
    • Reference Example 5 Synthesis of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Sodium hydride (60% in oil, 76 mg) was suspended in DMF (8 ml). 1-Ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (190 mg) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. Methyl iodide (0.19 ml) was added to the mixture, and stirred at room temperature for 3 days. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was concentrated to dryness under reduced pressure to give the title compound (169 mg) as a yellow powder.
  • 1H-NMR (CDCl3) δppm:
  • 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.65-3.76 (1H, m), 3.85 (3H, s), 4.12-4.24 (1H, m), 6.73 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).
    • Reference Example 6 Synthesis of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • A 1.0 M boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg) at 0° C., and stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction with the mixture solvent (dichloromethane:methanol=10:1) was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (156.4 mg) as a white powder.
  • 1H-NMR (CDCl3) δppm:
  • 0.90 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.55 (3H, s), 3.41 (3H, s), 3.66-3.78 (1H, m), 4.12-4.23 (1H, m), 6.79 (1H, d, J=2.7 Hz), 6.84 (1H, dd, J=8.8 and 2.7 Hz), 6.88 (1H, d, J=2.7 Hz), 7.18 (1H, d, J=8.8 Hz).
    • Reference Example 7-Synthesis of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g) and potassium carbonate (1.2 g) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (2.18 g) as a colorless oil.
  • 1H-NMR (CDCl3) δppm:
  • 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.21-2.38 (2H, m), 3.40 (3H, s), 3.63-3.89 (4H, m), 4.10-4.26 (2H, m), 6.74 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=2.8 and 9.0 Hz), 7.21 (1H, d, J=9.0 Hz).
    • Reference Example 8 Synthesis of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (2.18 g) and sodium iodide (4.8 g) were added to acetone (50 ml), and heated under reflux for 8.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to give the title compound (2.76 g) as a colorless oil.
  • 1H-NMR (CDCl3) δppm:
  • 0.87 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.26-2.34 (2H, m), 3.39 (2H, t, J=6.6 Hz), 3.65-3.76 (1H, m), 3.41 (3H, s), 4.07 (2H, t, J=5.8 Hz), 4.12-4.24 (1H, m), 6.74 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).
    • Reference Example 9 Synthesis of 3-iodoquinolin-4-ol
  • Potassium carbonate (5.2 g) was added to a DMF solution (50 ml) of 4-hydroxy quinoline (5.0 g) and the mixture was stirred. Iodine (9.6 g) was added to the mixture, followed by stirring at room temperature for 3 hours. A saturated sodium hydrogencarbonate aqueous solution (73 ml) of 25% sodium sulfite, and water (50 ml) were added to the reaction mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was washed with water and dried to give the title compound (9.0 g) as a white powder.
  • mp: 288 to 294° C. (dec.)
    • Reference Example 10 Synthesis of 3-bromoquinolin-4-ol
  • N-Bromosuccinimide (1.3 g) was added to a DMF solution (15 ml) of 4-hydroxy quinoline (1.0 g) and the mixture was stirred at room temperature for 15 hours. A sodium hydrogencarbonate aqueous solution of 25% sodium sulfite was added to the mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was dissolved in a mixture of ethyl acetate and methanol, and an insoluble matter was removed by filtration. The filtrate was condensed under reduced pressure, and the residue was washed with ethyl acetate and dried to give the title compound (1.1 g) as a white powder.
  • mp: 286 to 287° C.
    • Reference Example 11 Synthesis of 3-bromo-1H-quinolin-2-one
  • Hydrogen peroxide solution (5.9 ml) was added to a THF solution (16 ml) of methyltrioxorhenium (VII) (24 mg). The mixture was stirred for 10 minutes at room temperature. 3-Bromoquinoline (4.0 g) was added thereto, and the mixture was stirred at room temperature for four days. Ethyl acetate (20 ml) was added to the reaction mixture. 20% Sodium sulfite aqueous solution (30 ml) was added slowly to the mixture under ice cooling. The mixture was stirred at room temperature. The organic layer was condensed to a half volume under reduced pressure. Ethyl acetate (20 ml) and 15% potassium carbonate aqueous solution (19 ml) were added thereto, and the organic layer was extracted. 15% Potassium carbonate aqueous solution (19 ml) of p-toluenesulfonyl chloride (4 g) were added thereto. The mixture was stirred for 10 minutes at room temperature. The generated insoluble matter was separated, washed with ethyl acetate, water, and then with ether, and dried to give the title compound (3.2 g) as a white powder.
  • mp: 263 to 265° C.
    • Reference Example 12 Synthesis of 1-(pyridin-3-yl)-2,3-dihydrobenzoimidazol-2-one
  • N,N′-Carbonyldiimidazole (0.57 g) was added to a DMF solution (5 ml) of N-pyridine-3-ylbenzene-1,2-diamine (0.5 g). The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.5 g) as a pale whitish purple powder.
