DESCRIPTION

IN 1-POSITION DURCH EINEN RING SUBSTITUIERTE BENZO [1, 4] DIAZEPINE ZUR VERWENDUNGS ALS ANTIDEPRESSIVA

TECHNICAL FIELD [0001]

The present invention relates to a novel benzodiazepine compound.

BACKGROUND ART [0002]

Three monoamines known as serotonin, norepinephrine, and dopamine function as neurotransmitters in vivo. Therefore, drugs having inhibitory effects on the reuptake of these monoamines have been used widely as therapeutic drugs for diseases associated with the central or peripheral nervous system. [0003]

Most of drugs previously used in the treatment of depression selectively inhibit the reuptake of norepinephrine or serotonin. Examples of such drugs include imipramine (first-generation antidepressant) , maprotiline (second-generation antidepressant) , selective serotonin reuptake inhibitors (SSRIs, third-generation antidepressants) represented by fluoxetine, and serotonin and/or norepinephrine reuptake inhibitors (SNRIs, fourth-

generation antidepressants) represented by venlafaxine (Miura et al., Rinshoseishinyakuri, 2000, 3:311-318). [0004]

However, all of these drugs require a period as long as 3 weeks or longer for exerting their therapeutic effects and, in addition, fail to exert sufficient therapeutic effects on approximately 30% of patients with depression (Phil Skolnick, European Journal of Pharmacology, 1999, 375: 31-40) .

DISCLOSURE OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0005]

An object of the present invention is to provide a drug that has a wide therapeutic spectrum and can exert sufficient therapeutic effects in a short period, compared with antidepressants known in the art.

MEANS FOR SOLVING THE PROBLEMS [0006]

The present inventors have conducted diligent studies to attain the object and have consequently found that a benzodiazepine compound represented by the general formula (1) shown below can be used in the production of the desired drugs. The present invention has been completed based on these findings. [0007]

The present invention provides a

benzodiazepine compound or a salt thereof according to Item 1 shown below. Item 1.

A benzodiazepine compound represented by the general formula (1) or a salt thereof: [0008] [Formula 1]

[0009] wherein R ¹ represents

(1.1) a hydrogen atom,

(1.2) a lower alkyl group,

(1.3) a lower alkenyl group,

(1.4) a hydroxy-lower alkyl group,

(1.5) a cyclo-lower alkyl-substituted lower alkyl group,

(1.6) a cyclo-lower alkenyl-substituted lower alkyl group,

(1.7) a bicyclo[2.2.1] heptenyl-lower alkyl group,

(1.8) a phenyl-lower alkyl group (which may have a hydroxy group (s) on the phenyl group),

(1.9) a pyrrolyl-lower alkyl group (which may have a lower alkyl group (s) on the pyrrolyl group),

(1.10) a pyrazolyl-lower alkyl group (which may have a

group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the pyrazolyl group) ,

(1.11) an imidazolyl-lower alkyl group (which may have a lower alkyl group(s) on the imidazolyl group),

(1.12) a pyridyl-lower alkyl group (which may have a lower alkyl group (s) on the pyridyl group),

(1.13) an indolyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group on the indolyl group) ,

(1.14) an indazolyl-lower alkyl group (which may have a lower alkyl group (s) on the indazolyl group),

(1.15) a benzimidazolyl-lower alkyl group (which may have a lower alkyl group (s) on the benzimidazolyl group) ,

(1.16) a tetrahydropyranyl-lower alkyl group,

(1.17) a furyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a halogen-substituted lower alkyl group on the furyl group) ,

(1.18) a thienyl-lower alkyl group (which may have a group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the thienyl group) ,

(1.19) an imidazopyridyl-lower alkyl group,

(1.20) an oxazolyl-lower alkyl group (which may have a lower alkyl group (s) on the oxazolyl group),

(1.21) a furopyridyl-lower alkyl group,

(1.22) a thiazolyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group on the thiazolyl group) ,

(1.23) a thienopyridyl-lower alkyl group,

(1.24) an imidazothiazolyl-lower alkyl group, or

(1.25) a furyl-lower alkenyl group;

R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group; R ³ represents

(3.1) a hydrogen atom,

(3.2) a halogen atom,

(3.3) a cyano group,

(3.4) a hydroxy group,

(3.5) a lower alkyl group,

(3.6) a lower alkoxy group,

(3.7) a lower alkoxy-lower alkoxy group,

(3.8) a hydroxy-lower alkyl group,

(3.9) a lower alkylthio group,

(3.10) a lower alkoxycarbonyl group,

(3.11) a tri (lower alkyl) silyloxy-lower alkyl group,

(3.12) an amino group which may have a lower alkyl group (s) ,

(3.13) a phenyl group which may have a group (s) selected from the group consisting of a lower alkoxy group, a nitro group, and an amino group,

(3.14) a piperazinyl group which may have a lower alkyl

group (s) ,

(3.15) an imidazolyl group,

(3.16) a pyrazolyl group,

(3.17) a triazolyl group,

(3.18) a pyridyl group,

(3.19) a pyridazinyl group which may have a lower alkyl group (s) ,

(3.20) a pyrimidinyl group, or

(3.21) a pyrazinyl group; R ⁴ represents

(4.1) a hydrogen atom,

(4.2) a halogen atom,

(4.3) a lower alkyl group,

(4.4) a halogen-substituted lower alkyl group,

(4.5) a lower alkoxy group,

(4.6) a lower alkynyl group,

(4.7) a cyano group,

(4.8) an amino group which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group,

(4.9) an amino-lower alkyl group (which may have a lower alkyl group (s) on the amino group),

(4.10) an amino-lower alkynyl group (which may have a lower alkyl group (s) on the amino group),

(4.11) a lower alkoxycarbonyl group,

(4.12) a hydroxy-lower alkyl group,

(4.13) a lower alkoxy-lower alkyl group,

(4.14) a tri (lower alkyl) silyloxy-lower alkyl group,

(4.15) a lower alkylsulfonyl group which may have a naphthyl group (s),

(4.16) a phenyl group,

(4.17) a pyrrolidinyl group,

(4.18) a piperidinyl group,

(4.19) a morpholinyl group, or

(4.20) a pyridazinyl group which may have a lower alkyl group (s) , or

R ³ and R ⁴ may be bonded together to form a lower alkylenedioxy group or -CH=CH-CH=CH-; R ⁵ represents a hydrogen atom or a halogen atom; R ⁶ represents

(6.1) a phenyl group which may have a group selected from the group consisting of a halogen atom; a lower alkyl group; a halogen-substituted lower alkyl group; a lower alkylthio group; a lower alkoxy group; a halogen- substituted lower alkoxy group; a hydroxy group; an amino group which may have a lower alkyl group; an aminosulfonyl group which may have a lower alkyl group; a cyano group; a phenyl group; a pyrrolidinyl group which may have an oxo group; an imidazolyl group; an oxazolyl group; and a thiazolyl group which may have a lower alkyl group,

(6.2) a dihydroindenyl group which may have an oxo group (s) ,

(6.3) a naphthyl group which may have a group (s) selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group,

and a lower alkylthio group,

(6.4) a fluorenyl group,

(6.5) a pyridyl group which may have a group (s) selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,

(6.6) a pyridazinyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a phenyl group,

(6.7) a pyrimidinyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.8) a pyrazinyl group which may have a lower alkyl group (s),

(6.9) an indolyl group which may have a group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a tri-lower alkylsilyl group, a lower alkoxy group, a cyano group, a lower alkoxy carbonyl group, a halogen-substituted lower alkyl group and a phenylsulfonyl group (which may have a lower alkyl group (s) on the phenyl group(s)),

(6.10) an indazolyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom and a tri-lower alkylsilyl group,

(6.11) an indolinyl group which may have a lower alkanoyl group (s),

(6.12) a quinolyl group which may have a group (s)

selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkoxy group,

(6.13) a dihydroquinolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and an oxo group,

(6.14) a tetrahydroquinolyl group which may have a group (s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkoxy group, and a phenyl-lower alkyl group (which may have a lower alkoxy group (s) on the phenyl group),

(6.15) an isoquinolyl group,

(6.16) a quinoxalinyl group which may have a phenyl group (s),

(6.17) a pyrazolopyridyl group,

(6.18) a benzofuryl group,

(6.19) a dihydrobenzofuryl group,

(6.20) a benzodioxolyl group,

(6.21) a dihydrobenzodioxinyl group,

(6.22) a benzodioxinyl group,

(6.23) a dihydrobenzodioxepinyl group,

(6.24) a thienyl group which may have a lower alkyl group (s) ,

(6.25) a benzothienyl group which may have a group (s) selected from the group consisting of a halogen atom and a lower alkyl group,

(6.26) a dihydrobenz [b] [1, 4] oxazinyl group which may have a group (s) selected from the group consisting of

an oxo group, a lower alkyl group, and a lower alkoxy group,

(6.27) a thiazolyl group,

(6.28) a benzothiazolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group,

(6.29) a thienopyridyl group,

(6.30) a thienopyrimidinyl group,

(6.31) a carbazolyl group (which may have a lower alkyl group (s) on the carbazolyl group), or,

(6.32) a tetrahydrocyclopenta[b] indolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and a tri-lower alkylsilyl group: and R ⁷ represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy-lower alkyl group, a phenyl- lower alkyl group, or a tri (lower alkyl) silyloxy-lower alkyl group.

[0010]

A preferable example of the compound of the general formula (1) of the present invention is a benzodiazepine compound represented by the general formula (1) or a salt thereof:

[0011]

[Formula 2]

[0012] wherein R ¹ represents

(1.1) a hydrogen atom,

(1.2) a lower alkyl group,

(1.3) a lower alkenyl group,

(1.4) a hydroxy-lower alkyl group,

(1.5) a cyclo-lower alkyl-substituted lower alkyl group,

(1.6) a cyclo-lower alkenyl-substituted lower alkyl group,

(1.7) a bicyclo[2.2.1] heptenyl-lower alkyl group,

(1.8) a phenyl-lower alkyl group (which may have 1 to 3 (more preferably 1) hydroxy group (s) on the phenyl group) ,

(1.9) a pyrrolyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the pyrrolyl group) ,

(1.10) a pyrazolyl-lower alkyl group (which may have 1 to 3 (more preferably 1 to 2) group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the pyrazolyl group) ,

(1.11) an imidazolyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the imidazolyl group) ,

(1.12) a pyridyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the pyridyl group) ,

(1.13) an indolyl-lower alkyl group (which may have 1

to 3 (more preferably 1) group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group on the indolyl group) ,

(1.14) an indazolyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the indazolyl group) ,

(1.15) a benzimidazolyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the benzimidazolyl group) ,

(1.16) a tetrahydropyranyl-lower alkyl group,

(1.17) a furyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a halogen-substituted lower alkyl group on the furyl group) ,

(1.18) a thienyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the thienyl group) ,

(1.19) an imidazo [1, 2-b] pyridyl-lower alkyl group,

(1.20) an oxazolyl-lower alkyl group (which may have 1 to 2 lower alkyl group (s) on the oxazolyl group),

(1.21) a furo [2, 3-c] pyridyl-lower alkyl group,

(1.22) a thiazolyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group on the thiazolyl group) ,

(1.23) a thieno [3, 2-c] pyridyl-lower alkyl group,

(1.24) an imidazo [2, 1-b] thiazolyl-lower alkyl group, or

(1.25) a furyl-lower alkenyl group;

R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group; R ³ represents

(3.1) a hydrogen atom,

(3.2) a halogen atom,

(3.3) a cyano group,

(3.4) a hydroxy group,

(3.5) a lower alkyl group,

(3.6) a lower alkoxy group,

(3.7) a lower alkoxy-lower alkoxy group,

(3.8) a hydroxy-lower alkyl group,

(3.9) a lower alkylthio group,

(3.10) a lower alkoxycarbonyl group,

(3.11) a tri (lower alkyl) silyloxy-lower alkyl group,

(3.12) an amino group which may have 1 to 2 lower alkyl group (s) ,

(3.13) a phenyl group which may have 1 to 3 (more preferably 1) group (s) selected from the group consisting of a lower alkoxy group, a nitro group, and an amino group,

(3.14) a piperazinyl group which may have 1 to 3 (more preferably 1) lower alkyl group (s),

(3.15) an imidazolyl group,

(3.16) a pyrazolyl group,

(3.17) a 1,2, 4-triazolyl group,

(3.18) a pyridyl group,

(3.19) a pyridazinyl group which may have 1 to 3 (more

preferably 1} lower alkyl group(s),

(3.20) a pyrimidinyl group, or

(3.21) a pyrazinyl group; R ⁴ represents

(4.1) a hydrogen atom,

(4.2) a halogen atom,

(4.3) a lower alkyl group,

(4.4) a halogen-substituted lower alkyl group,

(4.5) a lower alkoxy group,

(4.6) a lower alkynyl group,

(4.7) a cyano group,

(4.8) an amino group which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group,

(4.9) an amino-lower alkyl group (which may have 1 to 2 lower alkyl group (s) on the amino group),

(4.10) an amino-lower alkynyl group (which may have 1 to 2 lower alkyl group (s) on the amino group),

(4.11) a lower alkoxycarbonyl group,

(4.12) a hydroxy-lower alkyl group,

(4.13) a lower alkoxy-lower alkyl group,

(4.14) a tri (lower alkyl) silyloxy-lower alkyl group,

(4.15) a lower alkylsulfonyl group which may have 1 to 2 naphthyl group (s),

(4.16) a phenyl group,

(4.17) a pyrrolidinyl group,

(4.18) a piperidinyl group,

(4.19) a morpholinyl group, or

(4.20) a pyridazinyl group which may have 1 to 3 (more preferably 1) lower alkyl group (s) , or R ³ and R ⁴ may be bonded together to form a lower alkylenedioxy group or -CH=CH-CH=CH-; R ⁵ represents a hydrogen atom or a halogen atom; R ⁶ represents

(6.1) a phenyl group which may have 1 to 3 group (s) selected from the group consisting of a halogen atom; a lower alkyl group; a halogen-substituted lower alkyl group; a lower alkylthio group; a lower alkoxy group; a halogen-substituted lower alkoxy group; a hydroxy group; an amino group which may have 1 to 2 lower alkyl group (s); an aminosulfonyl group which may have 1 to 2 lower alkyl group (s); a cyano group; a phenyl group; a pyrrolidinyl group which may have 1 oxo group; an imidazolyl group; an oxazolyl group; and a thiazolyl group which may have 1 to 3 (more preferably 1) lower alkyl group (s) ,

(6.2) a 2, 3-dihydroindenyl group which may have 1 oxo group (s) ,

(6.3) a naphthyl group which may have 1 to 5 (more preferably 1 to 3, even more preferably 1) group (s) selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.4) a fluorenyl group,

(6.5) a pyridyl group which may have 1 to 3 (more preferably 1 to, 2) group (s) selected from the group

consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,

(6.6) a pyridazinyl group which may have 1 to 3 (more preferably 1) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a phenyl group,

(6.7) a pyrimidinyl group which may have 1 to 3 (more preferably 1 to 2) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.8) a pyrazinyl group which may have 1 to 3 (more preferably 1 to 2) lower alkyl group (s),

(6.9) an indolyl group which may have 1 to 3 group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a tri-lower alkylsilyl group, a lower alkyl group, a cyano group, a lower alkoxycarbonyl group, a halogen-substituted lower alkyl group and a phenylsulfonyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the phenyl group) ,

(6.10) an indazolyl group which may have 1 to 3 (more preferably 1 to 2) group (s) selected from the group consisting of lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom, a tri-lower alkylsilyl group

(6.11) an indolinyl group which may have 1 to 3 (more preferably 1) lower alkanoyl group (s),

(6.12) a quinolyl group which may have 1 to 3 (more

preferably 1 to 2) group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkoxy group,

(6.13) a dihydroquinolyl group which may have 1 to 3 (more preferably 1 to 2) group (s) selected from the group consisting of a lower alkyl group and an oxo group,

(6.14) a tetrahydroquinolyl group which may have 1 to 3 group (s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkoxy group, and a phenyl-lower alkyl group (which may have 1 to 3 (more preferably 1) lower alkoxy group (s) on the phenyl group) ,

(6.15) an isoquinolyl group,

(6.16) a quinoxalinyl group which may have 1 to 3 (more preferably 1) phenyl group (s),

(6.17) a pyrazolo [3, 4-b] pyridyl group,

(6.18) a benzofuryl group,

(6.19) a 2, 3-dihydrobenzofuryl group,

(6.20) a benzo [d] [1, 3] dioxolyl group,

(6.21) a 2, 3-dihydrobenzo [b] [1, 4] dioxinyl group,

(6.22) a 4H-benzo[d] [1,3] dioxinyl group,

(6.23) a 3, 4-dihydro-2H-benzo[b] [1, 4]dioxepinyl group,

(6.24) a thienyl group which may have 1 lower alkyl group,

(6.25) a benzothienyl group which may have 1 to 3 (more preferably 1) group (s) selected from the group

consisting of a halogen atom and a lower alkyl group,

(6.26) a 3, 4-dihydro-2H-benz [b] [1, 4] oxazinyl group which may have 1 to 3 group (s) selected from the group consisting of an oxo group, a lower alkyl group, and a lower alkoxy group,

(6.27) a thiazolyl group,

(6.28) a benzothiazolyl group which may have 1 to 3 (more preferably 1) group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group,

(6.29) a thieno[3,2-b]pyridyl group or a thieno[2,3- b]pyridyl group,

(6.30) a thieno [3, 2-d] pyrimidinyl group,

(6.31) a carbazolyl group (which may have 1 to 3 (more preferably 1) lower alkyl group (s) on the carbazolyl group) , or,

(6.32) a tetrahydrocyclopenta [b] indolyl group which may have 1 to 3 (more preferably 1) group (s) selected from the group consisting of a lower alkyl group and a tri- lower alkylsilyl group: and

R ⁷ represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy-lower alkyl group, a phenyl- lower alkyl group, or a tri (lower alkyl) silyloxy-lower alkyl group. [0013]

The present invention provides a pyrrolidine compound, a composition comprising said compound, an agent comprising said compound, a use of said compound,

a method for treating a disorder, and a process for producing said compound, as described in Items 1 to 12 below.

[0014]

Item 1. h benzodiazepine compound represented by the general formula (1) or a salt thereof: [Formula 1]

wherein R ¹ represents

(1.1) a hydrogen atom,

(1.2) a lower alkyl group,

(1.3) a lower alkenyl group,

(1.4) a hydroxy-lower alkyl group,

(1.5) a cyclo-lower alkyl-substituted lower alkyl group,

(1.6) a cyclo-lower alkenyl-substituted lower alkyl group,

(1.7) a bicyclo [2.2.1] heptenyl-lower alkyl group,

(1.8) a phenyl-lower alkyl group (which may have a hydroxy group (s) on the phenyl group),

(1.9) a pyrrolyl-lower alkyl group (which may have a lower alkyl group (s) on the pyrrolyl group),

(1.10) a pyrazolyl-lower alkyl group (which may have a

group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the pyrazolyl group) ,

(1.11) an imidazolyl-lower alkyl group (which may have a lower alkyl group(s) on the imidazolyl group),

(1.12) a pyridyl-lower alkyl group (which may have a lower alkyl group(s) on the pyridyl group),

(1.13) an indolyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group on the indolyl group) ,

(1.14) an indazolyl-lower alkyl group (which may have a lower alkyl group (s) on the indazolyl group),

(1.15) a benzimidazolyl-lower alkyl group (which may have a lower alkyl group (s) on the benzimidazolyl group) ,

(1.16) a tetrahydropyranyl-lower alkyl group,

(1.17) a furyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a halogen-substituted lower alkyl group on the furyl group) ,

(1.18) a thienyl-lower alkyl group (which may have a group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the thienyl group) ,

(1.19) an imidazopyridyl-lower alkyl group,

(1.20) an oxazolyl-lower alkyl group (which may have a lower alkyl group (s) on the oxazolyl group),

(1.21) a furopyridyl-lower alkyl group,

(1.22) a thiazolyl-lower alkyl group (which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group on the thiazolyl group) ,

(1.23) a thienopyridyl-lower alkyl group,

(1.24) an imidazothiazolyl-lower alkyl group, or

(1.25) a furyl-lower alkenyl group;

R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group; R ³ represents

(3.1) a hydrogen atom,

(3.2) a halogen atom,

(3.3) a cyano group,

(3.4) a hydroxy group,

(3.5) a lower alkyl group,

(3.6) a lower alkoxy group,

(3.7) a lower alkoxy-lower alkoxy group,

(3.8) a hydroxy-lower alkyl group,

(3.9) a lower alkylthio group,

(3.10) a lower alkoxycarbonyl group,

(3.11) a tri (lower alkyl) silyloxy-lower alkyl group,

(3.12) an amino group which may have a lower alkyl group (s),

(3.13) a phenyl group which may have a group (s) selected from the group consisting of a lower alkoxy group, a nitro group, and an amino group,

(3.14) a piperazinyl group which may have a lower alkyl

group (s) ,

(3.15) an imidazolyl group,

(3.16) a pyrazolyl group,

(3.17) a triazolyl group,

(3.18) a pyridyl group,

(3.19) a pyridazinyl group which may have a lower alkyl group (s) ,

(3.20) a pyrimidinyl group, or

(3.21) a pyrazinyl group; R ⁴ represents

(4.1) a hydrogen atom,

(4.2) a halogen atom,

(4.3) a lower alkyl group,

(4.4) a halogen-substituted lower alkyl group,

(4.5) a lower alkoxy group,

(4.6) a lower alkynyl group,

(4.7) a cyano group,

(4.8) an amino group which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group,

(4.9) an amino-lower alkyl group (which may have a lower alkyl group (s) on the amino group),

(4.10) an amino-lower alkynyl group (which may have a lower alkyl group (s) on the amino group),

(4.11) a lower alkoxycarbonyl group,.

(4.12) a hydroxy-lower alkyl group,

(4.13) a lower alkoxy-lower alkyl group,

(4.14) a tri (lower alkyl) silyloxy-lower alkyl group,

(4.15) a lower alkylsulfonyl group which may have a naphthyl group (s),

(4.16) a phenyl group,

(4.17) a pyrrolidinyl group,

(4.18) a piperidinyl group,

(4.19) a morpholinyl group, or

(4.20) a pyridazinyl group which may have a lower alkyl group (s) , or

R ³ and R ⁴ may be bonded together to form a lower alkylenedioxy group or -CH=CH-CH=CH-; R ⁵ represents a hydrogen atom or a halogen atom; R ⁶ represents

(6.1) a phenyl group which may have a group selected from the group consisting of a halogen atom; a lower alkyl group; a halogen-substituted lower alkyl group; a lower alkylthio group; a lower alkoxy group; a halogen- substituted lower alkoxy group; a hydroxy group; an amino group which may have a lower alkyl group; an aminosulfonyl group which may have a lower alkyl group; a cyano group; a phenyl group; a pyrrolidinyl group which may have an oxo group; an imidazolyl group; an oxazolyl group; and a thiazolyl group which may have a lower alkyl group,

(6.2) a dihydroindenyl group which may have an oxo group (S) ,

(6.3) a naphthyl group which may have a group (s) selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group,

and a lower alkylthio group,

(6.4) a fluorenyl group,

(6.5) a pyridyl group which may have a group (s) selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,

(6.6) a pyridazinyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a phenyl group,

(6.7) a pyrimidinyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.8) a pyrazinyl group which may have a lower alkyl group (s) ,

(6.9) an indolyl group which may have a group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a tri-lower alkylsilyl group, a lower alkoxy group, a cyano group, a lower alkoxycarbonyl group, a halogen-substituted lower alkyl group and a phenylsulfonyl group (which may have a lower alkyl group (s) on the phenyl group(s)),

(6.10) an indazolyl group which may have a group (s) selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom and a tri-lower alkylsilyl group

(6.11) an indolinyl group which may have a lower alkanoyl group (s),

(6.12) a quinolyl group which may have a group (s)

selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkoxy group,

(6.13) a dihydroquinolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and an oxo group,

(6.14) a tetrahydroquinolyl group which may have a group (s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkoxy group, and a phenyl-lower alkyl group (which may have a lower alkoxy group (s) on the phenyl group),

(6.15) an isoquinolyl group,

(6.16) a quinoxalinyl group which may have a phenyl group (s) ,

(6.17) a pyrazolopyridyl group,

(6.18) a benzofuryl group,

(6.19) a dihydrobenzofuryl group,

(6.20) a benzodioxolyl group,

(6.21) a dihydrobenzodioxinyl group,

(6.22) a benzodioxinyl group,

(6.23) a dihydrobenzodioxepinyl group,

(6.24) a thienyl group which may have a lower alkyl group (s) ,

(6.25) a benzothienyl group which may have a group (s) selected from the group consisting of a halogen atom and a lower alkyl group,

(6.26) a dihydrobenz [b] [1, 4] oxazinyl group which may have a group (s) selected from the group consisting of

an oxo group, a lower alkyl group, and a lower alkoxy group,

(6.27) a thiazolyl group,

(6.28) a benzothiazolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group,

(6.29) a thienopyridyl group,

(6.30) a thienopyrimidinyl group,

(6.31) a carbazolyl group (which may have a lower alkyl group(s) on the carbazolyl group), or,

(6.32) a tetrahydrocyclopenta [b] indolyl group which may have a group (s) selected from the group consisting of a lower alkyl group and a tri-lower alkylsilyl group: and R ⁷ represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy-lower alkyl group, a phenyl- lower alkyl group, or a tri (lower alkyl) silyloxy-lower alkyl group.

[0015] Item 2.

A benzodiazepine compound represented by the general formula (1) or a salt thereof according to item 1: wherein R ¹ represents

(1.1) a hydrogen atom,

(1.2) a lower alkyl group,

(1.3) a lower alkenyl group,

(1.4) a hydroxy-lower alkyl group,

(1.5) a cyclo-lower alkyl-substituted lower alkyl

group,

(1.6) a cyclo-lower alkenyl-substituted lower alkyl group,

(1.7) a bicyclo [2.2.1] heptenyl-lower alkyl group,

(1.8) a phenyl-lower alkyl group (which may have 1 hydroxy group on the phenyl group) ,

(1.9) a pyrrolyl-lower alkyl group (which may have 1 lower alkyl group on the pyrrolyl group) ,

(1.10) a pyrazolyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the pyrazolyl group) ,

(1.11) an imidazolyl-lower alkyl group (which may have 1 lower alkyl group on the imidazolyl group) ,

(1.12) a pyridyl-lower alkyl group (which may have 1 lower alkyl group on the pyridyl group) ,

(1.13) an indolyl-lower alkyl group (which may have 1 group selected from the group consisting of a lower alkyl group and a lower alkanoyl group on the indolyl group) ,

(1.14) an indazolyl-lower alkyl group (which may have 1 lower alkyl group on the indazolyl group) ,

(1.15) a benzimidazolyl-lower alkyl group (which may have 1 lower alkyl group on the benzimidazolyl group) ,

(1.16) a tetrahydropyranyl-lower alkyl group,

(1.17) a furyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a halogen-substituted lower alkyl group

on the furyl group) ,

(1.18) a thienyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a halogen atom and a lower alkyl group on the thienyl group) ,

(1.19) an imidazo [1, 2-b]pyridyl-lower alkyl group,

(1.20) an oxazolyl-lower alkyl group (which may have 1 to 2 lower alkyl group (s) on the oxazolyl group),

(1.21) a furo [2, 3-c]pyridyl-lower alkyl group,

(1.22) a thiazolyl-lower alkyl group (which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a lower alkoxy group on the thiazolyl group) ,

(1.23) a thieno [3, 2-c] pyridyl-lower alkyl group,

(1.24) an imidazo [2, 1-b] thiazolyl-lower alkyl group, or

(1.25) a furyl-lower alkenyl group;

R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group; R ³ represents

(3.1) a hydrogen atom,

(3.2) a halogen atom,

(3.3) a cyano group,

(3.4) a hydroxy group,

(3.5) a lower alkyl group,

(3.6) a lower alkoxy group,

(3.7) a lower alkoxy-lower alkoxy group,

(3.8) a hydroxy-lower alkyl group,

(3.9) a lower alkylthio group,

(3.10) a lower alkoxycarbonyl group,

(3.11) a tri (lower alkyl) silyloxy-lower alkyl group,

(3.12) an amino group which may have 1 to 2 lower alkyl group (s) ,

(3.13) a phenyl group which may have 1 group selected from the group consisting of a lower alkoxy group, a nitro group, and an amino group,

(3.14) a piperazinyl group which may have 1 lower alkyl group,

(3.15) an imidazolyl group,

(3.16) a pyrazolyl group,

(3.17) a 1,2, 4-triazolyl group,

(3.18) a pyridyl group,

(3.19) a pyridazinyl group which may have 1 lower alkyl group,

(3.20) a pyrimidinyl group, or

(3.21) a pyrazinyl group; R ⁴ represents

(4.1) a hydrogen atom,

(4.2) a halogen atom,

(4.3) a lower alkyl group,

(4.4) a halogen-substituted lower alkyl group,

(4.5) a lower alkoxy group,

(4.6) a lower alkynyl group,

(4.7) a cyano group,

(4.8) an amino group which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group,

(4.9) an amino-lower alkyl group (which may have 1 to 2 lower alkyl group (s) on the amino group),

(4.10) an amino-lower alkynyl group (which may have 1 to 2 lower alkyl group (s) on the amino group),

(4.11) a lower alkoxycarbonyl group,

(4.12) a hydroxy-lower alkyl group,

(4.13) a lower alkoxy-lower alkyl group,

(4.14) a tri (lower alkyl) silyloxy-lower alkyl group,

(4.15) a lower alkylsulfonyl group which may have 1 to 2 naphthyl group (s),

(4.16) a phenyl group,

(4.17) a pyrrolidinyl group,

(4.18) a piperidinyl group,

(4.19) a morpholinyl group, or

(4.20) a pyridazinyl group which may have 1 lower alkyl group, or

R ³ and R ⁴ may be bonded together to form a lower alkylenedioxy group or -CH=CH-CH=CH-; R ⁵ represents a hydrogen atom or a halogen atom; R ⁶ represents

(6.1) a phenyl group which may have 1 to 3 group (s) selected from the group consisting of a halogen atom; a lower alkyl group; a halogen-substituted lower alkyl group; a lower alkylthio group; a lower alkoxy group; a halogen-substituted lower alkoxy group; a hydroxy group; an amino group which may have 1 to 2 lower alkyl group (s); an aminosulfonyl group which may have 1 to 2 lower alkyl group (s); a cyano group; a phenyl group; a

pyrrolidinyl group which may have 1 oxo group; an imidazolyl group; an oxazolyl group; and a thiazolyl group which may have 1 lower alkyl group,

(6.2) a 2, 3-dihydroindenyl group which may have 1 oxo group,

(6.3) a naphthyl group which may have 1 group selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.4) a fluorenyl group,

(6.5) a pyridyl group which may have 1 to 2 group(s) selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group,

(6.6) a pyridazinyl group which may have 1 group selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a phenyl group,

(6.7) a pyrimidinyl group which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio group,

(6.8) a pyrazinyl group which may have 1 to 2 lower alkyl group (s) ,

(6.9) an indolyl group which may have 1 to 3 group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a tri-lower alkylsilyl group, a lower alkoxy group, a cyano group , a lower alkoxy- carbonyl group, a halogen-substituted lower alkyl group and a phenylsulfonyl group (which may have 1 lower

alkyl group on the phenyl group) ,

(6.10) an indazolyl group which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom and a tri-lower alkylsilyl group

(6.11) an indolinyl group which may have 1 lower alkanoyl group,

(6.12) a quinolyl group which may have 1 to 2 group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkoxy group,

(6.13) a dihydroquinolyl group which may have 1 to 2 group (s) selected from the group consisting of a lower alkyl group and an oxo group,

(6.14) a tetrahydroquinolyl group which may have 1 to 3 group (s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkoxy group, and a phenyl-lower alkyl group (which may have 1 lower alkoxy group on the phenyl group) ,

(6.15) an isoquinolyl group,

(6.16) a quinoxalinyl group which may have 1 phenyl group,

(6.17) a pyrazolo [3, 4-b] pyridyl group,

(6.18) a benzofuryl group,

(6.19) a 2, 3-dihydrobenzofuryl group,

(6.20) a benzo [d] [1, 3] dioxolyl group,

(6.21) a 2, 3-dihydrobenzo[b] [1, 4]dioxinyl group,

(6.22) a 4H-benzo[d] [1, 3] dioxinyl group,

(6.23) a 3, 4-dihydro-2H-benzo [b] [1, 4] dioxepinyl group,

(6.24) a thienyl group which may have 1 lower alkyl group,

(6.25) a benzothienyl group which may have 1 group selected from the group consisting of a halogen atom and a lower alkyl group,

(6.26) a 3, 4-dihydro-2H-benz [b] [1, 4]oxazinyl group which may have 1 to 3 group (s) selected from the group consisting of an oxo group, a lower alkyl group, and a lower alkoxy group,

(6.27) a thiazolyl group,

(6.28) a benzothiazolyl group which may have 1 group selected from the group consisting of a lower alkyl group and a lower alkoxy group,

(6.29) a thieno[3, 2-b]pyridyl group or a thieno[2,3- b]pyridyl group,

(6.30) a thieno [3, 2-d] pyrimidinyl group,

(6.31) a carbazolyl group (which may have 1 lower alkyl group on the carbazolyl group) , or,

(6.32) a tetrahydrocyclopenta [b] indolyl group which may have 1 group selected from the group consisting of a lower alkyl group and a tri-lower alkylsilyl group: and R ⁷ represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy-lower alkyl group, a phenyl- lower alkyl group, or a tri (lower alkyl) silyloxy-lower alkyl group.

[0016] Item 3.

A benzodiazepine compound represented by the general formula (1) or a salt thereof according to item

2, wherein

R ³ and R ⁴ are bonded together to form a lower alkylenedioxy group [0017] Item 4.

