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HK1167391B - 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

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Publication number
HK1167391B
HK1167391B HK12108042.7A HK12108042A HK1167391B HK 1167391 B HK1167391 B HK 1167391B HK 12108042 A HK12108042 A HK 12108042A HK 1167391 B HK1167391 B HK 1167391B
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Hong Kong
Prior art keywords
ethyl
optionally substituted
alkyl
methyl
oxo
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HK12108042.7A
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German (de)
French (fr)
Chinese (zh)
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HK1167391A1 (en
Inventor
邦生 大岛
修二 松村
北斗 山边
直博 矶野
宪昭 武村
伸一 平良
孝 押山
康宏 校条
刚 长濑
昌孝 植田
康雄 古贺
直 中山
贤司 辻前
利幸 小野川
国宪 田井
元宏 丝谷
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大塚制药株式会社
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Priority claimed from PCT/JP2010/064545 external-priority patent/WO2011021726A2/en
Publication of HK1167391A1 publication Critical patent/HK1167391A1/en
Publication of HK1167391B publication Critical patent/HK1167391B/en

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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) 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 (2) 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

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 America 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 atria 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 occurence 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 in human atria (Nature 374, 135-141 (1995)). Accordingly, a pharmacologically acceptable substance that selectively blocks the IKur current (the Kvl. 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. WO 96/40655 A1 relates to compounds represented by structural formula (I) which are useful in the treatment of arrhythmia.
WO 01/10216 A1 relates to 1H-Benzo[e][1,4]diazepin-2-one compounds which are selective IKs antagonists, method of treatment or prevention of cardiac arrhythmias, such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury, and pharmaceutical compositions containing the 1H-Benzo[e][1,4]diazepin-2-one compounds.
SUMMARY OF THE INVENTION
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 14 below.
  • Item 1. A diazepine compound represented by General Formula (1) or a salt thereof, wherein R1, R2, R3, and R4 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-alkyl or C1-6-alkoxy C1-6-alkyl; R2 and R3 may be linked to form C1-6-alkylene; A1 is C1-6-alkylene optionally substituted with one or more hydroxyls; Y1 and Y2 are each independently -N= or -CH=; R5 is group represented by wherein R6 and R7 are each independently hydrogen or C1-6-alkyl, cyclo C3-6-alkyl, aryl or heterocyclic group, each of which is optionally substituted; 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, C2-6-alkenylene,-CO-, -SO2-, or -CONH-, wherein each of the alkylene and C2-6-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 C1-6-alkyl, phenyl C1-6-alkyl and phenyl.
  • Item 2. A diazepine compound or a salt thereof according to Item 1, wherein R6 and R7 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-alkyl, aryl or heterocyclic group, each of which is optionally substituted, and XA and XB are each independently a bond, C1-6-alkylene, C2-6-alkenylene, -CO-, -SO2-, -C1-6-alkylene-SO2-, -C1-6-alkylene-CO-, -C2-6-alkenylene-CO-, -C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -N(C1-6-alkyl)-C1-6-alkylene-, -CO-N(C1-6-alkyl)-C1-6-alkylene-, -O-C1-6-alkylene-, -N(phenyl C1-6alkyl)-C1-6-alkylene-,-CO-C1-6-alkylene-CO-, -CO-NH-C1-6-alkylene-, -C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-, -C1-6-alkylene-N(C1-6-alkyl) -C1-6-alkylene-O-,-C1-6-alkylene-NH-C1-6-alkylene-, -C1-6-alkylene-SO2-NH-C1-6-alkylene-,-N(C1-6-alkyl) -CO-C1-6-alkylene-, -N(C1-6-alkyl) -C1-6-alkylene-CO-, -N(C16-alkyl)-C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-, -N(phenyl)-C1-6-alkylene-CO-, -N(phenyl)-C1-6-alkylene-CO-, -NH-CO-, -NH-CO-C1-6-alkylene-, -NH-C1-6-alkylene-, -O-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -O-C1-6-alkylene-CO-, -NH-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -S-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -SO2-N(C1-6-alkyl)-C1-6-alkylene-, -SO2-NH-C1-6-alkylene-, -C2-6-alkenylene-CO-N(C16-alkyl)-C1-6-alkylene-, C1-6-alkylene-N(phenyl C1-6-alkyl)-C1-6-alkylene-, -N(phenyl C1-6-alkyl)-C1-6-alkylene-, -N(phenyl) -C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, or -CO-C1-6-alkylene-O-CO-C1-6-alkylene-O-.
  • Item 3. A diazepine compound or a salt thereof according to Item 2, wherein R6 and R7 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-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, C1-6-alkyl, cyclo C3-8-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-alpyridyl, 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) C1-6-alkyl;(3) cyclo C3-8-alkyl optionally substituted with one or more phenyl C1-6-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) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C1-6-alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;(4-5) C1-6-alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and C1-6-alkyl amino;(4-6) pyridyl;(4-7) thienyl;(4-8) piperazinyl optionally substituted with one or more C1-6-alkyls ;(4-9) phenyl;(4-10) pyrazolyl optionally substituted with one or more C1-6-alkyls;(4-11) pyrimidinyl optionally substituted with one or more C1-6-alkyls;(4-12) piperidyl optionally substituted with one or more C1-6-alkyls;(4-13) furyl;(4-14) carboxy;(4-15) C1-6-alkoxycarbonyl;(4-16) amino optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-6-alkanoyl and C1-6-alkylsulfonyl;(4-17) C1-6-alkylthio;(4-18) triazolyl;(4-19) imidazolyl;(4-20) pyrrolidinyl optionally substituted with one or more oxos;(4-21) C1-6-alkylsulfonyl;(4-22) C1-4-alkylenedioxy optionally substituted with one or more halogens;(4-23) nitro;(4-24) oxazolyl;(4-25) thiazolyl optionally substituted with one or more C1-6-alkyls;(4-26) C1-6-alkanoyl; and(4-27) morpholinyl;(5) naphthyl;(6) furyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, C1-6-alkoxycarbonyl and phenyl;(7) thienyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-4-alkylenedioxy, carboxy, halogen, pyridyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, oxazolyl and furyl;(8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, C1-6-alkyl and halogen;(9) pyrazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy; cyclo C3-8-alkyl; halogen; phenyl optionally substituted with C1-6-alkoxy; furyl and thienyl;(10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and phenyl;(11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, C1-6-alkyl, thienyl and furyl;(12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy; phenyl; phenoxy and C1-6-alkanoylamino;(13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and C1-6-alkoxycarbonyl;(14) triazolyl optionally substituted with one or more C1-6-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 C1-6-alkanoyl and C1-6-alkylsulfonyl;(15-4) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6-alkoxy, C1-6-alkanoyloxy, cyclo C3-8-alkyl amino, C1-6-alkyl amino, C16-alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;(15-5) oxo;(15-6) hydroxyl;(15-7) C1-6-alkoxy optionally substituted with one or more phenyls;(15-8) pyrrolidinyl;(15-9) C1-6-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 C1-6-alkyl and phenyl;(17) pyridazinyl;(18) pyrazinyl optionally substituted with one or more phenyl C1-6-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 C1-6-alkyls;(23) indolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-6-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 C1-6-alkyls;(25) benzothienyl optionally substituted with one or more C1-6-alkyls;(26) benzimidazolyl optionally substituted with one or more C1-6-alkyls;(27) 2,3-dihydrobenzo[b]furyl;(28) benzofuryl optionally substituted with one or more halogens;(29) indazolyl optionally substituted with one or more C1-6-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 C1-6-alkyl optionally substituted with C1-6-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, C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy, halogen, furyl, pyridyl and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and C1-6-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 C1-6-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 C1-6-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, C1-6-alkyl and C1-6-alkanoyl;(40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-6-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 C1-6-alkyls, C1-6-alkoxy, C1-6-alkyl and oxo(43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, pyridyl C1-6-alkyl, aralkyl, C1-6-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 C1-6-alkyls, C1-6-alkoxy, C1-6-alkyl and oxo;(45) chromanyl optionally substituted with one or more C1-6-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 C1-6-alkyl and oxo;(53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-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) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, C1-6-alkoxy, imidazolyl, and morpholinyl;(4a-5) C1-6-alkoxy;(4-10) pyrazolyl optionally substituted with one or more C1-6-alkyls;(4a-16) amino optionally substituted with one or more C1-6-alkylsulfonyls;(4-18) triazolyl;(4-19) imidazolyl;(4-23) nitro;(4-26) C1-6-alkanoyl; and(4-27) morpholinyl;(6a) furyl optionally substituted with one or more C1-6-alkyls optionally substituted with halogen;(7a) thienyl optionally substituted with one or more C1-6-alkyls;(8a) imidazolyl optionally substituted with one or more C1-6-alkyls;(9a) pyrazolyl optionally substituted with one or more C1-6-alkyls optionally substituted with C1-6-alkoxy;(10a) oxazolyl optionally substituted with one or more C1-6-alkyls;(11a) isoxazolyl optionally substituted with one or more C1-6-alkyls;(12a) thiazolyl optionally substituted with one or more C1-6-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 C1-6-alkanoyl and C1-6-alkylsulfonyl;(15-4) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6-alkoxy, C1-6-alkanoyloxy, cyclo C3-8-alkyl amino, C1-6-alkyl amino, C16-alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyls;(15-5) oxo; (15a-7) C1-6-alkoxy;(15-9) C1-6-alkanoyl;(15-11) phenoxy;(15-12) pyrazolyl; and(15-14) N-oxide(16a) pyrimidinyl optionally substituted with one or more C1-6-alkyls;(17) pyridazinyl(18) pyrazinyl optionally substituted with one or more phenyl C1-6-alkoxys;(23a) indolyl optionally substituted with one or more C1-6-alkyls; (24a) imidazo[1,2-a]pyridyl;(24b) imidazo[1,5-a]pyridyl optionally substituted with one or more C1-6-alkyls;(26) benzimidazolyl optionally substituted with one or more C1-6-alkyls;(29) indazolyl optionally substituted with one or more C1-6-alkyls; (30a) furo[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;(30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;(31a) furo[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;(31b) 4,5-dihydrofuro[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy;(32a) thieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-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 C1-6-alkyl;(33a) thieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;(33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-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 C1-6-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 C1-6-alkyl, etc.), pyridyl C1-6-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 C1-6-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, C1-6-alkyl, C1-6-alkoxy C1-6-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-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-(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 any one of Items 1 to 10, 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 any one of Items 1 to 10 for use in the prevention and/or treatment of arrhythmia.