  • mp: 232 to 233° C. (dec.).
    • Reference Example 13 Synthesis of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • Sodium hydride (60% in oil, 0.32 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 2-Methyl-5H-furo[3,2-c]pyridin-4-one (0.57 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde dimethylacetal (2.3 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (2 ml) was added to an acetone solution (10 ml) of the residue, and the liquid was stirred at 70° C. for 10 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.56 g) as a white solid.
  • 1H-NMR (DMSO-D6), δppm: 2.36 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 4.94-4.98 (m, 1H), 6.04 (d, J=6.4 Hz, 2H), 6.52 (s, 1H), 6.59 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.4 H, 1H).
    • Reference Example 14 Synthesis of 5-(1H-benzoimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • 5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (2.1 g) and o-phenylenediamine (1.1 g) were suspended in ethanol (20 ml) Sodium hydrogensulfite (5.2 g) was added, and the mixture was heated and stirred overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (2.25 g).
  • 1H NMR (CDCl3), δppm: 2.36 (3H, s), 5.44 (2H, s), 6.55 (1H, s), 6.73 (1H, d, J=7.4 Hz), 7.05-7.15 (2H, m), 7.43 (1H, d, J=7.0 Hz), 7.50 (1H, d, J=8.3 Hz), 7.70 (1H, d, J=7.4 Hz).
    • Reference Example 15 Synthesis of 3-(pyridin-3-yl)-1H-quinolin-4-one
  • 2N Hydrochloric acid (10 ml) was added to a DMF solution (5 ml) of 4-chloro-(3-pyridin-3-yl)quinoline (0.51 g), and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2N sodium hydroxide aqueous solution (10 ml) was added dropwise under ice cooling. The mixture was stirred. The precipitated insoluble matter was separated, washed with water and ether, and dried to give the title compound (0.35 g) as a pale whitish purple powder.
  • mp: 240 to 242° C. (dec.)
    • Reference Example 16 Synthesis of 5-[{1-(3-chloropropyl)-1H-benzoimidazol-2-yl}methyl]-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • 5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.75 g), 1-bromo-3-chloropropane (1.3 ml), and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.18 g) as a colorless oily matter.
  • 1H NMR (CDCl3), δppm: 2.02-2.09 (2H, m), 2.41 (3H, s), 3.54 (2H, t, J=6.1 Hz), 4.55-4.61 (2H, m), 5.56 (2H, s), 6.51-6.53 (2H, m), 7.24-7.32 (2H, m), 7.40-7.46 (1H, m), 7.54 (1H, d, J=5.9 Hz), 7.73-7.79 (1H, m).
    • Reference Example 17 Synthesis of 5-(3-chloropropyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one
  • Methane sulfonyl chloride (0.24 ml) was added to a dichloromethane solution (10 ml) of 5-(3-hydroxypropyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and triethylamine (0.45 ml). The mixture was stirred at room temperature for two days. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.16 g) as a white amorphous solid.
  • 1H NMR (CDCl3), δppm: 2.25-2.41 (2H, m), 2.41 (3H, s), 3.56 (2H, t, J=6.1 Hz), 4.18 (2H, t, 6.6 Hz), 6.48 (1H, d, J=7.4 Hz), 6.55 (1H, s), 7.17 (1H, d, J=7.4 Hz).
    • Reference Example 18 Synthesis of 7-(2-chloroethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.2 g) and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (24 ml). The mixture was heated to 70° C. to be dissolved. 1-Bromo-2-chloroethane (1.9 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.4 g) as a colorless oily matter.
  • 1H NMR (CDCl3), δppm: 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.64-3.77 (1H, m), 3.85 (2H, t, J=5.7 Hz), 4.03-4.15 (1H, m), 4.26 (2H, t, J=5.7 Hz), 6.77 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz).
    • Reference Example 19 Synthesis of 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 10% Palladium on carbon (0.7 g) was added to a methanol solution (30 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(3-nitropyridin-4-ylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.8 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure to give the title compound (1.4 g) as an orange amorphous solid.
  • 1H NMR (CDCl3), δppm: 0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.12-2.24 (2H, m), 3.40 (3H, m), 3.40-3.52 (2H, m), 3.63-3.74 (1H, m), 4.03-4.14 (3H, m), 6.51 (1H, d, J=5.4 Hz), 6.75-6.76 (1H, m), 6.84 (1H, dd, J=9.0, 2.8 Hz), 7.22 (1H, d, J=9.0 Hz), 7.93 (1H, s), 7.98 (1H, d, J=5.4 Hz).
    • Example 1 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenylpiperidin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • Potassium carbonate (0.54 g), sodium iodide (0.21 g), and 2-phenyl piperidine (0.23 g) were added to a DMF solution (15 ml) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.44 g). The mixture was stirred at 70° C. for 5 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried with anhydrous magnesium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1). The purified product was condensed under reduced pressure. A 4N-Hydrogen chloride ethyl acetate solution (0.2 ml) was added to an ethyl acetate solution (10 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (0.18 g) as a white amorphous solid.