A benzodiazepine compound represented by the general formula (1) or a salt thereof according to item

3, wherein R ¹ is

(1.2) a lower alkyl

R ² is a hydrogen atom or a halogen atom,

R ⁵ is a hydrogen atom,

R ⁶ is

(6.1) a phenyl group which may have 1 to 2 group (s) selected from the group consisting of a halogen atom and a lower alkoxy group

(6.3) a naphthyl group which may have 1 group selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group,

(6.9) an indolyl group which may have 1 to 3 group (s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group , a lower alkoxycarbonyl group, a halogen- substituted lower alkyl group and a tri-lower alkylsilyl group,

(6.10) an indazolyl group which may have 1 to 2

group (s) selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, a halogen atom and a tri-lower alkylsilyl group

(6.18) a benzofuryl group,

(6.20) a benzo [d] [1, 3] dioxolyl group,

(6.25) a benzothienyl group

(6.31) a carbazolyl group which may have 1 lower alkyl group on the carbazolyl group, or

(6.32) a tetrahydrocyclopenta[b] indolyl group which may have 1 group selected from the group consisting of lower alkyl group and a tri-lower alkylsilyl group [0018]

Item 5.

A pharmaceutical composition comprising a benzodiazepine compound of general formula (1) or a salt thereof according to item 1 as an active ingredient and a pharmaceutically acceptable carrier. [0019] Item 6.

A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a benzodiazepine compound of General Formula (1) or a salt thereof according to item 1. [0020] Item 7.

A prophylactic and/or therapeutic agent according to item 6, wherein the disorder is selected

from the group consisting of hypertension; depression; anxiety disorders; phobia; post-traumatic stress disorder; acute stress syndrome; avoidant personality disorder; body dysmorphic disorder; premature ejaculation; eating disorders; obesity; chemical dependence to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines; cluster headache; migraine; pain; Alzheimer disease; obsessive compulsive disorder; panic disorder; memory disorders; Parkinson's disease; endocrine disorders; vasospasm; cerebellar ataxia; gastrointestinal disorders; negative syndromes in schizophrenia; premenstrual syndrome; fibromyalgia syndrome; stress incontinence; Tourette syndrome; trichotillomania; kleptomania; male impotence; attention-deficit hyperactivity disorder (ADHD) ; chronic paroxysmal hemicrania; chronic fatigue; cataplexy; sleep apnea syndrome and headache. [0021] Item 8.

A prophylactic and/or therapeutic agent according to item 6, wherein the disorder is selected from the group consisting of: depression selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed episode; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; minor depression; recurrent brief depressive disorder; intractable depression/chronic depression; double

depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing's disease, hypothyroidism, hyperparathyroidism syndrome, Addison's disease, amenorrhea and lactation syndrome, Parkinson's disease, Alzheimer's disease, intracerebral bleeding, diabetes, chronic fatigue syndrome and cancer; presenile depression; senile depression; depression in children and adolescents; depression induced by medicines such as interferon; and depression caused by adjustment disorder) ; and anxiety disorder selected from the group consisting of anxiety caused by adjustment disorder and anxiety caused by nerve disorder selected from the group consisting of head injury, brain infection, and inner ear disorder. [0022] Item 9.

Use of a benzodiazepine compound of General Formula (1) or a salt thereof according to any one of items 1 to 4 as a drug. [0023] Item 10.

Use of a benzodiazepine compound of General Formula (1) or a salt thereof according to any one of items 1 to 4 as a serotonin reuptake inhibitor and/or a norepinephrine reuptake inhibitor and/or a dopamine reuptake inhibitor. [0024]

Item 11 .

A method for treating or preventing disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising administering a benzodiazepine compound of General Formula (1) or a salt thereof according to any one of items 1 to 4 to human or animal. [0025] Item 12.

A process for producing a benzodiazepine compound represented by General Formula (1) :

or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are defined as above in item 1, by reacting the compound represented by the general formula (3)

(3)

wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are defined as above in item 1 with the compound represented by the general

formula (4)

R ⁶ X ₁

(4)

wherein R ¹ and Xi are defined as above in item 1. [0026]

Preferable examples or embodiments of various definitions incorporated in the scope of the present invention described herein will be explained below in detail. [0027]

Examples of a lower alkyl group can include linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1, 2, 2-trimethylpropyl, 3, 3-dimethylbutyl, 2-ethylbutyl, isohexyl, and 3- methylpentyl groups, etc. [0028]

Examples of a lower alkenyl group can include linear or branched alkenyl groups having 1 to 3 double bonds and 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms) , unless otherwise specified, and the lower alkenyl group encompasses both trans and cis forms. More specifically, it includes vinyl, 1-propenyl, 2- propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1- methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-

butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 2-penten- 4-yl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 3, 3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1, 3, 5-hexatrienyl, 1, 3-hexadienyl, and 1, 4-hexadienyl groups, etc.

[0029]

Examples of a hydroxy-lower alkyl group can include the lower alkyl groups exemplified above

(preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) which have 1 to 5, preferably 1 to 3 hydroxy groups, unless otherwise specified. More specifically, it includes hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 1-hydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, 2, 3-dihydroxypropyl, 4-hydroxybutyl, 3, 4-dihydroxybutyl, 1, l-dimethyl-2-hydroxyethyl, 5- hydroxypentyl, 6-hydroxyhexyl, 3, 3-dimethyl-3- hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4- trihydroxybutyl, and perhydroxyhexyl groups, etc.

[0030]

A hydroxy-lower alkyl group encompasses those having hydroxy group (s) protected with a protecting group. Examples of the protecting group in the hydroxy-lower alkyl group can include linear or branched alkyl groups having 1 to 6 carbon atoms

(preferably 1 to 4 carbon atoms) , lower alkanoyl groups

(preferably, linear or branched alkanoyl groups having

1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) , and phenyl-lower alkyl groups whose lower alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) , unless otherwise specified. [0031]

Examples of a protected hydroxy-lower alkyl group can include the lower alkyl groups exemplified above which have protected hydroxy group (s) (preferably, the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) which have 1 to 5, preferably 1 to 3 lower alkoxy groups, lower alkanoyloxy groups, or phenyl- lower alkoxy groups (which may have 1 to 3 (preferably 1) substituents such as halogen atoms on the phenyl group) , unless otherwise specified. More specifically, it includes methoxymethyl, 2-methoxyethyl, 2- ethoxyethyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n- butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 2- sec-butoxyethyl, 2-n-pentyloxyethyl, 2- isopentyloxyethyl, 2-neopentyloxyethyl, 2-n- hexyloxyethyl, 2-isohexyloxyethyl, 2- (3- methylpentyloxy) ethyl, 2-formyloxyethyl, 2- acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-isobutyryloxyethyl, 2-pentanoyloxyethyl, 2-tert- butylcarbonyloxyethyl, 2-hexanoyloxyethyl, 2- benzyloxyethyl, 2- (2-phenylethoxy) ethyl, 2-(l-

phenylethoxy) ethyl, 2- (3-phenylpropoxy) ethyl, 2- (4- phenylbutoxy) ethyl, 2- (5-phenylpentyloxy) ethyl, 2- (6- phenylhexyloxy) ethyl, 2- (1, l-dimethyl-2- phenylethoxy) ethyl, 2- (2-methyl-3-phenylpropoxy) ethyl, 3-ethoxypropyl, 2, 3-diethoxypropyl, 4-ethoxybutyl, 3,4- diethoxybutyl, 1, l-dimethyl-2-ethoxyethyl, 5- ethoxypentyl, 6-ethoxyhexyl, 3, 3-dimethyl-3- ethoxypropyl, 2-methyl-3-ethoxypropyl, and 2,3,4- triethoxybutyl groups, etc.

Examples of a cyclo-lower alkyl group can include cycloalkyl groups having 3 to 8 carbon atoms (cyclo-C3-C8 alkyl groups) , unless otherwise specified. Examples of the cyclo-C3-C8 alkyl groups can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc. [0032]

Examples of a cyclo-lower alkyl-substituted lower alkyl group can include lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) and _, which are substituted by one of the cyclo-C3-C8 alkyl groups exemplified above, unless otherwise specified. More specific examples thereof can include cyclopropylmethyl, cycloheptylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 1-cyclobutylethyl, 3-cyclopentylpropyl, 4-cycloheptylbutyl, 5- cyclooctylpentyl, 6-cyclohexylhexyl, 3-

cyclopropylpropyl, and 4-cyclohexylbutyl groups, etc. [0033]

Examples of a cyclo-lower alkenyl group can include cycloalkenyl groups having 3 to 8 carbon atoms (cyclo-C3-C8 alkenyl groups) , unless otherwise specified. Examples of the cyclo-C3-C8 alkenyl groups can include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl groups, etc. [0034]

Examples of a cyclo-lower alkenyl-substituted lower alkyl group can include lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) and which are substituted by one of the cyclo-C3-C8 alkenyl groups exemplified above, unless otherwise specified. More specific examples thereof can include cyclopropenylmethyl, cyclohexenylmethyl, 2-cyclohexenylethyl, 1- cyclobutenylethyl, 3-cyclopentenylpropyl, 4- cycloheptenylbutyl, 5-cyclooctenylpentyl, 6- cyclohexenylhexyl, 3-cyclopropenylpropyl, and 4- cyclohexenylbutyl groups, etc. [0035]

Examples of a bicyclo [2.2.1] heptenyl-lower alkyl group can include the lower alkyl groups exemplified above (preferably, linear or branched alkyl

groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) which have 1 to 3 (more preferably 1) bicyclo [2.2.1] heptenyl groups. More specific examples thereof can include bicyclo [2.2.1] heptenylmethyl, 2- bicyclo [2.2.1] heptenylethyl, 1- bicyclo [2.2.1] heptenylethyl, 3- bicyclo [2.2.1] heptenylpropyl, and 4- bicyclo [2.2.1] heptenylbutyl groups, etc. [0036]

Examples of a phenyl-lower alkyl group can include the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) which have 1 to 3 (more preferably 1) phenyl groups, unless otherwise specified. More specific examples thereof include benzyl, phenethyl, 3- phenylpropyl, benzhydryl, trityl, 4-phenylbutyl, 5- phenylpentyl, and 6-phenylhexyl groups. [0037]

Examples of a pyrrolyl-lower alkyl group can include pyrrolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 2- or 3-) pyrrolylmethyl, 1- (or 2- or 3-){l- (or 2- or 3-)pyrrolyl}ethyl, and 1- (or 2- or 3-){l- (or 2- or 3- ) pyrrolyl }propyl groups, etc.

[ 0038 ]

Examples of a pyrazolyl-lower alkyl group can include pyrazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 3- or 4-) pyrazolylmethyl, 1- (or 2-){l- (or 3- or A- )pyrazolyl} ethyl, and 1- (or 2- or 3-){l- (or 3- or A- ) pyrazolyl} propyl groups, etc. [0039]

Examples of an imidazolyl-lower alkyl group can include imidazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 2-, A-, or 5-) imidazolylmethyl, 1- (or 2-){l- (or 2-, A-, or 5-) imidazolyl} ethyl, and 1- (or 2- or 3-){l- (or 2-, A-, or 5-) imidazolyl} propyl groups, etc. [0040]

Examples of a pyridyl-lower alkyl group can include pyridyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3- or 4-)pyridylmethyl, 1- (or 2-) {2- (or 3- or 4-

)pyridyl} ethyl, and 1- (or 2- or 3-) {2- (or 3- or 4- )pyridyl}propyl groups, etc. [0041]

Examples of an indolyl-lower alkyl group can include indolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 2-, 3-, 4-, 5-, 6-, or 7-) indolylmethyl, 1- (or 2-){l- (or 2-, 3-, 4-, 5-, 6-, or 7-) indolyl} ethyl, and 1- (or 2- or 3-){l- (or 2-, 3-, 4-, 5-, 6-, or 7- ) indolyl } propyl groups, etc. [0042]

Examples of a lower alkanoyl group can include linear or branched alkanoyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) , unless otherwise specified. More specifically, it includes formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups, etc. [0043]

Examples of an indazolyl-lower alkyl group can include indazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) . More specifically, it includes 1-

(or 2-, 3-, A-, 5-, 6-, or 7-) indazolylmethyl, 1- (or 2-){l- (or 2-, 3-, A-, 5-, 6-, or 7-) indazolyl} ethyl, and 1- (or 2- or 3-){l- (or 2-, 3-, 4-, 5-, 6-, or 7- ) indazolyl }propyl groups, etc.

Examples of a benzimidazolyl-lower alkyl groups can include benzimidazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 2-, A-, 5-, 6-, or 7- ) benzimidazolylmethyl, 1- (or 2-){l- (or 2-, A-, 5-, 6- , or 7-) benzimidazolyl}ethyl, and 1- (or 2- or 3-){l- (or 2-, A-, 5-, 6-, or 7-)benzimidazolyl}propyl groups, etc. [0044]

Examples of a tetrahydropyranyl-lower alkyl group can include tetrahydropyranyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3- or 4-) tetrahydropyranylmethyl, 1- (or 2-) {2- (or 3- or 4-) tetrahydropyranyl} ethyl, and 1- (or 2- or 3-) {2- (or 3- or 4-) tetrahydropyranyl} propyl groups, etc. [0045]

Examples of a furyl-lower alkyl group can

include furyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3-) furylmethyl, 1- (or 2-) {2- (or 3-) furyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-) furyl}propyl groups, etc. [0046]

Examples of a thienyl-lower alkyl group can include thienyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3-) thienylmethyl, 1- (or 2-) {2- (or 3-) thienyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-) thienyl }propyl groups, etc. [0047]

Examples of an imidazopyridyl-lower alkyl group can include imidazopyridyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3-, 5-, 6-, 7-, or 8- ) imidazopyridylmethyl, 1- (or 2-) {2- (or 3-, 5-, 6-, 7- , or 8-) imidazopyridyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-, 5-, 6-, 7-, or 8-) imidazopyridyl} propyl groups,

etc .

[ 0048 ]

Examples of an oxazolyl-lower alkyl group can include oxazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 1- (or 2-, 4-, or 5-)oxazolylmethyl, 1- (or 2-){l- (or 2-, 4-, or 5-)oxazolyl}ethyl, and 1- (or 2- or 3-){l- (or 2-, 4-, or 5-)oxazolyl}propyl groups, etc.

[0049]

Examples of a furopyridyl-lower alkyl group can include furopyridyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2-

(or 3-, 4-, 5-, or 7-) furopyridylmethyl, 1- (or 2-) {2-

(or 3-, 4-, 5-, or 7-) furopyridyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-, 4-, 5-, or 7-) }furopyridyl }propyl groups, etc.

[0050]

Examples of a thiazolyl-lower alkyl group can include thiazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4

carbon atoms) ) . More specifically, it includes 1- (or 2-, A-, or 5-) thiazolylmethyl, 1- (or 2-){l- (or 2-, A- , or 5-)thiazolyl}ethyl, and 1- (or 2- or 3-){l- (or 2- , A-, or 5-) thiazolyl}propyl groups, etc. [0051]

Examples of a thienopyridyl-lower alkyl group can include thienopyridyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3-, 4-, 6-, or 7-) thienopyridylmethyl, 1- (or 2- ){2- (or 3-, A-, 6-, or 7-) thienopyridyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-, A-, 6-, or 7- ) } thienopyridyl} propyl groups, etc. [0052]

Examples of an imidazothiazolyl-lower alkyl group can include imidazothiazolyl-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) . More specifically, it includes 2- (or 3-, 5-, or 6-

) imidazothiazolylmethyl, 1- (or 2-) {2- (or 3-, 5-, or 6-) imidazothiazolyl} ethyl, and 1- (or 2- or 3-) {2- (or 3-, 5-, or 6-) imidazothiazolyl Jpropyl groups, etc. [0053]

Examples of a furyl-lower alkenyl group can

include furyl-lower alkenyl groups whose lower alkenyl moiety is any of the lower alkenyl groups exemplified above (preferably, linear or branched alkenyl groups having 2 to 6 carbon atoms (more preferably 2 to 4 carbon atoms)) . More specifically, it includes 1- (or 2-) {2- (or 3-)furyl}vinyl, 1- (or 2- or 3-) {2- (or 3- )furyl}-1- (or 2-)propenyl, 1- (or 2-, 3-, or 4-) {2- (or 3-)furyl}-1- (or 2- or 3-)butenyl, and 1- (or 2-, 3-, A-, or 5-) {2- (or 3-)furyl}-1- (or 2-, 3-, or 4- ) pentenyl groups, etc. [0054]

Examples of a halogen atom include fluorine, chlorine, bromine, and iodine atoms, unless otherwise specified. [0055]

Examples of a lower alkoxy group can include linear or branched alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) , unless otherwise specified. More specifically, it includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy groups, etc. [0056]

Examples of a protecting group for the hydroxy group can include lower alkyl groups (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon

atoms) ) , lower alkanoyl groups (preferably, linear or branched alkanoyl groups having 1 to 6 carbon atoms

(more preferably 1 to 4 carbon atoms) ) , and phenyl- lower alkyl groups whose lower alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms

(preferably 1 to 4 carbon atoms) and which may have 1 to 3 (preferably 1) substituents such as halogen atoms on the phenyl group, unless otherwise specified.

[0057]

Examples of a protected hydroxy group can include the lower alkoxy groups exemplified above, lower alkanoyloxy groups whose lower alkanoyl moiety is any of the lower alkanoyl groups exemplified above, and phenyl-lower alkoxy groups whose lower alkoxy moiety is any of the lower alkoxy groups exemplified above (which may have 1 to 3 (preferably 1) substituents such as halogen atoms on the phenyl group) , unless otherwise specified. More specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3- methylpentyloxy, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert- butylcarbonyloxy, hexanoyloxy, benzyloxy, 4- chlorobenzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3- phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6- phenylhexyloxy, 1, l-dimethyl-2-phenylethoxy, and 2- methyl-3-phenylpropoxy groups, etc.

[ 0058 ]

Examples of a lower alkoxy-lower alkoxy group can include the lower alkoxy groups exemplified above (preferably, linear or branched alkoxy groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) which have 1 to 3, preferably 1, of the lower alkoxy groups exemplified above (preferably, linear or branched alkoxy groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), unless otherwise specified. More specifically, it includes methoxymethoxy, 2-methoxyethoxy, 1-ethoxyethoxy, 2- ethoxyethoxy, 2-isobutoxyethoxy, 2, 2-dimethoxyethoxy, 2-methoxy-1-methylethoxy, 2-methoxy-1-ethylethoxy, 3- methoxypropoxy, 3-ethoxypropoxy, 2-isopropoxyethoxy, 3- isopropoxypropoxy, 3-n-butoxypropoxy, 4-n- propoxybutoxy, l-methyl-3-isobutoxypropoxy, 1,1- dimethyl-2-n-pentyloxyethoxy, 5-n-hexyloxypentoxy, and 1-ethoxyisopropoxy groups, etc. [0059]

Examples of a lower alkylthio group can include linear or branched alkylthio groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) , unless otherwise specified. More specifically, it includes methylthio, ethyl.thio, n-propylthio, isopropylthio, n- butylthio, tert-butylthio, n-pentylthio, and n- hexylthio groups, etc. [0060]

Examples of the lower alkoxycarbonyl group

can include alkoxycarbonyl groups whose lower alkoxy moiety is any of the lower alkoxy groups exemplified above (preferably, linear or branched alkoxy groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) , unless otherwise specified. More specifically, it includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, sec-butoxycarbonyl, n- pentyloxycarbonyl, neopentyloxycarbonyl, n- hexyloxycarbonyl, isohexyloxycarbonyl, and 3- methylpentyloxycarbonyl groups . [0061]

Examples of a tri (lower alkyl)silyl group can include tri (lower alkyl)silyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) , unless otherwise specified. More specifically, it includes trimethylsilyl, triethylsilyl, triisopropylsilyl, tri (n-butyl) silyl, and triisobutylsilyl groups, etc. [0062]

Examples of a tri (lower alkyl) silyloxy-lower alkyl group can include tri (lower alkyl) silyloxy-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon

atoms (more preferably 1 to 4 carbon atoms) ) , unless otherwise specified. More specifically, it includes trimethylsilyloxymethyl, 1- (or 2- ) trimethylsilyloxyethyl, 1- (or 2- or 3- ) trimethylsilyloxypropyl, triethylsilyloxymethyl, 1- (or 2-) triethylsilyloxyethyl, 1- (or 2- or 3- ) triethylsilyloxypropyl, triisopropylsilyloxymethyl, 1- (or 2-) triisopropylsilyloxyethyl, and 1- (or 2- or 3- ) triisopropylsilyloxypropyl groups, etc. [0063]

Examples of a halogen-substituted lower alkyl group can include the lower alkyl groups exemplified above which are substituted by 1 to 7 (more preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2, 2-difluoroethyl, 2, 2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3, 3, 3-trifluoropropyl, heptafluoropropyl, 2,2,3,3, 3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4, 4, 4-trifluorobutyl, 4,4,4,3,3- pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2- chlorobutyl, 5, 5, 5-trifluoropentyl, 5-chloropentyl, 6, 6, 6-trifluorohexyl, 6-chlorohexyl, and perfluorohexyl groups, etc. [0064]

Examples of a lower alkynyl group can include linear or branched alkynyl groups having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms) , unless otherwise specified. More specifically, it includes ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2- propynyl, 2-pentynyl, 2-hexynyl, and 3, 3-dimethyl-1- butynyl groups, etc. [0065]

Examples of an amino-lower alkyl group can include the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) which have 1 to 5 (preferably 1) amino groups, unless otherwise specified. More specific examples thereof include aminomethyl, 2-aminoethyl, 1- aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1, l-dimethyl-2-aminoethyl, 2-methyl-3- aminopropyl, N,N-dimethylaminomethyl, N-methyl-N- ethylaminomethyl, N-methylaminomethyl, 2-(N- methylamino) ethyl, l-methyl-2- (N, N-dimethylamino) ethyl, l-methyl-2- (N, N-diethylamino) ethyl, 2- (N, N- dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2- (N, N- diisopropylamino) ethyl, 3- (N, N-dimethylamino) propyl, and 3- (N, N-diethylamino) propyl groups, etc. [0066]

Examples of an amino-lower alkynyl group can include the lower alkynyl groups exemplified above (preferably, linear or branched alkynyl groups having 2

to 6 carbon atoms (more preferably 2 to 4 carbon atoms)) which have 1 to 5 (preferably 1) amino groups, unless otherwise specified. More specific examples thereof include 1-aminoethynyl, 2-aminoethynyl, 3- amino-1-propynyl, 3-amino-2-propynyl, 4-amino-1- butynyl, 4-amino-2-butynyl, and 4-amino-3-butynyl groups, etc.

[0067]

Examples of a lower alkylsulfonyl group can include alkylsulfonyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above

(preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) ) , unless otherwise specified. More specifically, it includes methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, and 3-methylpentylsulfonyl groups, etc.

[0068]

Examples of a halogen-substituted lower alkoxy group can include the lower alkoxy groups exemplified above which are substituted by 1 to 7

(preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy,

bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2, 2, 2-trifluoroethoxy, pentafluoroethoxy, 2- chloroethoxy, 3,3, 3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3- chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4- trifluorobutoxy, 4, 4, 4, 3, 3-pentafluorobutoxy, 4- chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5- trifluoropentoxy, 5-chloropentoxy, 6, 6, 6- trifluorohexyloxy, and 6-chlorohexyloxy groups, etc. [0069]

The benzodiazepine compound represented by the general formula (1) can be produced by various methods. As an example, the benzodiazepine compound represented by the general formula (1) is produced by methods represented by the reaction formulas shown below.

[Reaction Formula-1]

(2) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are defined as above; and Z represents -CH ₂ - or -C(=O)-.

[0071]

A compound represented by the general formula

(2) can be subjected to a reduction reaction to thereby

produce the compound represented by the general formula

(1).

[0072]

Reaction conditions for chemical reduction and catalytic reduction known in the art can be applied to the reduction reaction.

[0073]

Preferable reducing agents used in chemical reduction can be exemplified by the combinations of hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and diisopropyl aluminum hydride), metals (e.g., tin, zinc, and iron), or metal compounds (e.g., chromium chloride and chromium acetate) with organic or inorganic acids

(e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid) .

[0074]

Preferable catalysts used in catalytic reduction can be exemplified by catalysts known in the art which are used in reduction using usual catalysts, such as platinum catalysts (e.g., platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wires), palladium catalysts (e.g., palladium sponge, palladium black, palladium oxide, palladium-carbon, colloidal palladium, palladium-barium sulfate, and palladium-barium carbonate), nickel catalysts (e.g., reduced nickel,

nickel oxide, and Raney nickel) , cobalt catalysts

(e.g., reduced cobalt and Raney cobalt), iron catalysts

(e.g., reduced iron and Raney iron), and copper catalysts (e.g., reduced copper, Raney copper, and Ullmann copper) .

[0075]

The present reaction is usually performed in a commonly used solvent that does not adversely affect the reaction, for example: water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol; ethers such as acetone, diethyl ether, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, and 1, 2-dichloroethane; esters such as methyl acetate and ethyl acetate; acetonitrile, N,N-dimethylformamide, pyridine, or other organic solvents; and mixtures thereof.

[0076]

The reaction temperature of the reduction reaction is not particularly limited. The reaction is usually performed under temperature conditions involving cooling to heating temperatures, preferably room temperature to 100 ⁰ C, and generally completed in approximately 0.5 to 10 hours.

[Reaction Formula-2]

[0077]

[ 0078 ] wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are defined as above; and Xi represents a leaving group or a group - B (OR ⁹ ) 2 (wherein two R ⁹ moieties are the same or different and each represents a hydrogen atom or a lower alkyl group) .

In the general formula (4), the leaving group represented by Xi can be exemplified by halogen atoms, lower alkanesulfonyloxy groups, arylsulfonyloxy groups, aralkylsulfonyloxy groups, and trihalomethanesulfonyloxy groups. Preferable examples of the leaving groups for the present reaction include halogen atoms. [0079]

Examples of the halogen atoms represented by Xi include fluorine, chloride, bromine, and iodine atoms . [0080]

The lower alkanesulfonyloxy groups represented by Xi can be exemplified specifically by linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy, tert- butanesulfonyloxy, n-pentanesulfonyloxy, and n- hexanesulfonyloxy groups. [0081]

Examples of the arylsulfonyloxy groups

represented by X ₁ can include: phenylsulfonyloxy groups which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and naphthylsulfonyloxy groups. The phenylsulfonyloxy groups which may have the substituents can be exemplified specifically by phenylsulfonyloxy, 4- methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4- nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2- nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy groups. The naphthylsulfonyloxy groups can be exemplified specifically by α-naphthylsulfonyloxy and β-naphthylsulfonyloxy groups. [0082]

Examples of the aralkylsulfonyloxy groups represented by Xi can include: linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a phenyl group which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a naphthyl group. The alkanesulfonyloxy groups which are substituted by the

phenyl group can be exemplified specifically by benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4- phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2- methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4- methoxybenzylsulfonyloxy, and 3- chlorobenzylsulfonyloxy. The alkanesulfonyloxy groups which are substituted by the naphthyl group can be exemplified specifically by α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy groups, etc.

[0083]

The trihalomethanesulfonyloxy groups represented by Xi can be exemplified specifically by trifluoromethanesulfonyloxy groups .

[0084]

When a compound of the general formula (4) wherein Xi represents a leaving group is used as a starting material, the compound represented by the general formula (1) is produced by the following method:

A compound represented by the general formula

(3) and the compound represented by the general formula

(4) can be reacted under a catalyst comprising tertiary phosphine and a palladium compound in the presence or absence of a basic compound without or in an inert solvent to thereby produce the compound represented by the general formula (1) .

[0085]

Examples of the inert solvent can include

commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them. [0086]

Basic compounds known in the art can be used widely. Examples thereof can include: 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, and lithium ^" carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metals such as sodium and potassium; other inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert- butoxide, sodium tert-butoxide, and potassium tert- butoxide; and other organic bases such as

triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1, 5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1, 4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds are used alone or as a mixture of two or more of them. [0087]

More preferable examples of the basic compound used in the present invention include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. [0088]

The palladium compound used in the present invention is not particularly limited. Examples thereof include: tetravalent palladium compounds such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium compounds such as palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichlorobis (benzonitrile) palladium (II) , dichlorobis (acetonitrile) palladium (II) , dichlorobis (triphenylphosphine) palladium (II) , dichlorotetraammine palladium (II), dichloro (cycloocta-

1, 5-diene) palladium (II), and palladium (II) trifluoroacetate; and zerovalent palladium compounds such as tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0) -chloroform complex, and tetrakis (triphenylphosphine) palladium (0) . These palladium compounds are used alone or as a mixture of two or more of them. [0089]

In the present invention, the amount of the palladium compound used is not particularly limited and usually ranges from 0.000001 to 20% by mol in terms of palladium with respect to 1 mol of the compound of the general formula (3) . When the palladium compound is used within this range, the compound of the general formula (1) can be synthesized with high selectivity. More preferably, the amount of the palladium compound used ranges from 0.0001 to 5% by mol in terms of palladium with respect to 1 mol of the compound of the general formula (3) for further improving activity and because the palladium compound used is expensive. [0090]

In the present invention, the tertiary phosphine used in combination with the palladium compound is not particularly limited. Examples thereof include: trialkylphosphines such as triethylphosphine, tri-cyclohexylphosphine, tri-isopropylphosphine, tri-n- butylphosphine, tri-isobutylphosphine, tri-sec- butylphosphine, and tri-tert-butylphosphine;

triarylphosphines such as triphenylphosphine, tri- pentafluorophenylphosphine, tri-o-tolylphosphine, tri- m-tolylphosphine, and tri-p-tolylphosphine; and phenoxyphosphines such as tri (2, 6- dimethylphenoxy) phosphine, tri (2-tert- butylphenoxy) phosphine, triphenoxyphosphine, tri (4- methylphenoxy) phosphine, and tri (2- methylphenoxy) phosphine. More preferably, the tertiary phosphine is specifically exemplified by tri-tert- butylphosphine. These tertiary phosphines are used alone or as a mixture of two or more of them. [0091]

Furthermore, in the present invention, the tertiary phosphine may be prepared in a complex form in advance and added thereto. Examples of the complex can include 2,2' -bis (diphenylphosphino) -1,1' -binaphthyl (racemic body), (R) -(+) -2, 2 ' -bis (diphenylphosphino) - 1,1' -binaphthyl, (S) - ( + ) -2, 2 ' -bis (diphenylphosphino) - 1, 1 ' -binaphthyl, and tri (tert-butyl) phosphonium tetraphenylborate . [0092]

In the present invention, the amount of the tertiary phosphine used may usually range from 0.01 to 10000 mol with respect to 1 mol of the palladium compound. When the amount of the tertiary phosphine used falls within this range, selectivity to the compound of the general formula (1) does not change. More preferably, the amount of the tertiary phosphine

used ranges from 0.1 to 10 mol with respect to 1 mol of the palladium compound for further improving activity and because the tertiary phosphine used is expensive. [0093]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0094]

The reaction is usually performed under temperature conditions involving room temperature to 200 ⁰ C, preferably room temperature to 150 ⁰ C, and generally completed in approximately 1 to 30 hours. [0095]

After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of interest. [0096]

Alternatively, the compound represented by the general formula (3) and the compound represented by the general formula (4) can be reacted in the presence of a copper catalyst and a ligand compound in the presence or absence of a basic compound without or in an inert solvent to thereby produce the compound represented by the general formula (1) . [0097]

Examples of the inert solvent include commonly used solvents that do not adversely affect the

reaction. Preferably, dioxane, N,N-dimethylformamide, pyridine, tetrahydrofuran, and the like can be used. Dioxane is particularly preferable.

Preferable examples of the basic compound include the basic compounds described above. Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate are particularly preferable.

Preferable examples of the copper catalyst include copper halides such as copper iodide. [0098]

Preferable examples of the ligand compound include trans-N, N-dimethyl-1, 2-cyclohexanediamine, ethylenediamine, N, N' -dimethylethylenediamine, 1,3- diaminopropane, and trans-1, 2-diaminocyclohexane.

The reaction temperature is not particularly limited. The reaction is usually performed at room temperature to heating temperature. Preferably, the reaction may be performed at room temperature to 150 ⁰ C for approximately 0.5 to 48 hours.

When a compound of the general formula (4) wherein Xi represents a group -B (OR ⁹ ) 2 is used as a starting material, the compound represented by the general formula (1) is produced by the following method:

The compound represented by the general formula (3) and the compound represented by the general formula (4) can be reacted in the presence of a copper

catalyst and a molecular sieve in the presence or absence of a basic compound without or in an inert solvent to thereby produce the compound represented by the general formula (1) . [0099]

Examples of the inert solvent include commonly used solvents that do not adversely affect the reaction. Preferable examples thereof can include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; amides such as dimethylformamide, dimethylacetamide, and N- methylpyrrolidone; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1 , 2-dichloroethane . [0100]

Examples of the basic compound include the basic compounds described above. Preferably, organic bases such as pyridine, triethylamine, tributylamine, and N-ethyldiisopropylamine are used. The amount of the basic compound used in the present reaction is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (3) . [0101]

Preferable examples of the copper catalyst can include copper (II) acetate and copper (II) chloride.

[ 0102 ]

The reaction temperature is not particularly limited. The reaction is usually performed under temperature conditions involving cooling to heating temperatures, preferably -10 to 150 ⁰ C, more preferably room temperature to 100 ⁰ C, and generally completed in approximately 0.5 to 10 hours.

[0103]

In each reaction in the Reaction Formula-2, the compound of the general formula (4) is usually used in an amount of at least 0.5 mol, preferably 0.5 to 5 mol, with respect to 1 mol of the compound of the general formula (3) .

[0104]

The compound of the general formula (2) and the compound of the general formula (3) used as starting materials in the Reaction Formulas-1 and -2 are produced from compounds known in the art, for example, by methods represented by Reaction Formulas

(A) , (B) , (C) , and (D) shown below. The compound of the general formula (4) used as a starting material in the Reaction Formula-2 is an easily obtainable compound known in the art or a compound easily produced by a method known in the art.