  • Item 14. Use of a diazepine compound or a salt thereof according to any one of Items 1 to 10 for the production of a pharmaceutical composition.
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):
  1. (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.;
  2. (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.;
  3. (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-beitzo[d]imidazolyl, etc.), quinolyl, dihydroquinolyl (e.g. 1,4.-dihydzoquinolyl, 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.;
  4. (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.;
  5. (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.;
  6. (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.;
  7. (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.;
  8. (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.;
  9. (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.;
  10. (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.;
  11. (k) unsaturated 3 to 8-membered, preferably 5 or 6- membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;
  12. (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.);
  13. (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
  14. (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, carboxyl, 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 substituent (1) to (54):
  1. (1) hydrogen;
  2. (2) lower alkyl;
  3. (3) cyclo lower alkyl optionally substituted with one or more phenyl lower alkoxys;
  4. (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-21):
    • (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. (5) naphthyl;
  6. (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. (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. (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl and halogen;
  9. (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. (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
  11. (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, thienyl and furyl;
  12. (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. (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl;
  14. (14) triazolyl optionally substituted with one or more lower alkyls;
  15. (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. (16) pyrimidinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl;
  17. (17) pyridazinyl;
  18. (18) pyrazinyl optionally substituted with one or more phenyl lower alkoxys;
  19. (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more halogens;
  20. (20) thieno[2,3-b]pyrazinyl;
  21. (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one or more phenyls;
  22. (22) benzothiazolyl optionally substituted with one or more lower alkyl;
  23. (23) indolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and halogen;
  24. (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. (25) benzothienyl optionally substituted with one or more lower alkyls;
  26. (26) benzimidazolyl optionally substituted with one or more lower alkyls;
  27. (27) 2,3-dihydrobenzo[b]furyl;
  28. (28) benzofuryl optionally substituted with one or more halogens;
  29. (29) indazolyle optionally substituted with one or more lower alkyls;
  30. (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. (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. (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. (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. (34) thieno[2,3-b]pyridyl;
  35. (35) benzo[1,3]dioxolyl optionally substituted with one or more halogens;
  36. (36) benzisoxazolyl;
  37. (37) pyrazolo[2,3-a]pyridyl;
  38. (38) indolizinyl;
  39. (39) 2,3-dihydroindolyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl and lower alkanoyl;
  40. (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. (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more oxo;
  42. (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. (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. (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. (45) chromanyl optionally substituted with one or more lower alkyls;
  46. (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one or more oxos;
  47. (47) 3,4-dihydroisoquinolyl optionally substituted with one or more oxos;
  48. (48) naphthyridinyl;
  49. (49) 1,4-benzodioxanyl;
  50. (50) cinnolinyl;
  51. (51) quinoxalinyl;
  52. (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. (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. (54) piperidyl optionally substituted with one or more aryl carbonyls (e.g., phenyl carboxyl).
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. (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 morphdlinyl;
      • (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 alkylsulfonyl;
      • (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, cycle 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) imidazol[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 preferable 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 tetracnethylene; 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. 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, bromide, 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, dichloromethane, 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-diazabiayclo[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), andtetrakis (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(diphenylohosphino)-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. 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 hydrogeriation 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. 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). 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. wherein R1, R2, R3, R4, R6, R7, XA, A1, Y1 and Y2 are the same as above; and R7a is hydrogen or lower alkyl. Example 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. wherein R1, R2, R3, R4, R6, R7, XA, AB, A1, X1, 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 adapted 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. 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. 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 (1g) 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 (1g), a compound may be obtained wherein the 1- and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R1a. wherein R1a, R4, R5, A1, X1, Y1 and Y2 are the same as above.
The reaction of the compound of Formula (li) 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. 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. 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 chlorine, 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 methanol; 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 (1g) with the compound of Formula (11) in Reaction Formula B. 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. 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. wherein R1, R2, R3, R4, R9, Y1 and Y2 are the same as above; and Tf is trifluorodnethanesulfonyl (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. 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 requited, 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. 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. 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. 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. 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 halving 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. 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. 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 potassiumphthalimide 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 Kvl.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.
■ Reference Example 1 • Synthesis of 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
Sodium ethoxide (204mg) was added to an ethanol solution (15ml) of N-(2-amino-5-methoxyphenyl)-N-methylmalonamic acid ethyl ester (266mg). 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 (176.3mg) 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, 44mg) was suspended in of DMF (8ml), 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 (220mg) was added thereto at the same temperature, and the mixture was stirred at 0°C for an hour. Ethyl iodide (187mg) 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 (190.2mg) 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 (1M, 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, 76mg) was suspended in of DMF (8ml). 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (190mg) was added thereto at 0°C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.19ml) 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 (169mg) 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, 128mg) was suspended in of DMF (10ml). 8-methoxy-1-methy-1,5-dihydrobenzo[b]1,4]diazepine-2,4-dione (176mg) was added thereto at 0°C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.25mg) 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 (161.6mg) 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]diazepi ne-2,4-dione
1.0M-boron tribromide/dichloramethane solution (1.22ml) was added to a dichloromethane solution (3ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepi ne-2,4-dione (169mg) 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=7.0Hz), 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 (50ml) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo [b][1,4]diazepine-2,4-dione(2.6g) was cooled with ice. After adding of triethylamine(1.5ml) to the solution, trifluoromethane sulfonic anhydride (1.9ml) was added, and the mixture was stirred at room temperature for 4 hours. Triethylamine (0.75ml) and trifluoromethane sulfonic anhydride (0.75ml) 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 (3.4g) as a white solid (yield = 86%). 1H-NMR (CDCl3) δppm: 0.87 (3H, s), 1.23 (3H, t, J =7.2Hz), 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]diazepi n-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 =12.7Hz), 3.43 (6H, s), 3.48 (1H, d, J =12.7Hz), 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] diazapin-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(0.12g), zinc cyanide(70mg), tris (dibenzylideneacetone) dipalladium(7mg), 1,1'-bis (diphenylphosphino) ferrocene (8mg), and zinc powder (2mg) were added to DMF (1ml), 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(77mg) 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]diazepi ne-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(1.0g) and Raney nickel(3.0g) were suspended in formic acid(10ml), 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(0.92g) 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 (0.59g), 2-(but-3-ynyl)isoindol-1,3-dione(0.3g), dichlorobis(triphenyl phosphine)palladium (II) (53mg), copper(I) iodide(29mg), and triethylamine (0.39ml) were added to DMF(4ml). The mixture was heated at 150°C (microwave reactor) for 10 minute. 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(0.51g) 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 = 6.3Hz), 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-2,9-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-be nzo[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(0.40g), ethyl acrylate(0.13g), dichlorobis (triphenylphosphine) palladium (II) (35mg),lithium chloride(64mg), and triethylamine(0.19ml) were added to DMF(4ml). 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(0.36g) 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(0.1g) was added to a methanol solution(10ml) 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(0.36g). 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(0.29g) 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(1ml) was added to a methanol (20ml) 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(1.1g). 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(0.97g) 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(1.0ml) and tert-butanol(10ml) were added to a THF solution (10ml) of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[ b][1,4]diazepm-7-yl) propionic acid(0.97g) and triethylamine(0.67ml). 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 (0.38g) 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, 0.36g) was suspended in DMF(10ml), and was cooled to 0°C in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one(1.0g) was added thereto at the same temperature, and the mixture was stirred at 0°C for an hour. Bromoacetaldehyde diethylacetal(2.6ml) 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 (5.8ml) was added to an acetone solution (20ml) 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(0.90g) 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 = 5.2 H, 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]di azepine-2,4-dione (1.11g) in BMF(15ml) was added sodium cyanide (0.59g) 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(0.84g) 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-be nzo[b][1,4]diazepin-7-yl)-acetonitrile (0.84g) was disolved in DMF(20ml), and was cooled to 0°C in ice water bath. Sodium hydride (60% in oil, 0.259g) was added thereto at the same temperature, and the mixture was stirred at 0°C for 0. 5 hours. Methyl iodide (0.405ml) 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(0.9g) 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 (20ml) and H2O(5ml) solution of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.25g) and 2-methyl-2-butene(3.25ml) were added sodium dihydrogenphosphate (0.92g) and sodium chlorite (2.081g), 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 (0.98g) 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 (0.678g) was added to an THF solution (2.3ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo [b] [1,4] diazepine-2,4-dione (0.23g), 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(0.24g) 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 (1.0g) was dissolved in THF(20ml) and was cooled to 0°C in ice water bath. Triethylamine(0.525ml) and ethyl chloroformate(0.325ml) were added to this solution and stirred for 30 minutes at same temperature. Sodium borohydride(0.36g) was added to the mixture under cooling in ice methanol bath. Methanol (0.64ml) 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 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(0.71g) 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]diazapine-7-carbonitrile