  • 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.12 (3H, t, J=7.0 Hz), 1.51 (3H, s), 1.89-3.22 (11H, m), 3.36 (3H, s), 3.62-3.97 (5H, m), 4.09-4.18 (1H, m), 6.53-6.54 (1H, m), 6.62-6.67 (1H, m), 7.16 (1H, d, J=9.0 Hz), 7.36-7.47 (3H, m), 7.61-7.90 (2H, m), 12.40 (1H, brs).
    • Example 2 Synthesis of 7-[3-((R)-2,4-dibenzylpiperazin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • The synthesis of the title compound was performed in the same manner as in Example 1 using appropriate starting materials.
  • 1H NMR (DMSO-d6), δppm: 0.75 (3H, s), 1.01 (3H, t, J=6.8 Hz), 1.33 (3H, s), 2.15-2.40 (2H, m), 2.83-3.90 (13H, m), 3.97-4.61 (7H, m), 6.96-7.01 (2H, m), 7.28-7.44 (9H, m), 7.59 (2H, br).
    • Example 3 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)benzimidazol-1-yl]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and potassium carbonate (0.9 g) were added to a DMF solution (2 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.43 g). The mixture was stirred at 60° C. overnight. After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.43 g) as a white amorphous solid.
  • 1H NMR (CDCl3), δppm: 0.85 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.12-2.23 (2H, m), 2.40 (3H, s), 3.38 (3H, s), 3.61-3.72 (1H, m), 3.95 (2H, t, J=5.7 Hz), 4.05-4.15 (1H, m), 4.65 (2H, t, J=6.5 Hz), 5.53 (2H, s), 6.49-6.55 (2H, m), 6.70-6.71 (1H, m), 6.74-6.80 (1H, m), 7.19 (1H, d, J=9.0 Hz), 7.24-7.27 (2H, m), 7.33-7.38 (1H, m), 7.54 (1H, d, J=7.5 Hz), 7.75-7.79 (1H, m).
    • Example 4 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)benzimidazol-1-yl]ethoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Potassium carbonate (0.58 g), sodium iodide (0.21 g), and 5-(1H-benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.39 g) were added to a DMF solution (30 ml) of 7-(2-chloroethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.47 g). The mixture was stirred at 65° C. overnight. The mixture was further stirred at 100° C. overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→85:15). The purified product was condensed to dryness under reduced pressure to give the title compound (0.44 g) as a white amorphous solid.
  • 1H NMR (CDCl3), δppm: 0.77 (3H, s), 1.09 (3H, t, J=7.1 Hz), 1.49 (3H, s), 2.40 (3H, s), 3.26 (3H, s), 3.61-3.74 (1H, m), 4.05-4.18 (1H, m), 4.24 (2H, t, J=5.0 Hz), 4.93 (2H, t, J=5.0 Hz), 5.55-5.66 (2H, m), 6.44-6.45 (1H, m), 6.51-6.54 (2H, m), 6.57-6.64 (1H, m), 7.00 (1H, d, J=9.0 Hz), 7.25-7.36 (2H, m), 7.58-7.62 (1H, m), 7.63 (1H, d, 7.6 Hz), 7.77-7.80 (1H, m).
    • Example 5 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenyl-benzoimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • 2-Phenyl-1H-benzimidazole (0.2 g) and potassium carbonate (0.29 g) were added to a DMF solution (5 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.49 g). The mixture was stirred at 60° C. for 7 hours. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (0.32 g) as a white powder.
  • mp: 132 to 134° C.
    • Example 6 Synthesis of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 4-Chloro-3-phenyl-1H-quinoline-2-one (0.3 g) was suspended in DMF (6 ml). Sodium hydride (60% in oil)(51 mg) was added, and the mixture was stirred for 15 minutes at room temperature. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.55 g) was added thereto and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:3). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether, thereby obtaining the title compound (0.28 g) as a white powder.
  • mp: 122 to 128° C.
    • Example 7 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)imidazo[4,5-c]pyridin-1-yl]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
  • A DMF solution (4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.37 g), and sodium hydrogensulfite (0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound (0.47 g) as a white amorphous solid.
  • 1H NMR (DMSO-d6), δppm: 0.70 (3H, s), 0.95 (3H, t, J=7.1 Hz), 1.30 (3H, s), 2.31-2.41 (2H, m), 2.40 (3H, s), 3.29 (3H, s), 3.60-3.70 (1H, m), 3.98-4.09 (1H, m), 4.16 (2H, t, J=6.0 Hz), 4.79 (2H, t, J=6.6 Hz), 5.67 (2H, s), 6.54 (1H, s), 6.80-6.85 (3H, m), 7.33 (1H, d, J=6.5 Hz), 7.76 (1H, d, J=7.5 Hz), 8.33 (1H, d, J=6.5 Hz), 8.60 (1H, d, J=6.5 Hz), 9.36 (1H, s).
    • Example 8 Synthesis of 7-[3-(3-bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • Under ice cooling, sodium hydride (60% in oil, 0.2 g) was added to a DMF solution (10 ml) of 3-bromo-1H-quinoline-2-one (1.0 g). The mixture was stirred at the same temperature for 15 minutes. Lithium bromide (0.76 g) was added to the mixture, and the liquid was stirred at the same temperature for another 15 minutes, and then at room temperature for an hour. The reaction mixture was cooled to 0° C., and 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.1 g) was added thereto. The mixture was stirred at room temperature for 2 hours, and at 50° C. for 8 hours. The reaction mixture was poured to ice water, and the generated insoluble matter was separated. The insoluble matter was dissolved in a mixed solvent of ethyl acetate and dichloromethane. The liquid was dried with sodium sulfate and condensed under reduced pressure. Ethyl acetate was added to the residue. The generated insoluble matter was separated and dried to give the title compound (1.2 g) as a white powder.