[Reaction Formula (A) ]

[0105]

[0106] wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ are defined as above; X ₂ represents a leaving group; and R ⁸ represents a lower alkoxy group.

Examples of the leaving group represented by X ₂ can include the same leaving groups as those represented by Xi. [0107]

1st Step

A compound represented by the general formula

(6) and a compound represented by the general formula

(7) can be reacted in the presence or absence of a basic compound without or in an inert solvent to thereby produce a compound represented by the general

formula (8) . [0108]

Examples of the inert solvent can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them. [0109]

Basic compounds known in the art can be used widely. Examples thereof can include: 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, and lithium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metals such as sodium and potassium; other inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide,

potassium methoxide, potassium ethoxide, lithium tert- butoxide, sodium tert-butoxide, and potassium tert- butoxide; and other organic bases such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1, 5-diazabicyclo [4.3.0] nonene-5

(DBN), 1, 8-diazabicyclo [5.4.0] undecene-7 (DBU), and 1, 4-diazabicyclo[2.2.2]octane (DABCO) . These basic compounds are used alone or as a mixture of two or more of them.

[0110]

More preferable examples of the basic compound used in the present invention include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0111]

The amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula

(6) .

[0112]

The compound of the general formula (7) is usually used in an amount of at least 0.5 mol, preferably 0.5 to 5 mol, with respect to 1 mol of the compound of the general formula (6) .

[ 0113 ]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0114]

The reaction is usually performed under temperature conditions involving room temperature to 200 ⁰ C, preferably room temperature to 150 ⁰ C, and generally completed in approximately 1 to 30 hours. [0115]

After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (8) of interest. [0116]

In this context, the compound of the general formula (6) and the compound of the general formula (7) used as starting materials in the 1st step are easily obtainable compounds known in the art or compounds easily produced by a method known in the art. [0117]

2nd Step

The compound represented by the general formula (8) can be subjected to a reduction reaction to thereby produce a compound represented by the general formula (9). The reduction reaction is performed under similar reaction conditions to those for the reaction

represented by in the Reaction Formula-1. [0118]

3rd Step

The compound represented by the general formula (9) can be subjected to a cyclization reaction to thereby produce a compound represented by the general formula (5a) . [0119]

The cyclization reaction is usually performed in the presence or absence of a basic compound. The present reaction is usually performed in a commonly used solvent that does not adversely affect the reaction. Examples of such a solvent can 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) , hexamethylphosphoric triamide, and acetonitrile. These solvents are used alone or as a mixture of two or more of them. [0120]

In the present reaction, examples of the basic compound include alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., calcium and magnesium), alkali metal hydrides (e.g.,

sodium hydride), alkaline earth metal hydrides (e.g., calcium hydride), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, and potassium tert- butoxide) , alkaline earth metal alkoxides (e.g., magnesium methoxide and magnesium ethoxide) , trialkylamines (e.g., trimethylamine and triethylamine) , picoline, 1,5- diazabicyclo [4.3.0] nonene-5, 1,4- diazabicyclo [2.2.2] octane, and 1,8- diazabicyclo [5.4.0]undecene-7. These basic compounds are used alone or as a mixture of two or more of them. [0121]

The amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (9) . [0122]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0123]

The reaction is usually performed under temperature conditions involving room temperature to 200 ⁰ C, preferably room temperature to 150 ⁰ C, and generally completed in approximately 1 to 30 hours. [0124]

After the completion of the reaction, the

reaction product can be treated by a standard method to obtain the compound of the general formula (9) of interest . [0125]

4th Step

The compound represented by the general formula (8) can be reacted with a reducing agent in the presence or absence of an acid without or in an inert solvent to thereby produce the compound represented by the general formula (5a) . [0126]

Examples of the inert solvent can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them. [0127]

Preferable examples of the acid include organic acids (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic

acid, para-toluenesulfonic acid, and monohydrates thereof) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, and sulfuric acid) . [0128]

Preferable examples of the reducing agent include: tin halide such as tin (II) chloride; copper halide such as copper (II) chloride; and combination between zinc and ammonium chloride. [Reaction Formula (B) ] [0129]

(14)

[ 0130 ] wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , and R ⁸ are defined as above .

5th Step

A compound represented by the general formula (10) can be reacted with phosgene or a phosgene equivalent (e.g., triphosgene) without or in an inert

solvent to thereby produce a compound represented by the general formula (11) . [0131]

Examples of the inert solvent can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them. [0132]

The amount of the phosgene or the phosgene equivalent (e.g., triphosgene) used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (10) . [0133]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0134]

The reaction is performed under temperature

conditions involving cooling temperature to 100 ⁰ C, preferably 0 ⁰ C to room temperature, and generally completed in approximately 1 to 30 hours. [0135]

After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (11) of interest .

In this context, the compound of the general formula (10) used as a starting material in the 5th step is an easily obtainable compound known in the art or a compound easily produced by a method known in the art. [0136]

6th Step

The compound represented by the general formula (11) and a compound represented by the general formula (12) can be reacted without or in an inert solvent to thereby produce a compound represented by the general formula (5b) . [0137]

Examples of the inert solvent can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and

isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them. [0138]

The compound of the general formula (12) is usually used in an amount of at least 0.5 mol, preferably 0.5 to 5 mol, with respect to 1 mol of the compound of the general formula (11) . [0139]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0140]

The reaction is usually performed under temperature conditions involving room temperature to 200 ⁰ C, preferably room temperature to 150 ⁰ C, and generally completed in approximately 1 to 30 hours. [0141]

After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (5b) of interest.

In this context, the compound of the general formula (12) used as a starting material in the 6th

step is an easily obtainable compound known in the art or a compound easily produced by a method known in the art . [0142]

7th Step

The compound represented by the general formula (10) or its reactive derivative at the carboxy group and a compound represented by the general formula (13) can be reacted to thereby produce a compound represented by the general formula (14). [0143]

Preferable examples of the reactive derivative at the carboxy group of the compound of the general formula (10) include acid halides, acid anhydrides, active amides, and active esters. Preferable examples of the reactive derivative include: acid chlorides; acid azides; aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, and trichloroacetic acid, or mixed acid anhydrides of these aliphatic carboxylic acids with acids, for example, aromatic carboxylic acids such as benzoic acid; symmetric acid anhydrides; active amides such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, and tetrazole; and active esters such as p- nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl

phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, and carboxymethyl thioester, or esters with N-hydroxy compounds such as N,N-dimethylhydroxylamine, 1-hydroxy- 2- (IH) -pyridone, N-hydroxysuccinimide, N- hydroxyphthalimide, and 1-hydroxy-lH-benzotriazole. The reactive derivative can be selected arbitrarily from among them according to the type of the compound of the general formula (10) to be used. [0144]

Examples of a reaction solvent can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These reaction solvents are used alone or as a mixture of two or more of them. [0145]

When the compound of the general formula (10) is used in a form of a free acid or a salt thereof in this reaction, the reaction is preferably performed in the presence of a condensing agent known in the art,

such as: N, N ¹ -dicyclohexylcarbodiimide; N-cyclohexyl- N ^f -morpholinoethylcarbodiimide; N-cyclohexyl-N ' - (4- diethylaminocyclohexyl) carbodiimide; N, N' - diethylcarbodiimide; N, N ¹ -diisopropylcarbodiimide; N- ethyl-N'- (3-dimethylaminopropyl) carbodiimide; N,N' - carbonylbis (2-methylimidazole) ; diethylphosphoryl cyanide (DEPC) ; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate; and triphenylphosphine. [0146]

The reaction may be performed in the presence of a basic compound. [0147]

Basic compounds known in the art can be used widely. Examples thereof can include: 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, and lithium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metals such as sodium and potassium; other inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; and other

organic bases such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, diinethylaniline, N-methylmorpholine, 1, 5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8- diazabicyclo[5.4.0] undecene-7 (DBU), and 1,4- diazabicyclo [2.2.2] octane (DABCO) . These basic compounds are used alone or as a mixture of two or more of them.

[0148]

Examples of a reaction solvent used in this reaction can include commonly used solvents that do not adversely affect the reaction, for example: 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; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These reaction solvents are used alone or as a mixture of two or more of them.

[0149]

The amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula

(10) .

[ 0150 ]

The amount of the condensing agent used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (10) . [0151]

The compound of the general formula (13) is usually used in an amount of at least 0.5 mol, preferably 0.5 to 5 mol, with respect to 1 mol of the compound of the general formula (10) . [0152]

The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure. [0153]

The reaction is usually performed under temperature conditions involving cooling temperature to 200 ⁰ C, preferably 0 ⁰ C to room temperature, and generally completed in approximately 1 to 30 hours. [0154]

After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (14) of interest. [0155]

In this context, the compound of the general formula (13) used as a starting material in the 7th

step is an easily obtainable compound known in the art or a compound easily produced by a method known in the art . [0156]

8th Step

The compound represented by the general formula (14) can be subjected to a cyclization reaction to thereby produce the compound represented by the general formula (5b) . The cyclization reaction is performed under similar reaction conditions to those for the reaction in the 3rd step. [0157]

[Reaction Formula (C) ] [0158]

ep 12

(17)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , and R ⁸ are defined as

above . [0159]

9th Step

A compound represented by the general formula (15) or its reactive derivative at the carboxy group and the compound represented by the general formula (13) can be reacted to thereby produce a compound represented by the general formula (16). The reaction is performed under similar reaction conditions to those for the reaction in the 7th step.

In this context, the compound of the general formula (15) used as a starting material in the 9th step is an easily obtainable compound known in the art or a compound easily produced by a method known in the art. [0160]

10th Step

The compound represented by the general formula (16) can be subjected to a reduction reaction to thereby produce a compound represented by the general formula (17) . The reduction reaction is performed under similar reaction conditions to those for the reaction in the 2nd step. [0161]

11th Step

A reaction for deriving the compound represented by the general formula (5b) from the compound represented by the general formula (17) is

performed under similar reaction conditions to those for the reaction in the 8th step. [0162]

12th Step

The compound represented by the general formula (16) can be reacted with a reducing agent in the presence or absence of an acid without or in an inert solvent to thereby produce the compound represented by the general formula (5b) . The reaction is performed under similar reaction conditions to those for the reaction in the 4th step. [0163]

[Reaction Formula (D) ] [0164]

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z, and Xi are defined

as above. [0165]

13th Step

A compound represented by the general formula (5) can be subjected to a reduction reaction to thereby produce the compound represented by the general formula (3) . The reduction reaction is performed under similar reaction conditions to those for the reaction represented by the Reaction Formula-1. [0166]

14th Step

The compound represented by the general formula (5) and the compound represented by the general formula (4) can be reacted to thereby produce the compound represented by the general formula (2) . The reaction is performed under similar reaction conditions to those for the reaction represented by the Reaction Formula-2. [0167]

The raw material compound used in each of the reaction formulas may be in a form of a preferable salt. Moreover, the compound of interest obtained in each reaction may form a preferable salt. Examples of these preferable salts include preferable salts of the compound of the general formula (1) exemplified below. [0168]

Examples of the preferable salts of the compound of the general formula (1) include

pharmacologically acceptable salts, for example: metal salts such as alkali metal salts (e.g., sodium salt and potassium salt) and alkaline earth metal salts (e.g., calcium salt and magnesium salt) ; ammonium salt; salts of other inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate) , alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate) , and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide) ; salts of other organic bases such as tri- (lower) alkylamine (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine) , pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (e.g., N-methylmorpholine) , 1,5- diazabicyclo[4.3.0]nonene-5 (DBN), 1,8- diazabicyclo [5.4.0]undecene-7 (DBU), and 1,4- diazabicyclo [2.2.2] octane (DABCO); other inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and other organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate. [0169]

Moreover, compounds in a form of a solvate (e.g., a hydrate or an ethanolate) added to the raw material or the compound of interest shown in each reaction formula are also included in each general formula. Preferable examples of the solvate include hydrates . [0170]

Each compound of interest obtained according to each of the reaction formulas can be isolated and purified from the reaction mixture, for example, by separating, after cooling, the reaction mixture into a crude reaction product by isolation procedures such as filtration, concentration, and extraction and subjecting the crude reaction product to usual purification procedures such as column chromatography and recrystallization. [0171]

The compound represented by the general formula (1) of the present invention also encompasses isomers such as geometric isomers, stereoisomers, and optical isomers, of course. [0172]

A pharmaceutical preparation comprising the compound of the present invention as an active ingredient will be described. [0173]

The pharmaceutical preparation is obtained by making the compound of the present invention into usual

dosage forms of pharmaceutical preparations and prepared using a diluent and/or an excipient usually used, such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants. [0174]

Such a pharmaceutical preparation can be selected from among various forms according to a therapeutic purpose. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). [0175]

Carriers known in the art for use for forming a tablet form can be used widely. Examples thereof include: excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinyl pyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter, and hydrogenated oil; absorption promoters such as quaternary ammonium bases

and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. [0176]

Furthermore, the tablets can be coated, if necessary, with a usual coating material to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film-coated tablets, and bilayer or multilayer tablets. [0177]

Carriers known in the art for use for forming a pill form can be used widely. Examples thereof include: excipients such as glucose, lactose, starch, cacao butter, hydrogenated plant oil, kaolin, and talc; binders such as gum arabic powder, powdered tragacanth, gelatin, and ethanol; and disintegrants such as laminaran and agar. [0178]

Carriers known in the art for use for forming a suppository form can be used widely. Examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride. [0179]

When the compound represented by the general formula (1) is prepared as injections, solutions,

emulsions, and suspensions are preferably sterile and isotonic with blood. Diluents known in the art for use for forming forms of these solutions, emulsions, and suspensions can be used widely. Examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the pharmaceutical preparation may contain common salt, glucose, or glycerin in an amount sufficient for preparing an isotonic solution and may contain usual solubilizers, buffers, soothing agents, and the like, and if necessary, coloring agents, preservatives, perfumes, flavoring agents, sweetening agents, and the like, and/or other drugs. [0180]

The amount of the compound of the present invention contained in the pharmaceutical preparation is not particularly limited and can be selected appropriately from within a wide range. The compound of the present invention is usually contained in an amount of preferably approximately 1 to 70% by weight in the pharmaceutical preparation. [0181]

A method for administering the pharmaceutical preparation according to the present invention is not particularly limited. The pharmaceutical preparation is administered by a method according to various dosage forms, the age, sex, and disease state of a patient,

and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. Moreover, injections can be administered through an intravenous route alone or as a mixture with a usual replacement fluid such as glucose or amino acid or can be administered alone through intramuscular, intradermal, hypodermic, or intraperitoneal route, if necessary. Suppositories are rectally administered. [0182]

The dose of the pharmaceutical preparation may be selected appropriately according to use, the age, sex, and disease state of a patient, and other conditions. The pharmaceutical preparation is usually administered once or several times a day at a daily dose of approximately 0.001 to 100 mg, preferably approximately 0.001 to 50 mg, per kg of body weight. [0183]

The dose varies depending on various conditions. Thus, in some cases, a dose smaller than this range suffices. In other cases, a dose exceeding this range is required.

ADVANTAGES OF THE INVENTION [0184]

A benzodiazepine compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine) .

[ 0185 ]

The benzodiazepine compound of the present invention has remarkably strong uptake inhibitory activity in in-vitro or ex-vivo tests on any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity. Moreover, the benzodiazepine compound of the present invention exhibits remarkably strong activity in brain microdialysis study against increase in any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity. [0186]

The benzodiazepine compound of the present invention has a wide therapeutic spectrum, compared with antidepressants known in the art. [0187]

The benzodiazepine compound of the present invention exerts sufficient therapeutic effects even in short-term administration. [0188]

The benzodiazepine compound of the present invention has excellent bioavailability, weak inhibitory activity on metabolic enzymes in the liver, few side effects, and excellent safety. [0189]

The benzodiazepine compound of the present invention also exerts strong activity in a mouse forced swimming test used in depression screening. Moreover,

the benzodiazepine compound of the present invention also exerts strong activity in a rat forced swimming test used in depression screening. Moreover, the benzodiazepine compound of the present invention also exerts strong activity in a reserpine-induced hypothermia test used in depression screening.

[0190]

The benzodiazepine compound of the present invention exerts strong activity in a marble burying behavior test of anxiety or stress disease model mice and in fear-conditioned stress models.

[0191]

The benzodiazepine compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamine (s) (serotonin, norepinephrine, and dopamine) and is therefore effective for treating various disorders associated with the reduced neurotransmission of serotonin, norepinephrine, or dopamine.

[0192]

Such disorders include hypertension, depression (e.g.: major depressive disorder; bipolar I disorder; bipolar II disorder; mixed episode; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; minor depression; recurrent brief depressive disorder; intractable depression/chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by

various physical diseases such as Cushing's disease, hypothyroidism, hyperparathyroidism syndrome, Addison's disease, amenorrhea and lactation syndrome, Parkinson's disease, Alzheimer's disease, intracerebral bleeding, diabetes, chronic fatigue syndrome and cancer; presenile depression; senile depression; depression in children and adolescents; depression induced by medicines such as interferon; and depression caused by adjustment disorder), anxiety disorder (e.g.: anxiety caused by adjustment disorder, anxiety caused by various diseases [e.g.: nerve disorders (head injury, brain infection, and inner ear disorder) ; cardiovascular disorders (cardiac failure and arrhythmia) ; endocrine disorders (hyperadrenalism and hyperthyroidism) ; and respiratory disorders (asthma and chronic obstructive pulmonary disease) ] , and generalized anxiety disorder), phobia (e.g., agoraphobia, social phobia, and simple phobia) , posttraumatic stress disorder, acute stress syndrome, avoidant personality disorder, body dysmorphic disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependence (e.g., addition to alcohol, cocaine, heroin, phenobarbital, nicotine, and benzodiazepines), cluster headache, migraine, pain, Alzheimer disease, obsessive compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorder, and age-related cognitive decline (ARCD) ) ,

Parkinson's disease (e.g., dementia in Parkinson's disease, neuroleptic agent-induced Parkinson's syndrome, and tardive dyskinesia) , endocrine disorders (e.g., hyperprolactinemia) , vasospasm (particularly, in the cerebral vasculature) , cerebellar ataxia, gastrointestinal disorders (which encompass changes in secretion and motility) , negative syndromes in schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, attention-deficit hyperactivity disorder (ADHD) , chronic paroxysmal hemicrania, chronic fatigue, cataplexy, sleep apnea syndrome, and headache (associated with angiopathy) . [0193]

In addition, the compounds of the present invention can exert effects such as decreasing the amount of administration, improving side effects, enhancing therapeutic efficacy or the like which could not attained by conventional treatment by administering with at least one clinically used drug(s) selected from the group consisting of (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors and (5) antidepressants. [0194] EXAMPLES

Hereinafter, the present invention will be

described more specifically with reference to Reference Examples, Examples, and Pharmacological Tests.

[0195]

Reference Example 1

Production of 7-methoxymethoxy-4-methyl-l, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-2-one

[ (2-Amino-5-methoxymethoxybenzyl) - methylamino] acetic acid ethyl ester (1.9 g, 6.6 mM) was dissolved in DMF (30 ml) . To the solution, sodium hydride (0.28 g, 7.3 mM) was added with stirring at room temperature, and the mixture was stirred at 70 ⁰ C for 3 hours. To the reaction mixture, a small amount of water was added to quench the reaction. Then, DMF was distilled off under reduced pressure, and the obtained residue was dissolved in dichloromethane and dried over magnesium sulfate. Dichloromethane was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography

(dichloromethane:methanol=100: l→20: 1) to obtain 7- methoxymethoxy-4-methyl-l, 3,4,5- tetrahydrobenzo[e] [1, 4] diazepin-2-one (0.90 g, yield: 60.0%, in a light yellow powder form) . 1H-NMR (CDC13) δ ppm : 2.53 (3H, s) , 3.38 (2H, s) , 3.47

(3H, s), 3.70 (2H, s), 5.15 (2H, s) , 6.89-6.93 (IH, m) , 6.97-7.01 (2H, m) , 7.92 (IH, brs) .

[0196]

Compounds of Reference Examples 2 to 4 shown below were produced in the same way as in Reference

Example 1 using appropriate starting materials. [0197]

Reference Example 2 7, 8-Dimethoxy-4-methyl-l _/ 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm : 2.55 (3H, s) , 3.29 (2H, s) , 3.66 (2H, s), 3.87 (3H, s) , 3.89 (3H, s), 6.54 (IH, m) , 6.80 (IH, s) , 8.10 (IH, brs) . [0198]

Reference Example 3

8-Methyl-5,7, 8, 9-tetrahydro-l, 3-dioxa-5, 8- diazacyclohepta [f] inden-6-one

¹ H-NMR (CDCl ₃ ) δ ppm : 2.52 (3H, s) , 3.25 (2H, s) , 3.59 (2H, s), 6.00 (2H, s), 6.55 (IH, s) , 6.77 (IH, s), 8.29 (IH, brs) . [0199]

Reference Example 4 7-Methoxy-4-methyl-l, 3, 4 , 5- tetrahydrobenzo [e] [1, 4] diazepin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm : 2.54 (3H, s) , 3.26 (2H, s) , 3.71 (2H, s), 3.81 (3H, s), 6.79-6.88 (2H, m) , 6.90-6.97 (IH, m) , 8.03 (IH, brs) . [0200]

Reference Example 5

Production of 7-chloro-4-methyl-l, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-2-one

[ (2-Nitro-5-chlorobenzyl)methylamino] acetic acid ethyl ester (1.1 g, 3.8 mM) was dissolved in

ethanol (15 ml) . To the solution, concentrated hydrochloric acid (3.5 ml) and tin (II) chloride dihydrate (2.O g, 11.5 mM) were added at room temperature, and the mixture was stirred for 15 hours. To the reaction mixture, a 5 N aqueous sodium hydroxide solution was added to adjust the pH of the mixture to an alkaline pH. Then, extraction with dichloromethane was performed 3 times, and the obtained organic layer was washed with water and then dried over magnesium sulfate. Dichloromethane was distilled off under reduced pressure to obtain 7-chloro-4-methyl-l, 3, 4, 5- tetrahydrobenzo[e] [1, 4] diazepin-2-one (0.67 g, yield: 82.7%, in a light yellow powder form) . [0201]

Reference Example 6

Production of 6-methoxy-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

5-Methoxy-lH-benzo [d] [1, 3] oxazine-2, 4-dione (10.0 g, 51.8 mM) and sarcosine (5.07 g, 56.9 mM) were stirred in DMF (50 ml) at 100 ⁰ C for 6 hours. The reaction mixture was cooled to room temperature. Then, ice water was added thereto, and the deposited crystals were collected by filtration. The crystals were dried to obtain 6-methoxy-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4]diazepine-2, 5-dione in a white solid form (6.70 g, yield: 59%) .

¹ H-NMR (DMSO-d6) δ ppm : 3.03 (3H, s) , 3.51 (IH, d, J = 15 z), 3.77 (3H, s) , 4.09 (IH, d, J = 15 Hz), 6.67 (IH,

d, J = 8 Hz), 6.85 (IH, d, J = 8 Hz), 7.36 (IH, t, J = 8 Hz) , 10.27 (IH, s) . [0202]

Compounds of Reference Examples 7 to 14 shown below were produced in the same way as in Reference Example 6 using appropriate starting materials. [0203]

Reference Example 7 8-Chloro-4-methyl-3,4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 3.11 (3H, s) , 3.89 (2H, s) , 7.15 (IH, d, J = 2.0Hz), 7.28 (IH, dd, J = 2.1, 8.5Hz), 7.76 (IH, d, J = 8.5Hz), 10.55 (IH, bs) . [0204]

Reference Example 8 4-Benzyl-8-chloro-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.90 (2H, s) , 4.76 (2H, s) , 7.15 (IH, d, J = 2.0 Hz), 7.22-7.41 (6H, m) , 7.83 (IH, d, J = 8.8 Hz) , 10.54 (IH, s) . [0205]

Reference Example 9

4-Methyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine-8-carboxylic acid 1H-NMR (DMSO-de) δ ppm : 3.13 (3H, s) , 3.88 (2H, s) , 7.65-7.87 (2H, m) , 7.84 (IH, d, J = 8.0 Hz), 10.59 (IH, s) , 13.32 (IH, brs) . [0206]

Reference Example 10

4-Ethyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine-2, 5-dione ¹ H-NMR (DMSOd ₆ ) δ ppm : 1.12 (3H, t, J = 7.1 Hz), 3.58 (2H, q, J = 7.1 Hz), 3.84 (2H, s) , 7.10 (IH, d, J = 7.9 Hz), 7.15-7.26 (IH, m) , 7.45-7.55 (IH, m) , 7.75 (IH, dd, J = 1.5, 7.9 Hz), 10.4 (IH, s) . [0207]

Reference Example 11

4-Ethyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine-8-carboxylic acid 1H-NMR (DMSO-d ₆ ) δ ppm : 1.12 (3H, t, J = 7.0 Hz), 3.58 (2H, q, J = 7.0 Hz), 3.87 (2H, s) , 7.68-7.84 (3H, m) , 10.56 (IH, s) . [0208]

Reference Example 12

7, 8-Dichloro-4-methyl-3, 4-dihydro-lH- benzo[e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 3.11 (3H, s) , 3.92 (2H, s) , 7.33 (1H, s) , 7.88(1H, s) , 10.61 (1H, s) . [0209]

Reference Example 13

4-Benzyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine-8-carboxylic acid 1H-NMR (DMSO-d ₆ ) δ ppm : 3.91 (2H, s) , 4.78 (2H, s) , 7.21-7.42 (5H, m) , 7.68-7.80 (2H, m) , 7.92 (IH, d, J = 8.1 Hz), 10.60 (IH, s) , 12.95-13.60 (IH, br) . [0210]

Reference Example 14

4-Ethyl-8-nitro-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 1.14 (3H, t, J = 7.0 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.94 (2H, s) , 7.95-7.99 (3H, m) , 10.77 (IH, br) . [0211]

Reference Example 15

Production of 4-methyl-8-nitro-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

Sodium hydride (60% oil, 4.49 g, 112 itiM) was added to a dimethylformamide (150 ml) solution of [ (2- amino-4-nitrobenzoyl)methylamino] acetic acid methyl ester (30.0 g, 112 inM) with stirring at 0 ⁰ C, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, ice water and subsequently hydrochloric acid were added, and the deposited crystals were collected by filtration. The obtained crystals were washed with water and then dried to obtain 4-methyl-8-nitro-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione in a yellow powder form (24.0 g, yield: 91%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 3.37 (3H, s) , 3.96 (2H, s) , 7.94 (IH, d, J = 2.1 Hz), 8.08 (IH, dd, J = 2.1, 8.6 Hz), 8.17 (IH, d, J = 8.6 Hz), 8.97 (IH, s) . [0212]

Compounds of Reference Examples 16 to 24 shown below were produced in the same way as in Reference Example 15 using appropriate starting

materials . [0213]

Reference Example 16 4-Benzyl-8-fluoro-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 3.90 (2H, s) , 4.76 (2H, s) , 6.89 (IH, dd, J = 2.5, 10.3Hz), 7.05-7.15 (IH, m) , 7.2- 7.4 (5H, m) , 7.88 (IH, dd, J = 6.6, 8.9Hz), 10.56 (IH, s) . [0214]

Reference Example 17 8-Fluoro-4-methyl-3,4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.29 (3H, s) , 3.91 (2H, s) , 6.70 (IH, dd, J = 2.3, 9.2Hz), 6.95-7.05 (IH, m) , 7.99 (IH, dd, J = 6.3, 8.8Hz), 8.11 (IH, br) . [0215]

Reference Example 18 9-Fluoro-4-methyl-3,4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.30 (3H, s) , 3.93 (2H, s) , 7.15- 7.35 (2H, m) , 7.7-7.8 (IH, m) , 7.97 (IH, br) . [0216]

Reference Example 19

7, 8-Difluoro-4-methyl-3, 4-dihydro-1H- benzo [e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.11 (3H, s) , 3.90 (2H, s) , 7.11 (1H, dd, J = 7.1, 11.7Hz), 7.72 (1H, dd, J = 8.9,

11.3Hz) , 10.53 (IH, br) . [0217]

Reference Example 20

4-Methyl-3, 4-dihydro-lH-naphtho [2, 3-e] [1, 4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 3.18 (3H, s) , 3.90 (2H, s) , 8.45-8.65 (3H, m) , 7.89 (1H, d, J = 8.1Hz) , 8.04 (1H, d, J = 8.1Hz) , 8.41 (1H, s) , 10.59 (1H, br) . [0218]

Reference Example 21

4, 8-Dimethyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine-2, 5- dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 2.32 (3H, s) , 3.10 (3H, s) , 3.82 (2H, s) , 6.89 (1H, s) , 6.95-7.1 (1H, m) , 7.64 (1H, d, J = 8.0Hz) , 10.38 (1H, s) . [0219]

Reference Example 22

6, 8-Dichloro-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.27 (3H, s) , 3.65 (IH, d, J = 14.3 Hz), 4.16 (IH, d, J = 15.1 Hz), 6.92 (IH, d, J = 1.9 Hz), 7.34 (IH, d, J = 1.9 Hz), 7.73 (IH, s) . [0220]

Reference Example 23

6, 8-Dimethoxy-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione MS : 251 (M+l) . [0221]

Reference Example 24

6, 8-Difluoro-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.27 (3H, s) , 3.96 (2H, br) , 6.51-6.55 (IH, m) , 6.74-6.81 (IH, m) , 7.68 (IH, s) . [0222]

Reference Example 25

Production of 7- (6-methylpyridazin-3-yl) -1-naphthalen- 2-y1-1, 2, 3, 5-tetrahydrobenzo [e] [1,4] diazepine-4- carboxylic acid tert-butyl ester

4-Benzyl-7- ( 6-methylpyridazin-3-yl) -1- naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine (189.5 mg, 0.42 mM) was dissolved in dichloromethane. To the solution, chloroformic acid 1-chloroethyl ester (0.15 ml, 1.4 mM) was added at room temperature, and the mixture was stirred overnight. The exhaustion of the raw material was confirmed, and the solvent was then distilled off from the reaction mixture. Methanol (10 ml) was freshly added thereto, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the obtained concentrate was then redissolved in methanol (10 ml) . To the solution, di- tert-butyl dicarbonate (0.15 ml, 0.65 mM) and triethylamine (0.18 ml, 1.3 mM) were added in an ice bath, and the mixture was stirred overnight, with the reaction temperature increased to room temperature. After the completion of the reaction, the solvent was

distilled off from the reaction mixture, and the residue was purified by NH-silica gel chromatography

(n-hexane: ethyl acetate=10 : 1—>3: 1) to obtain 7-(6- methylpyridazin-3-yl) -1-naphthalen-2-yl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester in a pale yellow powder form (119.2 mg, yield: 62%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.50(m, 9H), 2.78(s, 3H), 3.68-3.82(m, 2H). 3.82-4.00(m, 2H), 4.48(s, 1.2H), 4.58(s, 0.8H), 7.10-7.20(m, 2H), 7.20-7.33(m, 2H), 7.33-7.48(m, 2H), 7.58-7.85(m, 4H), 7.85-8.22(m, 2H) .

[0223]

Reference Example 26

Production of 1- (3, 4-dichlorophenyl) -1, 2, 3, 5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

1- (3, 4-Dichlorophenyl) -4-methyl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine (0.34 g, 1.1 mM) was dissolved in 1, 2-dichloroethane. To the solution, chloroformic acid 1-chloroethyl ester (0.32 g, 2.2 mM) was gradually added dropwise with stirring at room temperature, and the mixture was further stirred at room temperature for 15 hours. The reaction mixture was concentrated. Then, the concentrate was dissolved by the addition of methanol, and the mixture was stirred for 8 hours during heating to reflux. The reaction mixture was concentrated, and the obtained residue was dissolved in dichloromethane and washed

with an aqueous saturated sodium bicarbonate solution and then dried over magnesium sulfate. Dichloromethane was removed by concentration under reduced pressure, and the obtained residue was dissolved in methanol. To the solution, triethylamine (0.22 g, 2.2 itiM) was added. Then, di-tert-butyl dicarbonate (0.24 g, 1.1 mM) was added thereto with stirring, and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure, and the obtained residue was dissolved in dichloromethane, washed with water and then dried over magnesium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane: ethyl acetate=20: l-»10: 1) to obtain 1- (3, 4-dichlorophenyl) -1, 2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester (60 mg, yield: 13.7%, in a yellow oil form) .

¹ H-NMR (CDCl ₃ ) δ ppm : 1.25-1.58 (9H, m) , 3.56-3.78 (4H, m) , 4.19-4.49 (2H, m) , 6.45-6.83 (2H, m) , 7.05-7.51 (5H, m) . [0224]

Compounds of Reference Examples 27 to 63 shown below were produced in the same way as in Reference Example 26 using appropriate starting materials . [0225]

Reference Example 27

1- (3-Chloro-4-fluorophenyl) -1,2,3, 5-tetrahydro- benzo [e] [1, 4]diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.34-1.50 (9H, m) , 3.67 (4H, brs) , 4.22-4.43 (2H, m) , 6.45-6.58 (1H, m) , 6.60-6.73

(1H, m) , 6.94 (1H, t, J=5.3Hz) , 7.08-7.49 (5H, m) .

[0226]

Reference Example 28 l-Naphthalen-2-yl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.29-1.54 (9H, m) , 3.67-3.93 (4H, m) , 4.22-4.50 (2H, m) , 6.88-7.07 (2H, m) , 7.05-7.55

(5H, m) , 7.55-7.80 (3H, m) .

[0227]

Reference Example 29 1-Naphthalen-1-yl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.48 (9H, s) , 3.62-3.96 (4H, m) , 4.63-4.85 (2H, m) , 6.27-6.37 (IH, m) , 6.83-6.94 (2H, m) , 7.20-7.45 (4H, m) , 7.45-7.55 (IH, m) , 7.62-7.88

(3H, m) .