The synthesis of the title compounds 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-2,9-dioxa-2,3,9,5-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-ben zo[b] [1,4]diazepine-7-carbonitrile
1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrah ydro-1H-benzo [b] [1,4]diazepine-7-carbonitrile(1.0g) was disolved in DKF(10ml), and was cooled to 0°C in ice water bath. Sodium hydride (60% in oil, 0.167g) was added thereto at the same temperature, and the mixture was stirred at 0°C for 0.5 hours. Methyl iodide (0.261ml) was added thereto, and the mixture was stirred at room temperature overnight. Water(100ml) 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 (0.61g) 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-tetrahybo-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:25.2-253°C
■ Reference Example 45 5-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][ 1,9]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] [2,4]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-tet rahydro-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-ben zo[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), 5ppm: 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 Examples 50
1-Isobutyl-3,3,5-trimethyl-2,9-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]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: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]diaz epine-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]diaz epine-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 NNR (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. 1NMR (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), 8.15 (1H, d, J = 1.9 Hz), 10.0 (1H, s).
■ Reference Example 67 5-Cyclopropyl-1-cyciopropylmethyl-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. 52g) was added to a methanol solution (50ml) 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]diaze pine-2,4-dione(2.2g). 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(1.93g) as a brown solid. 1H-NM (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(0.5ml) was added to a methanol solution (60ml) 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(1.93g). 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 (1.2g) 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), 4.03-9.18 (1H, m), 7.02-7.0.9 (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(0.15ml) was added to a methanol solution (10ml) of 7- (4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione(0.51g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2g) 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(0.38g) 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 = 1.9Hz), 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-dihydr obenzo[b][1,4]diazepine-2,4-dione dihydrochloride,
(2-Methyl-4-oxo-4H-furo[3,2-c]pyridin 5-yl)acetaldehyde(0.18g) and acetic acid(0.1ml) were added to a 1,2-dichloroethane solution (5ml) of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino] butyl}-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione(0.38g). The mixture was stirred for 30 minutes at room temperature sodium triacetoxyborohydride(0.32g) 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 (1.0ml) was added to an ethyl acetate solution (20ml) 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 (0.43g) 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 (1N, 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]b utyl}-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 (1N, 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-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 = 7.1 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 (1N, 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-tr imethyl-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), 7.49-7.14 (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-3,1,5-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-dihyd robenzo[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 (6ml) was added to an ethyl acetate solution (20ml) of [2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] [1,9]diazepine-7-yl) ethyl] carbamic acid tert-butyl ester(0.38g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure to give the title compound(0.26g) as a pale orange amorphous solid. 1H-NM (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(0.1ml) and 4-pyridine carbaldehyde(0.094ml) were added to a methanol solution (10ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo [b][1,4]diazepine 2,4-dione hydrochloride (0.26g). The mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.11g) 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(0.21g) 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), 3.89 (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]e thyl}-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), 7.22-7.2.6 (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]e thyl}-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-dihydr obenzo[b][1,4]diazepine-2,4-dione dihydrochloride.
The synthesis of the title compounds 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), 9.36 (2H, br), 4.57 (2H, br), 6.54 (1H, s), 6.71 (1H, d, J = 7.2 Hz), 7.15.20 (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-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), 1.03 (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 (0.1g) was added to an acetic acid solution (20ml) of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepi ne-7-carbonitrile (0.3g), 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 (0.17g) 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), 3.338=33.42. (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] dia zepine-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]diazep ine-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]met hyl}-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), 4.09-9.18 (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-di hydrobenzo[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 (9ml) was added to a methanol solution (50ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][ 1,4]diazepine-7-carbaldehyde (2.2g) and 3-(2-aminoethyl)pyridine(1.0g). The mixture was stirred at room temperature for 2 hours. The reaction liquid was condensed under reduced pressure, and a methanol solution (50ml) of the residue was cooled with ice. Sodium borohydride (0.34g) 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. Then 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. 5g) as a colorless oily matter. 1H NMR (CDCl3) δppm : 0.82 (3H, s), 1.18 (3H, t, J = 7.1Hz), 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), 7.59 (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]pyrid in-5-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
Sodium borohydride (0.15g) was added to a methanol solution (150ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][ 1,4]diazepine-7-carbaldehyde(1.1g) and 5-(2-aminoethyl)-2-atethyl-5H-furo[3,2-c]pyridin-4-one(1.0g), 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 (1.1g) 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).
■ Exanple 28 · Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(4-oxo-4H-fuxo[3,2-c]pyridin-5-yl) e thylamino]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), 3.52 (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 (18, 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 (0.3g) was added to an acetic acid solution (20ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-ben-zo[b][ 1,4]diazepine-7-carbonitrile (1.4g), 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 (0.19g) 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]py ridin-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-metthyl-5H-furo[3,2-c]pyridine-4 -one (0.21g) and acetic acid (0.1ml) were added to a 1,2-dichloroethane solution (15ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl) amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38g), and the mixture was stirred for 30 minutes at room temperature . Sodium triacetoxy borohydride (0.42g) 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. 47g) 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-dihydrob enxo[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]py ridin-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]py ridin-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), 3.93-9.01 (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 performer 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 = 6.7Hz), 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), 6.59 (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-dihydroben zo[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 = 12.4Hz), 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-ox o-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]pyridi n-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dih ydrobenzo[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: 4.70 (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-dion e trihydrochloride
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.92g) and acetic acid (0.1ml) were added to a 1,2-dichloroethane solution (15ml) of (2-pyridine 3-ylethyl)pyridin-4-ylmethylamine (0.81g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.90g) 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 (1.0ml) was added to an ethyl acetate solution (20ml) 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 (0.83g) 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 (0.13ml) was added to an acetonitrile solution (6ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38g) and triethylamine (0.17ml) 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 (0.87ml) was added to an isopropyl alcohol solution (10ml) 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 (0.26g) 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)benza mide 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)benzenesulfona mide
Triethylamine (0.15ml) was added to a acetonitrile solution (6ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-yl-ethylamino)methyl]-1,5 -dihydrobenzo[b][1,4]diazepine-2,4-dione(0.35g). The mixture was cooled with ice. Benzenesulphonyl chloride (0.13ml) 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 (0.1g) 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-t rimethyl-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 (10Hz) 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-dihydrob enzo[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]py ridin-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-fu ro[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]py ridin-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), 3.36-4.10 (1H, m), 4.46-4.73 (2H, m), 7.00-7.70 (7H, m), 7.70-8.30 (2H, m), 8.52-8.8 (2H, m), 9.30-9.5.9 (1H, m), 10.90 (1H, bs).