  • mp: 168 to 169° C.
    • Example 9 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.
  • White powder
  • mp: 134 to 135° C.
    • Example 10 Synthesis of 1-ethyl-7-[3-(3-iodo-4-oxo-4H-quinolin-1-yl)propoxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.
  • White powder
  • mp: 97 to 106° C.
    • Example 11 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-3-(pyridin-3-yl)-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.
  • White powder
  • mp: 199 to 201° C.
    • Example 12 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.
  • White powder
  • mp: 174 to 177° C.
    • Example 13 Synthesis of 7-[3-(3-bromo-4-oxo-4H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.
  • White powder
  • mp: 180 to 183° C.
    • Example 14 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-2,3-dihydrobenzimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.27-2.41 (2H, m), 3.36 (3H, s), 3.6-3.78 (1H, m), 4.09 (2H, t, J=5.9 Hz), 4.11-4.26 (1H, m), 4.20 (2H, t, J=6.6 Hz), 6.68 (1H, d, J=2.8 Hz), 6.80 (1H, dd, J=2.8, 9.0 Hz), 6.99-7.14 (4H, m), 7.19 (1H, d, J=9.0 Hz), 7.33-7.47 (1H, m), 7.47-7.58 (4H, m).
    • Example 15 Synthesis of 1-ethyl-7-[3-(3-hydroxy-2-oxo-3-phenyl-2,3-dihydroindol-1-yl)prop oxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • White powder
  • mp: 153 to 156° C.
    • Example 16 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-(pyridin-3-yl)-2,3-dihydrobenzimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride
  • 1-(Pyridin-3-yl)-1,3-dihydrobenzimidazole-2-one (0.2 g) was suspended in DMF (6 ml). Sodium hydride (55% in oil, 48 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
  • 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45 g) was added to the mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to ice water (100 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 0.5N-hydrogen chloride ethanol solution (1.9 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (0.38 g) as a white powder.
  • White powder
  • mp: 119 to 125° C.
    • Example 17 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2′-oxospiro[[1,3]dioxolane-2,3′-indoline]-1′-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • White powder
  • mp: 143 to 147° C.
    • Example 18 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenylindol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • White powder
  • mp: 140 to 142° C.
    • Example 19 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), phenylboronic acid (0.12 g), tetrakis (triphenyl phosphine) palladium (0) (0.11 g), and potassium carbonate (0.39 g) were added to dioxane (5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound (0.34 g) as a white amorphous solid.
  • 1H NMR (CDCl3), δppm: 0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.27-2.42 (2H, m), 3.37 (3H, s), 3.62-3.80 (1H, m), 4.05-4.28 (3H, m), 4.62 (2H, t, J=7.2 Hz), 6.72 (1H, d, J=2.7 Hz), 6.83 (1H, dd, J=2.7, 9.0 Hz), 7.19 (1H, d, J=9.0 Hz), 7.20-7.30 (1H, m), 7.32-7.58 (5H, m), 7.60-7.67 (1H, m), 7.67-7.74 (2H, m), 7.84 (1H, s).
    • Example 20 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-3-phenyl-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.
  • White powder
  • mp: 150 to 152° C.
    • Example 21 Synthesis of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinolin-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.
  • White powder
  • mp: 159 to 161° C.
    • Example 22 Synthesis of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinoline-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione mesylate
  • Methanesulfonic acid (0.024 ml) was added to an ethyl acetate/isopropyl alcohol solution (1:1, 8 ml) of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinoline-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.2 g) at 0° C., which was stirred at the same temperature for 2 hours. The precipitated insoluble matter was separated, washed with isopropyl alcohol, and dried to give the title compound (0.19 g) as a white powder.
  • White powder
  • mp: 188 to 189° C.
    • Example 23 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-3,4-dihydro-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 10% Palladium on carbon (20 mg) was added to an ethanol/ethyl acetate solution (1:1, 4 ml) of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinoline-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.19 g). The mixture was subjected to catalytic reduction at 50° C. under normal pressure for 6 hours. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.1 g) as a white powder.
  • mp: 100 to 105° C.