[0228]

Reference Example 30 1-Benzo [b] thiophen-5-yl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.29-1.52 (8H, m) , 3.65-3.89 (4H, m) , 4.25-4.50 (2H, m) , 6.74-6.90 (1H, m) , 7.05-7.32 (5H, m) , 7.32-7.50 (2H, m) , 7.64 (1H, d, J = 8.9 Hz) . [0229]

Reference Example 31

1- [1- (Toluene-4-sulfonyl) -lH-indol-5-yl] -1, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.17-1.50 (9H, m) , 2.35 (3H, s) , 3.56-3.84 (4H, m) , 4.21-4.48 (2H, m) , 6.47 (IH, d, J = 3.5 Hz), 6.65-6.86 (2H, m) , 7.00-7.50 (6H, m) , 7.70- 7.80 (3H, m) . [0230]

Reference Example 32 l-(l-Methyl-lH-indol-5-yl) -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.52 (9H, m) , 3.60-3.85 (7H, m) , 4.43-4.60 (2H, m) , 6.35 (IH, d, J = 3.0 Hz), 6.76- 6.92 (2H,m), 6.94-7.06 (2H, m) , 7.06-7.20 (3H, m) , 7.20-7.45 (IH, m) . [0231]

Reference Example 33

1- (6-Methoxy-naphthalen-2-yl) -7- (6-methyl-pyridazin-3- yl) -1, 2, 3, 5-tetrahydrobenzo [e] [1, 4] diazepine-4- carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.50 (9H, m) , 2.77 (3H, s) , 3.60-4.70(9H, m) , 6.90-8.20 (HH, m) .

[ 0232 ]

Reference Example 34

1-Benzo [b] thiophen-5-yl-7- ( 6-methyl-pyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.26-1.55 (9H, m) , 2.77 (3H, s) , 3.60-4.70(6H, m) , 6.90-8.20(1OH, m) . [0233]

Reference Example 35

1- (3, 4-Dichloro-phenyl) -7- (6-methyl-pyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.60 (9H, m) , 2.78(3H, s), 3.40-4.70(6H, m) , 6.50-8.10 (8H, m) . [0234]

Reference Example 36 l-Naphthalen-2-yl-7-pyridin-4-yl-l, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.53 (9H, m) , 3.50-4.70 (6H, m) , 6.90-7.80(12H, m) , 8.60-8.70 (2H, m) . [0235]

Reference Example 37

1- (6-Methoxynaphthalen-2-yl) -7-pyridin-4-yl-l, 2, 3, 5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.55 (9H, m) , 3.50-4.70 (9H, m) , 6.85-7.20 (5H, m) , 7.40-7.80 (6H, m) , 8.60-8.70 (2H,

m) . [0236]

Reference Example 38

1-Benzo [b] thiophen-5-yl-7-pyridin-4-yl-l, 2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.53 (9H, m) , 3.50-4.70 (6H, m) , 6.90-7.80(1OH, m) , 8.60-8.70 (2H, m) . [0237]

Reference Example 39

1- (3, 4-Dichloro-phenyl) -7-pyridin-4-yl-1,2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.30-1.55 (9H, m) , 3.50-4.70 (6H, m) , 6.50-6.90(2H, m) , 7.10-7.80(6H, m) , 8.60-8.70 (2H, m) . [0238]

Reference Example 40

1- (3-Chloro-1-methyl-lH-indol-5-yl) -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.35-1.53 (9H, m) , 3.62-3.85 (7H, m) , 4.35-4.58 (2H, m) , 6.80 (1H, d, J = 2.2, 8.9 Hz) , 6.89-7.22 (6H, m) , 7.26-7.48 (1H, m) . [0239]

Reference Example 41

7-Imidazol-l-yl-1-naphthalen-2-yl-1,2, 3, 5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid

tert-butyl ester MS : 441 (M+l) . [0240]

Reference Example 42

7-Imidazol-1-yl-1- (6-methoxynaphthalen-2-yl) -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS : 471 (M+l) . [0241]

Reference Example 43

1-Benzo [b] thiophen-5-yl-7-imidazol-1-yl-l, 2,3,5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS : 447 (M+l) . [0242]

Reference Example 44

1-Benzo [b] thiophen-6-yl-7-imidazol-1-yl-l, 2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS : 447 (M+l) . [0243]

Reference Example 45

1- (3, 4-Dichloro-phenyl) -7-imidazol-1-yl-1,2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS : 459 (M+l) . [0244]

Reference Example 46

1- (3, 5-Difluoro-phenyl) -7-imidazol-1-yl-l, 2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS : 427 (M+l) . [0245]

Reference Example 47

1- (l-Triisopropylsilanyl-lH-indol-6-yl) -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.04 (18H, d, J = 7.5Hz), 1.3- 1.55 (12H, m) , 3.65-3.85 (4H, m) , 4.2-4.45 (2H, m) , 6.50 (IH, d, J = 3.1Hz), 6.65-6.75 (2H, m) , 7.0-7.15 (3H, m) , 7.15-7.25 (IH, m) , 7.3-7.5 (2H, m) . [0246]

Reference Example 48

1- (l-Triisopropylsilanyl-lH-indol-4-yl) -1,2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.12 (18H, d, J = 7.5Hz) , 1.35- 1.5 (9H, m) , 1.6-1.75 (3H, m) , 3.68 (2H, br) , 3.75-3.85 (2H, m) , 4.5-4.7 (2H, m) , 5.83 (1H, s) , 6.67 (1H, dd, J = 1.3, 7.8Hz) , 6.82 (1H, d, J = 7.4Hz) , 6.9-7.15 (4H, m) , 7.21 (1H, d, J = 8.3Hz) , 7.25-7.4 (1H, m) . [0247]

Reference Example 49

1- [1- (Toluene-4-sulfonyl) -lH-indol-6-yl] -1, 2, 3, 5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.37 (3H, s) , 3.6-3.85 (4H, m) , 4.2-4.4 (2H, m) , 6.51 (1H, d, J = 3.3Hz) , 6.63 (1H, dd, J = 2.2, 8.7Hz) , 7.11 (1H, d, J = 7.6Hz) , 7.15-7.35 (7H, m) , 7.38 (1H, d, J = 3.6Hz) , 7.62 (2H, d, J = 8.0Hz) . [0248]

Reference Example 50

1- [1- (Toluene-4-sulfonyl) -lH-indol-4-yl] -1, 2, 3, 5- tetrahydrobenzofe] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.36 (3H, s) , 3.55-3.65 (2H, m) , 3.65-3.75 (2H, m) , 4.45-4.65 (2H, m) , 5.71 (1H, d, J = 3.7Hz) , 6.55-6.65 (1H, m) , 6.85- 6.95 (1H, m) , 7.0-7-.05 (2H, m) , 7.2-7.3 (5H, m) , 7.63 (1H, d, J = 8.3Hz) , 7.75 (2H, d, J = 8.4Hz) . [0249]

Reference Example 51

1- (l-Triisopropylsilanyl-lH-indazol-5-yl) -1,2, 3, 5- tetrahydrobenzo[e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.13 (18H, d, J = 7.5Hz), 1.2-1.5 (9H, m) , 1.65-1.85 (3H, m) , 3.6-3.8 (4H, m) , 4.3-4.55 (2H, m) , 6.85-6.95 (IH, m) , 7.03 (IH, d, J = 7.9Hz), 7.05-7.15 (2H, m) , 7.15-7.3 (IH, m) , 7.3-7.45 (2H, m) , 8.08 (IH, s) . [0250]

Reference Example 52 1-Benzo [b] thiophen-6-yl-7- (6-methylpyridazin-3-yl) -

1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.77 (3H, s) , 3.74 (2H, br) , 3.86 (2H, br) , 4.4-4.65 (2H, m) , 6.8-7.0 (IH, m) , 7.1-7.35 (4H, m) , 7.39 (IH, d, J = 8.9Hz), 7.64 (IH, d, J = 8.7Hz), 7.75 (IH, d, J = 8.8Hz), 7.85- 8.2 (2H, m) . [0251]

Reference Example 53

1- (3-Fluoro-4-methylphenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.18 (3H, d, J = 1.1Hz), 2.77 (3H, s) , 3.55-3.85 (4H, m) , 4.3-4.6 (2H, m) , 6.35-6.55 (2H, m) , 6.9-7.05 (IH, m) , 7.15-7.3 (IH, m) , 7.40 (IH, d, J = 8.8Hz), 7.75 (IH, d, J = 8.8Hz), 7.85-8.2 (2H, m) . [0252]

Reference Example 54

7-(6-Methylpyridazin-3-yl) -1-p-tolyl-1,2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.28 (3H, s) , 2.76 (3H, s), 3.6-3.85 (4H, m) , 4.35-4.65 (2H, m) , 6.65-6.85 (2H, m) , 6.95-7.1 (2H, m) , 7.17 (IH, d, J = 8.3Hz), 7.37 (IH, d, J = 8.7Hz), 7.73 (IH, d, J = 8.5Hz) , 7.8-8.2 (2H, m) . [0253]

Reference Example 55

1-Benzo [1, 3] dioxol-5-yl-7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.75 (3H, s) , 3.55-3.8 (4H, m) , 4.35-4.65 (2H, m) , 5.91 (2H, s) , 6.3- 6.55 (2H, m) , 6.71 (IH, d, J = 8.4Hz), 7.05 (IH, d, J = 8.4Hz), 7.36 (IH, d, J = 8.8Hz), 7.71 (IH, d, J = 8.4Hz) , 7.75-8.15 (2H, m) . [0254]

Reference Example 56

1- (4-Chloro-3-methylphenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.27 (3H, s) , 2.77 (3H, s), 3.6-3.85 (4H, m) , 4.3-4.6 (2H, m) , 6.5- 6.7 (2H, m) , 7.15 (IH, d, J = 8.7Hz), 7.23 (IH, d, J = 8.3Hz), 7.39 (IH, d, J = 8.5Hz), 7.75 (IH, J = 8.6Hz), 7.8-8.2 (2H, m) . [0255]

Reference Example 57

1- (2, 3-Dichlorophenyl) -7- ( 6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.44 (9H, s) , 2.74 (3H, s) , 3.55- 3.85 (4H, m) , 4.55-4.8 (2H, m) , 6.52 (1H, d, J = 8.4Hz) , 7.1-7.45 (4H, m) , 7.6-8.15 (3H, m) . [0256]

Reference Example 58

1- (3-Chloro-4-methylphenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppiti : 1.25-1.55 (9H, m) , 2.28 (3H, s) , 2.77 (3H, s), 3.55-3.85 (4H, m) , 4.3-4.6 (2H, m) , 6.5- 6.7 (IH, m) , 6.7-6.9 (IH, m) , 7.04 (IH, d, J = 8.4Hz), 7.15-7.3 (IH, m) , 7.39 (IH, d, J = 8.6Hz), 7.75 (IH, d, J = 8.8Hz), 7.8-8.2 (2H, m) . [0257]

Reference Example 59

1- (3, 4-Dimethylphenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.19 (3H, s) , 2.20 (3H, s), 2.76 (3H, s) , 3.55-3.85 (4H, m) , 4.35- 4.65 (2H, m) , 6.55-6.75 (2H, m) , 7.00 (IH, d, J = 8.1Hz), 7.16 (IH, d, J = 8.3Hz), 7.37 (IH ,d, J = 8.5Hz), 7.73 (IH, d, J = 8.5Hz), 7.8-8.2 (2H, m) . [0258]

Reference Example 60

1- (3-Chloro-2-methylphenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.43 (9H, s) , 2.05-2.15 (3H, m) , 2.73 (3H, s), 3.5-3.95 (4H, m) , 4.45-4.9 (2H, m) , 6.39 (IH, d, J = 8.5Hz), 7.05-7.4 (4H, m) , 7.5-8.1 (3H, m) . [0259]

Reference Example 61

1- (4-Chloro-3-fluorophenyl) -7- (6-methylpyridazin-3-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.5 (9H, m) , 2.78 (3H, s) , 3.6-3.85 (4H, m) , 4.25-4.55 (2H, m) , 6.35-6.6 (2H, m) , 7.16 (1H, dd, J = 8.7, 8.7Hz) , 7.32 (1H, d, J = 8.3Hz) , 7.42 (1H, d, J = 8.6Hz) , 7.77 (1H, d, J = 8.8Hz) , 7.85- 8.25 (2H, m) . [0260]

Reference Example 62

7- (6-Methylpyridazin-3-yl) -1-m-tolyl-1,2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.55 (9H, m) , 2.27 (3H, s) , 2.77 (3H, s) , 3.6-3.85 (4H, m) , 4.35-4.6 (2H, m) , 6.5- 6.75 (3H, m) , 7.0-7.2 (1H, m) , 7.2-7.3 (1H, m) , 7.39 (1H, d, J = 8.5Hz) , 7.75 (1H, d, J = 8.8Hz) , 7.85-8.2 (2H, m) . [0261]

Reference Example 63 l-(3-Chloro-phenyl) -7- (6-methylpyridazin-3-yl) -1, 2, 3, 5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.3-1.55 (9H, m) , 2.78 (3H, s) , 3.6-3.85 (4H, m) , 4.3-4.6 (2H, m) , 6.55-6.85 (3H, m) , 7.11 (IH, dd, J = 8.2, 8.2Hz), 7.31 (IH, d, J = 8.3Hz), 7.41 (IH, d, J = 8.2Hz), 7.77 (IH, d, J = 8.7Hz), 7.85-

8 . 25 ( 2H, m) . [ 0262 ]

Reference Example 64

Production of 8-amino-4-methyl-1-naphthalen-2-yl-3, 4- dihydro-lH-benzo [e] [1,4] diazepine-2, 5-dione

10% palladium-carbon (250 mg) was added to a tetrahydrofuran/ethanol (350 ml/350 ml) solution of 4- methyl-l-naphthalen-2-yl-8-nitro-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione (2.5 g, 6.9 mM) . After hydrogen substitution, the mixture was heated at 50 ⁰ C for 3 hours. After the completion of the reaction, the catalyst was removed from the reaction mixture, and the residue was concentrated. The deposited solids were washed with n-hexane/ethyl acetate and then collected by filtration to obtain the compound 8-amino- 4-methyl-1-naphthalen-2-yl-3,4-dihydro-lH- benzo[e] [1, 4] diazepine-2, 5-dione (1.46 g, in a pale yellow solid form) .

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.12 (3H, s) , 3.80 (IH, br) , 4.28 (IH, br), 5.69 (2H, br) , 5.89 (IH, d, J = 2.0 Hz), 6.44 (IH, dd, J = 2.1, 8.5 Hz), 7.28-8.00 (8H, m) . [0263]

Reference Example 65

Production of 8-methanesulfonyl-4-methyl-3, 4-dihydro- lH-benzo [e] [1, 4] diazepine-2, 5-dione

An ethyl acetate (100 ml) solution of [ (4- methanesulfonyl-2-nitro-benzoyl)methylamino] acetic acid methyl ester (7.00 g, 21.2 mM) and tin (II) chloride

monohydrate (19.1 g, 84.8 mM) was subjected to reflux for 2 hours. The reaction mixture was cooled to room temperature. Then, an aqueous saturated potassium carbonate solution was added thereto, and insoluble matter was filtered off through celite. The filtrate was concentrated under reduced pressure to obtain 8- methanesulfonyl-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione in a pale yellow powder form (400 mg, yield: 7%) .

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.14 (3H, s) , 3.26 (3H, s) , 3.92 (2H, s) , 7.66 (1H, d, J = 1.1 Hz) , 7.74 (1H, dd, J = 1.1, 8.2 Hz) , 7.98 (1H, d, J = 8.2 Hz) , 10.72 (1H, brs) . [0264]

A compound of Reference Example 66 shown below was produced in the same way as in Reference Example 65 using appropriate starting materials. [0265]

Reference Example 66

7-Fluoro-4, 6-dimethyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 2.41 (3H, d, J = 2.7 Hz), 3.26 (3H, s), 3.55-3.68 (IH, m) , 4.05-4.20 (IH, m) , 6.78- 6.88 (IH, m) , 7.08 (IH, t, J = 8.7 Hz), 8.52 (IH, brs) . [0266]

Reference Example 67

Production of 4-methyl-8-trifluoromethyl-3, 4-dihydro- lH-benzo [e] [1, 4] diazepine-2, 5-dione

Sodium hydride (0.35 g, 60% oil) was added to a DMF (23 ml) solution of [ (2-amino-4- trifluoromethylbenzoyl)methylamino] acetic acid methyl ester (2.3 g, 8.0 mM) with ice-cooling. Then, the mixture was heated to 60 ⁰ C and stirred for 2 hours. Water was added to the reaction mixture, and the solvent was then distilled off under reduced pressure. Water was added to the residue, and the solids were collected by filtration, washed with water and n- hexane, and then dried to obtain 1.27 g of light grey white solids. Moreover, solids deposited in the filtrate were collected by filtration, washed with water, and dried to obtain 0.87 g of white solids. These solids were dissolved in DMF (20 ml) . To this solution, a DMF (15 ml) solution of diethyl cyanophosphate (1.2 ml, 8.0 mM) was added with ice- cooling. Triethylamine (1.1 ml, 8.0 mM) was added thereto, and the mixture was stirred at 5°C to room temperature for 5 hours. To the reaction mixture, ethyl acetate was added, and the resultant mixture was washed with 1 N hydrochloric acid and subsequently with a saturated saline and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture. Then, water was added to the residue, and the deposited solids were collected by filtration, washed with water, and then dried to obtain 4-methyl-8-trifluoromethyl-3, 4-dihydro- lH-benzo [e] [1, 4] diazepine-2, 5-dione in a white solid

form (1.50 g) .

¹ H-NMR (DMSOd ₆ ) δ ppm : 3.14 (3H, s) , 3.93 (2H, s) , 7.44 (1H, s) , 7.55 (1H, d, J = 8.3Hz) , 7.96 (1H, d, J = 8.2Hz) , 10.65 (1H, s) . [0267]

A compound of Reference Example 68 shown below was produced in the same way as in Reference Example 67 using appropriate starting materials. [0268]

Reference Example 68

8-Bromo-4-methyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 3.10(3H, s) , 3.88(2H, s) , 7.3O(1H, d, J=I.9Hz), 7.41(1H, dd, J=I.9, 8.5Hz), 7.68(1H, d, J=8.5Hz), 1O.52(1H, br) . [0269]

Reference Example 69

Production of 8-methoxy-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

10% palladium-carbon (0.17 g) was added to an ethanol (35 ml) solution of [ (4-methoxy-2- nitrobenzoyDmethylamino] acetic acid methyl ester (3.3 g, 12 mM) , and the compound was catalytically reduced at room temperature for 4 hours in a hydrogen atmosphere. The catalyst was filtered off through celite from the reaction mixture, and the filtrate was washed with ethanol. The solvent in the filtrate was distilled off under reduced pressure to obtain 2.89 g

of pale yellow oil as a residue. This oil was dissolved in DMF (30 ml) . To the solution, sodium hydride (0.52 g, 60% oil) was added, and the mixture was stirred at 60 ⁰ C for 2 hours. The reaction mixture was cooled to room temperature. Then, 0.5 N hydrochloric acid (70 ml) was added thereto, and the mixture was stirred. The deposited solids were collected by filtration, washed with water, and then dried to obtain 8-methoxy-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4 ] diazepine-2, 5-dione in a white solid form

(1.50 g) . Furthermore, the filtrate was subjected to extraction with ethyl acetate, and the extract was dried over magnesium sulfate. The solvent in the filtrate was distilled off under reduced pressure. Then, water was added to the residue, and the deposited solids were collected by filtration, washed with water, and then dried to obtain 8-methoxy-4-methyl-3, 4- dihydro-lH-benzo [e] [1, 4] diazepine-2, 5-dione in a white solid form (0.37 g) .

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.09 (3H, s) , 3.79 (3H, s) , 3.83 (2H, s) , 6.62 (1H, d, J = 2.5Hz) , 6.82 (1H, dd, J = 2.5, 8.8Hz) , 7.69 (1H, d, J = 8.8Hz) , 10.37 (1H, s) .

[0270]

Reference Example 70

Production of 4, 6, 7-trimethyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

[ (2,3-Dimethyl-6- nitrobenzoyl)methylamino] acetic acid methyl ester (2.72

g, 9.7 mM) was dissolved in ethanol/ethyl acetate (250 ml/150 ml). To the solution, 5% palladium-carbon (0.3 g) was added. After hydrogen substitution, the mixture was stirred at room temperature for 1 hour. 10% palladium-carbon (0.3 g) was added thereto. After hydrogen substitution again, and the mixture was stirred overnight at room temperature. After the completion of the reaction, the catalyst was removed from the reaction mixture, and the residue was concentrated to obtain a brown oil substance (2.41 g) . This substance was made into a dimethylformamide (30 ml) solution. To the solution, sodium hydride (0.7 g) was added, and the mixture was heated at 60 to 7O ⁰ C for 6 hours. After the completion of the reaction, water was added to the reaction mixture to stop the reaction, and dimethylformamide was distilled off using an evaporator. The residue was rendered acidic with a 1 N aqueous hydrochloric acid solution and then subjected to extraction with ethyl acetate. The extract was washed with a saturated saline, dried over sodium sulfate, and then concentrated to obtain 4,6,7- trimethyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine-2, 5- dione (2 g, in a crude, brown solid form) . 1H-NMR (CDCl ₃ ) δ ppm : 2.29 (3H, s) , 2.38 (3H, s) , 3.27 (3H, s), 3.57 (IH, d, J = 18 Hz), 4.11-4.16 (IH, m) , 6.71 (IH, d, J = 8.2 Hz), 7.17 (IH, d, J = 8.0 Hz), 7.73 (IH, br) . [0271]

A compound of Reference Example 71 shown below was produced in the same way as in Reference Example 70 using appropriate starting materials.

[0272]

Reference Example 71

4,6, 8-Trimethyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione 1H-NMR (CDCl ₃ ) δ ppm : 2.31 (3H, s) , 2.48 (3H, s) , 3.26

(3H, s), 3.60 (IH, br), 4.09 (IH, br) , 6.60 (IH, s) , 6.92 (IH, s) , 7.88 (IH, br) .

[0273]

Reference Example 72

Production of 4, 7, 8-trimethyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

10% palladium-carbon (0.3 g) was added to an ethanol/ethyl acetate (50 ml/50 ml) solution of [(4,5- dimethyl-2-nitrobenzoyl)methylamino] acetic acid methyl ester (0.99 g, 3.5 mM) . After hydrogen substitution, the mixture was stirred at room temperature for 4 hours. The catalyst was removed from the reaction mixture, and the residue was concentrated and made into a dimethylformamide (30 ml) solution. Then, sodium hydride (0.3 g) was added thereto, and the mixture was heated at 60 ⁰ C for 3 hours. The reaction mixture was concentrated. Then, an aqueous saturated ammonium chloride solution and ethyl acetate were added thereto, and the deposited solids were collected by filtration to obtain the compound 4, 7, 8-trimethyl-3, 4-dihydro-lH-

benzo [e] [1, 4] diazepine-2, 5-dione (0.11 g, 5.0 mM, pale yellow solid) . Furthermore, the filtrate was subjected to ethyl acetate, and the extract was dried over sodium sulfate and then concentrated. The deposited crystals were collected by filtration to obtain the compound 4,7, 8-trimethyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine- 2, 5-dione (0.38 g, 1.7 mM, in a pale yellow solid form) .

¹ H-NMR (DMSOd ₆ ) δ ppm : 2.22 (3H, s) , 2.23 (3H, s) , 3.09 (3H, s), 3.80 (2H, s) , 6.85 (IH, s) , 7.49 (IH, s) , 10.29 (IH, s). [0274]

Reference Example 73

Production of (S) -4-methyl-3-phenyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione

Zinc (9.8 g, 15 mM) was added to a methanol (50 ml) solution of methanesulfonic acid (S)-2-tert- butoxycarbonylamino-3-phenylpropyl ester (4.6 g, 15 mM) . To the solution, ammonium chloride (4 g, 75 mM) was added with ice-cooling, and the mixture was stirred at room temperature for 1 hour (this procedure produced gas) . Zinc was filtered off through celite from the reaction mixture, and the filtrate was then concentrated to about half the volume. To this concentrate, p-toluenesulfonic acid monohydrate (1.45 g, 7.6 mM) was added, and the mixture was subjected to reflux for 6 hours. The reaction mixture was concentrated and then separated by column

chromatography (n-hexane/ethyl acetate) to obtain the compound (S) -4-methyl-3-phenyl-3, 4-dihydro-lH- benzo[e] [1, 4] diazepine-2, 5-dione (2.01 g, 7.5 mM) . 1H-NMR (CDCl ₃ ) δ ppm : 3.52 (3H, s) , 5.37 (IH, s) , 6.70- 7.39 (8H, s), 7.74 (IH, d, J = 7.9 Hz), 8.23 (IH, br) . [0275]

Reference Example 74

Production of 3-ethyl-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

Zinc (8.9 g, 14 mM) was added to a methanol (40 ml) solution of 2- [methyl (2- nitrobenzoyl) amino] butyric acid methyl ester (3.8 g, 14 mM) . To the solution, ammonium chloride (3.7 g, 69 mM) was added with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Zinc was filtered off through celite from the reaction mixture, and the filtrate was then concentrated to about half the volume. To this concentrate, p-toluenesulfonic acid monohydrate (1.3 g, 6.8 mM) was added, and the mixture was subjected to reflux for 6 hours. The reaction mixture was concentrated and then separated by column chromatography (n-hexane/ethyl acetate) to obtain the compound 3-ethyl-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione (1.81 g, yield: 59%). ¹ H-NMR (CDCl ₃ ) δ ppm : 0.96 (3H, br) , 2.01-2.17 (2H, br m) , 3.12-3.38 (3H, br) , 3.89 (IH, br) , 6.95 (IH, d, J = 7.3 Hz), 7.26-7.30 (IH, m) , 7.45-7.50 (IH, m) , 7.78 (IH, br), 7.97 (IH, d, J = 7.7 Hz).

[ 0276 ]

Compounds of Reference Examples 75 to 104 shown below were produced in the same way as in Reference Example 74 using appropriate starting materials .

[0277]

Reference Example 75

( (S) -4-Methyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepin-3-yl) -acetic acid methyl ester ¹ H-NMR (DMSCKd ₆ ) δ ppm : 2.89-3.10 (2H, m) , 2.93 (3H, s), 3.59 (3H, s), 4.32-4.37 (IH, m) , 7.13 (IH, dd, J = 0.8, 7.8 Hz), 7.24-7.29 (IH, m) , 7.52-7.57 (IH, m) , 7.75 (IH, dd, J = 1.5, 7.8 Hz), 10.59 (IH, br) .

[0278]

Reference Example 76

7-Bromo-4-methyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (DMSOd ₆ ) δ ppm : 3.32 (3H, s) , 3.88 (2H, s) , 7.06 (IH, d, J = 8.6), 7.69 (IH, d, J = 2.5, 8.6 Hz), 7.82 (IH, d, J = 2.5 Hz), 10.55 (IH, s) .

[0279]

Reference Example 77

4-Benzyl-7-bromo-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione 1H-NMR (CDCl ₃ ) δ ppm : 3.81 (2H, s) , 4.85 (2H, s), 6.85

(IH, d, J = 8.5 Hz), 7.23-7.40 (5H, m) , 7.58 (IH, dd, J = 2.3, 8.6 Hz), 8.18 (IH, d, J = 2.3 Hz), 8.45-8.68

(IH, br) .

[ 0280 ]

Reference Example 78

7-Bromo-3, 4-dihydro-lH-benzo [e] [1,4] diazepine-2, 5-dione ¹ H-NMR (DMSO-de) : 3.62 (2H, d, J = 5.9 Hz), 7.06 (IH, d, J = 8.6 Hz), 7.70 (IH, dd, J = 2.5, 8.6 Hz), 7.83 (IH, d, J = 2.5 Hz), 8.65 (IH, t, J = 5.9 Hz), 10.45 (IH, s) . [0281]

Reference Example 79

7-Bromo-4-ethyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 1.09 (3H, t, J = 7.1 Hz), 3.46- 3.84 (2H, m) , 3.88 (2H, s) , 7.05 (IH, d, J = 8.6 Hz), 7.68 (IH, dd, J = 2.4, 8.6 Hz), 7.83 (IH, d, J = 2.4 Hz) , 10.53 (IH, br) . [0282]

Reference Example 80

4-Methyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine-8-carboxylic acid methyl ester ¹ H-NMR (DMSOd ₆ ) δ ppm : 3.13 (3H, s) , 3.88 (5H, s) , 7.69-7.79 (2H, m) , 7.87 (IH, d, J = 8.0 Hz), 10.61 (IH, s) . [0283]

Reference Example 81

4-Methyl-2 , 5-dioxo-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine-8-carboxylic acid ethyl ester ¹ H-NMR (DMSO-de) δ ppm : 1.31 (3H, t, J = 7.1 Hz), 3.11 (3H, s), 3.87 (2H, s) , 4.33 (2H, q, J = 7.1 Hz), 7.65-

7.75 (2H, m) , 7.85 (IH, d, J = 8.7 Hz), 10.57 (IH, s) . [0284]

Reference Example 82

8-Amino-4-methy1-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.04 (3H, s) , 3.76 (2H, s) , 5.79 (2H, s), 6.16 (IH, d, J = 2.0 Hz), 6.38 (IH, dd, J = 2.0, 8.6 Hz), 7.42 (IH, d, J = 8.6 Hz), 10.15 (IH, s) . [0285]

Reference Example 83

7-Amino-4-methyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.08 (3H, s) , 3.74 (2H, s) , 5.17 (2H, s), 6.70 (IH, dd, J = 2.5, 8.5 Hz), 6.78 (IH, d, J = 8.5 Hz), 6.92 (IH, d, J = 2.5 Hz), 9.96 (IH, s) . [0286]

Reference Example 84

8-Amino-4-ethyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 1.08 (3H, t, J = 7.0 Hz), 3.47- 3.54 (2H, m) , 3.75 (2H, br) , 5.78 (2H, br) , 6.15 (IH, d J = 2.0 Hz), 6.37 (IH, dd, J = 2.1, 8.5 Hz), 7.42 (IH, d, J = 8.5 Hz), 10.13 (IH, br) . [0287]

Reference Example 85

7-Dimethylamino-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazeρine-2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 2.89 (6H, s), 3.10 (3H, s) , 6.90-7.00 (3H, m) , 10.08 (IH, s) . [0288]

Reference Example 86

8-Dimethylamino-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.02 (6H, s), 3.25 (3H, s) , 3.88 (2H, s), 6.08 (IH, d, J = 2.5 Hz), 6.58 (IH, dd, J = 2.5, 9.0 Hz), 7.83 (IH, d, J = 8.9 Hz), 8.14 (IH, brs). [0289]

Reference Example 87

8-Diethylamino-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 1.18 (6H, t, J = 7.1 Hz), 3.24 (3H, s), 3.38 (4H, q, J = 7.1 Hz), 3.89 (2H, s), 6.02 (IH, d, J = 2.5 Hz), 6.54 (IH, dd, J = 2.5, 9.0 Hz), 7.75 (IH, br), 7.80 (IH, d, J = 9.0 Hz) . [0290]

Reference Example 88

8-Dimethylamino-4-ethyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 1.09 (3H, t, J = 7.1 Hz), 2.95 (6H, s), 3.53 (2H, q, J = 7.1 Hz), 3.78 (2H, s) , 6.29 (IH, d, J = 2.4 Hz), 6.58 (IH, dd, J = 2.4, 8.8 Hz), 7.57 (IH, d, J = 8.9 Hz), 10.15 (IH, br) . [0291]

Reference Example 89 4-Methyl-8-phenyl-3,4-dihydro-lH-

benzo [e] [1, 4 ] diazepine-2, 5-dione

¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.14(s, 3H), 3.91(s, 2H), 7.35- 7.86(m, 8H) , 10.52 (br, IH) . [0292]

Reference Example 90

8-Ethy1-4-methy1-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 1.18(t, J=7.6Hz, 3H), 2.62(d, J=7.6Hz, 2H), 3.11(s, 3H), 3.83(s, 2H), 6.92(d, J=I.6Hz, IH), 7.08(dd, J=I.6, 8.1Hz, IH), 7.66(d, J=8.1Hz, IH), 10.37 (br, IH) . [0293]

Reference Example 91

7-Ethy1-4-methy1-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 1.25 (t, J=7.6Hz, 3H), 2.69(d, J=7.6Hz, 2H), 3.29(s, 3H), 3.89(s, 2H), 6.87(d, J=8.2Hz, IH), 7.31 (dd, J=2.1, 8.2Hz, IH), 7.72(br, IH), 7.78(d, J=2.1Hz, IH) . [0294]

Reference Example 92

8-Butyl-4-methyl-3, 4-dihydro-lH-benzo [e] [1,4] diazepine- 2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 0.87-1.65(m, 7H), 2.63(t, J=7.5Hz, 2H), 3.28(s, 3H), 4.37(s, 2H), 6.75(d, J=I.5Hz, IH), 7.10 (dd, J=I.5, 8.0Hz, IH), 7.48(br, IH), 7.92(d, J=8.0Hz, IH) . [0295]

Reference Example 93 4-Methyl-8-propyl-3,4-dihydro-lH- benzo[e] [1, 4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 0.95 (3H, t, J=7.3Hz) , 1.61 (2H, sept, J=7.3Hz) , 2.61 (2H, t, J=7.3Hz) , 3.29 (3H, s) , 4.21 (2H, s) , 6.73 (1H, d, J=I.3Hz) , 7.1O (1H, dd, J=I.3, 8.1Hz) , 7.69 (1H, br) , 7.87 (1H, d, J=8.1Hz) . [0296]

Reference Example 94

7-Bromo-4-methyl-1-naphthalen-2-yl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione 1H-NMR (CDCl ₃ ) δ ppm : 3.31 (3H, s), 3.81 (IH, d, J=14.8Hz), 4.23(1H, d, J=14.8Hz), 6.50-8.50(1OH, m) . [0297]

Reference Example 95

7-Bromo-1- (3, 4-dichlorophenyl) -4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione 1H-NMR (CDCl ₃ ) δ ppm : 3.31 (3H, s), 3.81 (IH, d, J=14.5Hz), 4.24(1H, d, J=14.5Hz), 6.68(1H, d, J=8.7Hz), 7.08(1H, dd, J=2.5, 8.7Hz), 7.38(1H, d, J=2.5Hz), 7.49(1H, dd, J=2.5, 8.7Hz), 7.49(1H, J=8.7Hz, IH), 8.06(1H, d, J=2.5Hz) . [0298]

Reference Example 96

8-Bromo-4-methyl-1-naphthalen-2-yl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione [0299]

Reference Example 97

4-Methyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine-8-carboxylic acid dimethylamide ¹ H-NMR (CDCl ₃ ) δ ppm : 3.00 (3H, s), 3.14 (3H, s), 3.31

(3H, s), 3.90 (3.90, 2H), 7.13 (br, IH), 7.26-7.28 (IH, m), 7.99 (IH, d, J = 7.99 Hz), 8.49 (IH, br) .