■ Example 49 · Synthesis of 7-{[N-(2,4-dimethylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)ami no]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazep ine-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)benza mide 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-p yridin-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-y 1)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]py ridin-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-ylmet hyl)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-m ethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b] [1,4]dia zepine-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), (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-p yridin-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-dihydrob enzo[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]py ridin-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-nethyl-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]di azepine-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-methylpyrridin-3-ylmethyl)-N-(2-p yridin-4-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-done 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]py ridin-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]py ridin-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]py ridin-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]met hyl}-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]met hyl}-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]py ridin-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 (dimethyl 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]py ridin-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-dih ydrobenzo[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]dia zepine-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]d iazepine-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-py ridin-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-d6), 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 (BH, 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-d6), 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-d6), 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-4 H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trime thyl-1,5-dihydrobenzo[b] [1,4]diazepine-2,4-dione
The synthesis of the title compound was perfumed 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]py ridin-5-yl)ethyl]-N-(4-trifluoromethylpyridin-3-ylmethyl)amino]me thyl}-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 8 6 • Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-4-methylthiazol-5-ylmethyl)-N-(2-p yridin-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-ben zo[b] [1,4]diazepine-7-carbaldehyde (0.42.3g) and acetic acid(0.14g) were added to a 1,2-dichloroethane solution (10ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36g ). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48g) 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 (0.37g) 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]py ridin-5-yl)ethyl]-N-(5-trifluoromethylpyridin-3-ylmethyl)amino]me thyl}-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 (dimethyl ether) mp: 138-140°C
■ Example 88 • Synthesis of 1-ethyl-7-({N-(5-fluoropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4 H-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]py ridin-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-4 H-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]diazep ine-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-dio ne 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]me thyl}-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]me thyl}-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-methyloxaxol-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 = 1.4 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]py ridin-5-yl)ethyl]-N-(oxazol-5-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride
The synthesis of the title compounds 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), 0.33 (1H, br).
Example 97 · Synthesis of 7-({N-(2,4-dimethylthiazol-5-ylmethyl)-N- [2-(2-methyl-4-oxo-4H-fu ro[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl -1,5-dihydrobenxo[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]m ethyl}-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
Examples 99 · Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(quinolin-5 -ylmethyl) amino]methyl}1-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dio ne 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 7-1[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-dihydr obenzo[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-dihydr obenzo[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-dihydr obenzo[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-t rimethyl-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-t rimethyl-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-dihydr obenzo[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-4 H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trime thyl-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-dimethylpyridi n-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-t-rimethyl-1,5-dihydroben zo[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-eth yl)-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-ylme thyl-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-y1-ethyl)-thiazol-5-ylme thyl-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-ylme thyl-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-pyri din-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)-amin o]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diaze pine-2,4-dione ■ Example 115 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-pyridin-4-ylmethyl)-(2-pyri din-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-pyri din-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-pyri din-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-ylm ethyl)-amino]-methyl}-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-pyri din-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo [b][1,4]diazepine -2,4-done ■ Example 121 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(4-trifluorome thyl-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]diazepin e-2,4-dione ■ Example 123 7-(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amin o]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diaze pine-2,4-dione ■ Example 124 1-Ethyl-7-{[(3-hydroxy-benzyl)-(2-pyridin-3-yl-ethyl)-amino]-meth yl}-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-pyridi n-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2 1,4-dione ■ Example 128 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-furan-3-ylmethyl)-(2-pyridi n-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]diazepi ne-2,4-dione ■ Example 130 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(5-triflluorome thyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]di azepine-2,4-dione ■ Example 131 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-thiophen-2-ylmethyl)-(2-pyr idin-3-yl-ethyl) -amino]-methyl}-1,5-dihydro-benzo [b][1,4]diazepin e-2,4-dione ■ Example 132 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiophen-2-ylm ethyl-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)-ami no]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diaz epine-2,4-dione ■ Example 134 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-2-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepin e-2.,4-dione ■ Example 135 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-5-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepin e-2,4-dione ■ Example 136 1-Ethyl-3,3,5-trimethyl-7-{2-[(2-methyl-pyridin-3-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepin e-2,4-dione ■ Example 137 1-Ethyl-3,3,5-trimethyl-7-(2-[(4-methyl-pyridin-3-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-ethyl)-1,5-dihydro-benzo[b][1,4]diazepin e-2,4-dione ■ Example 138 1-Ethyl-3,3,5-trimethyl-7-{2-[(3-methyl-pyridin-2-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepin e-2,4-dione ■ Example 139 7-{2-[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-am ino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diaz epine-2,4-dione ■ Example 140 N-(2-{[[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1 H-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]d iazepine-2,4-dione ■ Example 142 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-2-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepi ne-2,4-dione ■ Example 143 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-5-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepi ne-2,4-dione ■ Example 144 1-Ethyl-3,3,5-trimethyl-7-{3-[(2-methyl-pyridin-3-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepi ne-2,4-diode ■ Example 145 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-pyridin-3-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepi ne-2,4-dione ■ Example 146 1-Ethyl-3,3,5-trimethyl-7-{3-[(3-methyl-pyridin-2-ylmethyl)-(2-py ridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepi ne-2,4-dione ■ Example 147 N-(2-{[[3-1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-7-yl)-propyl]-(2-pyridin-3-yl-ethyl)-amin o]-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-o xo-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)-7,5-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-o xo-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] pyr idin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihy dro-benzo[b][1,4]diazepine-2,4-dione ■ Example 155 7-({(2,4-Dimethyl-thiazol-5-ylmethyl)-[2-4-oxo-4H-furo3,2-c]pyr idin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihy dro-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-o xo-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-o xo-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-o xo-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]pyr idin-5-yl)-ethyl]-amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihy dro-benzo[b][1,4]diazepine-2,4-dione ■ Example 165 N-[2-({(-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-b enzo[b][1,4]diazepin-7-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methahesulfonamide ■ 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-be nzo[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-be nzo[b][1,4]diazepine-2,4-dione ■ Example 171 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyrid in-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5'-dihydr o-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-d ihydro-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]py ridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dih ydro-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-d ihydro-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] pyri din-5-yl)-ethyl]-oxazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-ben zo [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]pyri din-5-yl)-ethyl]-thiazol-5-ylmethyl-amino}-methyl)-1,5-dihydro-be nzo[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]pyri din-5-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-be nzo[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]pyri din-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-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]pyri din-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] pyri din-5-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-be nzo[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]pyri din-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methylt-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 18 6 N-[2-([(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-b enzo[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]p yridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-be nzo[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]pyr idin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benz o[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]pyr idin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benz o[b][1,4]diazepine-2,4-dione ■ Example 190 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(2-met hyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-d ihydro-benzo[b][1,4]diazepine-2,4-dione ■ Example 191 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(2-met hyl-4-oxo-4H-furo [3,2-c]pyridin-5-yl)-methyl]-amino} -methyl) -1,5-d ihydro-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-Ethy1-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyri din-5-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-meth yl}-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]pyri din-5-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-b enzo[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]pyri din-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-ethyl-4-oxo-4H-furo [3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethy 1-1,5-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]pyri din-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1,5 -dihydro-benzo[b][1,4]diazeptne-2,4-dione ■ Example 198 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyri din-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-b enzo[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]pyri din-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)-methanesulfonami de ■ 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-23,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(4-oxo-4H-furo[3,2-c]pyri din-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]py ridin-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]py ridin-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]py ridin-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-fur o[3,2-c]pyridin-5-yl)-e-thyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethy 1-1,5-dihydro-benzo[b][1,4]diazepin-2,4-dione ■ Example 215 N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(2-methyl-4-oxo-4H-furo[3 ,2-c]pyridin-1-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonami de ■ 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-trime thyl-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]py ridin-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]py ridin-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]py ridin-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]py ridin-5-yl)-ethly]-(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-trimethyl-4-oxo-4H-furo[3,2-c]py ridin-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-1 H-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]-methanesulfonami de ■ 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-trime thyl-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-trimethy 1-1,5-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-trimethy 1-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dion e ■ 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-trimethy 1-1,5-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-trimethy 1-1,5-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-trimethy 1-1,5-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]methanesulfo namide • 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-t rimethyl-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-dihydr o-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-dihydr o-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-dihydr