    • Example 24 Synthesis of 7-[3-(2,3-dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • Orange powder
  • mp: 162 to 163° C.
    • Example 25 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-2,3-dihydroindol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
  • 7-[3-(2,3-Dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.3 g) was suspended in hydrazine hydrate (3 ml), and the liquid was stirred for two hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=85:15). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.18 g) as a pale brownish white powder.
  • mp: 146 to 149° C.
    • Example 26 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propyl)(pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4 (3H,5H)-dione
  • The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.
  • 1H-NMR (CDCl3) δppm: 0.84 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.90-2.00 (m, 4H), 2.58 (t, J=6.8 Hz, 2H), 2.68 (t, J=6.8 Hz, 2H), 3.38 (s, 3H), 3.61 (s, 2H), 3.62-3.72 (m, 1H), 3.95-4.00 (m, 4H), 4.08-4.22 (m, 1H), 6.44 (d, J=7.3 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 6.75 (dd, J=9.0 and 2.7 Hz, 1H), 6.95 (d, J=7.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.25-7.27 (m, 2H), 7.45-7.52 (m, 2H), 7.60-7.70 (m, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.48 (d, J=1.5 Hz, 2H).
    • Example 27 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propyl)(pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4 (3H,5H)-dione dihydrochloride
  • A 4N-hydrogen chloride in ethyl acetate solution (0.3 ml) was added to an ethyl acetate solution (3 ml) of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propy 1) (pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (159 mg), and the mixture was stirred at room temperature for two hours. The reaction mixture was condensed under reduced pressure to give the title compound (178 mg) as a amorphous solid.
  • 1H-NMR (DMSO-d6) δppm: 0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.25 (br, 4H), 3.01-3.31 (m, 4H), 3.31 (s, 3H), 3.61-3.70 (m, 1H), 4.00-4.12 (m, 5H), 4.61 (br, 2H), 6.65 (d, J=7.4 Hz, 1H), 6.86-6.91 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.47-7.53 (m, 2H), 7.65-7.74 (m, 2H), 8.08 (br, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.80 (br, 2H).
    • Pharmacological Test 1 (1) Production of Human Kv1.5-Expressing CHO-K1 Cell Lines
  • CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.
  • Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).
  • The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.
    • (2) Production of CHO Cell Line Expressing Human GIRK1/4
  • CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.
  • Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).
  • TABLE 1
    Primer Sequence
    hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID
    GAAATTTG-3′ No. 1
    hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID
    AGTTC-3′ No. 2
    hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID
    ATTATGTCTGCACTCC-3′ No. 3
    hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID
    GA-3′ No. 4
    hGIRK1-A4 5′-CCGAGTGTAGGCGATCA SEQ ID
    CCC-3′ No. 5
    hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID
    GAATGCC-3′ No. 6
    hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID
    CCTCCC-3′ No. 7
    hGIRK4-S2 5′-AACCAGGACATGGAGAT SEQ ID
    TGG-3′ No. 8
    hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID
    CAC-3′ No. 9
  • The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM—002239) and GIRK4 (NM—000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.
    • (3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.
  • Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 40 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)
  • An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.
  • Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.
  • The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    NaCl 140 mM,
    KCl 4 mM,
    CaCl2 1.8 mM,
    MgCl2 1 mM,
    NaH2PO4 0.33 mM,
    HEPES 5 mM
    Glucose 5.5 mM (pH = 7.4)
  • Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.
  • The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.
  •
    KOH 100 mM,
    KCl 40 mM,
    Aspartic acid 70 mM,
    MgCl2 1 mM,
    MgATP 5 mM,
    K2 creatine phosphate 5 mM,
    HEPES 5 mM
    EGTA 5 mM (pH = 7.2)
    • (5) Measurement of Human Kv1.5 Current
  • While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μm of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μm of the test compound and then using an extracellular solution containing 10 μm of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.
  • The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (6) Measurement of Human GIRK1/4 Current
  • While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μm of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.
  • The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.
  • Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

  • Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)
    • (7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current
  • The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC50 value) was calculated according to the following nonlinear regression equation:

  • Relative current=1/(1+[Concentration of the compound]/IC50)nH
  • wherein nH is the Hill coefficient.
  • Table 2 shows the test results.
  • TABLE 2
    Test Compound KV1.5 IC50 (μM)
    Compound of Example 2 1.10
    Compound of Example 5 0.87
    Compound of Example 6 0.60
    Compound of Example 14 0.40
    Compound of Example 20 0.34
    Compound of Example 21 0.84
    Compound of Example 22 1.50

Claims (1)

1. An amino compound represented by General Formula (1):
Figure US20140343277A1-20141120-C01642
or a salt thereof,
wherein R1 and R2 are each independently hydrogen or organic group;
XA and XB are each independently a bond, alkylene, alkenylene, —CO—, —SO2—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO2—, —CO—, —O—, —NH—, —CONH— and —SO2NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in XA and XB is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl;
A1 is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo;
R3 is (i) a heterocyclic group which is optionally substituted with one or more substituents, or
(ii) an aryl group substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, carboxyl, halo-lower alkyl, lower alkanoyl lower alkyl, phenyl lower alkyl, cyclo lower alkyl, lower alkoxy, halo lower alkoxy, phenyl lower alkoxy, phenoxy, cyano, hydroxyl, halogen, nitro, lower alkyl thio, lower alkanoyl, lower alkoxy carbonyl, lower alkenyl, phenyl, triazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzo[d]oxazolyl, benzo[d]thiazolyl and the group represented by General Formula (2):
Figure US20140343277A1-20141120-C01643
wherein Y is a bond, lower alkylene, or —CO—; R4 and R5 are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, or lower alkanoyl; or R4 and R5 may be linked to form a ring together with the neighboring nitrogen, and the ring may optionally have one or more substituents.
US14/314,142 2009-08-21 2014-06-25 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation Abandoned US20140343277A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US23598109P 2009-08-21 2009-08-21
US23598309P 2009-08-21 2009-08-21
US23597309P 2009-08-21 2009-08-21
US35968610P 2010-06-29 2010-06-29
US13/388,442 US8822453B2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
PCT/JP2010/064545 WO2011021726A2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compound and pharmaceutical composition