[0300]

Reference Example 98

4-Methyl-8-pyrrolidin-1-yl-3, 4-dihydro-lH- benzo [e] [1,4] diazeρine-2, 5-dione

¹ H-NMR (DMSO-de) δ ppm : 1.94-1.99 (4H, m) , 3.06 (3H, s), 3.22-3.27 (4H, m) , 3.78 (2H, s) , 6.14 (IH, d, J =

2.3 Hz), 6.42 (IH, dd, J = 2.3, 8.8 Hz), 7.56 (IH, d, J = 8.8 Hz) , 10.17 (1H, s) .

[0301]

Reference Example 99

4-Methyl-8-piperidin-1-yl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 1.64-1.65 (6H, br m) , 3.25 (3H, s), 3.27-3.29 (4H, m) , 3.88 (2H, s) , 6.27 (IH, d, J =

2.4 Hz), 6.77 (IH, dd, J = 2.4, 9.0 Hz), 7.76 (IH, br) , 7.81 (IH, d, J = 9.0 Hz) .

[0302]

Reference Example 100

4-Methyl-8-morpholin-4-yl-3,4-dihydro-1H- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.23-3.26 (4H, m) , 3.26 (3H, s) , 3.83-3.89 (6H, m) , 6.28 (1H, d, J = 2.4 Hz) , 6.78 (1H, dd, J = 2.4, 8.9 Hz) , 7.80 (1H, br) , 7.86 (1H, d, J =

8 . 9 Hz ) . [ 0303 ]

Reference Example 101

4-Methyl-1-naphthalen-2-yl-3,4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.35 (3H, s) , 3.85 (IH, d, J = 14 Hz), 4.33 (IH, d, J = 14 Hz), 6.82-7.90 (HH, m) . [0304]

Reference Example 102

1-Benzo [b] thiophen-5-yl-4-methyl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 3.34 (3H, s) , 3.84 (IH, d, J = 14.2 Hz), 4.32 (IH, d, J = 14.2 Hz), 6.84 (IH, dd, J = 1.7, 7.6 Hz), 7.19-7.35 (4H, m) , 7.51 (IH, d, J = 5.5 Hz), 7.71 (IH, d, J = 2.0 Hz), 7.90-7.95 (2H, m) . [0305]

Reference Example 103

3, 4-Dimethyl-1-naphthalen-2-yl-3, 4-dihydro-lH- benzo [e] [1,4] diazepine-2, 5-dione

¹ H-NMR (CDCl ₃ ) δ ppm : 1.63 (3H, d, J = 6.9 Hz), 3.17 (3H, s), 4.49 (IH, q, J = 6.9 Hz), 6.84-6.87 (IH, m) , 7.30-7.37 (3H, m) , 7.48-7.55 (2H, m) , 7.74-7.98 (5H, m) . [0306]

Reference Example 104

1-Benzo [b] thiophen-5-yl-3, 4-dimethyl-3, 4-dihydro-lH- benzo[e] [1, 4] diazepine-2, 5-dione 1H-NMR (CDCl ₃ ) δ ppm : 1.61 (3H, d, J = 6.9 Hz), 3.16

(3H, s) , 4.47 (1H, q, J = 6.9 Hz) , 6.85-6.88 (1H, m) , 7.19-7.40 (4H, m) , 7.51 (1H, d, J = 5.4 Hz) , 7.70 (1H, d, J = 2.0 Hz) , 7.90 (2H, m) . [0307]

Reference Example 105

Production of 4, 6-dimethyl-2, 3, 4 , 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

Lithium aluminum hydride (2.97 g, 78.3 mM) was added to a tetrahydrofuran (100 ml) solution of 4, 6-dimethyl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine-2, 5- dione (8.00 g, 392 mM) with stirring with ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was cooled to ice temperature. Sodium sulfate decahydrate (20 g) was added thereto in small portions, and the mixture was stirred for 1 hour. Insoluble matter was filtered off through celite, and the solvent in the filtrate was distilled off under reduced pressure to obtain 4, 6-dimethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine in a yellow solid form (6.88 g, yield: quantitative) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.34 (3H, s) , 2.43 (3H, s) , 2.79- 2.88 (2H, m) , 3.07-3.18 (2H, m) , 3.70-3.84 (3H, m) , 6.61 (1H, d, J = 7.7 Hz) , 6.74 (1H, d, J = 7.7 Hz) , 6.95 (1H, d, J = 7.7 Hz) . [0308]

Compounds of Reference Examples 106 to 149 shown below were produced in the same way as in Reference Example 105 using appropriate starting

materials . [0309]

Reference Example 106

4-Methyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine ¹ H-NMR (CDCl ₃ ) δ ppm : 2.42 (3H, s) , 2.85-2.94 (2H, m) , 3.10-3.20 (2H, m) , 3.75 (2H, s), 3.89 (IH, brs), 6.70- 6.79 (IH, m) , 6.79-6.90 (IH, m) , 7.04-7.16 (2H, m) . [0310]

Reference Example 107

7-Fluoro-4, 6-dimethyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.26 (3H, d, J = 2.3 Hz), 2.42 (3H, s), 2.75-2.89 (2H, m) , 3.02-3.15 (2H, m) , 3.60- 3.78 (3H, m) , 6.50-6.60 (IH, m) , 6.75 (IH, t, J = 8.9 Hz) . [0311]

Reference Example 108

8-Methanesulfonyl-4-methyl-2, 3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.41 (3H, s) , 2.84-2.93 (2H, m) , 3.15-3.25 (2H, m) , 3.75 (2H, s) , 4.09-4.19 (1H, br) , 7.24-7.32 (2H, m) , 7.36 (1H, dd, J = 1.8, 7.8 Hz) . [0312]

Reference Example 109

Dimethyl- (4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1,4] diazepin-7-yl) -amine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.81-2.95 (8H, m) , 3.02-3.12 (2H, m) , 3.53-3.65 (IH, br) , 6.53-6.65 (2H, m) , 6.67 (IH, d,

J = 8 . 3 Hz ) .

[ 0313 ]

Reference Example 110

Dimethyl- (4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1,4] diazeρin-8-yl) -amine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.36 (3H, s) , 2.80-2.87 (2H, m) , 2.89 (6H, s), 3.07-3.17 (2H, m) , 3.63 (2H, s) , 3.70- 3.84 (IH, br) , 6.12 (IH, d, J = 2.5 Hz), 6.24 (IH, dd, J = 2.5, 8.2 Hz), 6.97 (IH, d, J = 8.2 Hz) .

[0314]

Reference Example 111

(4-Methyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepin- 8-yl) methanol

¹ H-NMR (DMSOd ₆ ) δ ppm : 2.23 (3H, s) , 2.60-2.72 (2H, m) , 2.88-3.00 (2H, m) , 3.49 (2H, s) , 4.36 (2H, d, - J = 5.5 Hz), 4.99 (IH, t, J = 5.6 Hz), 5.33 (IH, brs) , 6.62

(IH, dd, J = 1.4, 7.5 Hz), 6.77 (IH, d, J = 1.4 Hz), 6.96 (IH, d, J = 7.5 Hz) .

[0315]

Reference Example 112

4-Benzyl-8-chloro-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.93 (2H, m) , 3.11-3.20 (2H, m) , 3.63 (2H, s), 3.74 (2H, s) , 3.90 (IH, brs), 6.73-6.82

(2H, m) , 6.86 (IH, d, J = 7.8 Hz), 7.20-7.37 (5H, m) .

[0316]

Reference Example 113

(4-Benzyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1,4] diazepin-

8-yl) methanol

¹ H-NMR (CDCl ₃ ) δ ppm : 1.70 (1H, t, J = 5.9 Hz) , 2.94- 3.03 (2H, m) , 3.10-3.20 (2H, m) , 3.64 (2H, s) , 3.78 (2H, s) , 3.91 (1H, brs) , 4.62 (2H, d, J = 5.7 Hz) , 6.75-6.84 (2H, in) , 6.95 (1H, d, J = 7.4 Hz) , 7.20-7.38 (5H, m) . [0317]

Reference Example 114

4-Ethyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4]diazepine ¹ H-NMR (CDCl ₃ ) δ ppm : 1.13 (3H, t, J = 7.1 Hz), 2.55 (2H, q, J = 7.1 Hz), 2.93-3.02 (2H, m) , 3.07-3.19 (2H, m) , 3.80 (2H, s) , 3.86 (IH, brs), 6.74 (IH, d, J = 7.7 Hz), 6.83 (IH, dd, J = 1.1, 7.7 Hz), 7.02-7.17 (2H, m) . [0318]

Reference Example 115

2,3,4, 5-Tetrahydro-lH-benzo [e] [1,4] diazepine 1H-NMR (CDCl ₃ ) δ ppm : 1.30-1.80 (IH, br) , 3.02-3.20 (4H, m) , 3.85-4.00 (3H, m) , 6.72-6.90 (2H, m) , 7.02- 7.15 (2H, m) . [0319]

Reference Example 116

6-Methoxy-4-methyl-2, 3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.42 (3H, s) , 2.77-2.95 (2H, m) , 3.10-3.95 (2H, m) , 3.75-3.89 (6H, m) , 6.33-6.40 (IH, m) , 6.45 (IH, d, J = 8.1 Hz), 7.00 (IH, d, J = 8.1 Hz) . [0320]

Reference Example 117 8-Chloro-4-methyl-2, 3, 4, 5-tetrahydro-lH-

benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38 (3H, s) , 2.8-2.9 (2H, m) , 3.1-3.2 (2H, m) , 3.65 (2H, s) , 3.89 (1H, br) , 6.73 (1H, d, J = 2.0Hz), 6.79 (1H, dd, J = 2.0, 8.0Hz), 7.02 (1H, d, J = 8.0Hz) . [0321]

Reference Example 118

9-Fluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.40 (3H, s) , 2.8-2.95 (2H, m) , 3.1-3.25 (2H, m) , 3.74 (2H, s) , 4.32 (1H, br) , 6.65-6.8 (1H, m) , 6.85-7.0 (2H, m) . [0322]

Reference Example 119

6-Fluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.43 (3H, s) , 2.8-2.9 (2H, m) , 3.1-3.25 (2H, m) , 3.78 (2H, s) , 3.96 (1H, br) , 6.50 (1H, d, J = 7.9Hz), 6.58 (1H, dd, J = 8.9, 8.9Hz), 6.9- 7.05 (1H, m) . [0323]

Reference Example 120

7, 8-Difluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.37 (3H, s) , 2.75-2.9 (2H, m) , 3.0-3.2 (2H, m) , 3.62 (2H, s) , 3.77 (IH, br) , 6.54 (IH, dd, J = 6.9, 11.3Hz), 6.92 (IH, dd, J = 8.7, 10.7Hz). [0324]

Reference Example 121

4-Methyl-2, 3, 4, 5-tetrahydro-lH-naphtho [2,3- e] [1 _/ 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.42 (3H, s) , 2.9-3.0 (2H, in), 3.1-3.25 (2H, m) , 3.90 (2H, s) , 4.08 (IH, br) , 7.11

(IH, s), 7.2-7.3 (IH, m) , 7.3-7.4 (IH, m) , 7.55-7.65

(2H, m) , 7.70 (IH, d, J = 8.0Hz) .

[0325]

Reference Example 122

4-Methyl-8-trifluoromethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.40 (3H, s) , 2.8-2.9 (2H, m) , 3.1-3.25 (2H, m) , 3.73 (2H, s) , 4.02 (1H, br) , 6.97

(1H, s) , 7.07 (1H, dd, J = 0.9, 7.8Hz) , 7.20 (1H, d, J = 7.7Hz) .

[0326]

Reference Example 123 4 , 8-Dimethyl-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.26 (3H, s) , 2.38 (3H, s) , 2.8- 2.9 (2H, m) , 3.05-3.2 (2H, m) , 3.67 (2H, s) , 3.79 (1H, br) , 6.56 (1H, s) , 6.65 (1H, dd, J = 0.9, 7.5Hz) , 6.99

(1H, d, J = 7.5Hz) .

[0327]

Reference Example 124

8-Fluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine 1H-NMR (CDCl ₃ ) δ ppm : 2.39 (3H, s) , 2.8-2.9 (2H, m) ,

3.1-3.2 (2H, in) , 3.65 (2H, s) , 3.89 (1H, br) , 6.4-6.55

(2H, m) , 7.04 (1H, dd, J = 6.5, 8.2Hz) .

[0328]

Reference Example 125

4-Benzyl-8-fluoro-2, 3, 4, 5-tetrahydro-lH- benzofe] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.9-3.0 (2H, m) , 3.1-3.25 (2H, m) , 3.64 (2H, s) , 3.74 (2H, s) , 3.92 (IH, br) , 6.4-6.55

(2H, m) , 6.88 (IH, dd, J = 6.7, 7.9Hz), 7.2-7.4 (5H, m) .

[0329]

Reference Example 126

4-Benzyl-2, 3,4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine ¹ H-NMR (CDCl ₃ ) δ ppm : 2.95-3.05 (2H, m) , 3.1-3.2 (2H, m) , 3.65 (2H, s), 3.79 (2H, s) , 3.86 (IH, br) , 6.76

(IH, dd, J = 0.9, 7.8Hz), 7.05-7.15 (IH, m) , 6.95-7.0

(IH, m) , 7.05-7.15 (IH, m) , 7.2-7.4 (5H, m) .

[0330]

Reference Example 127 4, 7-Dimethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.24 (3H, s) , 2.38 (3H, s) , 2.8- 2.9 (2H, m) , 3.05-3.15 (2H, m) , 3.68 (2H, s) , 3.76 (IH, br), 6.64 (IH, d, J = 7.8Hz), 6.85-6.95 (2H, m) .

[0331]

Reference Example 128

8-Methoxy-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38 (3H, s) , 2.75-2.9 (2H, m) , 3.1-3.2 (2H, m) , 3.64 (2H, s) , 3.76 (3H, s) , 3.83 (1H, br) , 6.30 (1H, d, J = 2.5Hz) , 6.38 (1H, dd, J = 2.5, 8.2Hz) , 7.01 (1H, d, J = 8.2Hz) . [0332]

Reference Example 129

4-Methyl-8-propyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) 6 ppm : 0.92(t, J=7.5Hz, 3H), 1.60 (sextet, J=7.5Hz, 2H), 2.38(s, 3H), 2.49(t, J=7.5Hz, 2H), 2.80-2.88(m, 2H), 3.10-3.17(m, 2H), 3.67(S, 2H), 3.88(br, IH), 6.55(d, J=I.5Hz, IH), 6.65(dd, J=I.5, 7.5Hz, IH), 7.01(d, J=7.5Hz, IH) . [0333]

Reference Example 130

7-Ethyl-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.19(t, J=7.6Hz, 3H), 2.39(s, 3H), 2.55(q, J=7.6Hz, 2H), 2.83-2.90(m, 2H), 3.07- 3.18(m, 2H), 3.68(s, 3H), 3.77(br, IH), 6.66(d, J=7.8Hz, IH), 6.91(dd, J=I.8, 7.8Hz, IH), 6.95(d, J=I.8Hz, IH). [0334]

Reference Example 131

4-Methyl-8-phenyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.42 (s, 3H), 2.85-2.92 (m, 2H), 3.14-3.22(m, 2H), 3.75(s, 2H), 3.97(br, IH), 6.56(d,

J=I.7Hz, 1H) , 7.06 (dd, J=I.7, 7.7Hz, 1H) , 7.18 (d, J=7.7Hz, 1H) , 7.30-7.60 (m, 5H) . [0335]

Reference Example 132

8-Ethyl-4-methyl-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.20(t, J=7.6Hz, 3H), 2.38(s, 2H), 2.56(q, J=7.6Hz, 2H), 2.80-2.89 (m, 2H), 3.10- 3.15(m, 2H), 3.67(s, 2H), 3.68(br, IH), 6.57(s, IH), 6.68(d, J=7.6Hz, IH), 7.02(d, J=7.6Hz, IH) . [0336]

Reference Example 133

8-Butyl-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) 6 ppm : 0.70-1.80 (7H, m) , 2.37 (3H, s) , 2.40-3.30(6H, m) , 3.50-4.00 (3H, m) , 6.50-7.10 (3H, m) . [0337]

Reference Example 134

(4-Ethyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepin-8- yl) dimethylamine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.11 (3H, t, J = 7.2 Hz) , 2.53 (2H, q, J = 7.2 Hz) , 2.89 (6H, s) , 2.95-2.98 (2H, m) , 3.10-3.13 (2H, m) , 3.75 (2H, s) , 6.13 (1H, d, J = 2.5 Hz) , 6.25 (1H, dd, J = 2.5, 8.2 Hz) , 6.97 (1H, d, J = 8.2 Hz) . [0338]

Reference Example 135 (4-Ethyl-2,3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepin-8-

yl) methanol

¹ H-NMR (CDCl ₃ ) δ ppm : 1.12 (3H, t, J = 7.2 Hz), 2.54 (2H, q, J = 7.2 Hz), 2.95-2.98 (2H, m) , 3.11-3.13 (2H, m) , 3.80 (2H, s) , 4.60 (2H, s) , 6.75 (IH, s) , 6.80 (IH, ^' d, J = 7.5 Hz), 7.09 (IH, d, J = 7.5 Hz). [0339]

Reference Example 136

6, 8-Difluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.81-2.86 (2H, m) , 3.18-3.21 (2H, m) , 3.72 (2H, s) , 4.00 (IH, br) , 6.23-6.34 (2H, m) . [0340]

Reference Example 137

6, 8-Dimethoxy-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.40 (3H, s) , 2.76-2.79 (2H, m) , 3.13-3.16 (2H, m) , 3.72-3.79 (8H, m) , 5.92 (IH, d, J = 2.3 Hz), 6.05 (IH, d, J = 2.3 Hz) . [0341]

Reference Example 138

4, 6, 7-Trimethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.22 (3H, s) , 2.27 (3H, s) , 2.42 (3H, s), 2.81-2.84 (2H, m) , 3.08-3.12 (2H, m) , 3.79 (2H, s), 6.53 (IH, d, J = 7.9 Hz), 6.97 (IH, d, J = 7.9 Hz) . [0342]

Reference Example 139

4, 6, 8-Trimethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.21 (3H, s) , 2.31 (3H, s) , 2.4θ ^' (3H, s), 2.81-2.84 (2H, m) , 3.09-3.12 (2H, m) , 3.72 (2H, s), 6.43 (IH, s) , 6.57 (IH, s) . [0343]

Reference Example 140

4, 7, 8-Trimethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.16 (3H, s) , 2.18 (3H, s) , 2.37 (3H, s) , 2.83-2.88 (2H, m) , 3.08-3.11 (2H, m) , 3.66 (2H, s) , 6.54 (1H, s) , 6.87 (1H, s) . [0344]

Reference Example 141

4-Methyl-8-pyrrolidin-1-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.95-2.01 (4H, m) , 2.35 (3H, s) , 2.83-2.86 (2H, m) , 3.11-3.14 (2H, m) , 3.22-3.26 (4H, m) , 3.63 (2H, s) , 5.96 (IH, d, J = 2.3 Hz), 6.08 (IH ,dd, J = 2.3, 8.2 Hz), 9.95 (IH, d, J = 8.2 Hz) . [0345]

Reference Example 142

4-Methyl-8-piperidin-1-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.53-1.72 (6H, m) , 2.36 (3H, s) , 2.82-2.85 (2H, m) , 3.08-3.13 (6H, m) , 3.62 (2H, s) , 6.32 (IH, d, J = 2.4 Hz), 6.42 (IH, dd, J = 2.4, 8.2 Hz) , 6.97 (IH, d, J = 8.2 Hz) .

[ 0346 ]

Reference Example 143

4-Methyl-8-morpholin-4-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.37 (3H, s) , 2.83-2.86 (2H, m) , 3.10-3.15 (6H, m) , 3.63 (2H, s) , 3.83-3.86 (4H, m) , 6.29 (IH, d, J = 2.3 Hz), 6.40 (IH, dd, J = 2.3, 8.2 Hz), 7.01 (IH, d, J = 8.2 Hz).

[0347]

Reference Example 144

Diethyl ( 4-methyl-2 ,3,4, 5-tetrahydro-lH- benzo [e] [1,4] diazepin-8-yl) amine 1H-NMR (CDCl ₃ ) δ ppm : 1.13 (6H, t, J = 7.1 Hz), 2.36

(3H, s), 2.82-2.85 (2H, m) , 3.10-3.18 (2H, m) , 3.29

(4H, q, J = 7.1 Hz), 3.61 (2H, s) , 6.06 (IH, d, J = 2.5 Hz), 6.19 (IH, dd, J = 2.5, 8.3 Hz), 6.93 (IH, d, J =

8.3 Hz) . [0348]

Reference Example 145

(S) -3-Isopropyl-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 0.94 (3H, d, J = 6.6 Hz), 1.02 (3H, d, J = 6.7 Hz), 1.80-1.92 (IH, m) , 2.27 (3H, s) , 2.34-2.41 (IH, m) , 3.19-3.21 (2H, m) , 3.71 (IH, d, J = 15.2 Hz), 4.23 (IH, d, J = 15.2 Hz), 6.65 (IH, d, J =

7.4 Hz), 6.75-6.81 (H, m) , 7.03-7.08 (2H, m) . [0349]

Reference Example 146

(S) -3-Benzyl-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.34 (3H, s) , 2.80-3.11 (5H, m) , 3.84 (IH, d, J = 14.9 Hz), 4.19 (IH, d, J = 14.9 Hz), 6.66-6.69 (IH, m) , 6.79-6.84 (IH, m) , 7.04-7.10 (2H, m) , 7.18-7.33 (5H, m) . [0350]

Reference Example 147

3-Ethyl-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 0.98 (3H, t, J = 7.4 Hz), 1.45- 1.61 (2H, m) , 2.21 (3H, s) , 2.68-2.77 (IH, m) , 2.98- 3.11 (2H, m) , 3.87 (IH, d, J = 14.8 Hz), 4.08 (IH, d, J = 14.8 Hz), 6.70 (IH, dd, J = 1.1, 8.1 Hz), 6.79-6.84 (IH, m) , 7.05-7.10 (2H, m) . [0351]

Reference Example 148

(S) -4-Methyl-3-phenyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.21 (3H, m) , 3.28-3.40 (2H, m) , 3.53 (IH, dd, J = 3.2, 7.8 Hz), 3.80 (IH, d, J = 14.3 Hz), 3.90 (IH, br), 4.03 (IH, d, J = 14.3 Hz), 6.70 (IH, d, J = 7.9 Hz), 6.83-7.38 (8H, m) . [0352]

Reference Example 149

2- ( (S) -4-Methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepin-3-yl) ethanol 1H-NMR (CDCl ₃ ) δ ppm : 1.37-1.45 (IH, m) , 2.09-2.19 (IH,

in ) , 2.37 (3H, s) , 3.10-3.19 (3H, m) , 3.72-3.99 (4H, m) , 4.37 (1H, d, J = 15.2 Hz) , 6.70 (1H, d, J = 7.8 Hz) , 6.81-6.87 (1H, m) , 7.07-7.13 (2H, m) . [0353]

Reference Example 150

Production of 4-methyl-8-triisopropylsilanyloxymethyl- 2,3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine

Triisopropylsilyl chloride (8.90 ml, 41.8 mM) was added dropwise to a dimethylformamide (50 ml) solution of (4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepin-8-yl) methanol (6.70 g, 34.8 mM) and imidazole (7.10 g, 105 mM) at room temperature, and the mixture was stirred overnight. Then, water was added to the reaction mixture to stop the reaction, and extraction with ethyl acetate (50 ml) was performed 3 times. The organic layer was washed with water and a saturated saline and dried over magnesium sulfate. Then, the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (NH-silica gel; ethyl acetate/n- hexane=l/l) to obtain 4-methyl-8- triisopropylsilanyloxymethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4]diazepine in a white solid form (12.7 g, yield: quantitative) .

¹ H-NMR (CDCl ₃ ) δ ppm : 0.95-1.23 (21H, m) , 2.38 (3H, s) , 2.81-2.90 (2H, m) , 3.08-3.17 (2H, m) , 3.69 (2H, s) , 3.75-3.95 (IH, br) , 6.73-6.81 (2H, m) , 7.06 (IH, d, J = 7.5 Hz) .

[0354]

Compounds of Reference Examples 151 to 153 shown below were produced in the same way as in Reference Example 150 using appropriate starting materials . [0355]

Reference Example 151

4-Ethyl-8-triisopropylsilanyloxymethyl-2, 3,4,5- tetrahydro-lH-benzo [e] [1,4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.05-1.32 (24H, m) , 2.54 (2H, q, J = 7.2 Hz) , 2.96-2.99 (2H, m) , 3.11-3.14 (2H, m) , 3.80 (2H, s) , 4.75 (2H, s) , 6.76-6.80 (2H, m) , 7.06 (1H, d, J = 7.5 Hz) . [0356]

Reference Example 152

4-Methyl-7-triisopropylsilanyloxymethyl-2, 3,4,5- tetrahydro-lH-benzo [e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.04-1.21 (21H, m) , 2.38 (3H, s) , 2.85-2.88 (2H, m) , 3.10-3.13 (2H, m) , 3.70 (2H, s) , 4.73 (2H, s) , 6.69-6.72 (1H, m) , 7.07-7.10 (2H, m) . [0357]

Reference Example 153

(S) -4-Methyl-3- (2-triisopropylsilanyloxyethyl) -2,3,4,5- tetrahydro-lH-benzo [e] [1,4] diazepine 1H-NMR (CDCl ₃ ) δ ppm : 1.04-1.14 (21H, m) , 1.71-1.81 (2H, m) , 2.23 (3H, s) , 3.00-3.13 (3H, m) , 3.78-3.85 (3H, m) , 4.09 (IH, d, J = 14.9 Hz), 6.69 (IH, dd, J = 1.0, 8.1 Hz), 6.78-6.84 (IH, m) , 7.05-7.09 (2H, m) .

[ 0358 ]

Reference Example 154

Production of 1, 2, 3, 5-tetrahydrobenzo [e] [1, 4] diazepine- 4-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (14.7 g, 67.5 mM) was added to a methanol (100 ml) solution of 2,3,4,5- tetrahydro-lH-benzo[e] [1, 4] diazepine (10.0 g, 67.5 mM) with stirring at O ⁰ C, and the mixture was stirred overnight at room temperature. Methanol in the reaction mixture was distilled off, and ethyl acetate was added to the residue. The resultant mixture was washed with water and a saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel; ethyl acetate :n- hexane=l:20->l:5) to obtain 1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester in a pale yellow oil form (14.3 g, yield: 85%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 1.41 (9H, s) , 3.08-3.19 (2H, m) , 3.60-3.70 (2H,m), 3.91 (IH, brs) , 4.28-4.45 (2H, m) , 6.70-6.80 (IH, m) , 6.80-6.92 (IH, m) , 7.05-7.20 (2H, m) . [0359]

A compound of Reference Example 155 shown below was produced in the same way as in Reference Example 154 using appropriate starting materials. [0360]

Reference Example 155

7-Bromo-l, 2,3, 5-tetrahydro-benzo [e] [1,4] diazepine-4- carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.42 (9H, s) , 3.05-3.2 (2H, m) , 3.55-3.7 (2H, m) , 3.92 (IH, br) , 4.2-4.45 (2H, m) , 6.55-6.7 (IH, m) , 7.19 (IH, dd, J = 2.0, 8.3Hz), 7.25- 7.45 (IH, m) . [0361]

Reference Example 156

Production of 8-bromo-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

8-Bromo-4-methyl-3, 4-dihydro-lH- benzo [e] [1, 4] diazepine-2, 5-dione (6.25 g, 23.2 mM) was dissolved in THF. To the solution, dimethyl sulfide- borane (BH ₃ -DMS) (12 ml, 120 mM) was added dropwise with stirring at room temperature. After the completion of the dropwise addition, the reaction mixture was heated to reflux for 5 hours. After the completion of the reaction, dilute hydrochloric acid was added in small portions to the reaction mixture in an ice bath, and the mixture was stirred overnight. The pH of the reaction mixture was adjusted to an alkaline pH. Then, extraction with ethyl acetate was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=10: l-»2 : 1) to obtain yellow oil (5.08 g, yield: 91%).

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38(3H, s) , 2.80-2.90 (2H, m) , 3.10-3.20(2H, m) , 3.64(2H, s), 3.88(1H, br) , 6.85- 7.00 (3H, m) . [0362]

Compounds of Reference Examples 157 to 162 shown below were produced in the same way as in Reference Example 156 using appropriate starting materials . [0363]

Reference Example 157

7-Bromo-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38(3H, s) , 2.80-2.90 (2H, m) , 3.10-3.20(2H, m) , 3.66(2H, s) , 3.85(1H, br) , 6.61(1H, d, J=8.3Hz), 7.17(1H, dd, J=2.3, 8.3Hz), 7.23(1H, d, J=2.3Hz) . [0364]

Reference Example 158

4-Benzyl-7-bromo-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.90-3.05 (2H, m) , 3.10-3.15(2H, m) , 3.64(2H, s) , 3.74(2H, s) , 3.89(1H, br) , 6.64(1H, d, J=8.3Hz), 7.08(1H, d, J=2.3Hz), 7.18(1H, dd, J=2.3, 8.3Hz) , 7.20-7.40(5H, m) . [0365]

Reference Example 159

7-Bromo-4-ethyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.11 (3H, t, J = 7.2 Hz) , 2.54 (2H, q, J = 7.2 Hz) , 2.93-2.98 (2H, m) , 3.09-3.14 (2H, m) , 3.75 (2H, s) , 3.87 (1H, br) , 6.60 (1H, d, J = 8.3 Hz) , 7.16 (1H, dd, J = 2.3, 8.3 Hz) , 7.23 (1H, d, J = 2.3 Hz) . [0366]

Reference Example 160

7, 8-Dichloro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38 (3H, s) , 2.84-2.87 (2H, m) , 3.11-3.15 (2H, m) , 3.64 (2H, s) , 3.88 (IH, br) , 6.83 (IH, s) , 7.17 (IH, s) . [0367]

Reference Example 161

6, 8-Dichloro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.45 (3H, s) , 2.97-3.01 (2H, m) , 3.26-3.29 (2H, m) , 4.09 (2H, s) , 6.68 (IH, d, J = 2.0 Hz), 6.97(1H, d, J = 2.0 Hz). [0368]

Reference Example 162

7-Bromo-2, 3,4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine ¹ H-NMR (CDCl ₃ ) δ ppm : 1.67 (IH, br) , 3.0-3.15 (4H, m) , 3.85 (2H, s), 3.92 (IH, br) , 6.65 (IH, d, J = 8.3Hz), 7.16 (IH, dd, J = 2.4, 8.3Hz), 7.22 (IH, d, J = 2.3Hz). [0369]

Reference Example 163 Production of 1- (7-bromo-4-methyl-2, 3, 4, 5-

tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone

7-Bromo-4-methyl-2, 3,4, 5-tetrahydro-lH- benzo [e] [1, 4]diazepine (6.18 g, 25.6 inM) was dissolved in dichloromethane (100 ml) . To the solution, acetic anhydride (5 ml, 52.9 mM) , 4- (dimethylamino) pyridine

(DMAP) (3.2 g, 26.2 mM) , and pyridine (6.5 ml, 80.4 mM) were added, and the mixture was stirred overnight at room temperature. After the completion of the reaction, an aqueous potassium carbonate solution was added to the reaction mixture. Extraction with dichloromethane was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=3: l->2: 1) to obtain white powder (6.29 g, yield: 87%). 1H-NMR (CDCl ₃ ) δ ppm : 1.93(s, 3H), 2.34(s, 3H), 2.85- 3.00(m, 3H), 3.53(d, J=14.1Hz, IH), 3.80(d, J=14.1Hz, IH), 4.55-4.60 (m, IH), 7.05(d, J=8.0Hz, IH), 7.40- 7.50 (m, 2H) .

[0370]

Compounds of Reference Examples 164 to 167 shown below were produced in the same way as in Reference Example 163 using appropriate starting materials .

[0371]

Reference Example 164 1- (4-Benzyl-7-bromo-2, 3, 4, 5-

tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.93(s, 3H), 2.88-3.13 (m, 3H), 3.53(d, J=13.4Hz, IH), 3.59(d, J=13.4Hz, IH), 3.61(d, J=14.2Hz, IH), 3.77(d, J=14.2Hz, IH), 4.52-4.63(m, IH), 7.07(d, J=8.3Hz, IH), 7.23(d, J=2.3Hz, IH), 7.24- 7.39(m, 5H), 7.44(dd, J=2.3, 8.3Hz, IH) . [0372]

Reference Example 165 1- (8-Bromo-4-methyl-2, 3,4,5- tetrahydrobenzo[e] [1, 4] diazepin-1-yl) ethanone [0373]

Reference Example 166 1- (7-Bromo-4-ethyl-2, 3, 4, 5- tetrahydrobenzofe] [1, 4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.10 (3H, t, J = 7.1 Hz), 1.93 (3H, s), 2.44-2.54 (2H, m) , 2.88-3.02 (3H, m) , 3.67 (IH, d, J = 14.0 Hz), 3.77 (IH, d, J = 14.0 Hz), 4.55- 4.61 (IH, m) , 7.05 (IH, d, J = 8.0 Hz), 7.40-7.45 (2H, m) . [0374]

Reference Example 167

4-Methyl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine- 7-carboxylic acid methyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 2.41 (3H, s) , 2.86-2.89 (2H, m) , 3.22 (2H, br), 3.75 (2H, s) , 3.86 (3H, s) , 4.19 (IH, br), 6.70 (IH, d, J = 8.2 Hz), 7.76 (IH, dd, J = 1.9, 8.2 Hz) , 7.80 (IH, s) . [0375]

Reference Example 168

Production of 4-methyl-1- (2-nitrobenzenesulfonyl) -7- phenyl-2, 3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine

7-Bromo-4-methyl-1- (2-nitrobenzenesulfonyl) - 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4]diazepine (4.37 g, 10.3 mM) was dissolved in dimethoxyethane (50 ml) . To the solution, phenylboronic acid (1.7 g, 13.9 mM) , tetrakis (triphenylphosphine) palladium (0) (600 mg, 0.52 mM) , and a 2 M aqueous sodium carbonate solution (40 ml) were added, and the mixture was heated to reflux overnight in a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=2 : 1->1: 1) to obtain 4-methyl-1- (2-nitrobenzenesulfonyl) -7-phenyl- 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4]diazepine in a pale yellow oil form (2.87 g, yield: 66%) . 1H-NMR (CDCl ₃ ) δ ppm : 2.36(s, 3H), 2.84-3.89(m, 6H), 6.40-8.00(m, 12H) . [0376]

Compounds of Reference Examples 169 to 172 shown below were produced in the same way as in Reference Example 168 using appropriate starting materials. [0377]

Reference Example 169 1- (4-Methyl-7-pyridin-3-yl-2, 3,4,5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00(s, 3H), 2.40(s, 3H), 2.80- 3.02(m, 3H), 3.66(d, 13.9Hz, IH), 3.86(d, J=13.9Hz, IH), 4.60-4.70(m, IH), 7.26-7.90(m, 5H), 8.62(dd, J=I.6, 4.8Hz, IH), 8.85(d, J=O.7, 2.4Hz, IH) . [0378]

Reference Example 170 1- (4-Methyl-7-pyridin-4-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00 (s, 3H), 2.40(s, 3H), 2.82- 3.00(m, 3H), 3.67(d, J=13.7Hz, IH), 3.86(d, J=13.7Hz, IH), 4.55-4.70(m, IH), 7.26-7.72(m, 5H), 8.69(d, J=6.1Hz, 2H). [0379]

Reference Example 171 1- (4-Benzyl-7-pyridin-4-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.99(s, 3H), 2.95-3.19(m, 3H), 3.59(d, J=13.2Hz, IH), 3.64(d, 13.2Hz, IH), 3.74(d, J=14.2Hz, IH), 3.87(d, J=14.2Hz, IH), 4.60-4.73(m, IH), 7.26-7.37(m, 7H), 7.47(d, J=6.1Hz, 2H), 7.58(dd, J=2.2, 8.0Hz, IH), 8.68(d, J=6.1Hz, 2H) . [0380]

Reference Example 172 1- (4-Benzyl-7-pyridin-3-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 2.00 (s, 3H) , 2.97-3.19 (m, 3H) , 3.59 (d, J=13.3Hz, 1H) , 3.65 (d, J=13.3Hz, 1H) , 3.74 (d, J=14.1Hz, 1H) , 3.86 (d, J=14.1Hz, 1H) , 4.60-4.70 (m, 1H) , 7.26-7.90 (m, 10H) , 8.62 (dd, J=I.6, 4.8Hz, 1H) , 8.82 (d, J=I.8Hz, 1H) . [0381]

Reference Example 173

Production of 4-methyl-7-pyridin-3-yl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepine l-(4-Methyl-7-pyridin-3-yl-2, 3,4,5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone (1 g, 3.6 mM) was dissolved in acetic acid (5 ml) . To the solution, concentrated hydrochloric acid (5 ml) was added, and the mixture was heated to reflux for 6 hours. After the completion of the reaction, the pH of the reaction mixture was adjusted to an alkaline pH. Extraction with ethyl acetate was performed, and the extract was dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=10 : 1-»1 : 1) to obtain pale yellow oil (815 mg, yield: 94%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.45(s, 3H), 2.85-2.93 (m, 2H), 3.16-3.23(m, 2H), 3.76(s, 2H), 3.99(br, IH), 6.84(d, J=7.9Hz, IH), 7.26-7.85(m, 4H), 8.52(dd, J=I.5, 4.8Hz, IH) , 8.80 (d, J=2.3Hz, IH) . [0382]

Compounds of Reference Examples 174 to 176

shown below were produced in the same way as in Reference Example 173 using appropriate starting materials . [0383]

Reference Example 174

4-Methyl-7-pyridin-4-yl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.45(s, 3H), 2.85-2.95(m, 2H), 3.00-3.45(m, 2H), 3.77(s, 2H), 4.40(br, IH), 6.83(d, J=7.8Hz, IH), 7.23-7.72(m, 4H), 8.59(dd, J=I.6, 4.6Hz, 2H) . [0384]

Reference Example 175

4-Benzyl-7-pyridin-3-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.96-3.05 (m, 2H) , 3.18-3.25 (m 2H) , 3.70 (s, 2H) , 3.85 (s, 2H) , 4.02 (br, 1H) , 6.87 (d, J=8.1Hz, 1H) , 7.15-7.85 (m, 9H) , 8.51 (dd, J=I.6, 4.8Hz, 1H) , 8.78 (dd, J=O.7, 1.6Hz, 1H) . [0385]

Reference Example 176

4-Benzyl-7-pyridin-4-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.97-3.05 (m, 2H) , 3.20-3.25 (m, 2H) , 3.70 (s, 2H) , 3.85 (s, 2H) , 4.10 (br, 1H) , 6.86(d, J=8.1Hz, 1H) , 7.24-7.75 (m, 9H) , 8.58 (dd, J=I.6, 4.6Hz, 2H) . [0386]

Reference Example 177

Production of 1- (7-imidazol-1-yl-4-methyl-2, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone

1- (7-Bromo-4-methyl-2, 3, 4,5- tetrahydrobenzo [e] [1, 4 ] diazepin-1-yl) ethanone (3 g, 10.6 mM) was dissolved in l-methyl-2-pyrrolidone (NMP) (20 ml). To the solution, imidazole (1 g, 14.7 mM) , copper (I) iodide (0.2 g, 1.1 mM) , N,N'- dimethylethylenediamine (0.45 ml, 4.2 mM) , and cesium carbonate (7 g, 21.5 mM) were added, and the mixture was heated with stirring at 15O ⁰ C for 8 hours. After the completion of the reaction, the solvent was distilled off from the reaction mixture, and water was added to the mixture. Extraction with dichloromethane was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture to obtain l-(7- imidazol-1-yl-4-methyl-2, 3,4,5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone in a brown solid form (2.9 g, yield: quantitative). 1H-NMR (CDCl ₃ ) δ ppm : 1.92(s, 3H), 2.39(s, 3H), 2.87- 2.99(m, 3H), 3.57(d, J=13.9Hz, IH), 3.78(d, J=13.9Hz, IH), 4.60-4.69(m, IH), 6.90-8.00(m, 5H), 8.45(s, IH). [0387]

Compounds of Reference Examples 178 to 186 shown below were produced in the same way as in Reference Example 177 using appropriate starting materials .

[ 0388 ]

Reference Example 178

1- (4-Methyl-7- [1, 2, 4] triazol-1-yl-2, 3, 4, 5-tetrahydro- benzo [e] [1, 4] diazepin-1-yl) ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 1.97(s, 3H), 2.39(s, 3H), 2.87- 3.08(m, 3H), 3.67(d, 13.9Hz, IH), 3.88(d, J=13.9Hz, IH), 4.64-4.72(m, IH), 7.33(d, J=8.3Hz, IH), 7.63(dd, J=2.5, 8.3Hz, IH), 7.67(d, J=2.5Hz, IH), 8.13(s, IH), 8.57(s, IH). [0389]

Reference Example 179 1- (4-Benzyl-7-imidazol-1-yl-2, 3,4,5- tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm ^' : 1.95(s, 3H), 2.90-3.09(m, 3H), 3.60(s, 2H), 3.65(d, J=14.2Hz, IH), 3.77(d, J=14.2Hz, IH), 4.60-4.68(m, IH), 6.65-8.00(m, 10H), 8.41(s, IH). [0390]

Reference Example 180

1- (4-Benzyl-7- [1, 2, 4] triazol-1-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.97(s, 3H), 2.93-3.17 (m _f 3H), 3.59(d, J=13.3Hz, IH), 3.64(d, J=13.3Hz, IH), 3.74(d, J=14.1Hz, IH), 3.86(d, J=14.1Hz, IH), 4.60-4.69(m, IH), 7.26-7.38(m, 6H), 7.41(d, J=2.5Hz, IH), 7.65(dd, J=2.5, 8.4Hz, IH), 8.11(s, IH), 8.53(s, IH) . [0391]

Reference Example 181 l-(4-Methyl-7-pyrazol-1-yl-2,3,4,5-

tetrahydrobenzo [e] [1, 4]diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.97(3H, s) , 2.37(3H, s) , 2.80- 3.10(3H, m) , 3.66(1H, d, J=14.0Hz), 3.89(1H, d, J=14.0Hz), 4.50-4.70(1H, m) , 6.5O(1H, dd, J=I.8, 2.5Hz), 7.26(1H, d, J=8.4Hz), 7.62(1H, dd, J=2.5, 8.4Hz), 7.68(1H, d, J=2.5Hz), 7.74(1H, d, J=I.8Hz), 7.94 (IH, d, J=2.5Hz) .

[0392]

Reference Example 182

7-Imidazol-1-yl-4-methyl-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.44 (s, 3H), 2.84-2.90 (m, 2H), 3.15-3.20(m, 2H), 3.71(s, 2H), 4.01(br, IH), 6.81(d, J=8.2Hz, IH), 7.09(dd, J=2.6, 8.2Hz, IH), 7.11-7.20(m, 3H), 7.74(s, IH).

[0393]

Reference Example 183

4-Methyl-7- [1, 2, 4] triazol-1-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.43 (s, 3H), 2.86-2.92 (m, 2H), 3.15-3.22(m, 2H), 3.76(s, 2H), 4.03(br, IH), 6.83(d, J=8.3Hz, IH), 7.35 (dd, J=2.5, 8.3Hz, IH), 7.41 (d, J=2.5Hz, IH), 8.06(s, IH), 8.42(s, IH) .

[0394]

Reference Example 184

4-Benzyl-7-imidazol-1-yl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine 1H-NMR (CDCl ₃ ) δ ppm : 2.97-3.03(m, 2H), 3.17-3.23(m,

2H) , 3.69 (s, 2H) , 3.79 (s, 2H) , 4.03 (br, 1H) , 6.83 (d, J=8.3Hz, 1H) , 6.95 (d, J=2.5Hz, 1H) , 7.10 (dd, J=2.5, 8.3Hz, 1H) , 7.16 (s, 2H) , 7.24-7.40 (m, 5H) , 7.72 (s, 1H) . [0395]

Reference Example 185

4-Benzyl-7- [1, 2, 4] triazol-1-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.97-3.05(m, 2H), 3.17-3.25 (m, 2H), 3.69(s, 2H), 3.84(s, 2H), 4.06(br, IH), 6.86(d, J=8.4Hz, IH), 7.21-7.40(m, 7H), 8.06(s, IH), 8.39(s, IH) . [0396]

Reference Example 186

4-Methyl-7-pyrazol-1-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.85-2.95(m, 2H), 3.10-3.20 (m _f 2H), 3.77(s, 2H), 3.96(br, IH), 6.42(dd, J=I.6, 2.4Hz, IH), 6.80(d, J=8.4Hz, IH), 7.37(dd, J=2.6, 8.4Hz, IH), 7.45(d, J=2.6Hz, IH), 7.68(d, J=I.6Hz, IH), 7.81(d, J=2.4Hz, IH). [0397]

Reference Example 187

Production of 1- [7- (5, 5-dimethyl- [1, 3, 2] dioxaborinan-2- yl) -4-methyl-2, 3,4, 5-tetrahydrobenzo [e] [1, 4]diazepin-1- yl]ethanone

1- (7-Bromo-4-methyl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone (2 g, 7.1 mM) was dissolved in dimethyl sulfoxide (DMSO) (40 ml) .

To the solution, bis (neopentyl glycolato) diboron (2 g, 8.9 mM) , [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II) (170 mg, 0.2 mM) , and potassium acetate (2.1 g, 21.4 mM) were added, and the mixture was heated to reflux for 3 hours in a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture to quantitatively obtain brown oil. 1H-NMR (CDCl ₃ ) δ ppm : 0.90-1.05 (6H, m) , 1.97(3H, m) , 2.40(3H, m) , 2.85-3.05 (3H, m) , 3.50-3.95 ( 6H, m) , 4.50- 4.8O(1H, m) , 7.00-7.80(3H, m) . [0398]

Compounds of Reference Examples 188 to 207 shown below were produced in the same way as in Reference Example 187 using appropriate starting materials. [0399]

Reference Example 188

1- [4-Methyl-7- (4,4,5, 5-tetramethyl- [1, 3, 2] dioxaborolan- 2-yl) -2,3,4, 5-tetrahydrobenzo [e] [1,4] diazepin-1- yl] ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 1.35(12H, s) , 1.93(3H, s) , 2.33(3H, s), 2.80-3.10(3H, m) , 3.65(1H, d, J=13.9Hz), 3.83(1H, d, J=13.9Hz), 4.50-4.70 (IH, m) , 7.17(1H, d, J=8.1Hz), 7.70-7.80(2H, m) .

[ 0400 ]

Reference Example 189

1- [4-Benzyl-7- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan- 2-yl) -2, 3, 4, 5-tetrahydrobenzo [e] [1, 4] diazepin-1- yl] ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 1.22 (12H, s) , 1.99(3H, s) , 2.90- 5.80(8H, m) , 7.00-7.90(8H, m) . [0401]

Reference Example 190

1- [4-Methyl-8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan- 2-yl) -2,3,4, 5-tetrahydrobenzo [e] [1,4] diazepin-1- yl] ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 1.20-1.36 (12H, m) , 1.90-2.05 (3H, m) , 2.30-2.40 (3H, m) , 2.83-3.10 (3H, m) , 3.50-3.95 (2H, m) , 4.50-4.80(1H, m) , 6.40-8.30 (3H, m) . [0402]

Reference Example 191

1- [4-Methyl-7- (6-methylpyridazin-3-yl) -2, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-1-yl] ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00(s, 3H), 2.39(s, 3H), 2.78(s, 3H), 2.88-3.12 (m, 3H), 3.72(d, J=13.8Hz, IH), 3.90(d, J=13.8Hz, IH), 4.56-4.72(m, IH), 7.32(d, J=8.1Hz, IH), 7.41(d, J=8.7Hz, IH), 7.76(d, J=8.7Hz, IH), 7.99(dd, J=2.1, 8.1Hz, IH), 8.04 (d, J=2.1Hz, IH). [0403]

Reference Example 192 l-(4-Methyl-7-pyridin-2-yl-2, 3,4,5- tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone

¹ H-NMR (CDCl ₃ ) δ ppm : 1.98 (s, 3H) , 2.38 (s, 3H) , 2.96- 3.05 (m, 3H) , 3.72 (d, J=13.6Hz, 1H) , 3.90 (d, J=13.6Hz, 1H) , 4.58-4.74 (m, 1H) , 7.26-8.00 (m, 6H) , 8.71 (dd, J=I.7, 3.8Hz, 1H) . [0404]

Reference Example 193

1- [4-Benzyl-7- (6-methylpyridazin-3-yl) -2,3,4,5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl] ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00 (s, 3H), 2.78 (s, 3H), 2.95- 3.13(m, 3H), 3.58(d, J=13.2Hz, IH), 3.66(d, J=13.2Hz, IH), 3.80(d, J=14.4Hz, IH), 3.89(d, J=14.4Hz, IH), 4.60-4.70(m, IH), 7.26-7.37(m, 6H), 7.41(d, J=8.8Hz, IH), 7.71(d, J=8.8Hz, IH), 7.79(d, J=2.0Hz, IH), 8.03 (dd, J=2.0, 8.2Hz, IH) . [0405]

Reference Example 194

1- [4-Methyl-8- (6-methylpyridazin-3-yl) -2, 3, 4, 5- tetrahydrobenzo[e] [1, 4] diazepin-1-yl] ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.01(3H, s), 2.37(3H, s) , 2.78(s, 3H), 2.80-3.10(3H, m) , 3.66(1H, d, J=13.9Hz), 3.89(1H, d, J=13.9Hz), 4.60-4.70(1H, m) , 7.42(1H, d, J=8.7Hz), 7.44(1H, d, J=7.9Hz), 7.75(1H, J=8.7Hz), 7.9O(1H, dd, J=I.8, 7.9Hz), 7.99(1H, d, J=I.8Hz). [0406]

Reference Example 195 1- (4-Methyl-7-pyrazin-2-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.99(3H, s) , 2.40 (3H, s), 2.85-

3.10 (3H, m) , 3.73 (1H. d, J=13.9Hz) , 3.9O (1H, d, J=13.9Hz) , 4.55-4.75(1H, m) , 7.33(1H, d, J=8.0Hz) , 7.96(1H, dd, J=2.0, 8.0Hz) , 7.99 (1H, d, J=2.0Hz) , 8.55 (1H, d, J=2.5Hz) , 8.65 (1H, dd, J=I.6, 2.5Hz) , 9.05(1H, d, J=I.6Hz) . [0407]

Reference Example 196

1- (4-Methyl-7-pyrimidin-5-yl-2, 3, 4, 5- tetrahydrobenzo [e] [1,4] diazepin-1-yl) ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00(3H, s), 2.42 (3H, s) , 2.85- 3.10(3H, m) , 3.68(1H. d, J=13.8Hz), 3.86(1H, d, J=13.8Hz), 4.60-4.80(1H, m) , 7.35(1H, d, J=8.6Hz), 7.45-7.60(2H, m) , 8.97(2H, s) , 9.24(lH,s). [0408]

Reference Example 197

1- [7- (6-Chloro-pyridazin-3-yl) -4-methyl-2, 3,4,5- tetrahydrobenzo [e] [1,4] diazepin-1-yl] ethanone 1H-NMR (CDCl ₃ ) δ ppm : 2.00(s, 3H), 2.40(s, 3H), 2.90- 3.02(m, 3H), 3.72(d, J=13.9Hz, IH), 3.89(d, J=13.9Hz, IH), 4.62-4.70(m, IH), 7.34(d, J=8.1Hz, IH), 7.60(d, J=9.0Hz, IH), 7.85(d, J=9.0Hz, IH), 7.98 (dd, J=2.1, 8.1Hz, IH), 8.03(d, J=2.1Hz, IH). [0409]

Reference Example 198

4-Methyl-7- (6-methylpyridazin-3-yl) -2, 3, 4, 5-tetrahydro- lH-benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.44(s, 3H), 2.72(s, 3H), 2.84- 2.95(m, 2H), 3.18-3.25 (m, 2H), 3.81(s, 2H), 4.07(br,

1H) , 6.84 (d, J=8.1Hz, 1H) , 7.31 (d, J=8.9Hz, 1H) , 7.67 (d, J=8.9Hz, 1H) , 7.82 (dd, J=2.2, 8.1Hz, 1H) , 7.87 (d, J=2.2Hz, 1H) . [0410]

Reference Example 199

4-Methyl-7-pyridin-2-yl-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.43 (s, 3H) , 2.86-2.95 (m, 2H) , 3.16-3.25 (m, 2H) , 3.82 (s, 2H) , 4.03 (br, 1H) , 6.82 (d, J=8.1Hz, 1H) , 7.10-7.90 (m, 5H) , 8.60-8.68 (m, 1H) . [0411]

Reference Example 200

4-Benzyl-7- ( 6-methylpyridazin-3-yl) -2,3,4, 5-tetrahydro- lH-benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.72(s, 3H), 2.94-3.03 (m, 2H), 3.18-3.28(m, 2H), 3.70(s, 2H), 3.90(s, 2H), 4.09(br, IH), 6.87(d, J=8.2Hz, IH), 7.26-7.36(m, 6H), 7.64(d, J=8.8Hz, IH), 7.70(d, J=2.2Hz, IH), 7.85(dd, J=2.2, 8.2Hz, IH) . [0412]

Reference Example 201

4-Methyl-8- (6-methylpyridazin-3-yl) -2, 3, 4, 5-tetrahydro- lH-benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.42(s, 3H), 2.75(s, 3H), 2.86- 2.94(m, 2H), 3.16-3.24 (m, 2H), 3.77(s, 2H), 4.08(br, IH), 7.24 (d, J=7.8Hz, IH), 7.35(d, J=8.8Hz, IH), 7.39(dd, J=I.7, 7.8Hz, IH), 7.62(d, J=I.7Hz, IH), 7.72 (d, J=8.8Hz, IH).

[0413]

Reference Example 202

4-Methyl-7-pyrazin-2-yl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.45 (s, 3H) , 2.86-2.95 (m, 2H) , 3.19-3.25 (m, 2H) , 3.82 (s, 2H) , 4.09 (br, 1H) , 6.84 (d, J=8.2Hz, 1H) , 7.76 (dd, J=2.2, 8.2Hz, 1H) , 7.82 (d, J=2.2Hz, 1H) , 8.41 (d, J=2.5Hz, 1H) , 8.56(dd, J=I.6, 2.5Hz, 1H) , 8.96 (d, J=I.6Hz, 1H) . [0414]

Reference Example 203

4-Methyl-7-pyrimidin-5-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.46(s, 3H), 2.84-2.91 (m, 2H), 3.18-3.24(m, 2H), 3.76(s, 2H), 4.06(br, IH), 6.86(d J=7.9Hz, IH), 7.22-7.36(m, 2H), 8.90(s, 2H), 9.13(s, IH) . [0415]

Reference Example 204

1- [4-Ethyl-7- (6-methylpyridazin-3-yl) -2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl] ethanone 1H-NMR (CDCl ₃ ) δ ppm : 1.13 (3H, t, J = 7.1 Hz), 1.99 (3H, s), 2.45-3.63 (2H, m) , 2.78 (3H, s) , 2.94-3.03 (3H, m) , 3.87 (2H, s) , 4.63-4.68 (IH, m) , ^• 7.32 (IH, d, J = 8.1 Hz), 7.41 (IH, d, J = 8.7 Hz), 7.76 (IH, d, J = 8.7 Hz), 7.97 (IH, dd, J = 2.1, 8.1 Hz), 8.05 (IH, d, J = 2.1 Hz) . [0416]

Reference Example 205

4-Ethyl-7- (6-methylpyridazin-3-yl) -2, 3, 4, 5-tetrahydro- lH-benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 1.15 (3H, t, J = 7.2 Hz), 2.61 (2H, q, J = 7.2 Hz), 2.72 (3H, s) , 2.98-3.01 (2H, m) , 3.20-3.23 (2H, m) , 3.90 (2H, s), 6.84 (IH, d, J = 8.2 Hz), 7,31 (IH, d, J = 8.8 Hz), 7.68 (IH, d, J = 8.8 Hz), 7.80 (IH, dd, J = 2.1, 8.2 Hz), 7.88 (IH, d, J = 2.1 Hz) . [0417]

Reference Example 206

7- ( 4 , 4 , 5, 5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) - 1,2,3, 5-tetrahydrobenzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.32 (12H, s), 1.35-1.5 (9H, m) , 3.15-3.25 (2H, m) , 3.55-3.7 (2H, m) , 4.05 (IH, br) , 4.3-4.55 (2H, m) , 6.72 (IH, d, J = 7.4Hz), 7.54 (IH, d, J = 7.8Hz) , 7.6-7.8 (IH, m) . [0418]

Reference Example 207 7- (6-Methylpyridazin-3-yl) -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δ ppm : 1.41 (9H, s) , 2.73 (3H, s) , 3.24 (2H, br), 3.6-3.75 (2H, m) , 4.12 (IH, br) , 4.4-4.55 (2H, m) , 6.86 (IH, d, J = 8.2Hz), 7.33 (IH, d, J = 8.7Hz) , 7.4-8.1 (3H, m) . [0419]

Reference Example 208

Production of 4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1,4] diazepine-8-carbonitrile

8-Bromo-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine (1.28 g, 5.3 mM) was dissolved in DMF. To the solution, zinc cyanide (1.9 g, 16.2 mM) and tetrakis (triphenylphosphine) palladium (0) (620 mg, 0.54 mM) were added, and the mixture was then heated with stirring at 100 ⁰ C for 3 hours in a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=3: 1-»1: 1) to obtain a pale yellow solid (934.2 mg, yield: 94%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.41 (s, 3H), 2.82-2.90 (m, 2H), 3.13-3.22 (m, 2H), 3.72(s, 2H), 4.03(br, IH), 6.99(d, J=I.5Hz, IH), 7.11 (dd, J=I.5, 7.7Hz, IH), 7.19(d, J=7.7Hz, IH) . [0420]

Reference Example 209 Production of 7-bromo-4-methyl-1- (2- nitrobenzenesulfonyl) -2,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

7-Bromo-4-methyl-2,3,4,5-tetrahydro-lH- benzo [e] [1, 4 ] diazepine (5.99 g, 24.8 mM) was dissolved

in dichloromethane (70 ml) . To the solution, triethylamine (7 ml, 50.2 mM) , 4-dimethylaminopyridine (0.3 g, 2.5 mM) , and o-nitrobenzenesulfonyl chloride (6.6 g, 29.8 mM) were added, and the mixture was heated to reflux overnight. After the completion of the reaction, the reaction mixture was subjected to extraction with dichloromethane, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=2 : 1—>1: 2) to obtain yellow oil (4.31 g, yield: 41%) . 1H-NMR (CDCl ₃ ) δ ppm : 2.29(s, 3H), 2.88-3.90(m, 6H), 6.82(d, J=8.4Hz, IH), 7.13-7.40 (m, IH), 7.42(d, J=2.3Hz, IH), 7.64-7.76(m, 3H), 7.86(dd, J=I.3, 7.8Hz, IH). [0421]

Reference Example 210

Production of 4-methyl-7-phenyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

4-Methyl-1- (2-nitrobenzenesulfonyl) -7-phenyl- 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine (2.87 g, 6.8 mM) was dissolved in DMF (20 ml). To the solution, lithium hydroxide monohydrate (1.25 g, 29.8 mM) and thioglycolic acid (0.95 ml, 13.4 mM) were added, and the mixture was stirred at room temperature for 5 hours. After the completion of the reaction, water was added to the reaction mixture. Extraction with ethyl

acetate was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=2 : 1—»1: 1) to obtain red oil (1.62 g, yield: quantitative) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.44(s, 3H), 2.85-2.92(m, 2H), 3.13-3.21(m, 2H), 3.77(S, 2H), 3.94(br, IH), 6.80(d, J=8.0Hz, IH), 7.25-7.45(m, 5H), 7.53-7.68(m, 2H) . [0422]

Reference Example 211

Production of 1- [4-methyl-7- (4-methylpiperazin-1-yl) - 2,3,4, 5-tetrahydrobenzo [e] [1,4] diazepin-1-yl] ethanone

1- (7-Bromo-4-methyl-2, 3, 4, 5- tetrahydrobenzo[e] [1, 4] diazepin-1-yl) ethanone (2 g, 7.1 mM) , 1-methylpiperazine (1.2 ml, 10.8 mM) , palladium (II) acetate (160 mg, 0.7 mM) , tri-tert-butylphosphine tetrafluoroborate (200 mg, 0.7 mM) , and sodium tert- butoxide (1.7 g, 17.7 mM) were added to toluene (50 ml) , and the mixture was heated to reflux for 5 hours in a nitrogen atmosphere. After the completion of the reaction, the deposits were filtered off through celite from the reaction mixture. Then, the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel chromatography (n- hexane: ethyl acetate=2 : l→l: 1) to obtain red oil (2.2 g, yield: quantitative) . 1H-NMR (CDCl ₃ ) δ ppm : 1.93(s, 3H), 2.34(s, 3H), 2.36(s,

3H), 2.54-2.62(m, 4H), 2.85-3.00 (m, 3H), 3.16-3.28 (m, 4H), 3.48(d, J=13.8Hz, IH), 3.80(d, J=13.8Hz, IH), 4.50-4.60(m, IH), 6.72-6.83 (m, 2H), 7.04 (d J=2.6Hz, IH) . [0423]

Compounds of Reference Examples 212 to 214 shown below were produced in the same way as in Reference Example 211 using appropriate starting materials . [0424]

Reference Example 212

4-Methyl-7- (4-methylpiperazin-1-yl) -2,3,4, 5-tetrahydro- lH-benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.34 (s, 3H), 2.38 (s, 3H), 2.50- 2.60(m, 4H), 2.82-2.89(m, 2H), 3.02-3.13 (m, 6H), 3.69(S, 2H), 3.71(br, IH), 6.67(d, J=8.4Hz, IH), 6.71(dd, J=2.5, 8.4Hz, IH), 6.76(d, J=2.5Hz, IH) . [0425]

Reference Example 213 1- (4-Methyl-7-pyridazin-3-yl-2, 3, 4, 5- tetrahydrobenzo[e] [1, 4] diazepin-1-yl) ethanone [0426]

Reference Example 214

4-Methyl-7-pyridazin-3-yl-2, 3, 4, 5-tetrahydro-lH- benzofe] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.44 (s, 3H), 2.87-2.92 (m, 2H), 3.20-3.26(m, 2H), 3.82(s, 2H), 4.16(br, IH), 6.86(d J=8.2Hz, IH), 7.46(dd, J=4.8, 8.7Hz, IH), 7.78(dd,

J=I.6, 8.7Hz, 1H) , 7.83 (dd, J=2.1, 8.2Hz, 1H) , 7.90 (d, J=2.1Hz, 1H) , 9.06 (dd, J=I.6, 4.9Hz, 1H) . [0427]

Reference Example 215

Production of l-acetyl-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine-7-carboxylic acid methyl ester

Methanol (5 ml), triethylamine (1.2 ml, 8.8 itiM) , palladium acetate (40 ing, 0.18 mM) , and 1,3- bis (diphenylphosphino) propane (144 mg, 0.35 mM) were added to a dimethylformamide (20 ml) solution of l-(7- bromo-4-methyl-2, 3,4, 5-tetrahydrobenzo [e] [1,4] diazepin- 1-yl) ethanone (1.0 g, 3.5 mM) , and the mixture was stirred at 80 ⁰ C for 8 hours in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature. Then, the deposits were filtered off through celite. Water was added to the filtrate, and extraction with ethyl acetate (20 ml) was performed 3 times. The organic layer was washed with water and a saturated saline and dried over magnesium sulfate. Then, the solvent was removed by concentration under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate) to obtain 1- acetyl-4-methyl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine-7-carboxylic acid methyl ester in a clear oil form (450 mg, yield: 49%) . 1H-NMR (CDCl ₃ ) δ ppm : 1.95 (3H, s) , 2.35 (3H, s) , 2.87- 3.03 (3H, m) , 3.67 (IH, d, J = 13.9 Hz), 3.84 (IH, d, J = 13.9 Hz), 3.94 (3H, s) , 4.62-4.65 (IH, m) , 7.23-7.27

( 1H, m) , 7 . 97-8 . 00 ( 2H, m) . [ 0428 ]

Reference Example 216

Production of (4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1,4] diazeρin-7-yl) methanol

Lithium aluminum hydride (0.1 g, 2.6 mM) was added to a tetrahydrofuran (10 ml) solution of 4- methy1-2, 3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine-7- carboxylic acid methyl ester (158 mg, 0.72 mM) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled with ice-cooling again, and sodium sulfate ' decahydrate was added thereto to stop the reaction. Then, the mixture was stirred overnight at room temperature. Insoluble matter was filtered off through celite, and the filtrate was concentrated and purified by basic silica gel column chromatography (dichloromethane:methanol=5: 1) to obtain (4-methyl- 2,3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepin-7- yl)methanol in a white solid form (117 mg, yield: 85%) . ¹ H-NMR (CDCl ₃ ) δ ppm : 2.40 (3H, s) , 2.85-2.88 (2H, m) , 3.12-3.15 (2H, m) , 3.70 (2H, s) , 4.57 (2H, s) , 6.72 (IH, d, J = 7.8 Hz), 7.07-7.12 (2H, m) . [0429]

Reference Example 217

Production of 7-methoxymethoxy-4-methyl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1,4] diazepine

Lithium aluminum hydride (0.29 g, 7.6 mM) was

added to a 1,4-dioxane (20 ml) solution of 7- methoxymethoxy-4-methyl-1, 3,4,5- tetrahydrobenzo[e] [1, 4]diazepin-2-one (0.90 g, 3.8 rnM) , and the mixture was stirred under reflux for 3 hours. The reaction mixture was cooled with ice-cooling. Then, 5 N hydrochloric acid was added thereto to adjust the pH of the mixture to an acidic pH. Then, a 5 N aqueous sodium hydroxide solution was added thereto to adjust the pH of the mixture to a basic pH. Extraction with ethyl acetate (20 ml) was performed 3 times. The extract was washed with water and a saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7- methoxymethoxy-4-methyl-2, 3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine in a brown oil form (0.76 g, yield: 90%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.39 (3H, s) , 2.83-2.89 (2H, m) , 3.07-3.11 (2H, m) , 3.47 (3H, s) , 3.66 (2H, s) , 6.66 (IH, d, J=5.0Hz), 6.78 (IH, dd, J=I.7Hz and 5.1Hz), 6.85 (IH, d, J=6.9 Hz) . [0430]

Compounds of Reference Examples 218 to 222 shown below were produced in the same way as in Reference Example 217 using appropriate starting materials . [0431]

Reference Example 218 7, 8-Dimethoxy-4-methyl-2, 3, 4, 5-tetrahydro-lH-

benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.39 (3H, s) , 2.81-2.88 (2H, m) , 3.09-3.16 (2H, m) , 3.62 (2H, s) , 3.79-3.81 (7H, m with two s at 53.82 and 3.83), 6.33 (IH, s ), 6.67 (IH, s) . [0432]

Reference Example 219

8-Methyl-β, 7, 8, 9-tetrahydro-5H-l, 3-dioxa-5, 8-diaza- cyclohepta [f] indene

¹ H-NMR (CDCl ₃ ) δ ppm : 2.36 (3H, s) , 2.79-2.88 (2H, m) , 3.04-3.11 (2H, m) , 3.62 (2H, s) , 5.87 (2H, s) , 6.32 (1H, s) , 6.63 (1H, s) . [0433]

Reference Example 220

7-Methoxy-4-methyl-2, 3, 4 , 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.38 (3H, s) , 2.85-2.90 (2H, m) , 3.05-3.11 (2H, m) , 3.69 (2H, s) , 3.75 (IH, s) , 6.63- 6.69 (2H, m) , 6.71 (IH, d, J=I.6Hz) . [0434]

Reference Example 221

7-Fluoro-4-methyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.39 (3H, s) , 2.81-2.91 (2H, m) , 3.04-3.11 (2H, m) , 3.66 (2H, s) , 3.74-3.92 (IH, m) , 6.67 (IH, dd, J=2.9Hz and 5.1Hz), 6.72-6.88 (2H, m) . [0435]

Reference Example 222 7-Chloro-4-methyl-2, 3, 4, 5-tetrahydro-lH-

benzo[e] [1, 4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm : 2.39 (3H, s) , 2.83-2.89 (2H, m) , 3.09-3.15 (2H, m) , 3.67 (2H, s) , 3.79-3.81 (1H, m) , 6.67 (1H, d, J= 5.0Hz) , 7.03 (1H, dd, J=I.5Hz and 5.0Hz) , 7.11 (1H, d, J=4.3Hz) .

[0436]

Compounds of Reference Examples 223 to 225 shown below were produced in the same way as in Reference Example 69 using appropriate starting materials .

[0437]

Reference Example 223

9-Methyl-2, 3, 6,8,9, 10-hexahydro-l, 4-dioxa-6, 9-diaza- cyclohepta [b] naphthalene-7 , 10-dione

IH-NMR (DMSO-d6) δppm : 3.07 (3H, s) , 3.81 (2H, s) , 4.2-4.35 (4H, m) , 6.57 (IH, s) , 7.16 (IH, s) , 10.20

(IH, s).

[0438]

Reference Example 224

4-Methyl-3, 4, 9, 10-tetrahydro-lH, 8H-7, 11-dioxa-l, 4- diaza-benzo [1, 2; 4, 5] dicycloheptene-2, 5-dione IH-NMR (DMSO-d6) δppm : 2.12 (2H, tt, J=5.5, 5.5Hz), 3.08 (3H, s), 3.82 (2H, s) , 4.13 (2H, t, J=5.6Hz), 4.20

(2H, t, J=5.4Hz), 6.67 (IH, s) , 7.27 (IH, s) , 10.29

(IH, s).

[0439]

Reference Example 225 ll-fluoro-9-Methyl-2, 3, 6,8,9, 10-hexahydro-l, 4-dioxa-

6, 9-diaza-cyclohepta [b]naphthalene-7, 10-dione IH-NMR (DMSO) δppm : 3.05 (3H, s) , 3.39-3.80 (IH, br) , 3.80-4.50 (5H, m) , 6.43 (IH, d, J = 2.0 Hz), 10.23 (IH, s) . [0440]

Compounds of Reference Examples 226 to 228 shown below were produced in the same way as in Reference Example 105 using appropriate starting materials. [0441]

Reference Example 226

9-Methyl-2, 3,7,8,9, 10-hexahydro-6H-l, 4-dioxa-6, 9-diaza- cyclohepta [b] naphthalene

IH-NMR (CDC13) δppm : 2.35 (3H, s) , 2.8-2.9 (2H, m) , 3.0-3.1 (2H, m) , 3.61 (3H, bs) , 4.15-4.25 (4H, m) , 6.29 (IH, s) , 6.64 (IH, s) . [0442]

Reference Example 227

4-Methyl-2, 3, 4, 5, 9, 10-hexahydro-lH, 8H-7, 11-dioxa-l, 4- diaza-benzo [1, 2; 4, 5]dicycloheptene

IH-NMR (CDC13) δppm : 2.05-2.2 (2H, m) , 2.37 (3H, s) , 2.75-2.85 (2H, m) , 3.05-3.15 (2H, m) , 3.58 (2H, s) , 3.66 (IH, bs), 4.09 (2H, t, J=5.6Hz), 4.13 (2H, t, J=5.4Hz), 6.39 (IH, s) , 6.77 (IH, s) . [0443]

Reference Example 228 ll-fluoro-9-Methyl-2, 3, 7, 8, 9, 10-hexahydro-6H-l, 4-dioxa- 6, 9-diaza-cyclohepta [b] naphthalene

IH-NMR (CDC13) δppm : 2.39 (3H, s) , 2.78-2.88 (2H, m) , 3.55-3.88 (3H, m with d at 3.73, J=I.1 Hz), 4.24 (4H, s) , 6.10 (IH, d, J=2.0 Hz) . [0444]

Example 1

Production of 4-methyl-1-naphthalen-2-yl-8- triisopropylsilanyloxymethyl-2 ,3,4, 5-tetrahydro-lH- benzofe] [1, 4] diazepine

Palladium (II) acetate (96.6 mg, 0.430 mM) and tri-tert-butylphosphine tetrafluoroborate (125 mg, 0.430 mM) were added to a toluene (30 ml) suspension of 4-methyl-8-triisopropylsilanyloxymethyl-2, 3,4,5- tetrahydro-lH-benzo [e] [1, 4] diazepine (3.00 g, 8.6 mM) , 2-bromonaphthalene (1.96 g, 9.4 mM) , and sodium tert- butoxide (1.24 g, 12.9 mM) at room temperature. Degassing and argon substitution were repeated 3 times, and the mixture was then stirred at 90 ⁰ C for 2 hours. The reaction mixture was cooled to room temperature. Then, water (30 ml) and ethyl acetate (30 ml) were added thereto, and insoluble matter was filtered off through celite. The filtrate was washed twice with water and once with a saturated saline, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=l:4) to obtain 4-methyl-1-naphthalen-2-yl-8- triisopropylsilanyloxymethyl-2, 3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine in a clear oil form (4.10 g,

yield: 100%).

¹ H-NMR (CDCl ₃ ) δ ppm: 0.97-1.15 (21H, m) , 2.37 (3H, s) , 2.90-3.00 (2H, m), 3.67 (2H, s) , 3.80-3.91 (2H, m) , 4.79 (2H, s), 6.98-7.06 (2H, m) , 7.15-7.40 (5H, m) , 7.55-7.63 (2H, m) , 7.67 (IH, d, J = 7.9 Hz). [0445]

Example 2

Production of (4-methyl-l-naphthalen-2-yl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1,4] diazepin-8-yl) methanol

Tetrabutylammonium fluoride (1 N, 19.0 ml, 19.0 mM) was added dropwise to a THF (50 ml) solution of 4-methyl-1-naphthalen-2-yl-8- triisopropylsilanyloxymethyl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4]diazepine (4.50 g, 9.48 mM) with stirring at 0 ⁰ C, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure from the reaction mixture. Then, the residue was purified by silica gel column chromatography (dichloromethane:methanol=30: 1) to obtain (4-methyl-1-naphthalen-2-yl-2, 3, 4, 5-tetrahydro- lH-benzo [e] [1, 4] diazepin-8-yl) methanol in a white amorphous form (2.23 g, yield: 74%). Melting point: 129.2 to 134.8°C [0446]

Example 3

Production of 8-methoxymethyl-4-methyl-1-naphthalen-2- yl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine difumarate

Sodium hydride (60% oil, 96.7 mg, 2.42 mM) was added to a DMF (7.0 ml) solution of (4-methyl-1- naphthalen-2-yl-2 ,3,4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepin-8-yl) methanol (700 mg, 2.19 mM) with stirring at 0 ⁰ C, and the mixture was stirred for 30 minutes. Then, methyl iodide (137 μl, 2.19 mM) was added thereto. The reaction mixture was stirred at 0 ⁰ C for 1 hour. Then, ice water was added thereto to stop the reaction, and extraction with ethyl acetate (20 ml) was performed 3 times. The organic layer was washed with water and a saturated saline, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane=l : 4->l: 1) . The purified product was concentrated under reduced pressure to obtain 190 mg of clear oil. To an ethanol

(10 ml) solution of this oil, an ethanol (10 ml) solution of fumaric acid (66.3 mg, 0.572 mM) was added. Ethanol was distilled off under reduced pressure. Then, the residue was crystallized from ethanol/ethyl acetate to obtain 8-methoxymethyl-4-methyl-1- naphthalen-2-yl-2 ,3,4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine difumarate in a white powder form (120 mg, yield: 9.7%). Melting point: 154.5 to 156.8°C

[0447]

Example 4 Production of 1- (6-methoxy-naphthalen-2-yl) -2, 3, 4, 5-

tetrahydro-lH-benzo [e] [1,4] diazepine

1-Chloroethyl chloroformate (1.64 ml, 15.2 mM) was added dropwise to a 1, 2-dichloroethane (20 ml) solution of 4-benzyl-1- (6-methoxy-naphthalen-2-yl) - 2,3, 4, 5-tetrahydro-lH-benzo[e] [1,4] diazepine (3.00 g, 7.60 mM) at room temperature, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure from the reaction mixture. Methanol (20 ml) was added thereto, and the mixture was subjected to reflux for 1 hour. Methanol was distilled off under reduced pressure. Then, an aqueous saturated potassium carbonate solution was added thereto, and extraction with ethyl acetate (30 ml) was performed 3 times. The organic layer was washed with water and a saturated saline, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate :n-hexane=l : 4 ) . The purified product was concentrated under reduced pressure, and the residue was recrystallized from chloroform/isopropyl ether to obtain 1- (6-methoxy-naphthalen-2-yl) -2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepine in a white powder form (1.44 g, yield: 62%). Melting point: 119.5 to 121.1°C [0448]

Example 5

Production of 1- (lH-indol-5-yl) -4-methyl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepine

Tetrabutylammonium fluoride (IM-THF solution, 3.5 ml, 3.5 mM) was added to a tetrahydrofuran (20 ml) solution of 4-methyl-1- (1-triisopropylsilanyl-lH-indol- 5-yl)-2,3,4,5-tetrahydro-lH-benzo[e] [1, 4] diazepine (760 mg, 1.75 mM) with stirring at room temperature, and the mixture was stirred at room temperature for 5 minutes. The reaction solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate :n- hexane=l : 20—>1 : 10—»1 : 1) . The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/n-hexane to obtain 1- (lH-indol-5-yl) -4-methyl-2, 3, 4, 5-tetrahydro- lH-benzo[e] [1, 4]diazepine in a white powder form (400 mg, yield: 82%) . Melting point: 182.2 to 183.3°C [0449]

Example 6

Production of 1- [1- (toluene-4-sulfonyl) -lH-indol-5-yl] - 2,3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine

Trifluoroacetic acid (10 ml) was added to a dichloromethane (20 ml) solution of 1- [1- (toluene-4- sulfonyl) -lH-indol-5-yl] -1,2,3,5- tetrahydrobenzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester (1.00 g, 1.93 mM) , and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure from the reaction mixture. Then, an aqueous saturate potassium

carbonate solution was added thereto, and extraction with ethyl acetate (20 ml) was performed 3 times. The organic layer was washed with water and a saturated saline and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1- [1- (toluene-4-sulfonyl) -lH-indol-5-yl] - 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine in a white amorphous form (680 mg, yield: 84%) . 1H-NMR (CDCl ₃ ) δ ppm: 1.53 (IH, brs) , 2.35 (3H, s) , 3.05-3.15 (2H, m) , 3.69-3.78 (2H, m) , 3.86 (2H, s) , 6.47 (IH, d, J = 3.7 Hz), 6.74-6.8 (2H, m) , 7.05-7.16 (2H, m) , 7.16-7.32 (4H, m) , 7.45 (IH, d, J = 3.6 Hz), 7.71-7.80 (3H, m) . [0450]

Example 7

Production of 1- ( lH-indol-5-yl ) -2 , 3 , 4 , 5-tetrahydro-lH- benzo [e] [1, 4]diazepine fumarate

Sodium ethoxide (1.5 ml) was added to an ethanol (20 ml) solution of 1- [1- (toluene-4-sulfonyl) - lH-indol-5-yl] -2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine (650 mg, 1.56 mM) , and the mixture was subjected to reflux for 2 hours. Ethanol was distilled off under reduced pressure. Water (20 ml) was added thereto, and extraction with ethyl acetate (20 ml) was performed 3 times. The organic layer was washed with water and a saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by

silica gel column chromatography (ethyl acetate :n- hexane=l : 2-»l : 1->1:O) . The obtained oil was made into an ethanol (10 ml) solution, and an ethanol (10 ml) solution of fumaric acid (181 mg, 1.56 mM) was added thereto. Ethanol was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol/ethyl acetate to obtain 1- (lH-indol-5-yl) - 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine fumarate in a white powder form (590 mg, yield: quantitative) . Melting point: 204.8 to 207.1 ⁰ C [0451]

Example 8

Production of 8-bromo-4-methyl-1-naphthalen-2-yl- 2,3,4, 5-tetrahydro-lH-benzo [e] [1, 4 ] diazepine hydrochloride

8-Bromo-4-methyl-1-naphthalen-2-yl-3, 4- dihydro-lH-benzo[e] [1, 4] diazepine-2, 5-dione (4.5 g, 11.4 mM) was dissolved in THF. To the solution, dimethyl sulfide-borane (5.6 ml, 56 mM) was added dropwise with stirring at room temperature. After the completion of the dropwise addition, the reaction mixture was heated to reflux for 5 hours. After the completion of the reaction, dilute hydrochloric acid was added in small portions to the reaction mixture in an ice bath, and the mixture was stirred overnight. After the completion of the reaction, the pH of the reaction mixture was adjusted to an alkaline pH. Extraction with ethyl acetate was performed, and the

extract was then dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=20:l→4:l) . A 4 N HCl-ethyl acetate solution was added to an ethyl acetate solution of the free form, and the deposits were collected by filtration and dried under reduced pressure to obtain 8-bromo-4- methyl-1-naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine hydrochloride in a pale yellow powder form (1.67 g, 4.1 mM, yield: 41%). 1H-NMR (DMSO-d ₆ ) δ ppm : 2.83(s, 3H), 3.20-3.68(m, 2H), 3.70-4.10(m, IH), 4.10-4.70(m, 3H), 7.11(dd, J=2.4, 9.0Hz, IH), 7.20-7.65(m, 6H), 7.70-7.86(m, 3H), 10.85(br, IH). [0452]

Example 9

Production of 4-methyl-1-naphthalen-2-yl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1,4] diazepine-8-carbonitrile oxalate

8-Bromo-4-methyl-1-naphthalen-2-yl-2, 3,4,5- tetrahydro-lH-benzo [e] [1, 4] diazepine (1 g, 2.7 mM) was dissolved in DMF. To the solution, zinc cyanide (640 mg, 5.5 mM) and tetrakis (triphenylphosphine) palladium (0) (150 mg, 0.13 mM) were added, and the mixture was then heated with stirring at 100 ⁰ C for 3 hours in a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was subjected to

extraction with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=20: l-»10: 1) . An ethyl acetate solution of oxalic acid was added to an ethyl acetate solution of the free form, and the deposits were collected by filtration, recrystallized from acetone, and dried under reduced pressure to obtain 4-methyl-1-naphthalen-2-yl-2, 3, 4, 5-tetrahydro- lH-benzo [e] [1, 4] diazepine-8-carbonitrile oxalate in a pale yellow powder form (465 nag, 1.2 mM, yield: 42%) . ¹ H-NMR (DMSO-d ₆ ) δ ppm : 2.64(s, 3H), 3.03-3.36(m, 2H), 3.50-5.20(m, 4H), 7.10 (dd, J=2.4, 9.0Hz, IH), 7.22- 7.35(m, 2H), 7.42(dt, J=I.2, 6.9Hz, IH), 7.56-7.90(m, 6H) . [0453]

Example 10

Production of 8- (3, 3-dimethyl-but-1-enyl) -4-methyl-1- naphthalen-2-yl-2 ,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

8-Bromo-4-methyl-1-naphthalen-2-yl-2, 3,4,5- tetrahydro-lH-benzo[e] [1, 4] diazepine (241.9 mg, 0.66 mM) was dissolved in DMF. To the solution, 3,3- dimethyl-1-butyne (0.4 ml, 3.2 mM) , dichlorobis (triphenylphosphine) palladium (II) (50 mg, 0.07 mM) , copper (I) iodide (30 mg, 0.16 mM) , and diethylamine (0.2 ml, 1.9 mM) were added, and the

mixture was then heated with stirring at 60 ⁰ C for 5 hours in a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=20 : 1—>5 : 1) . The purified product was recrystallized from n-hexane- isopropyl ether and dried under reduced pressure to obtain 8- (3, 3-dimethyl-but-1-enyl) -4-methyl-1- naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo[e] [1, 4]diazepine in a white powder form (39 mg, 0.11 mM, yield: 16%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 1.28(s, 9H), 2.35(s, 3H), 2.88- 2.98(m, 2H), 3.67(s, 2H), 3.75-3.93(m, 2H), 6.95- 7.05(m, 2H), 7.15-7.27 (m, 4H), 7.37 (dt, J=I.2, 6.8Hz, IH) , 7.57-7.70(m, 3H) . [0454]

Example 11

Production of 4-methyl-1-naphthalen-2-yl- 2,3,4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine-8- carboxylic acid ethyl ester oxalate

4-Methyl-1-naphthalen-2-yl-2, 3,4,5- tetrahydro-lH-benzo [e] [1,4] diazepine-8-carbonitrile (277.1 mg, 0.88 mM) was dissolved in ethanol. To the solution, an aqueous solution (5 ml) of potassium hydroxide (250 mg, 4.5 mM) was added, and the mixture

was heated to reflux for 2 days. After the completion of the reaction, the reaction mixture was neutralized with dilute hydrochloric acid, and the solvent was distilled off from the mixture. Ethanol (10 ml) and thionyl chloride (SOCl ₂ ) (0.15 ml, 0.77 mM) were freshly added thereto, and the mixture was heated to reflux for 3 hours. The solvent was distilled off from the reaction mixture, and an aqueous potassium carbonate solution was then added to the residue. Extraction with ethyl acetate was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=20: l->10: 1) . An ethyl acetate solution of oxalic acid and acetone were added to an ethyl acetate solution of the free form. The deposits were collected by filtration and dried under reduced pressure to obtain 4-methyl-1-naphthalen- 2-yl-2, 3,4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine-8- carboxylic acid ethyl ester oxalate in a pale yellow powder form (265.2 mg, 0.59 mM, yield: 67%) . 1H-NMR (DMSO-de) δ ppm : 1.26(t, J=7.1Hz, 3H), 2.68(s, 3H), 3.15-3.34(m, 2H), 3.70-4.22(m, 4H), 4.27(q, J=7.1Hz, 2H), 7.07(dd, J=2.4, 9.0Hz, IH), 7.23-7.35(m, 2H), 7.41(dt, J=I.0, 8.0Hz, IH), 7.66-7.83 (m, 5H), 7.84(dd, J=I.6, 8.0Hz, IH) . [0455]

Example 12

Production of 4-methyl-7-methylsulfanyl-1-naphthalen-2- yl-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diazepine

7-Bromo-4-methyl-1-naphthalen-2-yl-2, 3,4,5- tetrahydro-lH-benzo [e] [1, 4] diazepine (613.6 mg, 1.67 mM) was dissolved in THF, and the solution was cooled to -78°C in a nitrogen atmosphere. A 1.58 M n-butyl lithium-hexane solution (1.2 ml, 1.9 mM) was added thereto, and the mixture was stirred at the same temperature as above for 30 minutes. Then, dimethyl disulfide (0.23 ml, 2.6 mM) was added thereto, and the mixture was stirred overnight, with the reaction temperature increased to room temperature. The reaction was stopped with an aqueous ammonium chloride solution. Extraction with ethyl acetate was performed, and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was purified by NH-silica gel chromatography (n-hexane: ethyl acetate=20 : 1—>5 : 1) to obtain 4-methyl-7-methylsulfanyl- l-naphthalen-2-yl-2,3,4,5-tetrahydro-lH- benzo[e] [1, 4] diazepine in a pale yellow amorphous form (209.5 mg, 0.63 mM, yield: 37%) .

¹ H-NMR (CDCl ₃ ) δ ppm : 2.52 (s, 3H), 2.59(s, 3H), 2.86- 2.96(m, IH), 3.28-3.38(m, IH), 3.65-3.90(m, 2H), 4.15- 4.30(m, 2H) . 7.00(dd, J=2.5, 9.0Hz, IH), 7.05-7.16 (m _f 2H), 7.22-7.32 (m, 3H), 7.41 (dt, J=I.1, 6.9Hz, IH), 7.58-7.90(M, 3H). [0456]

Example 13

Production of 1- (3, 4-dichloro-phenyl) -4-methyl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepin-7-ol hydrochloride

1- (3, 4-Dichloro-phenyl) -7-methoxymethoxy-4- methyl-2, 3, 4 , 5-tetrahydro-lH-benzo [e] [1,4] diazepine (0.72 g, 2.0 mM) was dissolved in methanol (20 ml) . To the solution, 6 N hydrochloric acid (2 ml) was added, and the mixture was stirred at 50 ⁰ C for 5 hours during heating to reflux. The reaction mixture was concentrated to dryness under reduced pressure, and the obtained solids were washed with diethyl ether and then filtered. The obtained powder was dried under reduced pressure to obtain 1- (3, 4-dichloro-phenyl) -4-methyl- 2,3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepin-7-ol hydrochloride (0.60 g, yield: 85.3%, in a white powder form) .

¹ H-NMR (DMSO-d ₆ ) δ ppm : 2.79 (3H, s) , 3.19-3.81 (3H, m) , 4.00-4.31 (3H, m) , 6.59 (IH, dd, J=I.6Hz and 5.4Hz), 6.87 (IH, d, J=I.7Hz), 6.90 (IH, dd, J=I.7Hz and 5.1Hz), 7.01 (IH, d, J=I.7Hz), 7.11 (IH, d, J=5.1Hz), 7.35 (IH, d, J=5.4 Hz), 9.97 (IH, s) , 10.95 (IH, brs) . [0457]

Example 14

Production of 6- (4-methyl-2, 3, 4, 5- tetrahydrobenzo [e] [1, 4] diazepin-1-yl) -3, 4-dihydro-lH- quinolin-2-one

Methanesulfonic acid (5 ml) and veratrole

(0.18 ml) were added to 1- (4-methoxybenzyl) -6- (4- methyl-2, 3,4, 5-tetrahydrobenzo [e] [1, 4] diazepin-1-yl) - 3, 4-dihydro-lH-quinolin-2-one (0.54 g, 1.3 mM) , and the mixture was stirred at room temperature for 1 day. A 10% aqueous potassium carbonate solution was added to the reaction mixture with ice-cooling. The pH of the mixture was adjusted to an alkaline pH (pH>8) . Extraction with dichloromethane was performed, and the extract was then dried over magnesium sulfate. The solvent was distilled off under reduced pressure from the reaction mixture. The residue was purified by NH- silica gel column chromatography (n-hexane-ethyl acetate) . The solvent was distilled off under reduced pressure from the purified product. Then, acetonitrile was added thereto, and the deposited solids were collected by filtration and dried to obtain 6- (4- methy1-2, 3,4, 5-tetrahydro-benzo [e] [1,4] diazepin-1-yl) - 3, 4-dihydro-lH-quinolin-2-one in a white solid form (247 mg, yield: 64%) . Melting point: 190 to 191°C

¹ H-NMR (CDCl ₃ ) δ ppm : 2.37 (3H, s) , 2.55-2.65 (2H, m) , 2.8-2.9 (4H, m) , 3.66 (2H, s) , 3.7-3.75 (2H, m) , 6.55- 6.65 (3H, m) , 7.05-7.2 (2H, m) , 7.2-7.35 (2H, m) , 7.65 (IH, br) . [0458] ■

Example 15

Production of (4-methyl-1-naphthalen-2-yl-2, 3, 4, 5- tetrahydro-lH-benzo[e] [1, 4] diazepin-7-yl) methanol

Lithium aluminum hydride (5 mg, 0.13 mM) was added to a THF (10 ml) solution of 4-methyl-1- naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine-7-carboxylic acid methyl ester (12 mg, 0.035 mM) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate was added thereto with ice-cooling, and the mixture was directly stirred overnight at room temperature. Insoluble matter was filtered off through celite from the reaction mixture, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain (4-methyl-1- naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4 ]diazepin-7-yl) methanol (7.9 mg, 0.025 mM, a pale yellow oil substance) .

¹ H-NMR (CDCl ₃ ) δ ppm ; 2.39 (3H, s) , 2.92-2.95 (2H, m) , 3.68 (3H, br) , 3.86 (2H, br) , 4.70 (2H, s) , 6.99-7.02 (2H, m) , 7.17-7.41 (5H, m) , 7.57-7.69 (3H, m) . [0459]

Example 16

Production of N- (4-methyl-1-naphthalen-2-yl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepin-8-yl) acetamide

Triethylamine (0.28 ml, 2.0 mM) and acetyl chloride (0.12 ml, 1.7 mM) were added to a dichloromethane (10 ml) solution of 4-methyl-1- naphthalen-2-yl-2, 3,4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepin-8-ylamine (200 mg, 0.66 mM) , and the mixture was stirred overnight at room temperature.

After the completion of the reaction, an aqueous saturated potassium carbonate solution was added to the reaction mixture. Extraction with chloroform was performed, and the extract was dried over sodium sulfate and then concentrated. The concentrate was separated by silica gel column chromatography (ethyl acetate) to obtain N- (4-methyl-1-naphthalen-2-yl- 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4 ] diazepin-8- yl)acetamide (21.5 mg, a pale yellow oil substance) . ¹ H-NMR (CDCl ₃ ) δ ppm ; 2.14 (3H, s) , 2.38 (3H, s) , 2.92- 2.96 (2H, m) , 3.68 (2H, s) , 3.86-3.88 (2H, m) , 7.02- 7.71 (10H, m) . [0460]

Example 17

Production of 3, 4-dimethyl-1-naphthalen-2-yl-2, 3, 4, 5- tetrahydro-lH-benzo [e] [1, 4] diazepine hydrochloride

Lithium aluminum hydride (686 mg, 18 mM) was added to a THF (10 ml) solution of 3, 4-dimethyl-1- naphthalen-2-yl-3, 4-dihydro-lH-benzo [e] [1, 4] diazepine- 2,5-dione (598.0 mg, 1.76 mM) , and the mixture was stirred for 6 hours during heating to reflux. Sodium sulfate decahydrate was added thereto with ice-cooling, and the mixture was directly stirred overnight at room temperature. Insoluble matter was filtered off through celite from the reaction mixture, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate) . A 4 N HCl-ethyl acetate solution was added to an ethyl acetate solution

of the free form, and the deposits were collected by filtration and dried under reduced pressure to obtain 3, 4-dimethyl-1-naphthalen-2-yl-2, 3, 4, 5-tetrahydro-lH- benzo [e] [1, 4] diazepine hydrochloride in a pale yellow amorphous form (264 mg, yield: 15%) .

¹ H-NMR (DMSO-d ₆ ) δ ppm ; {1.31(1.65H, d, J = 5.9 Hz), 1.40 (1.35H, d, J = 6.5 Hz), total 3H}, {2.53(s), 2.82 (s, with DMSO), total 3H}, 3.32-4.58 (5H, m) , 6.93-7.76 (HH, m) , {10.43 (0.45H, br) , 10.95 (0.55H, br) , total 1H}. [0461]

Example 18

Production of 4-methyl-1-naphthalen-2-yl-7- (4- aminophenyl) -2,3,4, 5-tetrahydro-lH- benzo[e] [1, 4] diazepine

4-Methyl-1-naphthalen-2-yl-7- (4-nitrophenyl) - 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4]diazepine (550 mg, 1.34 mM) was suspended in ethanol (60 ml) . To the suspension, an aqueous solution (10 ml) of ammonium formate (423 mg, 6.7 mM) and zinc powder (2.63 g, 40 mM) were added, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered off through celite from the reaction mixture, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium-

pressure liquid chromatography (silica gel; dichloromethane:methanol=20 : 1) . The purified product was concentrated under reduced pressure to obtain 4- methyl-1-naphthalen-2-yl-7- (4-aminophenyl) -2,3,4,5- tetrahydro-lH-benzo [e] [1, 4] diazepine in a light brown amorphous solid form (373 mg, yield: 73%) . 1H-NMR (CDCl ₃ ) δ ppm : 2.42 (3H, s) , 2.94-2.98 (2H, m) , 3.73 (4H, bs), 3.87-3.90 (2H, m) , 6.74-6.79 (2H, m) , 7.04-7.08 (2H, m) , 7.19-7.26 (2H, m) , 7.31-7.39 (3H, m) , 7.42-7.47 (3H, m) , 7.49-7.519 (3H, m) , 7.59-7.69 (3H, m) , 13.30 (IH, bs) . [0462]

Compounds of Examples 19 to 1299 shown in tables below were produced in the same way as in the Examples using corresponding appropriate starting materials. In these tables, for example, the produced compounds have physical properties such as a crystalline form, m.p. (melting point) , salt, ¹ H-NMR, and MS (mass spectrum) .

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477] [

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

0495

0496

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

0510

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0535]

[0536]

[0537]

[0538]

[0539]

OO

[0540]

OO IV)

[0541]

[0542]

OO

[0543]

[0544] [Table 82]

Example R ¹¹ R ¹ R' NMR Salt

1H-NMR ( DMSO-d6 ) δppm : 2.70(s, 3H), 2.95(s, 3H), 3.30-3.95(m, 3H), 4.30-4.80(m, 3H),

466 -H -H -H -H -Cl 6.47(d, J=8.5Hz, 1H), 7.25-7.70(m, 4H), 7.75(d, J=8.9Hz, 1H) ₁ 7.96(dd, J=2.2, 8.5Hz, 1H), Dihydrochloride 8.22(d, J=8.9Hz, 1H), 8.35(d, J=2.2Hz, 1H) ₁ 10.95(br, 1H)

1H-NMR ( DMSO-d6 ) δppm : 2.71(s, 3H), 2.91(s, 3H), 3.25-3.90(m, 3H), 4.25-4.60(m, 3H),

467 -H -Cl -H -H -H 6.80-7.00(m, 3H), 7.27(dd, J=8.3, 8.3Hz, 1H), 7.42(d, J=8.3Hz, 1H), 7.80(d, J=8.8Hz, 1H) ₁ Dihydrochloride 8.15-8.25(m, 2H), 8.49(d, J=2.0Hz, 1H), 10.75(br, 1H)

1H-NMR ( DMSO-d6 ) δppm : 2.73(s, 3H), 2.89(s, 3H), 3.32-4.10(m, 3H) ₁ 4.25-4.55(m, 3H),

468 -H -F -H -Cl -H 6.40-6.95(m, 3H), 7.53(d, J=8.3Hz, 1H), 7.88(d, J=8.9Hz, 1H), 8.25(dd, J=2.0, 8.3Hz, 1H), Dihydrochloride 8.32(d, J=8.9Hz, 1H), 8.52(d, J=2.0Hz, 1H) ₁ 11.11(br, 1H)

1H-NMR ( DMSO-d6 ) δppm : 2.75(s, 3H), 2.90(s, 3H) ₁ 3.30-4.00(m, 3H), 4.10-4.85(m.3H) ₁

469 -H -H -H -H -H 6.90-7.15(m, 3H), 7.20-7.40(m, 3H), 7.97(d, J=8.9Hz, 1H), 8.15(dd, J=2.2, 8.5Hz, 1H), 8.39(d, Dihydrochloride J=8.9Hz, 1H) ₁ 8.44(d, J=2.2Hz, 1H), 11.22(br, 1H)

470 -H -Cl -CH ₃ -H -H 1H-NMR ( DMSO-d6 ) δppm : 2.26(s, 3H), 2.74(s, 3H) ₁ 2.89(s, 3H), 3.20-3.85(m, 3H), 4.20- 4.99(m, 3H) ₁ 6.75-7.35(m, 4H), 7.85-8.50(m, 4H) ₁ 11.11(br, 1H) Dihydrochloride

1H-NMR ( DMSO-d6 ) δppm : 2.73(s, 3H),.2.89(s, 3H) ₁ 3.25-3.55(m, 2H) ₁ 3.71(s, 3H), 3.71-

471 -H -OCH ₃ -H -H -H 3.85(m, 1H) ₁ 4.05-4.65(m, 3H), 6.45-6.55(m, 3H), 7.10-7.25(m, 1H), 7.31(d, J=8.4Hz, 1H) ₁ 7.90(d, J=8.9Hz, 1H), 8.16(dd, J=2.1, 8.4Hz, 1H), 8.33(d, J=8.9Hz, 1H), 8.45(d, J=2.1Hz, 1H) ₁ Dihydrochloride 11.03(br, 1H)

1H-NMR ( DMSO-d6 ) δppm : 2.72(s, 3H), 2.90(s, 3H) ₁ 3.26-4.20(m, 3H), 4.20-4.60(m, 3H),

472 -H -F -H -H -H 6.60-6.82(m, 3H), 7.10-7.35(m, 1H), 7.44(d, J=8.4Hz, 1H), 7.84(d, J=8.9Hz, 1H), 8.21(dd, Dihydrochloride J=2.1, 8.4Hz, 1H), 8.27(d, J=8.9Hz, 1H), 8.49(d, J=2.1Hz, 1H) ₁ 10.87(br, 1H) 1H-NMR ( DMSO-d6 ) δppm : 2.17(s, 6H) ₁ 2.76(s, 3H) ₁ 2.90(s, 3H), 3.15-3.90(m, 3H), 4.12-

473 -H -CH ₃ -CH ₃ -H -H 4.70(m, 3H), 6.79(dd, J=2.3, 8.5Hz, 1H), 6.86(d, J=2.3Hz, 1H) ₁ 7.02-7.10(m, 2H) ₁ 8.00(d, Dihydrochloride

J=8.5Hz, 1H), 8.09(dd, J=2.3, 8.5Hz, 1H), 8.33-8.45(m, 2H), 12.20(br, 1H)

[0545]

Example R ¹ PT R ^1Z R R ¹ NMR Salt

1H-NMR ( DMSO-d6 ) δppm : 2.15 ( 3H, s ), 2.75 ( 3H, s ), 3.26 ( 2H, br ), 3.96 ( 2H,

479 -H -H -F -CH ₃ -H -H br ), 4.30 ( 2H, br ), 5.76 ( 2H, br ), 6.63 ( 1H, dd, J = 2.3, 8.4Hz ), 6.75 ( 1H, dd, J = 2.3, 12.8Hz ), 7.15 ( 1H, dd, J = 8.7, 8.7Hz ), 7.31 ( 1H, d, J = 8.4Hz ), 7.95 ( 1H, d, J = Trihydrochloride 8.8Hz ), 8.15 ( 1H, dd, J = 2.2, 8.4Hz ), 8.35-8.45 ( 2H, m ), 9.60 ( 2H, br ). 1H-NMR ( DMSO-d6 ) δppm : 2.26 ( 3H, s ), 2.77 ( 3H, s ), 3.26 ( 2H, br ), 3.97 ( 2H ₁

480 -H -H -H -CH ₃ -H -H br ), 4.35 ( 2H, br ), 6.0-7.6 ( 6H ₁ m ), 7.95-8.15 ( 2H ₁ m ), 8.36 ( 1H, d, J = 2.1Hz ), 8.48 Dihydrochloride ( 1H, d, J = 8.9Hz ), 9.72 ( 2H, br ).

1H-NMR ( DMSO-d6 ) δppm : 2.26 ( 3H, s ), 2.77 ( 3H, s ), 3.26 ( 2H ₁ br ), 3.98 ( 2H ₁ br ), 4.31 ( 2H, br ), 6.02 ( 2H, br ), 6.78 ( 1H ₁ dd, J = 2.9, 8.7Hz ), 6.96 ( 1H, d, J =

481 -H -H -CH ₃ -Cl -H -H 2.8Hz ), 7.26 ( 1H, d, J = 1.4Hz ), 7.29 ( 1H, d, J = 1.7Hz ), 8.02 ( 1H, d, J = 8.9Hz ), Trihydrochloride 8.15 ( 1H, dd, J = 2.2, 8.4Hz ), 8.41 ( 1H, d, J = 2.1Hz ), 8.46 ( 1H, d, J = 8.9Hz ), 9.70 ( 2H, br ).

1H-NMR ( DMSO-d6 ) δppm : 2.77 ( 3H, s ), 3.32 ( 2H, br ), 3.96 ( 2H, br ), 4.49 ( 2H,

482 -H -Cl -Cl -H -H -H br ), 6.52 ( 1H, d, J = 8.5Hz ), 6.7-7.85 ( 4H ₁ m ), 7.98 ( 1H ₁ dd, J =2.2, 8.6Hz ), 8.06 Dihydrochloride ( 1H, d, J = 8.9Hz ), 8.35 ( 1H ₁ d, J = 2.1Hz ), 8.47 ( 1H ₁ d, J = 8.9Hz ), 9.84 ( 2H, br ). 1H-NMR ( DMSO-d6 ) δppm : 2.25 ( 3H ₁ s ), 2.77 ( 3H ₁ s ), 3.26 ( 2H, br ), 3.98 ( 2H, br ), 4.33 ( 2H ₁ br ), 6.00 ( 1H, br ), 6.84 ( 1H, dd, J = 2.5, 8.4Hz ), 7.00 ( 1H, d, J =

483 -H -H -Cl -CH ₃ -H -H 2.4Hz), 7.24 (1H, d, J = 8.8Hz ), 7.27 (1H, d, J = 8.5Hz), 8.02(1H, d, J = 8.8Hz ), Dihydrochloride

8.15 ( 1H, dd, J = 2.2, 8.5Hz ), 8.41 ( 1H, d, J = 2.1Hz ), 8.47 ( 1H, d, J = 8.9Hz ), 9.69 (2H,br).

1H-NMR ( DMSO-d6 ) δppm : 2.17 ( 6H, s ), 2.76 ( 3H ₁ s ), 3.26 ( 2H, br ), 3.96 ( 2H,

484 -H -H -CH ₃ -CH ₃ -H -H br ), 4.35 ( 2H ₁ br ), 5.89 ( 1H ₁ br ), 6.78 ( 1H ₁ dd, J = 2.4, 8.1Hz ), 6.85 ( 1H, d, J = 2.2Hz ), 7.0-7.15 ( 2H, m ), 7.95-8.15 ( 2H ₁ m ), 8.35 ( 1H ₁ d, J = 2.1Hz ), 8.47 ( 1H ₁ d, J Dihydrochloride = 8.9Hz ), 9.68 ( 2H, br ).

[0547] [Table 85]

Example Rfz FT NMR Salt

1H-NMR ( DMSO-d6 ) δppm : 2.04 ( 3H, s ), 2.77 ( 3H, s ), 3.38 ( 2H, br ), 3.96 ( 2H, br ), 4.53 ( 2H, br ), 6.38 ( 1H, d, J = 8.6Hz ),

485 -H -CH ₃ -Cl -H -H -H 6.7 ( 1H, br ), 7.35-7.45 ( 2H, m ), 7.45-7.55 ( 1H, m ), 7.94 ( 1H ₁ dd, Dihydrochloride J = 2.2, 8.6Hz ), 8.10 ( 1H, d, J = 8.9Hz ), 8.33 ( 1H ₁ d, J = 2.1Hz ), 8.51 ( 1H ₁ d, J = 8.9Hz ), 9.91 ( 2H, br ). 1H-NMR ( DMSO-d6 ) δppm : 2.76 ( 3H, s ), 3.27 ( 2H ₁ br ), 4.00 ( 2H, br ), 4.29 ( 2H, br ), 5.04 ( 1H, br ), 6.65 ( 1H, dd, J = 2.2,

486 -H -H -F -Cl -H -H 9.0Hz ), 6.96 ( 1H, dd, J = 2.8, 12.6Hz ), 7.39 ( 1H, dd, J = 8.9, Dihydrochloride 8.9Hz ), 7.45 ( 1H, d, J = 8.4Hz ), 7.95-8.05 ( 1H, m ), 8.21 ( 1H ,dd, J = 2.2, 8.4Hz ), 8.4-8.5 ( 2H, m ), 9.69 ( 2H, br ). 1H-NMR ( DMSO-d6 ) δppm : 2.25 ( 3H, s ), 2.79 ( 3H, s ), 3.26 ( 2H, br ), 3.99 ( 2H, br ), 4.33 ( 2H, br ), 5.97 ( 1H, br ), 6.7-6.85

487 -H -H -CH ₃ -H -H -H ( 3H, m ), 7.1-7.25 ( 2H, m ), 8.11 ( 1H, d, J = 8.9Hz ), 8.12 ( 1H, dd, Dihydrochloride J = 2.2, 8.5Hz ), 8.40 ( 1H, d, J = 2.1Hz ), 8.55 ( 1H, d, J = 8.9H ), 9.79 ( 2H ₁ br ).

1H-NMR ( DMSO-d6 ) δppm : 2.79 ( 3H, s ), 3.27 ( 2H, br ), 4.02 ( 2H, br ), 4.31 ( 2H ₁ br ), 5.84 ( 1H, br ), 6.8-7.0 ( 3H, m ), 7.2-7.3

488 -H -H -Cl -H -H -H ( 1H, m ), 7.39 ( 1H, d, J = 8.4Hz ), 8.07 ( 1H, d, J = 8.3Hz ), 8.20 Dihydrochloride ( 1H ₁ dd, J = 2.1, 8.4Hz ), 8.45 ( 1H, d, J = 2.0Hz ), 8.52 ( 1H, d, J = 8.3Hz ), 9.78 ( 2H, br ).

[0548]

[0549]

[0550] [Table 88]

br), 4.05^.22 (3H ₁ br m),

497 dd, J = 9.0, 16.3 Hz), 11.27 Hydrochloride (1H, br), 3.85 (1H, br), 4.02-4.19 (3H, br m), 6.12 (2H, s), 6.83

498 8.9 Hz), 7.21-7.21 (2H, m), 7.28 (1H, d, J = 5.4 Hz), 7.68 (1H, d, J Hydrochloride Hz), 11.10 (1H, br) br), 4.14 (3H, br m), 6.12 (2H, s), 6.81 (1H, dd, J = 1.7, 8.8

499 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = U Hz), 7.43 (1H, dd, J Hydrochloride Hz), 11.11 (1H, br) (2H, s), 3.76-3.79 (2H, m), 5.94 (2H, s), 6.41-6.43 (1H, m),

500 (1H, t, J = 2.3 Hz), 7.17 (1H, d, J = 2.8 Hz), 7.25 (1H, d, J

[0551] [Table 89]

J

Oxalate

br

[0552] [Table 90]

Example R Melting point (°C) Salt

505

506

507

508 -CH ₃ 136-138

[0553]

[0554] [Table 92]

dd, J = 10.9, 12.4 Hz), 3.01-3.06 (1H, m), 3.36-

512 (3H, m), 6.40 (1H, s), 6.69 (1H ₁ dd, J = 2.0, 9.1 J = 10.5, 13.1 Hz), 3.01 (1H, dd, J = 3.6, 13.1

513 .16 (3H, m), 3.86 (3H, s), 6.47 (1H, br), Hz), 6.91-7.43 (13H, m) , br m), 2.36 (0.5H, br m), total 1H}, {2.56

514 = 4.2 Hz), total 3H}, 3.33-4.79 (5H, m), 7.00- Hydrochlor ⁱ de br), 10.54 (0.5H, br), total 1H} Hz), 2.87

515 total 3H}, Hydrochlor ⁱ de

516 3.36-4.65 Hydrochloride br), total 1H}

[0555] [Table 93]

s), total 3H}, 3.87-5.04 (5H, m), 7.04-

519 br) Hydrochloride 11 (1H, m), 2.31 (3H, s), 3.22 (1H, brm),

520 (1H, d, J = 14.8 Hz), 7.04-7.40 (8H, m), 7.59- 2.09 (1H, br m), 2.33 (3H, s), 3.15-3.19 (1H, m),

521 (3H, s), 4.35 (1H, d, J = 14.6 Hz), 7.03-7.28 J = 8.9 Hz) .86 (2H ₁ m), 3.17-3.23 (1H ₁ m), 3.53-3.61

522 m), 7.03-7.38 (8H, m), 7.55-7.68 (3H, m)

[0556]

[0557] [Table 95]

Example R Melting point (°C) Salt

524

525

[0558]

[0559] [Table 97]

[0560]

[0561]

[0562] [Table 100]

[0563] [Table 101]

[0564] [Table 102]

[0565] [Table 103]

[0566] [Table 104]

[0567] [Table 105]

[0568]

[0569]

[0570] [Table 108]

[0571]

[0572] [Table 110]

Example R Melting point (°C) Salt

567 Hydrochloride

568 190-193 Hydrochloride

569 Hydrochloride

570 Hydrochloride

571 Hydrochloride

[0573]

[0574]

[0575] [Table 113]

_L L

Example R ¹¹ R" _Rl , R ¹⁴ R ^1S MS(M+1)

628 -H -CH ₃ -H -H -OCH ₃ 283

629 -H -H -H -Cl -CH ₃ 287

630 -H -Cl -H -H -OCH ₃ 303

631 -H -H -F -H -Cl 291

632 -H -Cl -H -H -CH ₃ 287

633 -H -H -CH ₃ -H -CH ₃ 267

634 -H -H -OCH ₃ -OCH ₃ -H 299

635 -H -CH ₃ -H -H -CH ₃ 267

636 -H -H -CH ₃ -CH ₃ -H 267

637 -H -H -F -CN -H 282

638 -H -Cl -H -H -Cl 307

639 -H -H -Cl -H -Cl 307

640 -H -H -OCH ₃ -CH ₃ -H 283

641 -H -H -C ₆ H ₅ -H -H 315

642 -H -H -CN -Cl -H 298

643 -H -H -OH -H -H 255

644 -H -H -Cl -H -H 273

645 -H -H -H -CN -H 264

646 -H -H -H -H 257

647 -H -F -H -CN -H 282

648 -H -H -OCH ₃ -H -OCH ₃ 299

[0576]

[0577]

[0578] [Table 116]

Example MS(M+1)

668 295

[0579]

[0580]

[0581] [Table 119]

Example MS(M+1)

689 358

[0582] [Table 120]

Example MS(M+1)

[0583] [Table 121]

704 289

[0584] [Table 122]

Example MS(M+1)

[0585] [Table 123]

720 296

[0586]

[0587] [Table 125]

Example R MS(M+1)

[0588]

[0589] [Table 127]

Example R ¹¹ R ¹² R ¹³ R ¹⁴ R ¹⁵ MS(M+1)

759 -H -H -CH ₃ -CF ₃ -H 413

760 -H -H -OCH ₃ -CF ₃ -H 429

761 -H -H -H -C U- H(CH ₃ ) ₂ -H 373

762 -H -H -SC ₂ H ₅ -H ^R -H 391

763 -H -H -H -OCH(CH ₃ ) ₂ -H 389

764 -H -Cl -H -F -H 383

765 -H -CH ₃ -OCH ₃ -CH ₃ -H 389

766 -H -CH ₃ -H -CH ₃ -H 359

767 -H -H -CH ₃ -H 363

768 -H -H -Cl -F -H 383

769 -H -H -H -F -H 349

770 -H -H -CH ₃ -Cl -H 379

771 -H -F -F -F -H 385

772 -H -F -H -H -CH ₃ 363

773 -H -CH ₃ -H -H -F 363

774 -H -H -OCH ₃ -F -H 379

775 -H -H -Cl -CH ₃ -H 379

776 -H -H -C ₃ H ₇ -H -H 373

111 -H -CH ₃ -H -H -Cl 379

778 -H -H -H -Cl -CH ₃ 379

779 -H -Cl -H -H -OCH ₃ 395

780 -H -Cl -H -H -CH ₃ 379

781 -H -H -H -C ₂ H ₅ -H 359

782 -H -F -H -F -F 385

783 -H -F -OCH ₃ -F -H 397

784 -H -F -F -H -OCH ₃ 397

785 -H -H -CH ₃ -H -CH ₃ 359

[0590] [Table 128]

Example R ¹¹ R ¹² R ¹³ R ¹⁴ R ¹⁵ MS(M+1)

786 -H -F -F -OCH ₃ -H 397

787 -H -H -OCH ₃ -OCH ₃ -H 391

788 -H -H -H -Cl -H 365

789 -H -CH ₃ -H -H -CH ₃ 359

790 -H -H -CH ₃ -H 359

791 -H -Cl -H -H ^R -Cl 399

792 -H -H -Cl -H -Cl 399

793 -H -H -OCH ₃ -CH ₃ -H 375

794 -H -H -CN -Cl -H 390

795 -H -CH ₃ -F -CH ₃ -H 377

796 -H -H -F -Cl -H 383

797 -H -H -Cl -H -H 365

798 -H -H -H -CN -H 356

799 -H -H -H -H -H 331

800 -H -H -F -H -H 349

801 -H -H -CN -F -H 374

802 -H -H -CN -CH ₃ -H 370

[0591]

[0592] [Table 130]

Example MS(M+1)

818 389

[0593] [Table 131]

Example MS(M+1)

826 383

[0594] [Table 132]

Example MS(M+1)

[0595]

[0596] [Table 134]

Example R ¹¹ R ¹³ R ¹⁴ R ¹³ MS(M+1)

840 -H -H -OC ₂ H ₅ -H -H 361

841 -H -H -OCF ₃ -H -H 401

842 -H -H -H -H -CH ₃ 331

843 -H -H -CF ₃ -H -H 385

844 -H -H -CN -H -H 342

845 -H -H -N(CH ₃ ) ₂ -H -H 360

846 -H -H -H -CH ₃ -H 331

847 -H -H -H -H -O _Li . CH ₃ 347

848 -H -H -H -OCH ₃ -H 347

849 -H -H -H -OC ₂ H ₅ -H 361

850 -H -H -H -SCH ₃ -H 363

851 -H -H -H -N(CH ₃ ) ₂ -H 360

852 -H -H -H -H -CN 342

853 -H -H -H -CF ₃ -H 385

854 -H -H -F -H -CH ₃ 349

855 -H -H -Cl -CF ₃ -H 419

856 -H -H -CH ₃ -H -H 331

857 -H -H -C(CH ₃ ) ₃ -H -H 373

858 -H -H -H -H -CF ₃ 385

859 -H -H -H -Cl -Cl 385

860 -H -Cl -H -Cl -H 385

861 -H -H -SCH ₃ -H -H 363

862 -H -H -CH(CHa) ₂ -H -H 359

863 -H -H -C ₂ Hs -H -H 345

864 -H -H -F -CF ₃ -H 403

865 -H -H -H -CF ₃ 403

866 -F -H -H -CF ₃ -H 403

[0597] [Table 135]

Example R ¹¹ R ¹² R ¹³ R ¹⁴ R ¹⁶ MS(M+1)

867 -H -H -Cl -H -Cl 385

868 -H -Cl -H -H -Cl 385

869 -OCH ₃ -H -H -OCH ₃ -H 377

870 -H -H -H -H _L L -Cl 351

871 -H -H -OCH ₃ -H -H 347

872 -H -H -H -CH ₃ -CH ₃ 345

873 -H -F -H -H -OCH ₃ 365

874 -H -H -Cl -H -CH ₃ 365

875 -H -H -Cl -Cl -H _LL . 385

876 -H -H -F -F -H 353

877 -H -F -H -F -H 353

878 -H -H -CF ₃ -F -H 403

879 -H -H -H -CF ₃ 403

880 -H -H -CF ₃ -H -F 403

881 -H -F -H -CF ₃ -H 403

882 -H -H -CH ₃ -CF ₃ -H 399

883 -H -H -OCH ₃ -CF ₃ -H 415

884 -H -H -H -CH(CH ₃ ) ₂ -H 359

885 -H -H -Cl -H -F 369

887 -H -H -H -OCH(CHs) ₂ -H 375

888 -H -Cl -H -F -H 369

889 -H -CH ₃ -OCH ₃ -CH ₃ -H 375

890 -H -H -F -F 371

891 -H -CH ₃ -H -CH ₃ -H 345

892 -H -H -CH ₃ -F -H 349

893 -H -H -Cl -F -H 369

[0598] [Table 136]

_{L LL} . _L L

Example R ^U R ¹² R ¹³ R ¹⁴ R ¹⁵ MS(M+1)

894 -F -H -F -H 371

895 -H -H -F -H -F 353

896 -H -F -H -H -F 353

897 -H -H -H -F -H 335

898 -H -H -CH ₃ -Cl -H 365

899 -H -CH ₃ -H -H -F 349

900 -H -H -OCH ₃ -F -H 365

901 -H -H -Cl -CH ₃ -H 365

902 -H -H -C ₃ H ₇ -H -H 359

903 -H -CH ₃ -H -H -Cl 365

904 -H -H -H -Cl -CH ₃ 365

905 -H -Cl -H -H -OCH ₃ 381

906 -H -H -F -H -Cl 369

907 -H -Cl -H -H -CH ₃ 365

909 -H -H -F 371

910 -H -OCH ₃ -F -H 383

911 -H -F -F -H -OCH ₃ 383

912 -H -H -CH ₃ -H -CH ₃ 345

913 -H -F -F -OCH ₃ -H 383

914 -H -H -OCH ₃ -OCH ₃ -H 377

915 -H -H -H -Cl -H 351

916 -H -CH ₃ -H -H -CH ₃ 345

917 -H -H -CH ₃ -CH ₃ -H 345

918 -H -H -F -CN -H 360

919 -H -Cl -H -H -Cl 385

920 -F -H -OCH ₃ -F -H 383

[0599] [Table 137]

U-

Example R ¹¹ R ¹² R ¹³ R ¹⁴ R ¹⁵ MS(M+1)

921 -H -H -Cl -H -Cl 385

922 -H -H -OCH ₃ -CH ₃ -H 361

923 -H -H -CN -Cl -H 376

924 -H -CH ₃ -CH ₃ -H 363

925 -H -H -F -Cl -H 369

926 -H -H -Cl -H -H 351

927 -H -H -H -CN -H 342

928 -H -H -H -H -H 317

929 -H -H -F -H -H 335

930 -H -F -H -CN -H 360

931 -H -H -CN -F -H 360

932 -H -H -CN -CH ₃ -H 356

933 -H -H -OCH ₃ -H -OCH ₃ 377

[0600]

[0601] [Table 139]

Example R MS(M+1)

945 373

[0602]

[0603]

[0604] [Table 142]

Example MS(M-H)

968 369

[0605]

[Table 143]

Example R ⁶ MS(M+1)

[0606] [Table 144]

Example R MS(M+1)

984 373

[0607]

[0608]

[0609]

[0610] [Table 148]

Example R MS(M+1)

[0611] [Table 149]

Example MS(M+1)

[0612] [Table 150;

Example R MS(M+1)

[0613]

[0614]

[0615] [Table 153]

Example R MS(M+1)

[0616]

[0617]

[0618] [Table 156]

Example R ⁶ NMR Melting point (°C) Salt

1H-NMR ( CDCI3 ) δppm : 1.14 ( 18H, d, J = 7.5Hz ), 1.6-1.75 ( 3H, m ), 2.1-2.2 ( 2H, m ), 2.37 ( 3H ₁ s ), 2.8-2.9 ( 2H ₁ m ),

1064 3.61 ( 2H ₁ s ), 3.65-3.75 ( 2H ₁ m ), 4.05-4.2 ( 4H ₁ m ), 6.48 ( 1H ₁ d, J = 2.5Hz ), 6.63 ( 1H, s ), 6.70 ( 1H ₁ dd, J = 2.4. 8.9Hz ), 6.88 ( 1H ₁ s ), 7.05 ( 1H ₁ d, J = 2.4Hz ), 7.18 ( 1H ₁ d, J = 3.2Hz ), 7.31 ( 1H, d, J =9.0Hz ).

1.4-1.55 ), 2.85-

1065 ( 4H ₁ m ), 6.91 8.6Hz ). 1.55- ( 2H ₁ d, J = ( 1H, dd,

: 1.15 (18H, d, J = 7.50), 1.62-1.70 m), 2.41 (3H, s), 2.86-2.89 (2H, m),

1067 , s), 4.04-4.14 (4H, m), 6.23 (1H ₁ (1H, s), 7.16-7.21 (2H, m), 7.35

1H-NMR (CDCI3) δppm : 1.14 (18H, d, J = 7.59Hz), 1.82-1.90 (3H ₁ m), 2.06-2.09 (m, 2H), 2.41 (3H, s), 2.86-2.88 (2H, m), 3.71-3.73 (2H, m), 3.80 (2H, s), 3.97-4.08 (2H ₁ m), 4.09-4.13 (2H ₁ m), 6.02-6.03 (1H ₁ m), 6.19 (1H, s), 6.76 (1H, d, J = 8.16Hz), 6.88 (1H, s), 7.11-7.15 (2H, m).

[0619] [Table 157]

Example NMR Melting point (°C) Salt

1H-NMR ( CDCI3 ) δppm : 2.15-2.25 ( 2H, m ), 2.36 ( 3H ₁ s ), 2.85-2.95 ( 2H ₁ m ), 3.53 ( 2H, s ), 3.83 ( 2H, br ), 4.15-

1071 4.25 ( 4H, m ), 6.84 ( 1H, s ), 6.9-7.0 ( 2H, m ), 7.01 ( 1H, 101.5-102.5 dd, J 2.5, 9.0Hz ), 7.15-7.25 ( 1H, m ), 7.3-7.4 ( 1H ₁ m ), 7.55-7.65 ( 2H, m ), 7.66 ( 1H ₁ d, J = 8.0Hz ).

m ), 2.75 ( 3H ₁

1078 ( 7H ₁ m ), 6.35-6.5 m ), 10.96 ( 1H, 236.2 Hydrochloride

m ), 2.77 ( 3H ₁ ( 7H, m.), 6.65

1079 ( 1H, d, J = 256.0 - 257.5 Hydrochloride ), 11.00 ( 1H,

[0620] [Table 158]

1H-NMR ( CDCI3 ) δppm : 2.39 ( 3H, s ), 2.8-2.95 ( 2H ₁ m ), 3.7- 3.85 ( 4H, m ), 4.05-4.25 ( 4H, m ), 5.78 ( 1H, dd, J = 2.3,

1085 2.3Hz ), 6.25 ( 1H, s ), 6.73 ( 1H, d, J = 7.4Hz ), 6.78 ( 1H, S ), 219.5-221.0 6.94 ( 1H, dd, J = 2.8, 2.8Hz ), 7.01 ( 1H, d, J = 8.1Hz ), 7.13 ( 1H, dd, J = 7.8, 7.8Hz ), 8.13 ( 1H, br ).

1H-NMR ( DMSO-d6 ) δppm : 2.77 ( 3H, s ), 3.33 ( 2H, br ), 3.90 ( 2H, br ), 4.16 ( 2H, s ), 4.24 ( 4H, s ), 5.76 ( 1H, S ), 6.44 ( 1H,

1086 s ), 6.93 ( 1H, dd, J = 2.1, 9.0Hz ), 7.08 ( 1H, s ), 7.15 ( 1H, d, J Oxalate = 2.0Hz ), 7.42 ( 1H, d, J = 9.1Hz ), 7.91 ( 1H, s ).

[0621] [Table 159]

1H-NMR (CDCI3) δppm : 2.41 (3H ₁ s), 2.87-2.91 (2H, m), 3.62-3.65 (2H ₁ m), 3.80 (3H ₁ s), 3.85 (2H, s), 4.10-4.16 (4H, m), 5.91 (1H, S) ₁ 6.53-6.54 (1H ₁ m), 6.72 (1H ₁ s), 7.06 (1H, d, J = 3.13), 7.15 (1H ₁ d, J = 8.63), 7.22 (1H, s).

[0622]

1H-NMR ( CDCI3 ) δppm : 1.13 ( 18H, d, J = 7.5Hz ), 1.65-1.85 ( 3H, m ), 2.35 ( 3H, s ), 2.85-2.95 ( 2H, m ), 3.60 ( 2H, s ), 3.7-3.8

1106 ₃ ( 2H, m ), 4.2-4.3 ( 4H, m ), 6.62 ( 1H, s ), 6.80 ( 1H, s ), 6.89 ( 1H, dd, J = 2.4, 9.2Hz ), 7.01 ( 1H, d, J = 2.2Hz ), 7.35 ( 1H, d, J = 9.2Hz), 8.06 (1H ₁ d, J = 0.8Hz).

= 7.6 Hz) ₁ 1.57-1.77 3.65-6.75 (2H ₁ m), 3.82 m), 6.66-6.88 (3H, m),

(3H, q, J m), 4.25 (1H, d,

(3H, (2H, (1H, (1H, m).

1H-NMR (CDCI3) δppm : 1.14 (18H, d, J = 7.59), 1.84-1.89 (3H,

1110 m), 2.39 (3H, s), 2.86-2.89 (2H ₁ m), 3.71-3.72 (2H, m), 3.82 (2H, S) ₁ 4.11-4.18 (4H ₁ m), 6.04-6.05 (1H, m), 6.11 (1H, s), 6.74-6.76 (2H, m), 7.10-7.16 (2H,m).

1H-NMR (CDCI3) δppm : 1.15 (18H, d, J = 7.50), 1.62-1.69 (3H,

1111 m), 2.39 (3H ₁ s), 2.86-2.89 (2H, m), 3.62-3.65 (2H, m), 3.79 (2H, S) ₁ 4.11-4.17 (4H, m), 6.15 (1H ₁ s), 6.52-6.53 (1H, m), 6.72 (1H ₁ S) ₁ 7.15-7.20 (2H ₁ m), 7.33 (1H, d, J = 8.43).

), 1.55-1.75 ( 2H, s ), 3.65-

1112 J = 2.2, 15.8Hz ), K ), 6.79 ( 1H, s ),

1H-NMR ( CDCI3 ) δppm : 1.15(18H ₁ d, J=7.5Hz), 1.66(3H, sept, J=7.5Hz), 2.44(3H, s), 2.85-3.00(2H, m), 3.60-3.72(2H, m), 3.78-

1113 3.94(2H, m), 4.10-4.25(4H ₁ m), 6.15(1H ₁ S) ₁ 6.60-6.70(1H ₁ m), 6.72(1H ₁ s), 6.82-6.94(1H, s), 7.15-7.25(2H, m).

[0623] [Table 161]

1H-NMR ( DMSO-d6 ) δppm : 2.80 ( 3H, d, J = 3.9Hz ), 3.2-3.5 ( 2H, m ), 3.6-3.8 ( 1H, m ), 3.95-4.35 ( 7H, m ),

1117 5.93 ( 2H, d, J = 2.5Hz ), 6.30 ( 1H, dd, J = 0.9, 8.4Hz ), 299.0 - 300.0 Hydrochroride 6.41 ( 1H, s ), 6.59 ( 1H, dd, J = 0.9, 7.7Hz ), 6.76 ( 1H, dd, J = 8.1, 8.1Hz ), 7.08 ( 1H, s ), 10.50 ( 1H, br ). 1H-NMR ( DMSO-d6 ) δppm : 2.75 ( 3H ₁ s ), 3.15-3.45

1118 ( 2H ₁ m ), 3.78 ( 1H, br ), 3.9-4.2 ( 3H, m ), 4.29 ( 4H, s ), 6.35-6.45 ( 1H, m ), 6.75-6.85 ( 2H ₁ m ), 7.17 ( 1H, s ), 221.0-223.0 Hydrochroride 7.24 ( 1H ₁ dd, J = 9.5, 19.7Hz ), 11.15 ( 1H ₁ br ).

[0624] [Table 162]

Example Melting point (°C) Salt

[0625]

[0626]

[0627] [Table 165]

Example NMR Melting point (°C) Salt

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[ 0638 ]

Pharmacological Study 1

Measurement of serotonin (5-HT) uptake inhibitory activity of test compound using rat brain synaptosome Male Wistar rats were decapitated, and their brains were removed and dissected to remove the frontal cortex. The separated frontal cortex was placed in a 20-fold weight of a 0.32 molar (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction. [0639]

Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml) . [0640] Specifically, a solvent, unlabeled 5-HT, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and

preincubated at 37°C for 10 minutes. Then, a tritium- labeled 5-HT solution (final concentration: 8 nM) was added thereto to initiate uptake reaction at 37°C. 10 minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold ' saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured. [0641]

An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled 5-HT (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 154.

[0642]

[ 0643 ]

Pharmacological Study 2

Measurement of norepinephrine (NE) uptake inhibitory activity of test compound using rat brain synaptosome Male Wistar rats were decapitated, and their brains were removed and dissected to remove the hippocampus. The separated hippocampus was placed in a 20-fold weight of a 0.32 molar (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction. [0644]

Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml) . [0645] Specifically, a solvent, unlabeled NE, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and

preincubated at 37°C for 10 minutes. Then, a tritium- labeled NE solution (final concentration: 12 nM) was added thereto to initiate uptake reaction at 37°C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured. [0646]

An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled NE (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 155.

[0647]

[ 0648 ]

Pharmacological Study 3

Measurement of dopamine (DA) uptake inhibitory activity of test compound using rat brain synaptosome Male Wistar rats were decapitated, and their brains were removed and dissected to remove the corpus striatum. The separated corpus striatum was placed in a 20-fold weight of a 0.32 molar (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction. [0649]

Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml) . [0650] Specifically, a solvent, unlabeled DA, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and

preincubated at 37°C for 10 minutes. Then, a tritium- labeled DA solution (final concentration: 2 nM) was added thereto to initiate uptake reaction at 37°C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured. [0651]

An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled DA (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 156.

[0652]

[ 0653 ]

Pharmacological Study 4 Forced swimming test

This test was conducted according to the method of Porsolt et al. (Porsolt, R. D., et al.,

Behavioural despair in mice: A primary screening test for antidepressants. Arch. int. Pharmacodyn. Ther., 229, pp 327-336 (1977) ) . [0654] A test compound was suspended in a 5% gum arabic/saline (w/v) , and this suspension was orally administered to male ICR mice (CLEA Japan, Inc. (JCL), 5 to 6 week old) . One hour later, the mice were placed in a water tank having a water depth of 9.5 cm and a water temperature of 21 to 25°C and immediately thereafter allowed to try to swim for 6 minutes. Then, a time during which the mouse was immobile (immobility time) was measured for the last 4 minutes. A SCANET MV-20 AQ system manufactured by Melquest Ltd. was used in the measurement and analysis of the immobility time. [0655]

In this experiment, the animals treated with the test compounds exhibited a reduction in immobility time. This demonstrates that the test compounds are useful as antidepressants.