o-benzo[b][1,4]diazepine-2,4-dione - Example 234 1-Ethyl-3,3,5-trimethyl-7-(3-{(4methyl-pyridin-3-ylmethyl)-[2-(4 -axo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-anino}-propyl)-1,5-dihydr o-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-dihydr o-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-1 H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(4-oxo-4H-furo[3,2-c]pyr idin-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]py ridin-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]py ridin-5-yl)-ethyl]-(4-methyl-thiazol-S-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]py ridin-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]py ridin-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]py ridin-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)-am ino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b] [1,4]dia zepine-2,4-dione ■ Example 244 7-(3-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-fur o[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimeth yl-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-1 H-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]-methanesulfonam ide ■ 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-trim ethyl-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]py ridin-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]py ridin-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]py ridin-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]py ridin-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]py ridin-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-1 H-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]-methanesulfonam ide ■ Example 253 7- (3-{(2,5-Dimethyl-2H-pyrazol-3-yhmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trim ethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione ■ Example 254 7-{3-[[2-(2,7-Dimthyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-( 4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimeth yl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dio ne ■ 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-trimeth yl-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-trimeth yl-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-trimeth yl-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]-1-propyl}-1-ethyl-3,3,5-trimeth yl-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]-methanesulfonamide ■ Example 260 7-{3-[[2-(2,7-Dimethyl-9-oxo-4H-foro[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-dihy dro-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]py ridin-6-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1 ,5-dihydro-benzo[b][14]diazepine-2,4-dione ■ Example 263 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-methyl-7-oxo-7H-thieno[2,3-c]py ridin-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-dihy dro-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]py ridin-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]py ridin-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-isoqui nolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b] [1,4]diazep ine-2,4-dione ■ Example 26B 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]diaze pine-2,9-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]diaze pine-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] diaze pine-2,4-dione ■ Example 271 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-2-ylmethyl)-[2-(1-o xo-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-o xo-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-ben zo[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-ben zo[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]diaze pine-2,9-dione ■ Example 276 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-4-ylmethyl)-[2-(1-o xo-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-isoquinoli n-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-o xo-2-H-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]diaze pine-2,4-dione ■ Example 280 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-pyridin-3-ylmethyl)-[2-(1-o xo-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-dihydr o-benzo[b][1,4]diazepine-2,4-dione ■ Example 282 1-Ethyl-7-{((2-methoxy-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinol in-2-yl)-ethy]-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-ben zo [b] [1,4]diazepine-2,4-dione ■ Example 284 N-[2-({{1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,9,5-tetrahydro-1H-b enzo [b] [1,4]diazepin-7-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-e thyl]-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-isoquinalin-2-yl)-ethyl ]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b] [1,4]diazepi ne-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]diazepi ne-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-b enzo[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]diaz epine-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-2,9-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-be nzo[b] [1,4] diazepine-2, 4-dione ■ Example 295 7-({(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin -2-yl)-methyl]-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][1,9]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-be nzo[b][1,4]diazepine-2,4-dione ■ Example 300 . 7- (2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinol in-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-b enzo[b][1,4]diazepine-2, 4-dione ■ Example 305 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinol in-2-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydr o-benzo[b] [1,4]diazepine-2,4-dione ■ Example 306 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-3-ylmethyl)-[2-(2-o xo-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-o xo-2H-quinolln-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]m ethyl}-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-trismethyl-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-oxa-4 H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-tri 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: 197-199*C
■ Example 314 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-methyl-7-oxo-7 H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-tri 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: 190-193°C
■ Example 315 1-Ethyl-3,3,5-trimethyl-7-{[N-(4-methylthiazol-2-ylmethyl)-N-(2-p yridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b] [1,4]diazepine-2,4-dione dihydrochloride
The synthesis of the title compound was performer 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 (2H, 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-d ihydrobenzo[b][1,4]diazepine-2,4-dione
The synthesis of the title compounds 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-trimet hyl-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-trimet hyl-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-trimet hyl-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-ox o-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-d 6), δ 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}me thyl)-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-y 1)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimet hyl-1,5-dihydrobenzo[b][1,4]diazepina-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-y 1)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimet hyl-1,5-dihydrobanzo[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-d 6), 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-d 6). 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)aceta mide 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-1 H-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: 158.7-160.6°C
■ Example 329 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-be nzo[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-tet rahydro-1H-benzo[b] [1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4 H-furo[3,2-c]pyridin-5-yl)ethyl]amino)methyl)pyridine (0.3g), zinc cyanide(120mg), tris(dibenzylideneacetone)dipalladium(24mg), 1,1'-bis(diphenylphosphino)ferrocene(14mg), and zinc powder(3.4mg) were added to DMF (3ml), 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(1.35g) 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-pyrid in-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(0.5g), 1-methyl-3-indoleacetic acid (0.27g), and 1-hydroxybenzotriazole (HOBT) (0.24g) in acetonitrile (10 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (WSC)(0.30g) 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 (1.1ml) was added to a 2-propanol solution (5ml) 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(0.26g) 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]py ridin-5-yl)ethyl]-N-(1-pyridin-3-ylethyl)amino}methyl)-1,5-dihydr obenzo[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)isobu tyramide 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(0.5g), 2-Phenylisobutyric acid(0.24g), and diisopropylethylamine(0.23ml) in DMF(10 ml), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.50g) 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 (5ml) 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(0.35g) as a white amorphous. 1H NMR (DMS0-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), 7.56-880 (3H, m)
■ Example 333 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-berzo{ b][1,4]diazepin-7-ylmethyl)-3-phenyl-N-(2-pyridin-3-ylethyl)propi onamide 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-y 1)-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]py ridin-5-yl)ethyl]N-(pyridin-3-ylmethyl)amino}methyl)-1,5-dihydrob enzo[b][1,4]diazepine-2,4-dione
The synthesis of the title compound was performed in the game 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-henzo[ b][1,4]diazepin-7-ylmethyl)-2-(3-methyl-2-oxo-2,3-dihydrobenzoimi dazol-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-dihydrobenzoimidaz ol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride (0.26g), cesium carbonate (0.43g), and methyl iodide(0.04ml) were added to DMF(5ml), 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 (0.44ml) was added to a 2-propanol solution (5ml) 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 (0.20g) 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]py ridin-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-tr imethyl-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]py ridin-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-me thyl-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 11H 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), 3.11and 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-4 H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trime thyl-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-tetraydro-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]pyrid in-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)-2-ethyl-3,3,5-t rimethyl-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-p yridin-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]pyri din-5-yl)ethyl]-(3-methylpyridin-2-ylmethyl)amino}methyl)-1,5-dih ydrobenzo[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-dihydiobenzo[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-d 6), 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-trimet hyl-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-d 6), 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=7.5Hz), 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-dihyd robenzo[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]py ridin-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-trimet hyl-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-trimeth yl-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-dihydrobeazo[b][1,4]diazepine-2,4-dione trihydrochloride
1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]me thyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45g), 5-bromoquinoline (0.25g), tris(dibenzylideneacetone)dipalladium(5.4mg), xantphos(10mg), and cesium carbonate (0.46g) were added to toluene (9ml), 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 (1ml) was added to a ethanol solution (5ml) 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 (0.20g) as a yellow amorphous. 1H NMR (DMSO-d6), δppm : 0.55 (3H, s), 0.99 (3H, t, J=7.0Hz), 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-fur o [3,2-c]pyridin-5-yl)ethyl] amino}methyl)pyridine-2-carbonitrile (0 .40g) and Raney nickel (1.2g) were suspended in formic acid (8ml), 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 (33mg) 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=0.9Hz), 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=0.4Hz, 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]py ridin-5-yl)ethyl]N-(quinolin-5-yl)amino}methyl)-1,5-dihydrobenzo[ b][1,4]diazapine-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-pyr idin-3-ylethyl)propionamide
Sodium hydride (55% in oil) (52mg) was suspended in DMF(7ml), 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 (210mg) 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 (0.03ml) 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=90:30). The purified product was condensed to dryness to give the title compound (20mg) 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) (52mg) was suspended in DMF (7ml), 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-3H-benzo[ b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide(210mg) 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 (0.03ml) 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 (17mg) 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 (1 H, 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-meth yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-tri 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 1H NMR (DMSO-d 6), 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-trimet hyl-1,5-dihydrobenzo[b][1,4]diazeplne-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]a mino}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-5-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-meth yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3, 3-dimet hyl-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-meth yl-4-oxo-4H-furo[3,2-clpyridin-5-yl)ethyl]amino}methyl}-3,3-dimet hyl-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] py ridin-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]py ridin-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-d ihydrobenzo[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-methylpyxidin-3-ylmethyl)amino}met hyl)-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}met hyl)-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}me thyl)-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-Cyclopropylmeth.yl-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}me thyl)-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-ymethylpyridin-3-ylmethyl)-N-[2-( 2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydr obenzo[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-d imethyl-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-m ethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-di 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: 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 folowing compounds were obtained in the same manner as in Examples above using appropriate starting materials.
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■ Example 583 1-Ethyl-3,3,5-trimethyl-7-{(N-[2- (2-methyl-4-oxo-4H-furo[3,2-c]py ridin-5-yl)ethyl]-N-(pyrimidin-5-ylmethyl)amino}methyl)-1,5-dihyd robenzo[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-trinethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-ben zo[b][1,4]diazepine-7-carbaldehyde(0.203g) and acetic acid (0.063ml) were added to a 1,2-dichloroethane solution (5ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride(.0.235g) 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(0.205g) 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-dihydnobenzo[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-ben zo [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-l-ylmethyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-di one
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-triinethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-o xo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino]methyl}-1,5-dihydr obenzo[b][1,4]diazepine-2,4-dione
The synthesis of the title compound was perfumed 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-o xo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]nethyl}-1,5-dihydr obenzo[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 1-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino ]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrybenzo[b][1,4]diazepin e-2,4-dione
1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205g) was added to a methanol solution (10ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine -2,4(3H,5H)-dione (0.213g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022g) 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(0.400g) 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]diazepin e-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), 7.12-7.19 (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-m ethyl-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 compounds was performed in the same manner as in Example 30 using appropriate starting materials. ivory powder mp: 14.6-148°c
■ Example 593 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-({N-[2-(7-methyl-4-oxo-4H-fu ro[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-dihy drobenzo[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-m ethyl-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 NMH (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)-3,3,3-trimethyl=7-{[N-[2-(2-methyl-4-oxo-4H-fu ro[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), 2.93 (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)-H-[2-(2-methyl-4-oxo-4H-furo[ 3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydr obenzo[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), 4.22-9.35 (1H, m), 4.35-4.43 (1H, m), 6.24 (1H, dd, J=0.62, 7.4 Hz), 6.97 (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) (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-dihydr o-benzo[b][1,9]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-behzo[b][1,4]diazepine-2,9-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=7.0Hz), 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 (SH,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]py ridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5 -dihydrobenzo[b][1,41diazepine-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]py ridin-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 tittle 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-meth yl-4-oxo-4H-furo [3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimet hyl-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-yl methyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]ami no}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]m 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. 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]m 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. 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-meth yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-tri methyl-1,5-dihydrobenzo[b][2,4]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)me thyl]-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]py ridin-5-yl)ethyl]-N-(3-pyrazol-1-ylbenzyl)amino]methyl}-1,5-dihyd robenzo[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=7.4Hz), 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]py ridin-5-yl)ethyl]-N-(2-pyrazol-1-yl-benzyl)amino]methyl}-1,5-dihy drobenzo[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]py ridin-5-yl)ethyl]pyrazin-2-ylmethylamino}methyl)-1,5-dihydro-benz o[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-trimeth yl-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=3.2Hz), 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-me thylamino]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]di azepine-2,4-dione (247mg) was dissolved in DMF(2ml), and was cooled to 0°C in ice water bath. Sodium hydride (60% in oil, 13.56mg) was added thereto at the same temperature, and the mixture was stirred at 0°C for 0.5 hours. Methyl iodide (73.5mg) 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 (169mg) 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-dihydroben zo[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-meth yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimet hyl-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-be nzo[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-be nzo[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 (5ml) was added to an THF solution (5ml) 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-dih ydro-benzo[o][1,4]diazepine-2,4-dione (0.52g), and the mixture was stirred at room temperature for 1 hour. 2N-Sodium hydroxide solution (5ml) 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 (0.35g) 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-dihydrobenz o[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-dihydr o-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-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: 154-157°C
Example 627 1-Ethyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyrid in-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-di hydrobenzo[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]pyrid in-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-di hydrobenzo[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-meth yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-tri 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: 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-dihydr obenzo[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-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 (Ether) mp: 142-144°C
Example 632 1-Ethyl-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyrid in-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-di hydrobenzo[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]pyrid in-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-di hydrobenzo[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]py ridin-5-yl)ethyl]-N-(pyridazin-4-ylmethyl)amino}methyl)-1,5-dihyd robenzo[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}methy 1)-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-2H-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-dihydr obenzo[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]diazepin e-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-dihydr obenzo[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]py ridin-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-m ethyl-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-di one
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-methoxymethylpyri din-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)e thyl]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-trimeth yl-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-dihy drobenzo[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 .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-dihyd robenzo[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-dih ydrobenzo[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 perfumed 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. 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-d ihydrobenzo[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)meth yl]-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-trimeth yl-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-trimeth yl-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-m ethyl-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-di one
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-m ethyl-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-di one
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-m ethyl-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-di one
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-({H-(2-methoxymethylpyri din-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)e thyl]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-be nzo[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-trimet hyl-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-be nzo[b] [1,4]diazepin-7-yl)methyl) (2-(2-methyl-4-oxofuro[3,2-c]pyri din-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-be nzo[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-met hyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)-3,3,5-tr imethyl-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-qu inolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine -2,4-dione
Trifluoroacetic acid (43.2mg) was added to a dichloromethane solution (5ml) 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 (208mg), 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(148mg) 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-t etrahydro-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-dih ydro-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-be nzo[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-methoxymethylpyri din-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)le thyl]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 NM (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 (47mg) were added to a methanol solution(10ml) 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 (0.59g)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(0.42g) 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-methoxymethylpyri din-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)e thyl]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-d 6), 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-ylm 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 : -0.09-0.03 (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), 1.45-7.48 (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]py ridin-5-yl)ethyl]-N-(2-morpholin-4-ylmethylbenzyl)amino]methyl}-1 ,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
Morpholine(0.06ml) and acetic acid(0.1ml) were added to a 1,2-dichloroethane solution(7ml) of 2-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3, 4,5-tetrahydro-1H-be nzo[b] [1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.35g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.20g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by dichlorome thane. 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 (0.30g) 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-fur o[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihy drobenzo[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]py ridin-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=0.9Hz), 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-1-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 = 7.1Hz), 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-q uinolin-1-ylmethyl)benzyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]d iazepine-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 (CMSO-d 6), 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 = 7.4Hz), 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-ylmet hyl)-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-be nzo [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 □1) 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-d 6), 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-d 6), 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]py ridin-5-yl)ethyl]-N-(2-pyrrolidin-1-ylmethylpyridin-3-ylmethyl)am ino]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-d 6), 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-ylmeth yl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}met hyl)-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-d 6), 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-yl methyl)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]py ridin-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-q uinolin-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)ethylami no)methyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione, followed by deprotection of TBDMS group with tetrabutylammonium fluoride. 1H MMR (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-dihy drobenzo[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), 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-dihy drobenzo[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 7.09 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 perfumed 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=7.1Hz), 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)am ino]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(0.6ml) was added to a dichloromethane solution (6ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]dia zepine-2,9-dione(1.0g). The mixture was cooled with ice. 2-Nitrobenzenesulphonyl chloride(0.80g) 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 magnecium 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(1.38g) 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]meth yl}-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]py ridin-5-yl)ethyl]-N-(2-methyl-1-oxypyridin-3-ylmethyl)anino]methy l}-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]py ridin-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]me thyl}-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=7.1Hz), 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]-m 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 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-methyl-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)ethylami no]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0g) was added to a methanol solution (15ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][ 1,4]diazepine-7-carbaldehyde (1.46g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23g) 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(1.92g) 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-dihydrob enzo[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, 6.1Hz), 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, 4.2Hz).
Example 723 7-{[(4-Chloro-pyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trim 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 : 0.83 (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=5.3Hz), 8.44 (1H, d, J=5.3Hz), 8.60 (1H, s).
Example 724 7-{[(2-Chloropyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trime thyl-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)c arbamic 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), 3.76-3.8.6 (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)e thylamino]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), 7.7.3-7.22 (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)c arbamate (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-d ione
The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials. 1H NMR (CDCl3), δppmn: 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]met hyl}-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)a mino]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]m ethyl}-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. 1HNMR (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)ethyl]benzenesulfonamide
Tributyl phosphine(1.2ml) and 1,1'-(azodicarbonyl)dipiperidine (1.17g) were added to a toluene solution(100ml) of 2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide (1.39g), and 1-ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.94g). 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 (0.54g) 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) ethyla mino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione
Lithium hydroxide(3.2g), and thioglycolic acid(2.4ml) were added to a DMF solution (27.4ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-ben zo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinoli n-2-yl)ethyl]benzenesulfonamide (4.56g). 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 (2.24g) 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-1-7-{[(2-methoxymethylpyridin-3-ylmthyl)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-ylmethy l)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. 1M 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), 4.0.7-4.15 (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-dimethy-8-{[(2-methylpyridin-3-ylmethyl)amino]met hyl}-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 = 6.7Hz), 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), 3.39-3.96 (1H, m), 3.9.0 (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-ylme thyl)carbamic acid tert-butyl ester (188mg) was disolved in DMF (20ml), and was cooled to 0°C in ice water bath. Sodium hydride (60% in oil, 19.7mg) was added thereto at the same temperature, and the mixture was stirred at 0°c for 0.5 hours. Methyl iodide (0.028ml) 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(162mg) 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-ylme thyl)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), 3.73-3.01 (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-benz o[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).
Examples 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-ylmeth yl)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-dihydropy ridin-3-ylmethyl) carbamic acid tert-butyl ester (536mg) was disolved in DMF(20ml), and was cooled to 0°C in ice water bath. Sodium hydride (60% in oil, 56.1mg) was added thereto at the same temperature, and the mixture was stirred at 0 °C for 0. 5 hours. Methyl iodide (0. 081ml) 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 (550mg) 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 musing 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-trime thyl-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 7 65 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{(2-methyl pyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepin e-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-methoxymethylpyridi n-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), 0.34-0.49 (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-methyl pyridin-3-ylmethyl)-amino]methyl}-1,5-dihydro-benzo[b][1,4]diazep ine-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-methoxymethylpyridi n-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-y imethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazep ine-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-trimethy 1-1,5-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-ylmthyl)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 77 6 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-trimethy 1-1,5-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-tetrahydr o-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N'-[2-(2-methyl-4-oxo-4H-f uro[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonami de
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=1.0Hz), 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-tetrahydr o-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N'-[2-(1-methyl-4-oxo-4H-f uro[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonami de
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=8.3Hz), 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]methanesulfo namide
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-trim 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. 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-trim 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. 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 = 6.4Hz), 4.06-4.16 (1H, m), 6.42 (1H, dd, J = 0.8 and 7.4 Hz), 6.55 (1H, t, J = 1.0Hz), 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=8.2Hz), 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-trimethy 1-1,5-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]diazepin e-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-trimethy 1-1,5-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]py ridin-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-1 H-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]methanesulfo namide Example 791 N-[3-({N'-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1 H-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-be nzo[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-d6), 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-fur o[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihy drobenzo[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]py ridin-5-yl)ethyl]-N-(2-morpholin-4-ylbenzyl)amino]methyl}-1,5-dih ydro-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]py ridin-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-o xo-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-o xo-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]py ridin-5-yl)ethyl]-N-(2-pyrazol-1-ylpyridin-3-ylmethyl)amino]methy 1}-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-trimet hyl-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]-e thyl}-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 folowing compounds were obtained in the same manner as in Examples above using appropriate starting materials.
803 489
804 500
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807 505
808 519
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812 489
813 568
814 517
815 520
816 557
817 534
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855 573
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858 624
859 573
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871 574
872 559
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879 586
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882 557
883 546
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885 570
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987 571
988 584
989 406
990 421
991 448
992 434
993 452
994 436
995 440
996 392
997 448
998 438
999 435
1000 435
1001 421
1002 421
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1004 435
1005 406
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1007 420
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1022 452
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1035 468
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1038 435
Examples 1039 to 1614
The folowing compounds can be obtained in the same manner as in Examples above using appropriate starting materials.
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Examples 1615 to 1625
The folowing compounds were obtained in the same manner as in Examples above using appropriate starting materials.
1615 460
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Pharmacological Test 1 (1) Production of human Kv1.5-expressing CHO-K1 cell lines
CHO-K1 cell lines stably expressing human Kvl.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 Kvl. 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 Kvl.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 cDNR 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'-ATGTCTGCACTCCGAAGAAAATTTG-3* SEQ ID No.1
HGIBK1-A 5'-TTATGTGAAGCGATCAGAGTTC-3' SEQ ID No.2
hGIRK1-F2 5'-GCAGGGTACCCCTTCGTATTATGTCTGCACTCC-3' SEQ ID No.3
hGIRK1-A3 5'-GGTGTCTGCCGAGATTTGA-3' SEQ ID No.4
hGIRK1-A4 5'-CCGAGTGTAGGCGATCACCC-3' SEQ ID No.5
hGIRK4-S 5'-ATGGCTGGCGATTCTAGGAATGCC-3' SEQ ID No.6
hGIRK4-A 5'-TCTCACCGAGCCCCTGGCCTCCC-3' SEQ ID No.7
hGIRK4-S2 5'-AACCAGGACATGGAGATTGG-3' SEQ ID No.8
hGIRK4-2 5'-GAGAACAGAAAAGCGGACAC-3' SEQ ID No.9
The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NH_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 IHM 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,
1.8 mM,
1 mM,
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,
1 mM,
MgATP 5 mM,
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,
1.8 mM,
1 mM,
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,
1 mM,
MgATP 5 mM,
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 →..-60 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 pM 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 Kvl.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)™ wherein nH is the Hill coefficient.
Table 2 shows the test results. Table 2
Test Compound
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
SEQUENCE LISTING
  • <110> OTSUKA PHARMACEUTICAL CO., LTD.
  • <120> NITROGEN-CONTAINING COMPOUND AND PHARMACEUTICAL COMPOSITION
  • <130> P10-88
  • <150> US 61/235,973 <151> 2009-08-21
  • <150> US 61/235,981 <151> 2009-08-21
  • <150> US 61/235,983 <151> 2009-08-21
  • <150> US 61/359,686 <151> 2010-06-29
  • <160> 9
  • <170> PatentIn version 3.4
  • <210> 1 <211> 25 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 1 atgtctgcac tccgaaggaa atttg    25
  • <210> 2 <211> 22 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 2 ttatgtgaag cgatcagagt tc    22
  • <210> 3 <211> 33 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 3 gcagggtacc ccttcgtatt atgtctgcac tcc    33
  • <210> 4 <211> 19 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 4 ggtgtctgcc gagatttga    19
  • <210> 5 <211> 20 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 5 ccgagtgtag gcgatcaccc    20
  • <210> 6 <211> 24 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 6 atggctggcg attctaggaa tgcc    24
  • <210> 7 <211> 23 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 7 tctcaccgag cccctggcct ccc    23
  • <210> 8 <211> 20 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 8 aaccaggaca tggagattgg    20
  • <210> 9 <211> 20 <212> DNA <213> Artificial
  • <220> <223> Primer
  • <400> 9 gagaacagga aagcggacac    20

Claims (14)

  1. A diazepine compound represented by General Formula (1) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-alkyl C1-6-alkoxy C1-6-alkyl; R2 and R3 may be linked to form C1-6-alkylene; A1 is C1-6-alkylene optionally substituted with one or more hydroxyls; Y1 and Y2 are each independently -N= or -CH=; R5 is a group represented by wherein R6 and R7 are each independently hydrogen or C1-6-alkyl, cyclo C3-8-alkyl, aryl or heterocyclic group, each of which is optionally substituted; 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 C1-6-alkyl, phenyl C1-6-alkyl and phenyl.
  2. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R6 and R7 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-alkyl, aryl or heterocyclic group, each of which is optionally substituted, and XA and XB are each independently a bond, C1-6-alkylene, C2-6-alkenylene, -CO-, -SO2-, -C1-6-alkylene-SO2-, -C1-6--alkylene-CO-, -C2-6-alkenylene-CO-, -C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -N(C1-6-alkyl)-C1-6-alkylene-, -CO-N(C1-6-alkyl)-C1-6-alkylene-, -O-C1-6-alkylene-, -N(phenyl C1-6-alkyl)-C1-6-alkylene-, -CO-C1-6-alkylene-CO-, -CO-NH-C1-6-alkylene-, -C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-, -C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-O-, -C1-6-alkylene -NH-C1-6-alkylene-, -C1-6-alkylene-SO2-NH-C1-6-alkylene-, -N(C1-6-alkyl)-CO-C1-6-alkylene-, -N(C1-6-alkyl)-C1-6-alkylene-CO-, -N(C1-6-alkyl)-C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-, -N(phenyl)-C1-6-alkylene-CO-, -N(phenyl) -C1-6-alkylene-CO-, -NH-CO-, -NH-CO-C1-6-alkylene-, -NH-C1-6-alkylene-, -O-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -O-C1-6-alkylene-CO-, -NH-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -S-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, -SO2-N(C1-6-alkyl)-C1-6-alkylene-, -SO2-NH-C1-6-alkylene-, -C2-6-alkenylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, C1-6-alkylene-N(phenyl C1-6-alkyl)-C1-6-alkylene-, -N(phenyl C1-6-alkyl)-C1-6-alkylene-, -N(phenyl)-C1-6-alkylene-CO-N(C1-6-alkyl)-C1-6-alkylene-, or -CO-C1-6-alkylene-O-CO-C1-6-alkylene-O-.
  3. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R5 and R7 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-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.
  4. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R6 and R7 are each independently hydrogen, C1-6-alkyl, cyclo C3-8-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[2,5-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.
  5. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R6 and R7 are each independently selected from the group consisting of the following substituents (1) to (54):
    (1) hydrogen;
    (2) C1-6-alkyl;
    (3) cyclo C3-8-alkyl optionally substituted with one or more phenyl C1-6-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) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C1-6-alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;
    (4-5) C1-6-alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and C1-6-alkyl amino;
    (4-6) pyridyl;
    (4-7) thienyl;
    (4-8) piperazinyl optionally substituted with one or more C1-6-alkyls;
    (4-9) phenyl;
    (4-10) pyrazolyl optionally substituted with one or more C1-6-alkyls;
    (4-11) pyrimidinyl optionally substituted with one or more C1-6-alkyls;
    (4-12) piperidyl optionally substituted with one or more C1-6-alkyls;
    (4-13) furyl;
    (4-14) carboxy;
    (4-15) C1-6-alkoxycarbonyl;
    (4-16) amino optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-6- alkanoyl and C1-6-alkylsulfonyl,
    (4-17) C1-6-alkylthio;
    (4-18) triazolyl;
    (4-19) imidazolyl;
    (4-20) pyrrolidinyl optionally substituted with one o= more oxos;
    (4-21) C1-6-alkylsulfonyl;
    (4-22) C1-4-alkylenedioxy optionally substituted with one or more halogens;
    (4-23) nitro;
    (4-24) oxazolyl;
    (4-25) thiazolyl optionally substituted with one or more C1-6-alkyls:
    (4-26) C1-6-alkanoyl; and
    (4-27) morpholinyl;
    (5) naphthyl;
    (6) furyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, C1-6-alkoxycarbonyl and phenyl;
    (7) thienyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-4-alkylenedioxy, carboxy, halogen, pyridyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, oxazolyl and furyl;
    (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, C1-6-alkyl and halogen;
    (9) pyrazolyl cationally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen, or C1-6-alkoxy; cyclo C3-8-alkyl; halogen; phenyl optionally substituted with C1-6-alkoxy; furyl and thienyl;
    (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and phenyl;
    (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, C1-6-alkyl, thienyl and furyl;
    (12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy; phenyl; phenoxy and C1-6-alkanoylamino;
    (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and C1-6-alkoxycarbonyl;
    (14) triazolyl optionally substituted with one or more C1-6-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 C1-6-alkanoyl and C1-6-alkylsulfonyl;
    (15-4) C1-6-alkyl optionally substituted with one or more substituants selected from the group consisting of halogen, C1-6-alkoxy, C1-6-alkanoyloxy, cyclo C3-8 alkyl amino, C1-6-alkyl amino, C1-6-alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyle;
    (15-5) oxo;
    (15-6) hydroxyl;
    (15-7) C1-6-alkoxy optionally substituted with one or more phenyls;
    (15-8) pyrrolidinyl;
    (15-9) C1-6-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 C1-6-alkyl and phenyl;
    (17) pyridazinyl;
    (18) pyrazinyl optionally substituted with one or more phenyl C1-6-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 C1-6-alkyls;
    (23) indolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, C1-6-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 C1-6-alkyls;
    (25) benzothienyl optionally substituted with one or more C1-6-alkyls;
    (26) benzimidazolyl optionally substituted with one or more C1-6-alkyls;
    (27) 2,3-dihydrobenzo[b]furyl;
    (28) benzofuryl optionally substituted with one or more halogens;
    (29) indazolyl optionally substituted with one or more C1-6-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 C1-6-alkyl optionally substituted with C1-6-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, C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy, halogen, furyl, pyridyl and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and C1-6-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 C1-6-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 C1-6-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, C1-6-alkyl and C1-6-alkanoyl;
    (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-6-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 C1-6-alkyls, C1-6-alkoxy, C1-6-alkyl and oxo
    (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, pyridyl C1-6-alkyl, aralkyl, C1-6-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 C1-6-alkyls, C1-6-alkoxy, C1-6-alkyl and oxo;
    (45) chromanyl optionally substituted with one or more C1-6-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 C1-6-alkyl and oxo;
    (53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and oxo, and
    (54) piperidyl optionally substituted with one or more aryl carbonyls.
  6. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 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) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, C1-6-alkoxy, imidazolyl, and morpholinyl;
    (4a-5) C1-6-alkoxy;
    (4-10) pyrazolyl optionally substituted with one or more C1-6-alkyls;
    (4a-16) amino optionally substituted with one or more C1-6-alkylsulfonyls;
    (4-18) triazolyl;
    (4-19) imidazolyl;
    (4-23) nitro;
    (4-26) C1-6-alkanoyl; and
    (4-27) morpholinyl;
    (6a) furyl optionally substituted with one or more C1-6-alkyls optionally substituted with halogen;
    (7a) thienyl optionally substituted with one or more C1-6-alkyls;
    (8a) imidazolyl optionally substituted with one or more C1-6-alkyls;
    (9a) pyrazolyl optionally substituted with one or more C1-6-alkyls optionally substituted with C1-6-alkoxy;
    (10a) oxazolyl optionally substituted with one or more C1-6-alkyls;
    (11a) isoxazolyl optionally substituted with one or more C1-6-alkyls;
    (12a) thiazolyl optionally substituted with one or more C1-6-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 C1-6-alkanoyl and C1-6-alkylsulfonyl;
    (15-4) C1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6-alkoxy, C1-6-alkanoyloxy, cyclo C3-8-alkyl amino, C1-6-alkyl amino, C1-6-alkanoyl amino, hydroxyl and pyrrolidinyl optionally substituted with one or more hydroxyis;
    (15-5) oxo;
    (15a-7) C1-6-alkoxy;
    (15-9) C1-6-alkanoyl;
    (15-11) phenoxy;
    (15-12) pyrazolyl; and
    (15-14) N-oxide
    (16a) pyrimidinyl optionally substituted with one or more C1-6-alkyls;
    (17) pyridarinyl
    (18) pyrazinyl optionally substituted with one or more phenyl, C1-6-alkoxys;
    (23a) indolyl optionally substituted with one or more C1-6-alkyls; (24a) imidazo[1,2-a]pyridyl;
    (24b) imidazo[1,5-a]pyridyl optionally substituted with one or more C1-6-alkyls;
    (26) benzimidazolyl optionally substituted with one or more C1-6-alkyls;
    (29) indazolyl optionally substituted with one or more C1-6-alkyls;
    (30a) furo[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;
    (30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;
    (31a) furo[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;
    (31b) 4,5-dihydrofuro[3,2-c]pyriiyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl optionally substituted with halogen or C1-6-alkoxy;
    (32a) thieno[2,3-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-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 C1-6-alkyl;
    (33a) thieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-alkyl;
    (33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted with one or more substituents selected from the group consisting of oxo and C1-6-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 C1-6-alkyl;
    (42a) quinolyl, optionally substituted with one or more oxos;
    (43a) 1,2,3,4-tetrahydrocuinolyl optionally substituted with one or more substituents selected from the group consisting of aralkyl (e.g., phenyl C1-6-alkyl, etc.), pyridyl C1-6-alkyl and oxo;
    (44) 1,2-dihydroquinoly optionally substitutes one or more oxos; and
    (53) 2,3-dihydrobenzo[d]imidazolyl optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl and oxo.
  7. A diazepine cortmound or a pharmaceutically acceptable salt thereof according to claim 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, C1-6-alkyl, C1-6-alkoxy C1-6-alkyl, and C1-6-alkylsulfonylamino.
  8. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 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-dihyd robenzo[b][1,4]diazepine-2,4-dion,
    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-dihydr obenzo[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)benza mide,
    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)benzenesulfona mide,
    7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-t rimethyl-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-b enzo[b][1,4]diazepin-7-ylmethyl)(2-pyridin-3-ylethyl)amino]methyl }phenyl)methanesufonamide,
    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-t rimethyl-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-trimet hyl-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-trimet hyl-1,5-dihydrobenzo [b][1,4]diazagine-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-pyrid in-3-ylethyl)acetamide.
  9. A diazepine compound according to claim 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-dihyd robenzo[b][1,4]diazepine-2,4-dione dihydrochloride, 1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-fluro[3,2-c] pyridin-3-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydr obenzo[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-dihydro benzo[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)benza mide hydrochloride, N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,3-tetrahydro-1H-benzo[ b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfona mide, 7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl)-1-ethyl-3,3,5-t rimethyl-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-b enzo[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]methy}-1-ethyl-3,3,5-t rimethyl-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-trimet hyl-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-trimet hyl-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-pyrid in-3-ylethyl)acetamide hydrochloride.
  10. A diazepine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y1 and Y2 are each -CH=.
  11. A pharmaceutical composition comprising a diazepine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and a pharmacologically acceptable carrier.
  12. A pharmaceutical composition according to claim 11 for use in the prevention and/or treatment of arrhythmia.
  13. A diazepine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for use in the prevention and/or treatment of arrhythmia.
  14. Use of a diazepine compound or of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the production of a pharmaceutical composition.
HK12108042.7A 2009-08-21 2010-08-20 Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation HK1167391B (en)

Applications Claiming Priority (9)

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
US61/235,973 2009-08-21
US61/235,981 2009-08-21
US61/235,983 2009-08-21
US35968610P 2010-06-29 2010-06-29
US61/359,686 2010-06-29
PCT/JP2010/064545 WO2011021726A2 (en) 2009-08-21 2010-08-20 Nitrogen-containing compound and pharmaceutical composition

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HK1167391B true HK1167391B (en) 2014-08-01

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