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/JP2010/064545 Division WO2011021726A2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compound and pharmaceutical composition
US13/388,442 Division US8822453B2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation

Publications (1)

Publication Number Publication Date
US20140343277A1 true US20140343277A1 (en) 2014-11-20

Family

ID=43014533

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/388,442 Expired - Fee Related US8822453B2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
US14/314,189 Expired - Fee Related US9212187B2 (en) 2009-08-21 2014-06-25 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
US14/314,142 Abandoned US20140343277A1 (en) 2009-08-21 2014-06-25 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US13/388,442 Expired - Fee Related US8822453B2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
US14/314,189 Expired - Fee Related US9212187B2 (en) 2009-08-21 2014-06-25 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation

Country Status (25)

Country Link
US (3) US8822453B2 (en)
EP (3) EP2746272A1 (en)
JP (2) JP5769700B2 (en)
KR (1) KR20120081973A (en)
CN (1) CN102482234B (en)
AR (1) AR078098A1 (en)
AU (2) AU2010285621A1 (en)
CA (1) CA2771579A1 (en)
CO (1) CO6440511A2 (en)
DK (1) DK2467364T3 (en)
ES (1) ES2477221T3 (en)
HK (1) HK1167391A1 (en)
HR (1) HRP20140636T1 (en)
IL (2) IL217101A0 (en)
IN (1) IN2012DN01985A (en)
MX (1) MX2012002149A (en)
NZ (1) NZ598918A (en)
PL (1) PL2467364T3 (en)
PT (1) PT2467364E (en)
RU (1) RU2012110553A (en)
SG (1) SG177316A1 (en)
SI (1) SI2467364T1 (en)
TW (1) TWI481601B (en)
WO (1) WO2011021726A2 (en)
ZA (1) ZA201201025B (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102639512B (en) * 2009-08-21 2015-12-09 大塚制药株式会社 The preparation method of benzo [b] [Isosorbide-5-Nitrae] diaza *-2,4-dione compounds
CA2871190C (en) * 2011-06-03 2019-01-15 Queen's University At Kingston Substituted diarylamines and use of same as antioxidants
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN102627597B (en) * 2012-04-25 2013-10-23 山东轻工业学院 Indole-3-carboxaldehyde isobutyryl hydrazone derivatives and preparation method thereof
EP2996692B1 (en) 2013-05-14 2021-06-30 Medizinische Hochschule Hannover Means and methods for treating cancer
WO2015051241A1 (en) 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
NZ718430A (en) 2013-10-04 2021-12-24 Infinity Pharmaceuticals Inc Heterocyclic compounds and uses thereof
EA201691872A1 (en) 2014-03-19 2017-04-28 Инфинити Фармасьютикалз, Инк. HETEROCYCLIC COMPOUNDS FOR APPLICATION IN THE TREATMENT OF PI3K-GAMMA-MEDIATED DISORDERS
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
CN114230571A (en) 2015-09-14 2022-03-25 无限药品股份有限公司 Solid forms of isoquinolinones, methods of making, compositions containing, and methods of use thereof
WO2017161116A1 (en) 2016-03-17 2017-09-21 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors
WO2017214269A1 (en) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2018112843A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506239A (en) * 1991-08-23 1996-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative and platelets aggregation inhibitory agent

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133056A (en) * 1961-05-15 1964-05-12 May & Baker Ltd N-phenylpiperazine derivatives of tetrahydrobenzodiazepines
BE707667A (en) 1966-12-14 1968-06-07
US4001408A (en) 1966-12-14 1977-01-04 Roussel-Uclaf Substituted heterocyclic compounds, processes and composition including those
US3984398A (en) 1966-12-14 1976-10-05 Roussel-Uclaf 1,5-Benzodiazepine-2,4-diones
GB1460936A (en) * 1974-10-01 1977-01-06 Beecham Group Ltd Benzodiazepines
JPS545981A (en) * 1977-06-10 1979-01-17 Otsuka Pharmaceut Co Ltd Carbostyryl derivatives
IE46852B1 (en) 1977-06-10 1983-10-05 Otsuka Pharma Co Ltd Novel carbostyril derivatives
JPS54163825A (en) * 1978-06-15 1979-12-26 Otsuka Pharma Co Ltd Phosphoesterase inhibitor
JPS5579372A (en) * 1978-12-08 1980-06-14 Otsuka Pharmaceut Co Ltd Preparation of carbostyril derivative
JPS56122356A (en) * 1980-02-29 1981-09-25 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JPS5780322A (en) * 1980-11-05 1982-05-19 Otsuka Pharmaceut Co Ltd Cardiotonic agent
JPS6010008B2 (en) * 1982-07-12 1985-03-14 大塚製薬株式会社 Platelet aggregation inhibitor
JP2753622B2 (en) * 1988-05-02 1998-05-20 大塚製薬株式会社 Carbostyril derivative
US5053514A (en) * 1988-08-10 1991-10-01 Otsuka Pharmaceutical Company, Limited Cardiotonics
JPH0296133A (en) 1988-10-01 1990-04-06 Fuji Photo Film Co Ltd Silver halide color photographic sensitive material
JPH03148223A (en) * 1989-11-02 1991-06-25 Otsuka Pharmaceut Co Ltd Inhibitor of blood platelet aggregation
BR9200951A (en) * 1991-03-21 1992-11-17 Hoffmann La Roche COMPOUNDS, PROCESS FOR ITS PRODUCTION, PHARMACEUTICAL PREPARATIONS AND USE
JPH05194405A (en) * 1991-08-23 1993-08-03 Otsuka Pharmaceut Co Ltd Carbostyril derivative and platelet aggregation suppressing agent
PE27497A1 (en) 1994-04-15 1997-08-07 Glaxo Inc DERIVATIVES OF 1,5 BENZODIAZEPINA
US5700797A (en) 1995-06-07 1997-12-23 Merck & Co, Inc. N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-3-amides
US5691331A (en) * 1995-06-07 1997-11-25 Merck & Co., Inc. N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3yl) -3- amides
JP2964029B2 (en) * 1995-10-05 1999-10-18 大塚製薬株式会社 Carbostyril derivative
TW338037B (en) * 1995-10-05 1998-08-11 Otsuka Pharma Co Ltd Carbostyril derivatives possessing platelet aggregation inhibitory activity, antithrombotic activity, intima thinkening, inhibitory activity and phosphoriesterase inhibitory activity, their preparation and pharmaceutical composition
GB0008179D0 (en) 2000-04-05 2000-05-24 Glaxo Group Ltd Chemical process
AU6895000A (en) * 1999-08-09 2001-03-05 Merck & Co., Inc. Antiarrhythmic compounds
US6949542B2 (en) 2002-02-06 2005-09-27 Hoffman-La Roche Inc. Dihydro-benzo[b][1,4]diazepin-2-one derivatives
US7772433B2 (en) 2002-02-28 2010-08-10 University Of Tennessee Research Foundation SARMS and method of use thereof
CN100406007C (en) * 2002-12-20 2008-07-30 安姆根有限公司 Asthma and allergic inflammation modulators
AR055203A1 (en) * 2005-08-31 2007-08-08 Otsuka Pharma Co Ltd BENZOTIOPHENE DERIVATIVES WITH ANTIPSYTICAL PROPERTIES
JP2007290984A (en) * 2006-04-21 2007-11-08 Kowa Co Cofilin binder and anticancer agent having cofilin binder as active ingredient
JP4785881B2 (en) 2007-02-27 2011-10-05 大塚製薬株式会社 Medicine
AR070449A1 (en) * 2008-02-22 2010-04-07 Otsuka Pharma Co Ltd BENZODIAZEPIN COMPOUND AND PHARMACEUTICAL COMPOSITION

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506239A (en) * 1991-08-23 1996-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative and platelets aggregation inhibitory agent

Also Published As

Publication number Publication date
ES2477221T3 (en) 2014-07-16
EP2746272A1 (en) 2014-06-25
HRP20140636T1 (en) 2014-10-10
US20140343278A1 (en) 2014-11-20
WO2011021726A3 (en) 2011-06-16
EP2467364B9 (en) 2015-02-18
JP2015199748A (en) 2015-11-12
IL217101A0 (en) 2012-02-29
WO2011021726A2 (en) 2011-02-24
JP5769700B2 (en) 2015-08-26
IN2012DN01985A (en) 2015-07-24
AR078098A1 (en) 2011-10-12
SI2467364T1 (en) 2014-06-30
US8822453B2 (en) 2014-09-02
TW201111356A (en) 2011-04-01
KR20120081973A (en) 2012-07-20
TWI481601B (en) 2015-04-21
SG177316A1 (en) 2012-02-28
MX2012002149A (en) 2012-03-07
JP2013502378A (en) 2013-01-24
EP2727917A1 (en) 2014-05-07
US9212187B2 (en) 2015-12-15
PT2467364E (en) 2014-07-10
US20120225866A1 (en) 2012-09-06
AU2016210778A1 (en) 2016-08-25
DK2467364T3 (en) 2014-06-30
PL2467364T3 (en) 2014-12-31
AU2010285621A1 (en) 2012-01-12
IL247086A0 (en) 2016-09-29
CO6440511A2 (en) 2012-05-15
HK1167391A1 (en) 2012-11-30
EP2467364B1 (en) 2014-04-16
ZA201201025B (en) 2013-05-29
CN102482234A (en) 2012-05-30
EP2467364A2 (en) 2012-06-27
CN102482234B (en) 2016-04-13
CA2771579A1 (en) 2011-02-24
RU2012110553A (en) 2013-09-27
NZ598918A (en) 2014-03-28

Similar Documents

Publication Publication Date Title
US9212187B2 (en) Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
US8664217B2 (en) Benzodiazepine compound and pharmaceutical composition
JP2012184225A (en) Pharmaceutical composition
US10487075B2 (en) Substituted mono- and polyazanaphthalene derivatives and their use
WO2014049488A1 (en) Benzamide and heterobenzamide compounds
KR20170072242A (en) Heparan sulfate biosynthesis inhibitors for the treatment of diseases
JP5669481B2 (en) Pharmaceutical composition
US11952377B2 (en) Quinolines and azaquinolines as inhibitors of CD38
WO2023146511A1 (en) Compounds and methods of use thereof

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION