WO2009119528A1

WO2009119528A1 - Heterocyclic compound

Info

Publication number: WO2009119528A1
Application number: PCT/JP2009/055716
Authority: WO
Inventors: 栄治本多
Original assignee: 武田薬品工業株式会社
Priority date: 2008-03-24
Filing date: 2009-03-23
Publication date: 2009-10-01

Abstract

Disclosed is a compound having an inhibitory activity on the intake of a monoamine neurotransmitter. Specifically disclosed is a compound represented by formula (I) [wherein each symbol is as defined in the description] or a salt thereof. (I)

Description

Heterocyclic compounds

The present invention has an excellent monoamine neurotransmitter reuptake inhibitory activity, and is useful as a therapeutic / preventive agent for neurological diseases such as central diseases, particularly depression, anxiety and attention deficit hyperactivity disorder (ADHD). Related to a heterocyclic compound.

(Background of the Invention)
The monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA) are widely present in the brain and have various functions including neurotransmission via their receptors. . After they are released from the nerve endings, they are rapidly re-uptaked from the nerve gap by the respective transporters (serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT), and nerve transmission is terminated. . On the other hand, compounds exhibiting reuptake inhibitory activity are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents.
Examples of depression treatment drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine. Norepinephrine / dopamine reuptake inhibitors such as reuptake inhibitors (SNRI), bupropion, or monoamine oxidase inhibitors are used, all of which require several weeks to develop their effectiveness, improvement rate, or side effects. It cannot be said that the degree of satisfaction is necessarily high from the point (Non-Patent Documents 1 and 2).
TCA, SSRI and SNRI are not only for depression but also for symptomatic improvement in neurodegenerative diseases such as anxiety and attention deficit hyperactivity disorder and neurodegenerative diseases such as Alzheimer's disease, and pain treatment such as diabetic pain and myofibrosis. There are also reports that it is useful as a therapeutic agent for urinary diseases such as overactive bladder or gastrointestinal diseases such as irritable bowel syndrome.
Many other monoamine neurotransmitter reuptake inhibitors have been reported so far besides commercially available drugs. For example, cycloalkylamine derivatives (Patent Document 1), pyrrolidine derivatives (Patent Document 2), bicycloamine derivatives (Patent Document 3). ) And indole derivatives (Patent Document 4) are known.

On the other hand, as a lactam compound, Patent Document 5 discloses a formula as a prophylactic / therapeutic agent for blood coagulation related diseases.

The compound represented by these is described. Patent Document 6 discloses a formula as a therapeutic agent for central nervous system diseases.

The compound represented by these is described. Patent Document 7 discloses a prophylactic / therapeutic agent for inflammatory diseases and the like.

The compound represented by these is described. In Patent Document 8, as a prophylactic / therapeutic agent for central nervous disease, a formula

The compound represented by these is described. Patent Document 9 discloses a formula as a prophylactic / therapeutic agent for central nervous disease.

[Wherein, R ^a is a hydrogen atom, alkyl optionally substituted with halogen, etc., R ^b is aryl optionally substituted with halogen, etc., R ² , R ^{2 ′} , R ³ , R ^{3 ′} , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ and R ^{7 ′} independently represent a hydrogen atom or alkyl (provided that R ² , R ^{2 ′} , R ³ , R ^{3 ′} , R ⁵ , At least one of R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ and R ^{7 ′} is alkyl). The compound represented by this is described.

International Publication No. 2007/81857 Pamphlet International Publication No. 2006/121218 Pamphlet International Publication No. 2007/90886 Pamphlet International Publication No. 2007/62996 Pamphlet International Publication No. 2006/055951 Pamphlet International Publication No. 2007/028654 Pamphlet International Publication No. 2004/101529 Pamphlet International Publication No. 97/36893 Pamphlet International Publication No. 2006/84870 Pamphlet

Compounds that have reuptake inhibitory activity in brain monoamines (serotonin / norepinephrine / dopamine, etc.) are useful for the prevention or treatment of neuropsychiatric disorders such as depression, anxiety, attention deficit hyperactivity disorder (ADHD), etc. Conceivable. Therefore, it is desired to develop a novel compound having excellent brain monoamine reuptake inhibitory activity.
The present invention provides a novel compound (useful as a prophylactic / therapeutic agent for a neuropsychiatric disorder such as depression, anxiety, ADHD, etc.) having excellent brain monoamine reuptake inhibitory activity. It is an object of the present invention to provide a novel compound that is more effective and / or more effective and / or safer than drugs for preventing / treating diseases (SSRI and the like).

As a result of diligent search, the present inventors have shown that the novel compound shown in the following formula (I) has an unexpectedly superior pharmaceutical activity such as brain monoamines (serotonin / norepinephrine / dopamine) reuptake inhibitory activity. As a result, the present invention has been completed.

That is, the present invention
[1] Formula (I):

[Where,
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a group and thiazolyl having a substituent);
L is
(1) a bond, or (2) an optionally substituted C _1-3 (poly) methylene;
R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ² represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group;
m + n = 2 or 3 (where m and n are each an integer of 0 to 3);
Ring A is a 7- or 8-membered ring which may have a substituent other than R ¹ to R ⁵ (the substituents on the ring A are bonded to each other, together with the ring atom to which the substituent is bonded) A ring which may have a group may be formed)
Indicates. ]
[Wherein the following formula:

Or 6 salts thereof;
[2] The compound according to [1] above, wherein L is a bond;
[3] The compound according to the above [1], wherein ring A is a 7-membered ring (m = 2, n = 0);
[4] The compound according to [1] above, wherein ring A is a 7-membered ring (m = 2, n = 0) and L is a bond;
[5] Formula (I-II)

[Where,
R ^1a to R ^5a are the same or different and each represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group which may have a substituent,
R ^6a to R ^9a are the same or different and represent (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted C _1-6 alkyl group,
Any combination of R ^1a and R ^4a , R ^4a and R ^6a and R ^8a and R ^9a is bonded to each other to form — (CH ₂ ) n′— (where n ′ is an integer of 1 to 3). May be formed)
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of the above-mentioned [1] represented by
[6] Formula (I-III)

[Where,
R ^{1a ′} represents (1) a hydrogen atom or (2) a C _1-6 alkyl group which may be substituted with a phenyl group,
R ^{4a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group which may be substituted with a C _1-3 alkoxy group,
R ^{6a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group,
R ^{8a ′} and R ^{9a ′} are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C _1-6 alkyl group,
Any one of R ^{1a ′} and R ^{4a ′} , R ^{4a ′} and R ^{6a ′} and R ^{8a ′} and R ^{9a ′} is bonded to each other to form — (CH ₂ ) n′— (where n ′ Represents an integer of 1 to 3).
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of the above-mentioned [5], represented by
[7] Ar is (1) phenyl having a substituent,
(2) indanyl which may have a substituent,
(3) an indolyl optionally having a substituent,
(4) The compound according to [5] above, which is an optionally substituted benzofuranyl, or (5) an optionally substituted naphthyl;
[8] Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano , (E) methoxy and (f) phenyl having 1 or 2 substituents selected from phenyl,
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
(4) The compound according to the above [5], which is benzofuranyl, or (5) naphthyl optionally substituted with a C _1-3 alkoxy group;
[9] R ^{1a ′} represents (1) a hydrogen atom or (2) a C _1-6 alkyl group which may be substituted with a phenyl group,
R ^{4a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group which may be substituted with a C _1-3 alkoxy group,
R ^{6a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group,
R ^{8a ′} and R ^{9a ′} are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C _1-6 alkyl group,
Any one of R ^{1a ′} and R ^{4a ′} , R ^{4a ′} and R ^{6a ′} and R ^{8a ′} and R ^{9a ′} is bonded to each other to form — (CH ₂ ) n′— (where n ′ Represents an integer of 1 to 3).
Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl;
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
(4) A compound according to the above [6], which is benzofuranyl, or (5) naphthyl optionally substituted with a C _1-3 alkoxy group;
[10] Ring A is a 7-membered ring (m = 1, n = 1),
Ar is
(1) (a) fluorine atom, (b) chlorine atom, (c) C _1-6 alkyl _optionally having 1 to 3 halogen atoms, (d) cyano and (e) C _6-10 aryl Phenyl having 1 or 2 substituents selected from
(2) indanyl which may have a substituent, or (3) naphthyl which may have a substituent, and
The compound of the above-mentioned [1], wherein L is a bond;
[11] Formula (I-IV)

[Where,
R ^1b to R ^9b are the same or different and each represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group,
R ^6b and R ^7b may combine with each other to form — (CH ₂ ) n′— (where n ′ represents an integer of 1 to 3);
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of the above-mentioned [1] represented by
[12] Formula (IV)

[Where,
R ^{6b ′} and R ^{7b ′} are the same or different and each represents (1) a hydrogen atom or (2) a C _1-6 alkyl group,
R ^{6b ′} and R ^{7b ′} may combine with each other to form — (CH ₂ ) n′— (wherein n ′ represents an integer of 1 to 3);
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of the above-mentioned [11], represented by
[13] Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C _1-6 alkyl _optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
(2) the compound according to [11] above, which is indanyl optionally having substituent (s), or (3) naphthyl optionally having substituent (s);
[14]
R ^{6b ′} and R ^{7b ′} are the same or different and each represents (1) a hydrogen atom or (2) a C _1-6 alkyl group,
R ^{6b ′} and R ^{7b ′} may combine with each other to form — (CH ₂ ) n′— (wherein n ′ represents an integer of 1 to 3);
Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C _1-6 alkyl _optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
(2) Indanyl which may be substituted with an oxo group, or (3) The compound according to the above [12], which is naphthyl;
[15] Ring A is an 8-membered ring (m = 2, n = 1),
Ar is
(1) phenyl substituted with a halogen atom, or (2) naphthyl which may have a substituent, and
The compound of the above-mentioned [1], wherein L is a bond;
[16] Ring A is an 8-membered ring (m = 3, n = 0),
Ar is phenyl substituted with a halogen atom, and
The compound of the above-mentioned [1], wherein L is a bond;
[17] 1- (3,4-Dichlorophenyl) -1,4-diazepan-2-one (the compound of Example 1),
1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (compound of Example 6),
1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (compound of Example 101),
1- (3,4-dichlorophenyl) -3-propyl-1,4-diazepan-2-one (the compound of Example 106),
1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 25),
3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 117),
3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (the compound of Example 124), or a salt thereof;
[18] A prodrug of the compound according to [1] above;
[19] A medicament containing the compound according to [1] above or a salt thereof or a prodrug thereof;
[20] The medicament according to the above [19], which is a serotonin reuptake inhibitor and / or a norepinephrine reuptake inhibitor and / or a dopamine reuptake inhibitor;
[21] The medicament of the above-mentioned [19], which is a prophylactic or therapeutic drug for diseases caused by serotonin, norepinephrine, or dopamine;
[22] The medicament according to [19] above, which is a prophylactic or therapeutic drug for depression, anxiety, attention deficit hyperactivity disorder, or stress urinary incontinence;
[23] A method for inhibiting serotonin reuptake and / or a method for inhibiting norepinephrine reuptake, and / or a method comprising administering an effective amount of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof to a mammal. Dopamine reuptake inhibition method;
[24] A method for preventing or treating a disease caused by serotonin, norepinephrine, or dopamine, which comprises administering an effective amount of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof to a mammal. ;
[25] Depression, anxiety, attention deficit hyperactivity disorder in the mammal, characterized by administering an effective amount of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof to the mammal Or prevention or treatment of stress urinary incontinence;
[26] Use of the compound of the above-mentioned [1], a salt thereof or a prodrug thereof for producing a serotonin reuptake inhibitor and / or a norepinephrine reuptake inhibitor and / or a dopamine reuptake inhibitor;
[27] Use of the compound of the above-mentioned [1], a salt thereof or a prodrug thereof for producing a prophylactic or therapeutic agent for a disease caused by serotonin, norepinephrine or dopamine;
[28] Use of the compound of the above-mentioned [1], a salt thereof or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for depression, anxiety, attention deficit hyperactivity disorder or stress urinary incontinence;
About.

The compound of the present invention or a salt thereof or a prodrug thereof has excellent brain monoamines (such as serotonin / norepinephrine / dopamine) reuptake inhibitory activity, and therefore has a mental state such as depression, anxiety or attention deficit hyperactivity disorder. It is useful as a prophylactic / therapeutic agent for neurological diseases.

(Detailed description of the invention)
The present invention is described in detail below.

In the present specification, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
In the present specification, “C _1-6 alkyl” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
In the present specification, “C _2-6 alkenyl” refers to vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and the like.
In the present specification, “C _2-6 alkynyl” refers to ethynyl, propargyl, butynyl, 1-hexynyl and the like.
In the present specification, “C _3-8 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
In the present specification, “C _6-14 aryl” refers to phenyl, 1-naphthyl, 2-naphthyl, 2-anthryl and the like.

In the formula (I), Ar represents (1) phenyl having a substituent (the substituents of the phenyl are bonded to each other, and may have a substituent together with the carbon atom to which the substituent is bonded 4). Or a 7-membered saturated allocyclic ring, an optionally substituted 4- to 7-membered saturated heterocyclic ring or an optionally substituted benzene ring)), (2) a substituent Or (3) a monocyclic aromatic heterocyclic group optionally having a substituent (provided that pyrazolyl having a substituent, imidazolyl having a substituent, and (Excluding thiazolyl having a substituent).

As the “substituent” of “phenyl having a substituent” represented by Ar, for example, (1) a halogen atom (eg, chlorine atom),
(2) C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.),
(3) Nitro,
(4) cyano,
(5) having 1 to 3 substituents selected from a halogen atom and C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) C _1-6 alkyl, _optionally
(6) C _2-6 alkenyl optionally having 1 to 3 halogen atoms,
(7) C _2-6 alkynyl optionally having 1 to 3 halogen atoms,
(8) C _3-8 cycloalkyl _optionally having 1 to 3 halogen atoms,
(9) C _6-14 aryl _optionally having 1 to 3 halogen atoms,
(10) having 1 to 3 substituents selected from a halogen atom and C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) _Optional C _7-16 aralkyl (eg, benzyl, etc.),
(11) C _1-6 alkoxy optionally having 1 to 3 halogen atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.),
(12) C _1-6 alkylthio optionally having 1 to 3 halogen atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.),
(13) Mercapto,
(14) hydroxy,
(15) amino,
(16) mono-C _1-6 alkylamino (eg, methylamino, ethylamino, etc.),
(17) Mono-C _6-14 arylamino (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.),
(18) di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.),
(19) Di-C _6-14 arylamino (eg, diphenylamino),
(20) N—C _1-6 alkyl-N—C _6-14 aryl-carbamoyl (eg, N-methyl-N-phenylamino, etc.),
(21) Formyl,
(22) carboxy,
(23) Carbamoyl,
(24) C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.),
(25) C _3-8 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),
(26) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.),
(27) C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.),
(28) C _7-16 aralkyl-carbonyl (eg, phenylacetyl, phenylpropionyl, etc.),
(29) C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.),
(30) C _7-16 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.),
(31) 5- or 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinyl Carbonyl etc.),
(32) mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.),
(33) Di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.),
(34) C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.),
(35) N—C _1-6 alkyl-N—C _6-14 aryl-carbamoyl (eg, N-methyl-N-phenylcarbamoyl),
(36) N—C _1-6 alkyl-N— (5- to 10-membered non-aromatic heterocyclic group bonded by carbon atom) -carbamoyl (eg, N- (2-tetrahydrofuryl) -N-methylcarbamoyl) ),
(37) Thiocarbamoyl,
(38) 5- or 6-membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.),
(39) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.),
(40) C _6-14 arylsulfonyl (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.),
(41) C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl etc.),
(42) C _6-14 arylsulfinyl (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.),
(43) formylamino,
(44) C _1-6 alkyl-carbonylamino (eg, acetylamino etc.),
(45) C _6-14 aryl-carbonylamino (eg, phenylcarbonylamino, naphthylcarbonylamino, etc.),
(46) C _1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.),
(47) C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.)
(48) C _6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.),
(49) C _1-6 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.),
(50) C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.),
(51) C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
(52) mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.),
(53) Di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.),
(54) C _6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
(55) Nicotinoyloxy,
(56) (1 ′) C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and (2 ′) C _6-14 aryl (Eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.) optionally having 4 to 8 membered saturated cyclic amino (eg, morpholino, thiomorpholino, piperazine-1) -Yl, piperidino, pyrrolidin-1-yl, etc.),
(57) 5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1- , 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, etc.)
(58) 5- to 10-membered non-aromatic heterocyclic group (eg, 2- or 3-tetrahydrothienyl, 2- or 3-tetrahydrofuryl, 2-, 3- or 4-piperidyl, etc.),
(59) Sulfo,
(60) sulfino,
(61) C _6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.),
(62) a ureido optionally having 1 to 3 C _1-6 alkyls,
(63) a sulfonylureido optionally having 1 to 3 C _1-6 alkyls,
(64) C _6-14 arylthio (eg, phenylthio etc.),
(65) Carbamoyloxy,
(66) C _1-6 alkylcarbamoyloxy (eg, methylcarbamoyloxy etc.),
(67) N—C _1-6 alkyl-N—C _6-14 arylamino-carbonyloxy (eg, N-methyl-N-phenylaminocarbonyloxy etc.),
(68) C _1-3 (poly) methylene (eg, methylene, ethylene, trimethylene)
The number of substituents is 1 to 5 (eg, 2), and when the number of substituents is 2 or more, each substituent may be the same or different.

When “phenyl having a substituent” represented by Ar has two or more substituents, any two of these substituents are bonded to each other, together with the carbon atom to which the substituent is bonded, together with the substituent A 4- to 7-membered saturated allocyclic ring which may have a substituent, a 4- to 7-membered saturated heterocyclic ring which may have a substituent, or a benzene ring which may have a substituent. Good.
Examples of the ring formed by the “optionally substituted 4- to 7-membered saturated homocyclic ring” and “substituted phenyl” include, for example, bicyclo [4.2.0] octa-1, Examples include 3,5-triene, 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene and the like.
Examples of the ring formed by the “optionally substituted 4- to 7-membered saturated heterocyclic ring” and “phenyl having a substituent” include 2,3-dihydro-1-benzofuran, 2,3 -Dihydro-1H-indole, 1,3-dihydro-2-benzofuran, 2,3-dihydro-1H-isoindole, 3,4-dihydro-2H-chromene, 1,2,3,4-tetrahydroquinoline, 3 , 4-dihydro-1H-isochromene, 1,2,3,4-tetrahydroisoquinoline and the like.
The “4- to 7-membered saturated allocyclic ring optionally having substituent (s)” in the “ring formed by optionally substituted 4- to 7-membered saturated allocyclic ring and phenyl having substituent (s)” Examples of the “substituent” include a halogen atom, C _1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl), oxo and the like, and the number of substituents is 1 to 3.
The “optionally substituted 4- to 7-membered saturated heterocyclic ring” in the “ring formed by an optionally substituted 4- to 7-membered saturated heterocyclic ring and phenyl having a substituent” Examples of the “substituent” include a halogen atom, C _1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl), oxo and the like, and the number of substituents is 1 to 3.
Examples of the “substituent” of the “optionally substituted benzene ring” include a halogen atom, C _1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl) and the like. Is 1 to 3.

As the “condensed aromatic heterocyclic group” of the “optionally substituted condensed aromatic heterocyclic group” represented by Ar, for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thanthrenyl, phenatridinyl , Phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2 -B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl .
As the “substituent” of the “fused aromatic heterocyclic group optionally having substituent (s)” represented by Ar, the “substituent” of “phenyl having substituent (s)” represented by Ar above Similar ones are used. The “fused aromatic heterocyclic group” may have, for example, 1 to 5 substituents, preferably 1 to 3 substituents at the substitutable positions. When the number of substituents is 2 or more, The substituents may be the same or different.

As the “monocyclic aromatic heterocyclic group” of the “monocyclic aromatic heterocyclic group optionally having substituents” represented by Ar, for example, a nitrogen atom, a sulfur atom and Examples thereof include 5- or 6-membered aromatic heterocyclic groups containing 1 or more (for example, 1 to 4) heteroatoms selected from oxygen atoms. Specific examples include thienyl, furanyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, oxazolyl, isoxazolyl and the like.
As the “substituent” of the “monocyclic aromatic heterocyclic group optionally having substituent (s)” represented by Ar, the “substituent” of “phenyl having substituent (s)” represented by Ar above The above substituents may be used, for example, the substituent may have 1 to 5, preferably 1 to 3 substituents at substitutable positions. When the number of substituents is 2 or more, The groups may be the same or different.

Ar includes (1) a phenyl having a substituent (the C _4-7 cycloalkane optionally having a substituent together with the carbon atom to which the substituents of the phenyl are bonded to each other and the substituent is bonded); A benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a substituent which may have a substituent. Preferred 6-membered aromatic heterocyclic groups (pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) are preferred.
Among them, Ar includes (1) (1 ′) halogen atom, (2 ′) cyano, (3 ′) C _1-6 alkyl optionally having 1 to 3 halogen atoms, (4 ′ ) C _6-14 aryl, (5 ′) C _1-6 alkoxy and (6 ′) phenyl having 1 to 3 substituents selected from C _1-6 alkyl-carbonyl, (2) having 1 oxo Preferred are indanyl which may be present, (3) naphthyl which may have one C _1-6 alkoxy, (4) indolyl and (5) benzofuryl.
In particular, Ar has (1) (1 ′) fluorine atom, (2 ′) chlorine atom, (3 ′) bromine atom, (4 ′) cyano, (5 ′) 1 to 3 fluorine atoms. Optionally substituted methyl, (6 ′) phenyl, (7 ′) methoxy and (8 ′) phenyl having 1 to 3 substituents selected from acetyl, (2) indanyl optionally having 1 oxo , (3) naphthyl optionally having one methoxy, (4) indolyl and (5) benzofuryl are preferred.

In the formula (I), L represents (1) a bond or (2) C _1-3 (poly) methylene which may have a substituent.
_{Examples of} “C _1-3 (poly) methylene” include methylene, ethylene, trimethylene and the like.
The “substituent” of the “optionally substituted C _1-3 (poly) methylene” represented by L is the “substituent” of the “phenyl having a substituent” represented by Ar. And the number of substituents is 1 or 2.
L is preferably a bond.

In the formula (I), ring A represents a 7- to 8-membered ring optionally having a substituent other than R ¹ to R ⁵ , that is, m + n = 2 to 3 (m and n are each 0 Represents an integer of 3).
Ring A is preferably a 7-membered ring (m = 2, n = 0).
More preferably, ring A is a 7-membered ring (m = 2, n = 0), and L is a bond.
The substituents on the ring A (that is, substituents other than R ¹ to R ⁵ and R ¹ to R ⁵ ) are bonded to each other and may have a substituent together with the ring atom to which the substituent is bonded. A good ring (preferably a 3- to 8-membered homocyclic or heterocyclic ring) may be formed.
The “substituent” other than R ¹ , R ² , R ³ , R ⁴ and R ⁵ on ring A is the same as the “substituent” of “phenyl having a substituent” represented by Ar described above. , Oxo, thioxo and the like are used, and may have 1 to 5, preferably 1 to 3, at substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different.

Ring A has, in addition to R ¹ , R ² , R ³ , R ⁴ and R ⁵ , 1 to 2 substituents selected from halogen atoms, C _1-6 alkyl, hydroxy, oxo and ethylene. Preferred 7 to 8 membered rings are preferred. Among them, as ring A, in addition to R ¹ , R ² , R ³ , R ⁴ and R ⁵ , there may be one substituent selected from a fluorine atom, methyl, hydroxy, oxo and ethylene 7 An 8-membered ring is preferred.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a hydrocarbon group which may have a substituent.

Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ include alkyl and substituent optionally having substituent (s). Examples thereof include alkenyl which may have, alkynyl which may have substituent, cycloalkyl which may have substituent, aryl which may have substituent and the like.
The “optionally substituted alkyl” is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C _1-6 alkyl _optionally having 1 to 3 thereof.
Examples of the “optionally substituted alkenyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C _2-6 alkenyl which may have 1 to 3 thereof.
Examples of the “optionally substituted alkynyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C _2-6 alkynyl which may have 1 to 3 thereof.
Examples of the “optionally substituted cycloalkyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C _3-8 cycloalkyl _optionally having 1 to 3 groups.
As the “aryl optionally having substituent (s)”, for example, it may have 1 to 3 of the same “substituent” as the above-mentioned “phenyl having substituent (s)” represented by Ar. Good C _6-14 aryl and the like can be mentioned.

The substituents on ring A (that is, the substituents other than R ¹ to R ⁵ and R ¹ to R ⁵ ) may be bonded together to form a “having substituent” which may be formed together with the ring atom to which the substituent is bonded. Examples of the optionally substituted 3- to 8-membered homocyclic or heterocyclic ring include a C _3-8 cycloalkane which may have a substituent and a C _4-8 cyclo which may have a substituent. Examples include alkenes and 3- to 8-membered heterocycles which may have a substituent.
The “optionally substituted C _3-8 cycloalkane” is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, thioxo C _3-8 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane) which may have 1 to 3 substituents selected from the above.
The “optionally substituted C _4-8 cycloalkene” is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, thioxo C _4-8 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene) which may have 1 to 3 substituents selected from the above.
Examples of the “optionally substituted 3- to 8-membered heterocyclic ring” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, A 3- to 8-membered heterocyclic ring optionally having 1 to 3 substituents selected from thioxo and the like (eg, aziridine, oxirane, azetin, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiol) Morpholine and the like).
Specific examples of the ring formed by combining the substituents on ring A (that is, substituents other than R ¹ to R ⁵ and R ¹ to R ⁵ ) with the ring atoms to which the substituents are bonded include octahydro -1H-pyrrolo [1,2-a] [1,4] diazepin-1-one, 3,9-diazabicyclo [4.2.1] nonane-4-one, 3,9-diazabicyclo [4.2. 1] Nonan-2-one, 3,6-diazabicyclo [3.2.2] nonane-4-one, 5,8-diazaspiro [2.6] nonane-6-one, 5,8-diazaspiro [2. 6] nonan-4-one and the like.

R ¹ is preferably a hydrogen atom or an optionally substituted alkyl. Of these, R ¹ is preferably a hydrogen atom or C _1-6 alkyl _optionally having one C _6-14 aryl. In particular, R ¹ is preferably a hydrogen atom, methyl, ethyl, isopropyl or benzyl, more preferably a hydrogen atom, methyl or ethyl.
R ² is preferably a hydrogen atom or alkyl optionally having a substituent. Of these, a hydrogen atom or C _1-6 alkyl is preferable, and a hydrogen atom, methyl, ethyl, propyl, isopropyl or benzyl is more preferable. In particular, a hydrogen atom or methyl is preferable.
R ³ is preferably a hydrogen atom or an optionally substituted alkyl. Of these, a hydrogen atom or C _1-6 alkyl is preferable, and a hydrogen atom, methyl, ethyl, propyl, isopropyl or benzyl is more preferable. A hydrogen atom is particularly preferable.
R ⁴ is preferably a hydrogen atom or an optionally substituted alkyl. Among them, a hydrogen atom or _{C 1-6} alkoxy and _{C 6-14} _{C 1-6} alkyl is preferably optionally having one substituent selected from aryl, hydrogen atom, methyl, ethyl, propyl, isopropyl More preferred are butyl, isobutyl, tert-butyl, ethoxymethyl or benzyl.
R ⁵ is preferably a hydrogen atom.

In one embodiment of the present invention, among the compounds of the present invention represented by the formula (I) or a salt thereof, the formula (I-II) [wherein each symbol is as defined above. Or a salt thereof, that is, a compound in which, in the formula (I), L is a bond, m is 2, and n is 0 (ring A is a 7-membered ring) or The salt is preferred.
Preferable examples of the compound represented by the formula (I-II) or a salt thereof include the formula (I-III) [wherein each symbol is as defined above. Or a salt thereof, that is, a compound or a salt thereof in which R ^2a , R ^3a , R ^5a and R ^{7a in the} formula (I-II) are hydrogen atoms.
Preferred examples of the compound represented by the formula (I-III) or a salt thereof include
R ^{1a ′} represents (1) a hydrogen atom or (2) a C _1-6 alkyl group which may be substituted with a phenyl group,
R ^{4a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group which may be substituted with a C _1-3 alkoxy group,
R ^{6a ′} represents (1) a hydrogen atom, or (2) a C _1-6 alkyl group,
R ^{8a ′} and R ^{9a ′} are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C _1-6 alkyl group,
Any combination of R ^{1a ′} and R ^{4a ′} , R ^{4a ′} and R ^{6a ′} and R ^{8a ′} and R ^{9a ′} is bonded to each other to form — (CH ₂ ) n′— (where n ′ Represents an integer of 1 to 3).
Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl;
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
(4) benzofuranyl, or (5) naphthyl optionally substituted with a C _1-3 alkoxy group,
Examples thereof include a compound represented by the formula (I-III) or a salt thereof.

As another preferred example of the compound represented by the formula (I-II) or a salt thereof,
Ar is (1) phenyl having a substituent,
(2) indanyl which may have a substituent,
(3) an indolyl optionally having a substituent,
(4) benzofuranyl which may have a substituent, or (5) naphthyl which may have a substituent.
Examples thereof include a compound represented by the formula (I-II) or a salt thereof.
As another preferred example of the compound represented by the formula (I-II) or a salt thereof,
Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl;
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
(4) benzofuranyl, or (5) naphthyl optionally substituted with a C _1-3 alkoxy group,
Examples thereof include a compound represented by the formula (I-II) or a salt thereof.

In another embodiment of the present invention, among the compounds of the present invention represented by the formula (I) or a salt thereof, the formula (I-IV) [wherein each symbol is as defined above. Or a salt thereof, that is, a compound in which, in the formula (I), L is a bond, m is 1, and n is 1 (ring A is a 7-membered ring) or The salt is preferred.
Preferred examples of the compound represented by the formula (I-IV) or a salt thereof include the formula (IV) [wherein each symbol is as defined above. Or a salt thereof, that is, a compound or a salt thereof in which R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , R ^8b and R ^9b are hydrogen atoms in the formula (I-IV) Is mentioned.
Preferred examples of the compound represented by the formula (IV) or a salt thereof include
R ^{6b ′} and R ^{7b ′} are the same or different and each represents (1) a hydrogen atom or (2) a C _1-6 alkyl group,
R ^{6b ′} and R ^{7b ′} may combine with each other to form — (CH ₂ ) n′— (wherein n ′ represents an integer of 1 to 3),
Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C _1-6 alkyl _optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
(2) indanyl optionally substituted with an oxo group, or (3) naphthyl,
Examples thereof include compounds represented by the formula (IV) or salts thereof.

As another preferred example of the compound represented by the formula (I-IV) or a salt thereof,
Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C _1-6 alkyl _optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
(2) indanyl which may have a substituent, or (3) naphthyl which may have a substituent.
Examples thereof include compounds represented by the formula (IV) or salts thereof.

As a preferable compound of the present invention represented by the formula (I) or a salt thereof, in the formula (I), [1] ring A is a 7-membered ring (m = 2, n = 0), and Ar is (1) phenyl having a substituent (the substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, a 4- to 7-membered saturated allocyclic ring optionally having a substituent) A 4- to 7-membered saturated heterocyclic ring which may have a substituent or a benzene ring which may have a substituent) or (2) may have a substituent. A “7-membered homopiperazinone compound” is a 6-membered aromatic heterocyclic group and L is a bond.

That is, a compound represented by the following formula (hereinafter sometimes abbreviated as compound (Ia)) or a salt thereof is preferable.

[Where,
Ar ^a is (1) phenyl having a substituent (the substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, the optionally substituted 4- to 7-membered saturated allotrope) A ring, a 4- to 7-membered saturated heterocyclic ring optionally having substituent (s) or a benzene ring optionally having substituent (s)) or (2) having a substituent. A good 6-membered aromatic heterocyclic group;
L ^a is a bond;
R ^1a represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^2a represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^3a represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^4a represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^5a is a hydrogen atom or an optionally substituted hydrocarbon group; and Ring A ^a is a 7-membered ring optionally having a substituent other than R ^1a to R ^5a (the ring A ^a The above substituents may be bonded to each other to form an optionally substituted ring together with the ring atom to which the substituent is bonded.)
Indicates. ]

As compound (Ia),
Ar ^a is (1) (1 ′) a halogen atom, (2 ′) cyano, (3 ′) C _1-6 alkyl optionally having 1 to 3 halogen atoms, (4 ′) C _{6 -14} aryl, (5 ′) C _1-6 alkoxy and (6 ′) phenyl having 1 to 3 substituents selected from C _1-6 alkyl-carbonyl, (2) having 1 oxo Good indanyl, (3) naphthyl optionally having one C _1-6 alkoxy, (4) indolyl and (5) benzofuryl;
La is ^a bond;
R ^1a may have a hydrogen atom or one C _6-14 aryl, C _1-6 alkyl;
R ^2a is a hydrogen atom or C _1-6 alkyl;
R ^3a is a hydrogen atom;
R ^4a is (1) hydrogen atom or _{(2) C 1-6} alkoxy and _{C 6-14} _{C 1-6} alkyl optionally having one substituent selected from aryl;
R ^5a is a hydrogen atom; and ring A ^a is substituted with a substituent selected from a halogen atom, C _1-6 alkyl and C _2-4 alkylene in addition to R ^1a , R ^2a , R ^3a , R ^4a and R ^5a A compound which is a seven-membered ring which may have one or two is preferable.

Among these, as compound (Ia),
Ar ^a has (1) (1 ′) fluorine atom, (2 ′) chlorine atom, (3 ′) bromine atom, (4 ′) cyano, (5 ′) 1 to 3 fluorine atoms Phenyl having 1 to 3 (preferably 2) substituents selected from methyl (preferably trifluoromethyl), (6 ′) phenyl, (7 ′) methoxy and (8 ′) acetyl, 2) indanyl optionally having one oxo, (3) naphthyl optionally having one methoxy, (4) indolyl and (5) benzofuryl;
R ^1a is a hydrogen atom, methyl, ethyl, isopropyl or benzyl;
R ^2a is a hydrogen atom or methyl;
R ^3a is a hydrogen atom;
R ^4a is a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethoxymethyl or benzyl (provided that the alkyl is one together with the atom on ring A to form a ring) May be);
R ^5a is a hydrogen atom; and ring A ^a has 1 or 2 substituents selected from a fluorine atom and methyl in addition to R ^1a , R ^2a , R ^3a , R ^4a and R ^5a Alternatively, the substituents may be bonded to each other to form a cyclopropane ring together with the ring atom to which the substituent is bonded (more preferably, ring A ^a together with the substituent is 5,8-diazaspiro. [2.6] Nonane-6-one ring may be formed)
Compounds are preferred.

In particular, as the compound (Ia), the compounds described in Examples 1 to 19, 22 to 65, 82 to 112, and 116 to 127 are preferable.

As a preferred compound of the present invention represented by the formula (I) or a salt thereof, in the formula (I), [2] ring A is a 7-membered ring (m = 1, n = 1), and Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) C _{6 -10} is phenyl having 1 or 2 substituents selected from aryl, (2) indanyl which may have substituents, or (3) naphthyl which may have substituents, and L is “7-membered homopiperazinone compound” which is a bond is also mentioned.

That is, a compound represented by the following formula (hereinafter sometimes abbreviated as compound (Ib)) or a salt thereof is preferable.

[Where,
Ar ^b is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) C Phenyl having 1 or 2 substituents selected from _6-10 aryl, (2) indanyl optionally having substituents, or (3) naphthyl optionally having substituents;
L ^b is a bond;
R ^1b represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^2b represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^3b represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^4b represents a hydrogen atom or an optionally substituted hydrocarbon group;
R ^5b is a hydrogen atom or an optionally substituted hydrocarbon group; and Ring A ^b is a 7-membered ring optionally having a substituent other than R ^1b to R ^5b (on Ring A ^b Of the substituents may be combined with the ring atom to which the substituent is bonded to form an optionally substituted ring)
Indicates. ]

As compound (Ib),
Ar ^b is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C _1-6 alkyl optionally having 1 to 3 fluorine atoms, (d) cyano and (e) C Phenyl having 1 or 2 substituents selected from _6-10 aryl, (2) indanyl optionally having 1 oxo, or (3) naphthyl;
L ^b is a bond;
R ^1b is a hydrogen atom or C _1-6 alkyl;
R ^2b is a hydrogen atom;
R ^3b is a hydrogen atom;
R ^4b is a hydrogen atom;
A compound wherein R ^5b is a hydrogen atom; and ring A ^b is a 7-membered ring optionally having one C _2-4 alkylene in addition to R ^1b , R ^2b , R ^3b , R ^4b and R ^5b Is preferred.

Especially, as compound (Ib),
Ar ^b is a substitution selected from (1) (a) a fluorine atom, (b) a chlorine atom, (c) methyl optionally having 1 to 3 fluorine atoms, (d) cyano and (e) phenyl Phenyl having 1 or 2 groups, (2) indanyl optionally having 1 oxo, or (3) naphthyl;
L ^b is a bond;
R ^1b is a hydrogen atom or methyl;
R ^2b is a hydrogen atom;
R ^3b is a hydrogen atom;
R ^4b is a hydrogen atom;
A compound in which R ^5b is a hydrogen atom: and ring A ^b is a 7-membered ring optionally having one ethylene other than R ^1b , R ^2b , R ^3b , R ^4b and R ^5b is preferred.

In particular, as the compound (Ib), the compounds described in Examples 20, 21, 66 to 81 and 108 are preferable.

In still another embodiment of the present invention, among the compounds of the present invention represented by formula (I) or a salt thereof,
(I) Ring A is an 8-membered ring (m = 2, n = 1),
Ar is (1) phenyl substituted with a halogen atom, or (2) naphthyl which may have a substituent, and
L is a bond,
The compound represented by the formula (I) or a salt thereof;
(Ii) Ring A is an 8-membered ring (m = 3, n = 0),
Ar is phenyl substituted with a halogen atom, and
L is a bond,
The compound represented by the formula (I) or a salt thereof;
Is preferred.

As the compound of the present invention represented by the formula (I) or a salt thereof, particularly preferably,
1- (3,4-dichlorophenyl) -1,4-diazepan-2-one (compound of Example 1),
1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (compound of Example 6),
1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (compound of Example 101),
1- (3,4-dichlorophenyl) -3-propyl-1,4-diazepan-2-one (the compound of Example 106),
1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 25),
3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 117),
3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (the compound of Example 124),
Or a salt thereof.

(Production method)
The compound represented by the formula (I) (the following formula) or a salt thereof and a raw material compound thereof can be produced by a method known per se, for example, by a method shown in the following scheme.
Formula (I)

Hereinafter, “room temperature” usually indicates 0 to 30 ° C., and each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified. The compound in the formula includes a case where a salt is formed. Examples of such a salt include the same salts as the salt of compound (I).
The compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by this separation means.
Although the schematic diagram of the reaction formula is shown below, when a compound in the formula is commercially available, a commercially available product can be used as it is. In addition, when ring A has a substituent, the corresponding precursor also has the same substituent.
In the production methods described below, protecting groups P ¹ and P ² are protecting groups for nitrogen atoms of amines and amides, P ³ is a protecting group for alcohol oxygen atoms, and those known per se can be used. . For example, P ¹ and P ² are preferably tert-butyl carbamate, benzyl carbamate, benzyl and the like, and P ³ is preferably tert-butyl diphenylsilyl and the like. In addition, P ¹ itself may be R ¹ . Examples include methyl and benzyl.
Examples of the “leaving group” represented by X include a halogen atom (for example, chlorine atom, bromine atom, iodine atom, etc.), C _1-6 alkylsulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethane). Sulfonyloxy, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used.
In the production method described below, when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, reductive amination reaction, etc. The reaction is carried out according to a method known per se. Such methods include, for example, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformation). ) VCH Publishers Inc. Examples include the method described in 1989.
Each step described below can be carried out without solvent or by dissolving or suspending in an appropriate solvent. Examples of the “solvent” include hydrocarbon solvents, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, ketone solvents, esters. It refers to a system solvent, a carboxylic acid solvent, water, etc., and these may be used in a mixture of two or more at an appropriate ratio.

[Production method A]
Production of Compound (I)

(Process A-1)
Compound (III) can be produced by deprotection of compound (II). Deprotection can be performed, for example, according to the method described in Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999). Specifically, it is carried out by acid treatment, alkaline hydrolysis, catalytic hydrogenation reaction or the like. As the protecting group P ¹ , those known per se can be used. Preferred examples include tert-butyl carbamate, benzyl carbamate, benzyl, methyl and the like.
For example, when the protecting group P ¹ is tert- butyl carbamate, it can be deprotected by using an acid. Preferred examples of the “solvent” include ester solvents (for example, ethyl acetate and the like) and alcohol solvents (for example, ethanol and the like), and ester solvents are particularly preferable. Examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. In particular, hydrochloric acid, trifluoroacetic acid and the like are preferable.
The amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (II).
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
When the protecting group P ¹ is benzyl carbamate, deprotection can also be performed by a catalytic hydrogenation reaction or the like. The “catalytic hydrogenation reaction” can be performed in a hydrogen atmosphere in the presence of a catalyst. Examples of the catalyst include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst), platinum (eg, platinum oxide, platinum carbon, etc.), rhodium ( For example, rhodium carbon and the like.
The amount of the catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, per 1 mol of compound (II).
The “solvent” is preferably an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), an ether solvent (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), an ester solvent (eg, ethyl acetate, etc.), An acid solvent (for example, acetic acid etc.), water, or mixtures thereof are mentioned. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.

(Process A-2)
Compound (I) can be produced by alkylation, alkenylation, alkynylation, cycloalkylation or the like of compound (III). This reaction includes an alkylating agent corresponding to the substituent R ¹ (eg, iodomethane, benzyl bromide, etc.), an alkenylating agent (eg, allyl bromide), an alkynylating agent (eg, propargyl bromide), cycloalkyl, etc. An agent such as cyclopropylmethyl bromide can be used.
The amount of the alkylating agent used is usually 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
The “solvent” is preferably an amide solvent (for example, dimethylformamide, etc.).
In addition, this reaction may be performed by adding an appropriate base. As "base"
1) Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium) Amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), alkali metal or alkaline earth metal lower alkoxides (eg, sodium methoxide, Strong bases such as sodium ethoxide, potassium tert-butoxide and the like;
2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, Inorganic bases such as potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.); and 3) eg, triethylamine, ethyldiisopropylamine, N-methyl Amines such as morpholine; such as DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene), etc. Amidines; for example, pyridine, dimethylaminopyridine, imidazole, 2,6-lutidine And organic bases such as basic heterocyclic compounds. Preferred are sodium hydride, cesium carbonate, potassium carbonate and the like.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
In carrying out this reaction, the hydrogen atom on the nitrogen atom of compound (III) may be previously substituted with a metal atom, for example, an alkali metal such as lithium or sodium.

Compound (I) (when R ¹ is optionally substituted alkyl) can also be produced by reductive alkylation of compound (III). This reaction is carried out by subjecting compound (III) and an imine intermediate produced from the corresponding aldehyde or ketone to a reduction reaction.
The amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
The reduction reaction can be carried out by a method known per se, but is usually carried out by a reaction using a reducing agent or the “catalytic hydrogenation reaction” described in the above (Step A-1).
Examples of the “reducing agent” include an aluminum reagent (eg, lithium aluminum hydride (LiAlH ₄ ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), Alane (AlH ₃ ), etc.), boron reagent (eg, borane (BH ₃ ), 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride (NaBH (OAc) ₃ ) and the like. Borane, sodium triacetoxyborohydride and the like are preferable.
The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (III).
When a boron reagent is used, an acid may be added to accelerate the reaction. Preferred examples of the “acid” include acetic acid.
The amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalent, per 1 mol of compound (III).
In this case, the “solvent” is preferably an ether solvent (for example, tetrahydrofuran). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

Compound (III) can be produced by the method of [Production method G] in addition to (Step A-1).

[Production method G]
Production of compound (III)

Compound (III) includes, for example, compound (IIIe), and the compound (IIIe) can be produced by the following method.

Preparation of compound (IIIe) (L = bond, m = 3, n = 0)

(Process G-1)
Compound (IIIe) can be produced by a ring closure reaction by intramolecular alkylation of compound (XLVI).
Examples of the “base” to be added include amines, and triethylamine is particularly preferable.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLVI).
Further, an appropriate inorganic salt may be added. For example, tetra-n-butylammonium iodide is preferable.
The amount of the inorganic salt to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLVI).
The “solvent” is preferably a halogen-based solvent (eg, dichloromethane). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

Production of compound (XLVI)

(Process G-2)
This coupling reaction is performed by a method according to (Step B-4) described later.
Preferred examples of the “metal catalyst” include copper iodide. Examples of the “ligand” include 2- (2-methylpropanoyl) cyclohexanone, and examples of the “base” include cesium carbonate.
The amount of the metal catalyst to be used is generally 0.001 to 3 molar equivalents, preferably 0.001 to 0.3 molar equivalents, per 1 mol of compound (XLVII). The amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XLVII).
The amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XLVII).
Examples of the “solvent” include amide solvents (for example, dimethylformamide and the like). The reaction temperature can be −100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 48 hours.
(Process G-3)
This amidation reaction is carried out by a method according to (Step B-1) described later. For example, a method using an activated carboxylic acid derivative (acid halide or the like) is preferable.
In this case, the “solvent” is preferably a halogen-based solvent, an ether-based solvent, or a mixed solvent thereof with water, and a mixed solvent of 1,4-dioxane and water is particularly preferable. In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, sodium carbonate and the like are preferable.
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about −20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24. It's time.
(Process G-4)
This deprotection reaction is carried out by a method according to (Step A-1). For example, when the protecting group P ¹ is tert-butyl carbamate, the “solvent” is preferably an ester solvent (for example, ethyl acetate) or an ether solvent (for example, 1,4-dioxane). Ether solvents are preferred. Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. In particular, hydrochloric acid, trifluoroacetic acid and the like are preferable. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.

Compound (II) can be produced by the following [Production Method B] to [Production Method F]. [Production method B] and [Production method C] are compound (IIa) (L = bond, m = 2, n = 0), and [Production method D] is compound (IIa), (IIb) (L = bond). Hand, m = 1, n = 1), (IIc) (L = polymethylene chain, m + n = 2 or 3) and (IId) (L = bonded hand, m = 2, n = 1) ] Shows the production method of compound (IIb), and [Production method F] shows the production method of compound (IId).

[Production method B]
Production of Compound (IIa)

(Process B-1)
Compound (VI) can be produced by amidation of compound (IV). This amidation reaction is carried out by reacting the corresponding carboxylic acid derivative with a condensing agent (for example, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, 4- (4,6-dimethoxy [1.3.5] triazine- 2-yl) -4-methylmorpholinium chloride) or a reaction using an activated carboxylic acid derivative (such as acid chloride). The amount of the carboxylic acid derivative to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IV). The amount of the condensing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IV).
The “solvent” is preferably an amide solvent, and N, N-dimethylformamide is particularly preferable. In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IV).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process B-2)
Compound (VI) can also be produced by deprotecting only one protecting group of compound (V) having both protecting groups P ¹ and P ² . Deprotection can be performed by a method according to (Step A-1). Further, as the protecting groups P ¹ and P ² , those known per se can be used in combination. Specific examples include a combination of tert-butyl carbamate and benzyl, benzyl and benzyl, and the like.
For example, when the combination of protecting groups is tert-butyl carbamate and benzyl, deprotection of only tert-butyl carbamate can be performed using an acid. The “solvent” is preferably an ester solvent (such as ethyl acetate) or an alcohol solvent (such as ethanol). Preferred examples of the “acid” include hydrochloric acid and trifluoroacetic acid.
The amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (V).
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
(Process B-3)
Compound (IIa) can be produced by a ring closure reaction of compound (VI). Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like.
In this reaction, a base may be added. As the “base”, the same “base” as described in the above (Step A-2) can be used, preferably sodium hydride, cesium carbonate, potassium carbonate and the like.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (VI).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

Production of compound (IV)

(Process B-4)
Although this coupling reaction can be carried out by a method known per se, it is usually carried out using a metal catalyst.
The amount of compound (VII) to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
Examples of the “metal catalyst” include copper catalysts (eg, copper iodide, copper bromide), palladium catalysts (eg, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium chloride). (II), known metal catalysts such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), etc., and a ligand (eg, 2-dicyclohexylphos Fino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, triphenylphosphine, tri-tert-butylphosphine, binaphthol, proline, 4,5-bis (diphenylphosphino) -9,9 -Dimethylxanthene or the like) may be added.
The amount of the metal catalyst to be used is generally 0.001 to 3 molar equivalents, preferably 0.001 to 0.3 molar equivalents, per 1 mol of compound (VIII) or compound (XI). The amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, but cesium carbonate, tripotassium phosphate and the like are preferable.
The amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
The “solvent” for this reaction is preferably a sulfoxide solvent or an amide solvent, particularly preferably dimethyl sulfoxide, N, N-dimethylformamide or the like. This reaction can be carried out at −100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is, for example, 1 minute to 10 days.
(Step B-5) (R ² = R ³ = H)
Although this reduction reaction can be carried out by a method known per se, it is usually carried out using a reducing agent. As the “reducing agent”, those similar to the “reducing agent” described in the above (Step A-2) can be used, and preferably lithium aluminum hydride, borane and the like.
The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (IX).
Examples of the “solvent” include ether solvents, and solvents such as diethyl ether and tetrahydrofuran are preferred. This reaction can be carried out at −100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process B-6)
The introduction reaction of this protecting group can be carried out according to the method described in, for example, Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999). Further, as the protective group P ^1, it is possible to use the known ones. Specific examples include tert-butyl carbamate and benzyl.
(Process B-7)
This deprotection reaction can be carried out by a method according to (Step A-1).
For example, when the protecting group P ¹ is benzyl and P ² is tert-butyl carbamate, only the protecting group P ² can be deprotected using an acid. Preferred examples of the “solvent” include ethyl acetate and ethanol, with ethyl acetate being particularly preferred. The “acid” is preferably a hydrochloric acid solution, trifluoroacetic acid or the like.
The amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (XII).
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
When the protecting groups P ¹ and P ² are benzyl, only one benzyl can be deprotected by “catalytic hydrogenation reaction”. Preferable examples of the catalyst include palladium (eg, palladium carbon, palladium hydroxide carbon, palladium oxide, etc.), platinum (eg, platinum oxide, platinum carbon, etc.), and the like.
The amount of the catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.1 molar equivalent, per 1 mol of compound (XII).
The “solvent” is preferably an alcohol solvent (for example, methanol, ethanol, propanol, butanol, etc.), and ethanol is particularly preferable. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.

Manufacture of compound (IX)

(Process B-8)
This coupling reaction can be carried out by a method according to (Step B-4).
The amount of compound (VII) to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XIII).
Preferably, copper iodide is used as the metal catalyst, L-proline is used as the ligand, and tripotassium phosphate is used as the base.
The amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XIII). The amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XIII). The amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XIII).
(Process B-9)
This amidation reaction can be carried out by a method according to (Step B-1). In this case, preferred protecting group P ¹ is benzyl, methyl or the like.

Production of compound (X)

(Process B-10)
This amidation reaction can be carried out by a method according to (Step B-1).
The amount of compound (XV) to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVI).
The “solvent” is preferably an amide solvent, and N, N-dimethylformamide is particularly preferable. In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
The amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVI) or compound (XIV).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Step B-11) (R ² = R ³ = H)
This reduction reaction can be carried out by a method according to (Step B-5). Preferably, the “reducing agent” is lithium aluminum hydride, borane or the like.
The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII) or compound (XIX).
Examples of the “solvent” include ether solvents, and solvents such as diethyl ether and tetrahydrofuran are preferred. This reaction can be carried out at −100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process B-12)
This alkylation reaction can be carried out by a method according to (Step A-2).
The amount of the alkylating agent (compound (XVIII)) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XV).
Preferred examples of the solvent include aromatic solvents, and particularly preferred is toluene. As the “base”, potassium carbonate is preferable. The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XV). The reaction temperature is usually about −100 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is preferably 0.5 to 24 hours.

Manufacture of compound (V)

(Process B-13)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). For example, when the protecting group P ¹ is benzyl, di-tert-butyl dicarbonate can be used to introduce tert-butyl carbamate as the protecting group P ² .
The amount of ditert-butyl dicarbonate to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IV).
In this case, examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process B-14)
This amidation reaction can be carried out by a method according to (Step B-1). For example, a method using a corresponding activated carboxylic acid derivative (acid halide or the like) is preferable. The amount of the carboxylic acid derivative to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XII). In this case, the “solvent” is preferably a halogen-based solvent or an ether-based solvent, and tetrahydrofuran is particularly preferable. In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XII).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

[Production Method C]
Production of Compound (IIa)

Compound (IIa) can be produced by a ring closure reaction of compound (XX). This ring-closing reaction can be carried out by a method according to (Step B-3). Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like. The “base” is preferably sodium hydride, potassium tert-butoxide or the like. The amount of the base to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XX).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

Manufacture of compound (XX)

(Process C-2)
This amidation reaction can be carried out by a method according to (Step B-1).
The amount of compound (XV) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXI).
Preferred examples of the condensing agent include 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride.
The amount of the condensing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXI).
The “solvent” is preferably an alcohol solvent, and ethanol is particularly preferable. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process C-3)
This deprotection reaction can be carried out by a method according to (Step A-1). For example, when the protecting group P ¹ is tert-butyl carbamate, the “solvent” is preferably an ester solvent (for example, ethyl acetate) or an alcohol solvent (for example, ethanol), particularly an ester solvent. Is preferred. Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. In particular, hydrochloric acid, trifluoroacetic acid and the like are preferable.
The amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (XXII).
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
(Process C-4)
This reductive alkylation reaction is performed by a method according to (Step A-2). As the alkylating agent, for example, 3-[(tert-butyldiphenylsilyl) oxy] propanal (Org. Lett. 9, 1951-1954 (2007)) is preferably used as the “reducing agent”. It is done. In particular, sodium triacetoxyborohydride is preferred.
The amount of the alkylating agent to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXIII). The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXIII).
The “acid” is preferably acetic acid.
The amount of the acid to be used is generally 0.1 to 5 molar equivalents, preferably 0.1 to 2 molar equivalents, per 1 mol of compound (XXIII).
The “solvent” is preferably an ether solvent (for example, tetrahydrofuran). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process C-5)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). As protective group ^{P 1,} for example, tert-butyl carbamate or the like are preferable. In this case, examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process C-6)
This deprotection reaction can be carried out according to the method described in, for example, Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999). As the protecting group P ³ , tert-butyldiphenylsilyl or the like is preferable. As a reagent for deprotection at that time, tetrabutylammonium fluoride or the like is preferable. The amount of tetrabutylammonium fluoride to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXV).
Examples of the “solvent” include ether solvents, and tetrahydrofuran is particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process C-7)
As a method for converting a hydroxy group to a leaving group X, for example, Organic Functional Group Preparations, 2nd edition, Academic Press, Inc., 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformations) VCH Publishers Inc. Examples include the method described in 1989. The leaving group X is preferably methanesulfonyloxy or the like. In this case, examples of the “solvent” include ether solvents, and tetrahydrofuran is particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.

[Production Method D]
Production of compound (IIa-d)

(Process D-1)
L = in the case of a bond hand;
Compound (IIa-d) can be produced by a coupling reaction of compound (XXVII) and compound (XXVIII).
This coupling reaction can be carried out by a method according to (Step B-4). The amount of compound (XXVII) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXVIII).
Preferably, tris (dibenzylideneacetone) dipalladium (0) and the like as the “metal catalyst”, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene and the like as the “ligand”, and “base ”Includes cesium carbonate and the like. The amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XXVIII). The amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XXVIII). The amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXVIII).
Examples of the “solvent” include aromatic solvents and ether solvents, and preferred are toluene, 1,4-dioxane and the like. The reaction temperature is usually −100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
When L = methylene chain;
Compound (IIa-d) can be produced by alkylation of compound (XXVIII).
This alkylation reaction can be carried out by a method according to (Step A-2). Examples of the alkylating agent (compound (XXVII)) include 3,4-dichlorobenzyl bromide and the like.
The amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXVIII).
Examples of the “base” include sodium hydride and the like, and examples of the “solvent” include amide solvents, and N, N-dimethylformamide and the like are particularly preferable.
The amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXVIII).

Production of Compound (XXVIII) Compound (XXVIIIa) (in compound (XXVIII), where m = 2 and n = 0) is, for example, a method described in WO2006 / 9886 and Bioorganic Medicinal Chemistry Letters, 17, 1903-1907 (2007) Compound (XXVIIIb) (in compound (XXVIII), m = 1, n = 1) can be produced, for example, by a method according to WO 2006/56877 or Tetrahedron Letters, 32, 2469-2470 (1991). However, it can also be produced by the following method.

Manufacture of compound (XXVIIIa)

(Process D-2)
This reductive alkylation reaction can be carried out by a method according to (Step A-2). As the alkylating agent, for example, benzyl (3-oxopropyl) carbamate is preferable. As the “reducing agent”, a boron reagent and the like are preferable. In particular, sodium triacetoxyborohydride is preferred.
The amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXIX). The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXIX).
The “acid” is preferably acetic acid.
The amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (XXIX).
The “solvent” is preferably an ether solvent (for example, tetrahydrofuran). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process D-3)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). As protective group ^{P 1,} for example, tert- butyl carbamate and the like are preferable. In this case, examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
(Process D-4)
This deprotection reaction can be carried out by a method according to (Step A-1). For example, when the protecting group P ¹ is benzyl carbamate, deprotection can be performed by “catalytic hydrogenation reaction”. Examples of the “metal catalyst” include palladium and the like, particularly preferably palladium carbon and the like.
The amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, per 1 mol of compound (XXXI).
Examples of the “solvent” include alcohol solvents, and ethanol and the like are particularly preferable. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
(Process D-5)
Compound (XXVIIIa) can be produced by a ring closure reaction of compound (XXXII).
This ring-closing reaction can be carried out in a suitable solvent in the presence of a base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, sodium ethoxide, potassium carbonate and the like are preferable.
The amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXII).
Examples of the “solvent” include alcohol solvents, and ethanol is particularly preferable.
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 100 hours, preferably about 0.5 hours to about 72 hours. It's time.
The ring closure reaction can also be carried out by hydrolyzing the ester and then amidating. These reactions can be carried out according to a method known per se.

Manufacture of compound (XXVIIIa)

(Process D-6)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). For example, when the protecting group P ² is tert-butyl carbamate, benzyl can be introduced as the protecting group P ¹ by reductive alkylation with benzaldehyde.
The amount of benzaldehyde to be used is generally 0.1 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXXIII).
At this time, the “reducing agent” is preferably a boron reagent or the like. In particular, sodium cyanoborohydride and sodium triacetoxyborohydride are preferable. The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXIII).
The “acid” is preferably acetic acid.
The amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIII).
The “solvent” is preferably an ether solvent (for example, tetrahydrofuran). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process D-7)
This amidation reaction can be carried out by a method according to (Step B-1). For example, a method using a corresponding activated carboxylic acid derivative (acid halide or the like) is preferable. The amount of the carboxylic acid derivative to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIV).
In this case, the “solvent” is preferably a halogen-based solvent or an ether-based solvent, and tetrahydrofuran is particularly preferable. In addition, this reaction may be performed by adding an appropriate base. As the “base”, the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable. The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIV).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process D-8)
This ring-closing reaction can be carried out by a method according to (Step B-3). Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like.
In this reaction, a base may be added. As the “base”, the same “base” as described in the above (Step A-2) can be used, preferably sodium hydride, cesium carbonate, potassium carbonate and the like.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXV).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process D-9)
This deprotection reaction can be carried out by a method according to (Step A-1). When the protecting group ^{P 2} is benzyl, the reaction conditions known as Birch reduction (e.g., after dissolving metallic sodium in liquid ammonia at -78 ° C., and the like is added compound (XXXVI)) are preferred.

[Production Method E]
Production of Compound (IIb)

Compound (IIb) can be produced by a ring closure reaction of compound (XXXVII). This ring-closing reaction can be carried out by a method according to (Step B-3). Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like. As the “base”, sodium hydride, potassium tert-butoxide and the like are preferable.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXVII).
In addition, an inorganic salt such as sodium iodide may be added.
The amount of the inorganic salt to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXVII).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

Production of compound (XXXVII)

(Process E-2)
This reduction reaction can be performed by a method according to (Step A-1).
When the reduction reaction is carried out by catalytic hydrogenation reaction, platinum oxide or the like is preferable as the “metal catalyst”, acetic acid or an alcohol solvent as the “solvent”, and hydrochloric acid or the like as the additive. The amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XVII). The amount of the additive to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVII).
In the case of performing a reduction reaction using a reducing agent, examples of the “reducing agent” include a boron reagent, and sodium borohydride is particularly preferable.
The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII).
Examples of the “solvent” include alcohol solvents, and ethanol is particularly preferable. As an additive, cobalt (II) chloride or the like is preferable.
The amount of the additive to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process E-3)
This reductive alkylation reaction can be carried out by a method according to (Step A-2). Examples of the alkylating agent include chloroacetaldehyde. The amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXXVIII).
Examples of the “reducing agent” include a boron reagent, and sodium triacetoxyborohydride is particularly preferable.
The amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXVIII).
The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process E-4)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). As protective group ^{P 1,} for example, tert- butyl carbamate and the like are preferable. In this case, examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable. The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.

[Production Method F]
Production of Compound (IId)

Compound (IId) includes, for example, compound (XLV), and the compound (XLV) can be produced by the following method. Compound (IId) other than the compound (XLV) can also be produced by the same method as described below.

Manufacture of compound (XLV)

(Process F-1)
This alkylation reaction can be carried out by a method according to (Step A-2).
Examples of the alkylating agent include methyl 3-bromopropanoate. The amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XL).
Examples of the “base” to be added include amines. Particularly preferred is diisopropylethylamine.
The amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XL).
The “solvent” is preferably an amide solvent (for example, dimethylformamide, etc.). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
(Process F-2)
The introduction reaction of this protecting group can be carried out by a method according to (Step B-6). As protective group ^{P 1,} for example, tert- butyl carbamate and the like are preferable. In this case, examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable. The reaction temperature is usually about −50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
(Process F-3)
This deprotection reaction can be carried out by a method according to (Step A-1). For example, when the protecting group P ² is benzyl carbamate, deprotection can be performed by “catalytic hydrogenation reaction”. Examples of the “metal catalyst” include palladium and the like, particularly preferably palladium carbon and the like.
The amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XLIII).
Examples of the “solvent” include alcohol solvents, and ethanol and the like are particularly preferable. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
(Process F-4)
This ring-closing reaction can be carried out by a method according to (Step D-5).
As the “base”, for example, sodium methoxide and the like are preferable.
The amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLIV).
Examples of the “solvent” include alcohol solvents, and methanol is particularly preferable.
The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 48 hours. It's time.
The ring closure reaction can also be carried out by hydrolyzing the ester and then amidating. These reactions can be carried out according to a method known per se.

Compound (I) can be isolated and purified by a known means such as phase transfer, concentration, solvent extraction, fractional distillation, liquid conversion, crystallization, recrystallization, chromatography and the like.
When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
Examples of the salt of compound (I) include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, metal salts, ammonium salts, salts with organic bases, and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid Salts with organic acids such as acids, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and alkali metal salts (eg, sodium salts, potassium salts, etc.) when the compound has an acidic functional group ), Alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), and the like, and ammonium salts.

The compounds represented by the formula (I) of the present invention may be in the form of their prodrugs. A prodrug of compound (I) is a compound that is converted to compound (I) by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, (i) enzymatically causes oxidation, reduction, hydrolysis, etc. A compound that changes to compound (I), (ii) a compound that undergoes hydrolysis or the like by gastric acid or the like, and changes to compound (I).
As a prodrug of the compound (I) to be used, a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.) A compound in which hydroxy of (I) is acylated, alkylated, phosphorylated, borated or a salt thereof (eg, hydroxy of compound (I) is acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, Alanyloxy, dimethylaminomethylcarbonyloxy A compound converted into the like or a salt thereof, etc., a compound wherein the carboxy of the compound (I) is esterified or amidated, or a salt thereof (eg, the carboxy of the compound (I) is ethyl esterified, phenyl esterified, carboxyoxy Methyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl) methyl Esterified, cyclohexyloxycarbonyl esterified or methylamidated compounds, etc.).
These prodrugs can be produced by a method known per se or a modification thereof.

In addition, the prodrug of compound (I) is a compound that can be converted into compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, pages 163 to 198, The salt may be sufficient.

When the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are included in the compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).

Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. The crystal can be produced by crystallization by applying a crystallization method known per se.
Compound (I) may be a co-crystal.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I) and the like.
Compounds labeled with isotopes (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also encompassed in compound (I).
Furthermore, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (I).

Compound (I) or a salt thereof or a prodrug thereof (hereinafter abbreviated as a compound of the present invention) is a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) In contrast, as a substance having inhibitory activity on reuptake of brain monoamines (serotonin / norepinephrine / dopamine, etc.), it inhibits the reuptake of monoamines in the brain, and prevents neuropsychiatric disorders such as depression and anxiety Improve symptoms.
Since the compound (I) of the present invention has excellent properties as a pharmaceutical product such as low toxicity and few side effects, it has a neuropsychiatric disorder including depression, anxiety and attention deficit hyperactivity disorder (ADHD) ( For example, depression (cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression, etc.), anxiety (eg, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder) Etc.), ADHD, bipolar disorder, mania, recurrent depression, persistent mood emotion disorder (eg, mood circulatory disorder, dysthymia etc.), depressive neurosis, sleep disorder, diurnal rhythm disorder, eating Disorder, drug dependence, premenstrual tension, autism, mood disorders due to menopause, senile dementia, mild cognitive dysfunction, hypersomnia, various analgesia, various pains (neuropathic, inflammatory, etc.), muscle Fibrosis, Alzheimer's disease and parkin Neurodegenerative diseases such as neuropathy, mood disorders associated with neurodegenerative disorders, mood disorders and movement disorders associated with stroke and cerebrovascular disorders, fibromyalgia, psychosomatic disorders, manic depression, or posttraumatic stress disorder (Posttraumatic stress disorder) (disorder: PTSD), schizophrenia, anxiety, obsessive-compulsive disorder, obsessive-compulsive disorder, etc.), diabetes, obesity, urological diseases (such as stress urinary incontinence, dysuria), irritable bowel syndrome (IBS), IRS, premenstrual It is useful as a prophylactic / therapeutic agent for syndrome (PMS), functional gastroenteropathy (FD), digestive system diseases, etc., smoking cessation, and an addiction treatment.

The compounds of the present invention are low in toxicity and include pharmaceutical compositions mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, such as tablets (sugar-coated tablets, film-coated tablets, orally disintegrating tablets, etc.) ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, patches, etc., orally or parenterally (eg, topical, rectal, intravenous) Administration, etc.).

The content of the compound (I) in the present invention in the present invention is about 0.01 to about 100% by weight of the entire preparation.
The dosage varies depending on the administration subject, administration route, disease, etc., but when administered as an oral agent to an adult, for example, as a therapeutic agent for depression, the compound of the present invention is used in an amount of about 0.001 to about It is 20 mg / kg body weight, preferably about 0.01 to about 10 mg / kg body weight, more preferably about 0.05 to about 10 mg / kg body weight, and can be administered once or several times a day.

The pharmaceutical composition containing the compound of the present invention is considered to be one of the causes of the onset of depression, anxiety, etc., which is considered to be one of the causes of the onset, such as a decrease or functional impairment of serotonin, norepinephrine, dopamine, etc. It is expected to be useful for the treatment and prevention of neuropsychiatric disorders including ADHD.

In addition to the treatment of neuropsychiatric disorders (eg, depression, anxiety, ADHD, manic depression or PTSD, schizophrenia, etc.) and neuropsychiatric disorders, for example, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, muscle atrophy) Lateral sclerosis (ALS), Huntington's disease, spinocerebellar degeneration, multiple sclerosis (MS), head injury, spinal cord injury, cerebrovascular disorder, cerebrovascular dementia, spinal cord injury, polyglutamine disease ( Odontocytic red nucleus, Pallus leucoatrophy, bulbar spinal muscular atrophy, Machado-Jacob disease, spinocerebellar ataxia type 6, prion disease (Creutzfeldt-Jacob disease, Gerstmann-straussler-Scheinker disease), cerebrum Cortical basal ganglia degeneration, progressive supranuclear palsy, AIDS encephalopathy, muscular dystrophy, diabetic neuropathy, diabetic retinopathy Diabetic nephropathy, hepatic hard flame, alcoholic hepatitis, in order to adapt to diseases such as osteoporosis, in addition to the compounds of the present invention may be used in combination with other active ingredients.
Examples of such concomitant drugs include depression drugs, anxiety drugs such as benzodiazepines (chlorodiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam, etc.), mood stabilizers (lithium carbonate), 5 -HT2 antagonists (such as nefazodone), 5-HT1A agonists (such as tandospirone, buspirone, and Gepiron), CRF antagonists (such as Pexecerfont), β3 agonists (such as Amibegron), melatonin agonists (rameltheon, agomelatin), α2 antagonists Drugs (such as mirtazapine and cetiptiline), NK2 antagonists (such as Saledutant), GR antagonists (such as Mifepristone), NK-1 antagonists (such as Casopitant and Orvepitant), schizophrenia Therapeutic agents (chloropromazine, haloperidol, sulpiride, clozapine, aripiprazole, quetiapine, olanzapine, risperidone, etc.), acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, zanapezil, etc.), NMDA antagonists (eg, manmantine), β amyloid Protein production, secretion, accumulation, aggregation and / or deposition inhibitor [β-secretase inhibitor, γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (eg, PTI-00703, ALZHEMED (NC-531), PPI-368) (Special Tables Hei 11-514333), PPI-558 (Special Tables Hei 2001-500852), SKF-74652 (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-A Lloyd degrading enzymes, etc.], brain function stimulants (eg, aniracetam, nicergoline, etc.), other Parkinson's disease therapeutic agents [eg, dopamine receptor agonists (L-dopa, bromocriptene, pergolide, talipexol, pripepexol, cabergoline, Adamantadine, etc.), COMT inhibitors (eg, entacapone, etc.)], attention deficit hyperactivity disorder drugs (modafinil, etc.), amyotrophic lateral sclerosis drugs (eg, riluzole, etc.), Insomnia treatment (such as etizolam, zopiclone, triazolam, zolpidem, indiplon), hypersomnia (such as modafinil), diabetes treatment, non-steroidal anti-inflammatory (eg, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib , Rofecoxib, aspirin, indomethacin, etc. , Disease-modifying anti-rheumatic drugs (DMARDs), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (eg, Progesterone, estradiol, estradiol benzoate, etc.), parathyroid hormone (PTH), calcium receptor antagonist and the like.
Other active ingredients and the compound of the present invention are mixed according to a method known per se, and a single pharmaceutical composition (eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, In a sustained-release preparation, etc.) and may be used together, or each may be formulated separately and administered to the same subject at the same time or with a time difference.

The compound of the present invention is formulated with a pharmaceutically acceptable carrier, and is orally or parenterally as a solid preparation such as a tablet, capsule, granule or powder; or as a liquid preparation such as syrup or injection. Can be administered. In addition, it should be made into transdermal preparations such as patches, poultices, ointments (including creams), plasters, tapes, lotions, solutions and solutions, suspensions, emulsions, sprays, etc. You can also.

Examples of the pharmacologically acceptable carrier that may be used for the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials. For example, excipients, lubricants in solid preparations, Examples include binders, disintegrants, solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents. Further, if necessary, additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like.
Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

If necessary, for the purpose of taste masking, enteric coating, or sustained action, the oral preparation may be prepared by coating by a method known per se. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], and cellulose acetate phthalate. , Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (Rohm, methacrylic acid-acrylic acid copolymer), and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate; polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose Examples thereof include hydrophilic polymer substances such as sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Examples of soothing agents include benzyl alcohol. Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Examples of the antioxidant include sulfite and ascorbic acid.

The present invention is further explained in detail by the following reference examples, examples, formulation examples and test examples, but these examples are merely examples and do not limit the present invention, and the scope of the present invention. You may change in the range which does not deviate from.

Elution in column chromatography of Examples and Reference Examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, 60F ₂₅₄ manufactured by Merck Co., Ltd. or NH manufactured by Fuji Silysia Chemical Co., Ltd. is used as the TLC plate, and the solvent used as the elution solvent in column chromatography is used as the developing solvent, and UV is used as the detection method. A detector was adopted. As column silica gel, Kieselgel 60 (70 to 230 mesh), Kieselgel 60 (230 to 400 mesh), or Moritex Purif-Pack manufactured by Merck Co., Ltd. was used. As the basic silica gel for the column, basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Co., Ltd. or Purif-Pack manufactured by Moritex Co., Ltd. was used. NMR spectra were measured with a Bruker AVANCE-300 or Varian VNMRS-400 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts expressed as δ values, and coupling constants expressed in Hz. In the mixed solvent, the numerical value shown in parentheses is the volume mixing ratio of each solvent. Further,% in the solution represents the number of grams in 100 mL of the solution. Room temperature usually means a temperature of about 10 ° C to 30 ° C. The symbols in the examples have the following meanings.
NMR: nuclear magnetic resonance spectrum s: singlet
d: doublet
t: triplet
q: quartet
quint: quintet
dd: double doublet (double doublet)
m: multiplet
br: broad
brs: broad singlet
J: Coupling constant
THF: Tetrahydrofuran MeOH: Methanol DMF: N, N-dimethylformamide DMSO: Dimethyl sulfoxide LC / MS: Liquid chromatography-mass spectrometry spectrum ESI: Electrospray ionization method [M + H] ⁺ : Molecular ion peak TFA: Trifluoroacetic acid M: Molar concentration N: Normal concentration DMT-MM: 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride WSC: N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide HOBt: 1-hydroxybenzotriazole monohydrate HPLC: high performance liquid chromatography UV: ultraviolet light

LC-MS in Examples and Reference Examples was measured under the following conditions.
Analysis by LC-MS Measuring instrument: Waters LC-MS system HPLC: Agilent HP1100
MS: Micromass ZQ
HPLC conditions Column: CAPCELL PAK C18UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: Liquid A; 0.05% TFA-containing water, Liquid B; 0.05% TFA-containing acetonitrile Gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 2.00 minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.60 minutes (A liquid / B (Liquid = 90/10)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
The LC / MS measured values in Examples and Reference Examples indicate [M + H] ⁺ unless otherwise specified.
Purification by preparative HPLC in Examples and Reference Examples was performed under the following conditions.
Equipment: Gilson High Throughput Purification System Column: CombiPrep ODS-A S-5 μm, 50 × 20 mm (YMC)
Solvent: Solution A; 0.1% TFA-containing water, Solution B; 0.1% TFA-containing acetonitrile Gradient cycle: 0.00 minutes (A solution / B solution = 95/5), 1.00 minutes (A solution / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 5/95), 6.40 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A liquid / B Liquid = 95/5), 6.60 minutes (A liquid / B liquid = 95/5)
Flow rate: 25 mL / min, detection method: UV 220 nm

Example 1
1- (3,4-Dichlorophenyl) -1,4-diazepan-2-one monohydrochloride

To a solution of tert-butyl 4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepan-1-carboxylate (1.48 g) in ethyl acetate (2 mL) was added 4N hydrochloric acid ethyl acetate solution (4 mL). And stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (0.84 g, 69%).
LC / MS 258.9
NMR (DMSO-d ₆ ) δ: 1.98-2.12 (2H, m), 3.21-3.51 (2H, m), 3.87-3.96 (2H, m), 3.98-4.08 (2H, m), 7.34 (1H, dd , J = 8.7, 2.3 Hz), 7.67 (1H, d, J = 2.3 Hz), 7.70 (1H, d, J = 8.3 Hz), 9.83 (2H, brs).

Example 2
1- (3,4-Dichlorophenyl) -4-methyl-1,4-diazepan-2-one monohydrochloride

To a suspension of 1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride (0.30 g) in THF (10 mL) was added 35% formalin aqueous solution (0.40 mL), acetic acid (0 0.06 mL) and sodium triacetoxyborohydride (1.12 g) were added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (2.0 mL), and 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diethyl ether to give the title compound as white crystals (0.23 g, 74%).
LC / MS 273.4
NMR (DMSO-d ₆ ) δ: 2.07-2.21 (2H, m), 2.90 (3H, s), 3.35-3.57 (2H, m), 3.82-4.33 (4H, m), 7.35 (1H, dd, J = 8.7, 2.4 Hz), 7.66-7.73 (2H, m), 11.54 (1H, brs).

Example 3
1- (3,4-Dichlorophenyl) -4-ethyl-1,4-diazepan-2-one monohydrochloride

To a suspension of 1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride (0.30 g) in THF (10 mL), acetaldehyde (0.31 mL), acetic acid (0.06 mL) And sodium triacetoxyborohydride (1.12 g) were added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL), and 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol to give the title compound as white crystals (0.11 g, 34%).
LC / MS 287.4
NMR (DMSO-d ₆ ) δ: 1.29 (3H, t, J = 7.2 Hz), 2.17 (2H, brs), 3.19-3.32 (2H, m), 3.42-3.63 (2H, m), 3.83-3.98 ( 2H, m), 4.09-4.29 (2H, m), 7.36 (1H, dd, J = 8.7, 2.4 Hz), 7.67-7.74 (2H, m), 11.47 (1H, brs).

Example 4
1- (3,4-Dichlorophenyl) -4- (1-methylethyl) -1,4-diazepan-2-one monohydrochloride

To a suspension of 1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride (0.30 g) in THF (10 mL), acetone (0.40 mL), acetic acid (0.06 mL) And sodium triacetoxyborohydride (1.12 g) were added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified with a basic silica gel column (hexane only to ethyl acetate only), the obtained solid was dissolved in ethyl acetate (2.0 mL), and 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous solid (0.13 g, 39%).
LC / MS 301.4
NMR (DMSO-d ₆ ) δ: 1.26-1.40 (6H, m), 1.95-2.16 (1H, m), 2.28-2.45 (1H, m), 3.45 (2H, brs), 3.59-3.71 (1H, m ), 3.80 (1H, dd, J = 15.1, 6.8 Hz), 3.91 (1H, d, J = 14.4 Hz), 4.11 (1H, dd, J = 15.1, 10.2 Hz), 4.35 (1H, dd, J = 14.4, 7.6 Hz), 7.42 (1H, dd, J = 8.7, 2.3 Hz), 7.69 (1H, d, J = 8.7 Hz), 7.80 (1H, d, J = 2.7 Hz), 11.70 (1H, brs) .

Example 5
4-Benzyl-1- (3,4-dichlorophenyl) -1,4-diazepan-2-one

Cesium carbonate (0.22 g) was added to a solution of N- [3- (benzylamino) propyl] -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride (0.14 g) in DMF (3 mL). And stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate only) to give the title compound as a white solid (0.06 g, 51%).
LC / MS 349.0
NMR (DMSO-d ₆ ) δ: 1.78-1.91 (2H, m), 2.84-2.97 (2H, m), 3.57 (2H, s), 3.74 (2H, s), 3.78-3.87 (2H, m), 7.22-7.36 (6H, m), 7.58 (1H, d, J = 2.7 Hz), 7.65 (1H, d, J = 8.3 Hz).

Example 6
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -2-methyl-3-oxo-1,4-diazepane-1-carboxylate (0.75 g) in ethyl acetate (2 mL) solution in 4N hydrochloric acid ethyl acetate solution ( 5 mL) was added and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound as a pale brown solid (0.47 g, 76%).
LC / MS 273.3
NMR (DMSO-d ₆ ) δ: 1.40 (3H, d, J = 6.8 Hz), 1.87-2.14 (2H, m), 3.30-3.76 (3H, m), 4.18 (1H, dd, J = 15.5, 10.3 Hz), 4.55 (1H, t, J = 6.8 Hz), 7.35 (1H, dd, J = 8.5, 2.4 Hz), 7.68 (1H, s), 7.70 (1H, d, J = 6.6 Hz), 9.72 ( 1H, brs), 9.92 (1H, brs).

Example 7
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one

tert-Butyl 4- (3,4-dichlorophenyl) -2-methyl-3-oxo-1,4-diazepane-1-carboxylate (1.94 g) in ethyl acetate (15 mL) in 4N hydrochloric acid ethyl acetate solution ( 15 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with ethyl acetate. 8N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate alone) to give the title compound as a pale yellow oil (1.20 g, 85%).
LC / MS 273.1
NMR (DMSO-d ₆ ) δ: 1.33 (3H, d, J = 6.8 Hz), 1.78-1.88 (2H, m), 2.97-3.10 (1H, m), 3.39 (1H, dt, J = 13.5, 3.1 Hz), 3.60-3.72 (2H, m), 3.96-4.07 (1H, m), 7.09 (1H, dd, J = 8.5, 2.5 Hz), 7.36 (1H, d, J = 2.7 Hz), 7.43 (1H , d, J = 8.3 Hz).

Example 9
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one (low retention time)
Example 10
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one (large retention time)

1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one (1.20 g) was subjected to high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nippon Waters Co., Ltd.), column: CHIRALPAK IC (50 mm ID × 500 mm L manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) 100% hexane, B) ethanol = 100%, mixing ratio: A / B = 500/500, flow rate: 60 mL / min, column temperature: 30 Fractionation was performed using a sample injection amount of 100 mg (dissolved in 50 mL of mobile phase) at 0 ° C. The fraction containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2- ON (short retention time) (0.57 g,> 99% ee) was obtained.
LC / MS 273.1
Further, the fraction containing the optically active substance having the longer retention time is concentrated to give 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (large retention time) ( 0.57 g,> 99% ee).
LC / MS 273.1
The enantiomeric excess (ee) is high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID × 250 mm L, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane / ethanol / diethylamine = 850/150/1, flow rate: 1. Measurement was performed using 0 mL / min, column temperature: 30 ° C., sample concentration: 0.5 mg / mL (mobile phase), injection amount: 10 μL).

Example 11
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one monohydrochloride (low retention time)

To a solution of 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (low retention time) (0.57 g,> 99% ee) in ethyl acetate (10 mL) was added 4N hydrochloric acid Ethyl solution (1.1 mL) was added and stirred for 5 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.58 g, 89%).
LC / MS 273.1
NMR (DMSO-d ₆ ) δ: 1.38 (3H, d, J = 6.6 Hz), 1.94-2.06 (2H, m), 3.35-3.47 (2H, m), 3.65-3.76 (1H, m), 4.11- 4.26 (1H, m), 4.47-4.59 (1H, m), 7.33 (1H, dd, J = 8.7, 2.4 Hz), 7.65 (1H, d, J = 2.3 Hz), 7.71 (1H, d, J = 8.5 Hz), 9.45 (2H, brs).

Example 12
1- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one monohydrochloride (large retention time)

To a solution of 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (large retention time) (0.57 g,> 99% ee) in ethyl acetate (10 mL) was added 4N hydrochloric acid Ethyl solution (1.1 mL) was added and stirred for 5 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.51 g, 79%).
LC / MS 273.1
NMR (DMSO-d ₆ ) δ: 1.39 (3H, d, J = 6.8 Hz), 1.92-2.10 (2H, m), 3.35-3.45 (2H, m), 3.63-3.76 (1H, m), 4.11- 4.24 (1H, m), 4.46-4.61 (1H, m), 7.34 (1H, dd, J = 8.7, 2.4 Hz), 7.66 (1H, d, J = 2.3 Hz), 7.70 (1H, d, J = 8.7 Hz), 9.61 (2H, brs).

Example 13
1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl {3-[(2-bromobutanoyl) (3,4-dichlorophenyl) amino] propyl} carbamate (1.19 g) in DMF (10 mL) in sodium hydride (0.11 g, 60% oil) And stirred at 0 ° C. for 20 minutes and then at 80 ° C. for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column (hexane only to hexane / ethyl acetate = 1/1). The obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was distilled off under reduced pressure, the resulting solid was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.45 g, 54%).
LC / MS 287.2
NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4 Hz), 1.74-2.10 (4H, m), 3.39 (2H, brs), 3.63-3.75 (1H, m), 4.15-4.29 ( 1H, m), 4.36 (1H, brs), 7.35 (1H, dd, J = 8.7, 2.3 Hz), 7.68 (1H, d, J = 2.3 Hz), 7.70 (1H, d, J = 8.7 Hz), 9.51 (1H, brs), 9.79 (1H, brs).

Example 14
1- (3,4-Dichlorophenyl) -5-methyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -7-methyl-3-oxo-1,4-diazepan-1-carboxylate (0.59 g) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution ( 3 mL) was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethyl acetate to obtain the title compound as white crystals (0.42 g, 85%).
LC / MS 273.3
NMR (DMSO-d ₆ ) δ: 1.32 (3H, d, J = 6.6 Hz), 1.82-2.10 (1H, m), 3.34 (2H, s), 3.63-3.77 (2H, m), 4.14 (1H, dd, J = 15.5, 10.1 Hz), 4.34 (1H, d, J = 14.9 Hz), 7.35 (1H, dd, J = 8.7, 2.4 Hz), 7.68 (1H, d, J = 2.3 Hz), 7.70 ( 1H, d, J = 8.7 Hz),
9.47-10.25 (2H, m).

Example 15
1- (3,4-Dichlorophenyl) -6-methyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -6-methyl-3-oxo-1,4-diazepane-1-carboxylate (0.46 g) in ethyl acetate (3 mL) in 4N hydrochloric acid ethyl acetate solution ( 3 mL) was added and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound as a pale yellow amorphous solid (0.30 g, 80%).
LC / MS 273.1
NMR (DMSO-d ₆ ) δ: 0.90 (3H, d, J = 7.0 Hz), 2.96 (1H, dd, J = 12.6, 10.7 Hz), 3.22-3.45 (2H, m), 3.57 (1H, d, J = 15.4 Hz), 3.78 (1H, d, J = 14.7 Hz), 3.89-4.10 (1H, m), 4.25 (1H, d, J = 14.9 Hz), 7.34 (1H, dd, J = 8.7, 2.4 Hz), 7.67 (1H, d, J = 2.3 Hz), 7.70 (1H, d, J = 8.5 Hz), 9.92 (2H, brs).

Example 16
1- (3,4-Dichlorophenyl) -6,6-dimethyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -6,6-dimethyl-3-oxo-1,4-diazepane-1-carboxylate (0.46 g) in ethyl acetate (2 mL) in 4N ethyl acetate The solution (4 mL) was added and stirred at room temperature for 0.5 hour. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound as a white solid (0.23 g, 59%).
LC / MS 287.0
NMR (DMSO-d ₆ ) δ: 0.99 (6H, s), 3.11 (2H, s), 3.78 (2H, brs), 4.02 (2H, brs), 7.31 (1H, dd, J = 8.6, 2.4 Hz) , 7.61 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 8.7 Hz), 9.89 (2H, brs).

Example 17
1- (3,4-Dichlorophenyl) -6,6-difluoro-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -6,6-difluoro-3-oxo-1,4-diazepane-1-carboxylate (0.07 g) in ethyl acetate (1 mL) in 4N hydrochloric acid ethyl acetate The solution (4 mL) was added and stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with diethyl ether and dried under reduced pressure to give the title compound as a white solid (0.05 g, 75%).
LC / MS 295.1
NMR (DMSO-d ₆ ) δ: 3.72 (2H, t, J = 12.5 Hz), 4.02 (2H, s), 4.38 (2H, t, J = 11.9 Hz), 7.32 (1H, dd, J = 8.7, 2.3 Hz), 7.62 (1H, d, J = 2.3 Hz), 7.72 (1H, d, J = 8.7 Hz).

Example 18
5- (3,4-Dichlorophenyl) -5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

tert-Butyl 8- (3,4-dichlorophenyl) -7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate (0.28 g) in ethyl acetate (1 mL) with 4N ethyl acetate hydrochloride The solution (1 mL) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethyl acetate to obtain the title compound as white crystals (0.22 g, 94%).
LC / MS 285.0
NMR (DMSO-d ₆ ) δ: 0.55-0.61 (2H, m), 0.63-0.69 (2H, m), 3.18 (2H, s), 3.81 (2H, s), 4.10 (2H, s), 7.27 ( 1H, dd, J = 8.5, 2.5 Hz), 7.58 (1H, d, J = 2.7 Hz), 7.69 (1H, d, J = 8.7 Hz), 9.78 (2H, brs).

Example 19
5- (3,4-Dichlorophenyl) -7-methyl-5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

To a solution of tert-butyl 8- (3,4-dichlorophenyl) -6-methyl-7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate (1.85 g) in ethyl acetate (5 mL) 4N Hydrochloric acid ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethyl acetate to obtain the title compound as white crystals (0.65 g, 42%).
LC / MS 299.1
NMR (DMSO-d ₆ ) δ: 0.39-0.51 (1H, m), 0.55-0.75 (3H, m), 1.44 (3H, d, J = 6.8 Hz), 2.70 (1H, d, J = 13.4 Hz) , 3.03 (1H, d, J = 15.6 Hz), 3.53-3.77 (1H, m), 4.55-4.72 (2H, m), 7.29 (1H, dd, J = 8.7, 2.4 Hz), 7.60 (1H, d , J = 2.4 Hz), 7.68 (1H, d, J = 8.7 Hz), 9.92 (2H, brs).

Example 20
5- (3,4-Dichlorophenyl) -8-methyl-5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

5- (3,4-Dichlorophenyl) -5,8-diazaspiro [2.6] nonan-6-one monohydrochloride (0.77 g) in DMF (12 mL) at 0 ° C. with sodium hydride (0. 24 g, 60% oil) was added and stirred for 0.5 hour. Methyl iodide (0.18 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column (hexane / ethyl acetate = 1/1 to ethyl acetate only). The obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as white crystals (0.29 g, 35%).
LC / MS 299.0
NMR (DMSO-d ₆ ) δ: 0.52-0.81 (4H, m), 2.91 (3H, s), 3.12-4.33 (6H, m), 7.30 (1H, dd, J = 8.7, 2.4 Hz), 7.61 ( 1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 8.7 Hz), 11.56 (1H, brs).

Example 21
5- (3,4-Dichlorophenyl) -8-ethyl-5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

5- (3,4-Dichlorophenyl) -5,8-diazaspiro [2.6] nonan-6-one monohydrochloride (0.77 g) in DMF (12 mL) at 0 ° C. with sodium hydride (0. 24 g, 60% oil) was added and stirred for 0.5 hour. Ethyl iodide (0.23 mL) was added to the reaction mixture, the mixture was stirred at 0 ° C. for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column (hexane / ethyl acetate = 1/1 to ethyl acetate only). The obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as white crystals (0.36 g, 42%).
LC / MS 313.1
NMR (DMSO-d ₆ ) δ: 0.55-0.79 (4H, m), 1.30 (3H, t, J = 7.2 Hz), 3.15-4.30 (8H, m), 7.31 (1H, dd, J = 8.7, 2.4 Hz), 7.63 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 8.5
Hz), 11.47 (1H, brs).

Example 22
4-Benzyl-1- (3,4-dichlorophenyl) -7-methyl-1,4-diazepan-2-one

tert-Butyl benzyl {3-[(chloroacetyl) (3,4-dichlorophenyl) amino] butyl} carbamate (0.72 g) in ethyl acetate (3.0 mL) solution and 4N hydrochloric acid ethyl acetate solution (4.0 mL) After stirring at room temperature for 6 hours, the solvent was distilled off under reduced pressure. Cesium carbonate (0.94 g) was added to a DMF (14 mL) solution of the obtained residue, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.39 g, 75%).
LC / MS 363.0
NMR (DMSO-d ₆ ) δ: 1.10-1.29 (3H, m), 1.78-2.20 (2H, m), 2.66-2.85 (1H, m), 2.92-3.09 (1H, m), 3.45-3.56 (2H , m), 3.69-3.74 (2H, m), 3.92-4.10 (1H, m), 7.12-7.82 (8H, m).

Example 23
1- (3,4-Dichlorophenyl) -7-methyl-1,4-diazepan-2-one

1-chloroethyl chloroformate in a solution of 4-benzyl-1- (3,4-dichlorophenyl) -7-methyl-1,4-diazepan-2-one (0.39 g) in acetonitrile (11 mL) at 0 ° C. (0.13 mL) was added, and the mixture was stirred at 0 ° C. for 15 minutes and then at 75 ° C. for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. A solution of the residue in methanol (5.0 mL) was stirred at 75 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 1N aqueous hydrochloric acid and washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer to make it basic, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC, and the fractions collected were concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.09 g, 31%).
LC / MS 273.0
NMR (DMSO-d ₆ ) δ: 1.16 (3H, d, J = 8.0 Hz), 1.67-1.97 (2H, m), 2.78-3.13 (2H, m), 3.42-3.65 (2H, m), 3.96- 4.03 (1H, m), 7.18 (1H, dd, J = 8.5, 2.5 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.65 (1H, d, J = 8.3 Hz).

Example 24
1- (3,4-Dichlorophenyl) -7-methyl-1,4-diazepan-2-one monohydrochloride

To a solution of 1- (3,4-dichlorophenyl) -7-methyl-1,4-diazepan-2-one (0.09 g) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 5 minutes. Stir for minutes. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (0.08 g, 77%).
LC / MS 273.0
NMR (DMSO-d ₆ ) δ: 1.14 (3H, d, J = 7.0 Hz), 1.96-2.23 (2H, m), 3.34-3.41 (2H, m), 3.92 (1H, d, J = 15.1 Hz) , 4.05-4.30 (2H, m), 7.27 (1H, dd, J = 8.6, 2.4 Hz), 7.59 (1H, d, J = 2.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 9.74 ( 2H, brs).

Example 25
1-Naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride

To a solution of tert-butyl 4-naphthalen-2-yl-3-oxo-1,4-diazepan-1-carboxylate (0.79 g) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution (3 mL), and For 0.5 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and diethyl ether were added to the residue. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound as a white amorphous solid (0.32 g, 51%).
LC / MS 241.2
NMR (DMSO-d ₆ ) δ: 2.05-2.17 (2H, m), 3.34-3.41 (2H, m), 3.99-4.06 (2H, m), 4.09 (2H, s), 7.46 (1H, dd, J = 8.8, 2.0 Hz), 7.50-7.59 (2H, m), 7.81 (1H, d, J = 1.7Hz), 7.89-7.99 (3H, m), 9.59 (2H, brs).

Example 26
4- (3,4-Dichlorophenyl) -1,4-diazepan-5-one monohydrochloride

To a solution of tert-butyl 4- (3,4-dichlorophenyl) -5-oxo-1,4-diazepan-1-carboxylate (0.28 g) in ethyl acetate (2 mL) was added 4N hydrochloric acid ethyl acetate solution (4 mL). And stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate-diethyl ether to give the title compound as white crystals (0.12 g, 52%).
LC / MS 259.3
NMR (DMSO-d ₆ ) δ: 2.86-3.05 (2H, m), 3.34-3.46 (4H, m), 3.92-4.12 (2H, m), 7.32 (1H, dd, J = 8.7, 2.3 Hz), 7.60-7.73 (2H, m), 9.38 (2H, brs).

Example 27
5- (3,4-Dichlorophenyl) -5,8-diazaspiro [2.6] nonan-4-one monohydrochloride

tert-Butyl 8- (3,4-dichlorophenyl) -9-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate (0.24 g) in ethyl acetate (3 mL) in 4N ethyl acetate The solution (5 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.20 g, 100%).
LC / MS 285.1
NMR (DMSO-d ₆ ) δ: 1.09-1.25 (4H, m), 3.28-3.41 (4H, m), 4.02-4.10 (2H, m), 7.32 (1H, dd, J = 8.5, 2.5 Hz), 7.64-7.72 (2H, m), 9.42 (2H, brs).

The LC / MS analysis in Example 28 below was measured under the following conditions.
Measuring instrument: Waters LC / MS system HPLC part: Agilent HP1100
MS Department: Micromass ZMD
Column: CAPCELL PAK C18UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: A liquid; 0.05% TFA-containing water, B liquid; 0.04% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 2.00 minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.60 minutes (A liquid / B Liquid = 90/10) Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm MS conditions Ionization method: ESI
In addition, high-polar preparative HPLC purification in Example 28 below was performed under the following conditions.
Instrument: Gilson High Throughput Purification System Column: Combiprep Hydrosphere C18, 50 x 20 mm (YMC)
Solvent: A liquid; 0.1% TFA-containing water, B liquid; 0.1% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 98/2), 1.00 minutes (A liquid / B liquid = 98/2), 5.20 minutes (A liquid / B liquid = 60/40), 5.40 minutes (A liquid / B liquid = 5/95), 6.40 minutes (A liquid / B Liquid = 5/95), 6.50 minutes (liquid A / liquid B = 98/2), 6.60 minutes (liquid A / liquid B = 98/2), flow rate: 20 mL / min, detection method: UV 220 nm

Example 28
1-Naphthalen-2-yl-1,4-diazepan-2-one trifluoroacetate

Reaction vessel in which a toluene solution (500 μL; 100 μmol) of 2-bromonaphthalene (0.20 M) was added to a toluene solution (500 μL; 100 μmol) of 3-oxo-1,4-diazepan-1-carboxylate (0.20 M) Cesium carbonate (46 mg; 140 μmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (8.7 mg; 15 μmol) and tris (dibenzylideneacetone) dipalladium (0) (4. 6 mg; 5.0 μmol) was added in this order, and the reaction vessel was purged with argon and stirred at 100 ° C. for 48 hours. The reaction solution was returned to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL). The ethyl acetate solvent was distilled off under reduced pressure, and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to obtain the N-Boc form of the title compound. Next, TFA (1.5 mL) was added to this protected body, and after stirring at room temperature for 14 hours, TFA was distilled off under reduced pressure. The residue was dissolved in water (1 mL), and purified by high-polar preparative HPLC. The compound was obtained as a salt of TFA.
Yield: 13.8 mg
LC / MS analysis: purity 99%
MS (ESI +): 241 (M + H)

The compounds described in Tables 1-1 to 1-9 (Examples 29 to 87) were obtained in the same manner as Example 28.

Example 88
1- (3,4-Dichlorobenzyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorobenzyl) -3-oxo-1,4-diazepane-1-carboxylate (0.40 g) in ethyl acetate (2.0 mL) solution in 4N hydrochloric acid ethyl acetate solution (2 0.0 mL) and the mixture was stirred at room temperature for 6 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL), and 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added. The solvent was removed under reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound as a white amorphous solid (0.20 g, 59%).
LC / MS 273.1
NMR (DMSO-d ₆ ) δ: 1.75-1.86 (2H, m), 3.16-3.24 (2H, m), 3.50-3.56 (2H, m), 3.95 (2H, s), 4.54 (2H, s), 7.35 (1H, dd, J = 8.3, 2.3 Hz), 7.60 (1H, s), 7.62 (1H, d, J = 5.3 Hz), 9.75 (2H, brs).

Example 89
1- (4-Bromo-3-chlorophenyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (4-Bromo-3-chlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate (0.22 g) in ethyl acetate (5 mL) and 4N hydrochloric acid ethyl acetate solution (1. 5 mL) was added and stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-hexane to give the title compound as a white solid (0.16 g, 88%).
LC / MS 304.8
NMR (DMSO-d ₆ ) δ: 2.01 (2H, d, J = 4.5 Hz), 3.24-3.41 (2H, m), 3.92 (2H, d, J = 9.2 Hz), 4.03 (2H, s), 7.24 (1H, dd, J = 8.5, 2.4 Hz), 7.63 (1H, d, J = 2.3 Hz), 7.83 (1H, d, J = 8.6 Hz), 9.51 (2H, brs).

Example 90
1- (1-Benzofuran-5-yl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (1-benzofuran-5-yl) -3-oxo-1,4-diazepan-1-carboxylate (0.092 g) in ethyl acetate (2 mL) and 4N hydrochloric acid ethyl acetate solution (2. 0 mL) was added and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-diisopropyl ether to give the title compound as a colorless amorphous solid (0.059 g, 81%).
LC / MS 231.1
NMR (DMSO-d ₆ ) δ: 2.05 (2H, brs), 3.22-3.43 (2H, m), 3.81-3.95 (2H, m), 4.03 (2H, s), 7.19-7.36 (3H, m), 7.36-7.50 (2H, m), 9.77 (2H, brs).

Example 91
1- (4,5-Dichloro-2-fluorophenyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (4,5-dichloro-2-fluorophenyl) -3-oxo-1,4-diazepan-1-carboxylate (0.11 g) in ethyl acetate (2 mL) in 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to give the title compound as a white solid (0.076 g, 84%).
LC / MS 276.9
NMR (DMSO-d ₆ ) δ: 1.98-2.15 (2H, m), 3.26-3.36 (2H, m), 3.79-3.90 (2H, m), 4.06 (2H, s), 7.81 (1H, d, J = 7.3 Hz), 7.88 (1H, d, J = 9.8 Hz), 9.68 (2H, brs).

Example 92
1- (3,4-Dichloro-2-fluorophenyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichloro-2-fluorophenyl) -3-oxo-1,4-diazepane-1-carboxylate (0.021 g) in ethyl acetate (1 mL) solution in 4N hydrochloric acid ethyl acetate (1.0 mL) was added and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (0.015 g, 68%).
LC / MS 276.9
NMR (DMSO-d ₆ ) δ: 2.03 (2H, brs), 3.27-3.35 (2H, m), 3.84-3.92 (2H, m), 4.06 (2H, s), 7.37-7.47 (1H, m), 7.62 (1H, dd, J = 8.7, 1.9 Hz), 9.20 (2H, brs).

Example 93
1- (1H-Indol-5-yl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 5- [4- (tert-Butoxycarbonyl) -2-oxo-1,4-diazepan-1-yl] -1H-indole-1-carboxylate (0.075 g) in ethyl acetate (2 mL) To the mixture was added 4N hydrochloric acid ethyl acetate solution (2.0 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from methanol-ethyl acetate to give the title compound as a colorless amorphous solid (0.042 g, 90%).
LC / MS 230.1
NMR (DMSO-d ₆ ) δ: 2.05 (2H, brs), 3.34 (2H, s), 3.91 (2H, d, J = 9.4 Hz), 4.03 (2H, s), 7.29 (3H, d, J = 6.8 Hz), 7.41 (2H, d, J = 7.3 Hz), 9.76 (2H, brs).

Example 94
1- (1-Benzofuran-3-yl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (1-benzofuran-3-yl) -3-oxo-1,4-diazepan-1-carboxylate (0.057 g) in ethyl acetate (2 mL) in 4N hydrochloric acid ethyl acetate solution (1. 0 mL) was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous solid (0.030 g, 65%).
NMR (DMSO-d ₆ ) δ: 1.99-2.12 (2H, m), 3.28-3.37 (2H, m), 3.84-3.96 (2H, m), 4.03 (2H, s), 7.23-7.34 (3H, m ), 7.37-7.46 (2H, m), 9.76 (2H, brs).

Example 95
8-Benzyl-7-methyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one

tert-Butyl benzyl [(1-{[(2-bromopropanoyl) naphthalen-2-ylamino] methyl} cyclopropyl) methyl] carbamate (0.31 g) in ethyl acetate (2 mL) in 4N aqueous hydrochloric acid (4 mL) 2 mL) was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in DMF (5 mL), cesium carbonate (2.20 g) was added, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water and saturated brine in that order, and dried by adding sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column (hexane / ethyl acetate = 10/1 to 1/1) to give the title compound as a colorless amorphous solid (0.20 g, 80%).
LC / MS 371.2
NMR (CDCl ₃ ) δ: 0.03-0.24 (2H, m), 0.45-0.82 (2H, m), 1.48 (3H, d, J = 6.8 Hz), 2.21-2.43 (1H, m), 2.85-3.03 ( 2H, m), 3.24-3.44 (1H, m), 4.05 (2H, d, J = 3.4 Hz), 4.54-4.75 (1H, m), 7.27-7.56 (10H, m), 7.85 (2H, s) .

Example 96
7-Methyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonane-6-one

8-Benzyl-7-methyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one (0.19 g), palladium hydroxide (0.10 g), 6N aqueous hydrochloric acid ( A mixture of 0.17 mL) and methanol (5 mL) was stirred overnight at room temperature under an atmosphere of hydrogen gas (1 kg / cm ² ). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried by adding sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column (ethyl acetate / methanol = 1 / 0-4 / 1) to give the title compound as a colorless oil (0.13 g, 90%).
LC / MS 282.1
NMR (CDCl ₃ ) δ: 0.28-0.65 (4H, m), 1.39 (3H, d, J = 6.8 Hz), 2.42 (1H, d, J = 14.0 Hz), 2.72 (1H, brs), 2.96 (1H , d, J = 14.0 Hz), 3.44 (1H, dd, J = 14.0, 1.9 Hz), 3.82 (1H, m), 4.57 (1H, d, J = 15.1 Hz), 7.34 (1H, dd, J = 8.7, 1.9 Hz), 7.39-7.50 (2H, m), 7.61 (1H, d, J = 1.9 Hz), 7.69-7.88 (3H, m).

Example 97
7-Methyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

In an ice bath, 4N hydrochloric acid ethyl acetate solution (0.6 mL) was added 7-methyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one (0.13 g) in ethyl acetate. (1.0 mL) was added to the solution. The reaction solution was stirred at room temperature for 1 hour, and the precipitated white solid was collected by filtration and washed with ethyl acetate to obtain the title compound as a white solid (0.42 g, 68%).
LC / MS 282.1
NMR (DMSO-d ₆ ) δ: 0.46-0.83 (4H, m), 1.47 (3H, d, J = 6.6 Hz), 2.62-2.79 (1H, m), 3.11 (1H, d, J = 15.6 Hz) , 3.62-3.86 (1H, m), 4.56-4.85 (2H, m), 7.45 (1H, dd, J = 8.7, 2.1 Hz), 7.53 (2H, dd, J = 3.0, 0.9 Hz), 7.73 (1H , d, J = 1.9 Hz), 7.82-7.97 (3H, m), 9.84 (2H, brs).

Example 98
2- (3,4-Dichlorophenyl) octahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one

Octahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one (synthesized by the method described in Polish Journal of Chemistry, 59, 1243-1246 (1985)) (0.37 g), 4- Bromo-1,2-dichlorobenzene (0.31 mL), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.11 g), tris (dibenzylideneacetone) dipalladium (0) (0 0.055 g), cesium carbonate (1.09 g) and 1,4-dioxane (2.4 mL) were stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1/1) to give the title compound as a yellow oil (0.55 g, 59%).
NMR (CDCl ₃ ) δ: 1.71-1.96 (4H, m), 2.00-2.10 (1H, m), 2.43-2.50 (1H, m), 2.54-2.61 (1H, m), 2.67-2.73 (1H, m ), 3.14-3.18 (1H, m), 3.36 (1H, td, J = 12.0, 3.6 Hz), 3.43 (1H, dd, J = 9.8, 4.0 Hz), 3.60-3.65 (1H, m), 4.01 ( 1H, dd, J = 15.2, 12.0 Hz), 7.10 (1H, dd, J = 8.8, 2.8 Hz), 7.37 (1H, d, J = 2.8 Hz), 7.42 (1H, d, J = 8.8 Hz).

Example 99
2- (3,4-Dichlorophenyl) octahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one monohydrochloride

In an ice bath, a 4N hydrochloric acid 1,4-dioxane solution (0.6 mL) was added to 2- (3,4-dichlorophenyl) octahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one ( 0.42 g) in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hr, and the precipitated white solid was collected by filtration to give the title compound as a white solid (0.42 g, 68%).
LC / MS 299.1
NMR (DMSO-d ₆ ) δ: 1.83-1.90 (1H, m), 1.96-2.07 (2H, m), 2.09-2.24 (2H, m), 2.42-2.50 (1H, m), 3.15-3.17 (1H , m), 3.34-3.44 (1H, overlap H ₂ O peak), 3.66-3.75 (3H, m), 4.22 (1H, dd, J = 15.6, 11.6 Hz), 4.78 (1H, brs), 7.40 (1H , dd, J = 8.8, 2.4 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 2.4 Hz), 11.71 (1H, brs).

Example 100
2-Naphthalen-2-yloctahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one monohydrochloride

Octahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one (0.30 g), 2-bromonaphthalene (0.40 g), 4,5-bis (diphenylphosphino) -9 , 9-dimethylxanthene (0.086 g), tris (dibenzylideneacetone) dipalladium (0) (0.055 g), cesium carbonate (0.88 g) and 1,4-dioxane (2.0 mL) were mixed with nitrogen. The mixture was stirred at 100 ° C. for 12 hours under an atmosphere. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with a silica gel column (hexane / ethyl acetate = 1/1) to give 2-naphthalen-2-yloctahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-1. -On was obtained as a yellow oil (0.35 g, 64%). To this 1,4-dioxane (1.0 mL) solution, 4N hydrochloric acid 1,4-dioxane solution (0.48 mL) was added in an ice bath. The reaction mixture was stirred at room temperature for 1 hr, and the precipitated solid was collected by filtration to give the title compound as a pale yellow solid (0.21 g, 50%).
LC / MS 281.1
NMR (DMSO-d ₆ ) δ: 1.87-1.96 (1H, m), 1.99-2.09 (2H, m), 2.12-2.23 (1H, m), 2.25-2.35 (1H, m), 2.47-2.57 (1H , m), 3.18-3.23 (1H, m), 3.53-3.51 (1H, m), 3.74-3.73 (2H, m), 3.83 (1H, dd, J = 15.6, 5.6 Hz), 4.34 (1H, dd , J = 15.2, 11.6 Hz), 4.87 (1H, q, J = 8.0 Hz), 7.48-7.57 (3H, m), 7.88-7.96 (4H, m), 11.60 (1H, brs).

Example 101
1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one

A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to 1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one monohydrochloride (0.72 g), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.61 g, 95%).
LC / MS 287.0
NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.26-1.45 (1H, m), 1.57-1.75 (3H, m), 2.26 (1H, brs), 2.76-2.92 ( 1H, m), 3.12-3.24 (1H, m), 3.39 (1H, t, J = 6.6 Hz), 3.52-3.65 (1H, m), 4.04-4.18 (1H, m), 7.24 (1H, dd, J = 8.7, 2.7 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.63 (1H, d, J = 8.7 Hz).

Example 102
(3R) -1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (low retention time)

Example 103
(3S) -1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (large retention time)

1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (606 mg) was subjected to supercritical fluid chromatography (instrument: Multigram II (manufactured by METTLER TOLEDO), column: CHIRALPAK AD-H (20 mm ID × 250 mmL manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100%, C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 /0.4, flow rate: 50 mL / min, column temperature: 35 ° C., sample concentration: 10 mg / mL (methanol), injection amount: 5 mL). The fraction containing the optically active substance having a shorter retention time under the above supercritical fluid chromatography conditions was concentrated to give (3R) -1- (3,4-dichlorophenyl) -3-ethyl-1,4 -Diazepan-2-one (285 mg,> 99.9% ee) was obtained.
LC / MS 286.8
The fraction containing the optically active substance having the longer retention time was concentrated to give (3S) -1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (286 mg). > 99.9% ee).
LC / MS 286.8
The enantiomeric excess (ee) is determined by supercritical fluid chromatography (column: CHIRALPAK AD-H (4.6 mm ID × 250 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100% C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 / 0.4, flow rate: 2.35 mL / min, column temperature: 35 ° C., sample concentration: 0.5 mg / mL (Methanol), injection amount: 5 μL).

Example 104
(3R) -1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one monohydrochloride

To a solution of (3R) -1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (285 mg,> 99.9% ee) in ethyl acetate (2.0 mL) was added 4N hydrochloric acid. Ethyl acetate solution (2.0 mL) was added and stirred for 5 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as colorless plate crystals (0.26 g, 81%).
LC / MS 287.0
NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.76-2.08 (4H, m), 3.35-3.44 (2H, m), 3.61-3.80 (1H, m), 4.16- 4.29 (1H, m), 4.35 (1H, dd, J = 8.2, 4.2 Hz), 7.35 (1H, dd, J = 8.7, 2.4 Hz), 7.68 (1H, d, J = 2.4 Hz), 7.70 (1H , d, J = 8.7 Hz), 9.56 (2H, brs).

Example 105
(3S) -1- (3,4-Dichlorophenyl) -3-ethyl-1,4-diazepan-2-one monohydrochloride

To a solution of (3S) -1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (286 mg,> 99.9% ee) in ethyl acetate (2.0 mL) was added 4N hydrochloric acid. Ethyl acetate solution (2.0 mL) was added and stirred for 5 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.27 g, 85%).
LC / MS 287.0
NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.75-2.05 (4H, m), 3.35-3.47 (2H, m), 3.63-3.75 (1H, m), 4.16- 4.28 (1H, m), 4.35 (1H, dd, J = 8.3, 4.0 Hz), 7.34 (1H, dd, J = 8.6, 2.4 Hz), 7.68 (1H, d, J = 2.3 Hz), 7.70 (1H , d, J = 8.7 Hz), 9.50 (2H, brs).

Example 106
1- (3,4-Dichlorophenyl) -3-propyl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 4- (3,4-dichlorophenyl) -3-oxo-2-propyl-1,4-diazepane-1-carboxylate (1.05 g) in ethyl acetate (10 mL) and 4N hydrochloric acid ethyl acetate solution (10 mL) was added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.82 g, 93%).
LC / MS 302.0
NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 7.3 Hz), 1.31-1.52 (2H, m), 1.64-1.82 (1H, m), 1.85-2.08 (3H, m), 3.36- 3.42 (2H, m), 3.63-3.74 (1H, m), 4.16-4.29 (1H, m), 4.38 (1H, dd, J = 8.3, 4.1 Hz), 7.35 (1H, dd, J = 8.8, 2.4 Hz), 7.66-7.73 (2H, m), 9.62 (2H, brs).

Example 107
1- (3,4-Dichlorophenyl) -3- (1-methylethyl) -1,4-diazepan-2-one monohydrochloride

A solution of tert-butyl 4- (3,4-dichlorophenyl) -2- (1-methylethyl) -3-oxo-1,4-diazepan-1-carboxylate (0.21 g) in ethyl acetate (5.0 mL) 4N hydrochloric acid ethyl acetate solution (5.0 mL) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.17 g, 95%).
LC / MS 302.0
NMR (DMSO-d ₆ ) δ: 1.09 (3H, d, J = 7.0 Hz), 1.12 (3H, d, J = 7.0 Hz), 1.91-2.18 (2H, m), 2.25-2.41 (1H, m) , 3.24-3.37 (1H, m), 3.42-3.52 (1H, m), 3.71 (1H, dd, J = 15.9, 5.0 Hz), 4.03-4.33 (2H, m), 7.35 (1H, dd, J = 8.7, 2.3 Hz), 7.65-7.74 (2H, m), 9.36 (1H, brs), 9.93 (1H, brs).

Example 108
3-Butyl-1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 2-Butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate (0.94 g) in ethyl acetate (5.0 mL) and 4N hydrochloric acid Ethyl solution (5.0 mL) was added and stirred at room temperature overnight. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (0.82 g, 100%).
LC / MS 316.0
NMR (DMSO-d ₆ ) δ: 0.83-0.93 (3H, m), 1.23-1.43 (4H, m), 1.71-1.83 (1H, m), 1.88-2.05 (3H, m), 3.35-3.45 (2H , m), 3.63-3.75 (1H, m), 4.23 (1H, dd, J = 16.2, 8.5 Hz), 4.37 (1H, dd, J = 7.4, 3.9 Hz), 7.34 (1H, dd, J = 8.7 , 2.4 Hz), 7.65-7.75 (2H, m), 9.50 (1H, brs), 9.81 (1H, brs).

Example 109
1- (3,4-Dichlorophenyl) -3- (2-methylpropyl) -1,4-diazepan-2-one monohydrochloride

A solution of tert-butyl 4- (3,4-dichlorophenyl) -2- (2-methylpropyl) -3-oxo-1,4-diazepane-1-carboxylate (0.65 g) in ethyl acetate (5.0 mL) 4N hydrochloric acid ethyl acetate solution (5.0 mL) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.47 g, 86%).
LC / MS 316.0
NMR (DMSO-d ₆ ) δ: 0.86-0.96 (6H, m), 1.52-1.80 (2H, m), 1.86-2.12 (3H, m), 3.40 (2H, brs), 3.65-3.78 (1H, m ), 4.23-4.41 (2H, m), 7.35 (1H, dd, J = 8.7, 2.4 Hz), 7.66-7.77 (2H, m), 9.46 (1H, brs), 9.86 (1H, brs).

Example 110
3-tert-Butyl-1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride

tert-Butyl 2-tert-Butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate (0.30 g) in ethyl acetate (3.0 mL) was added 4N Hydrochloric acid ethyl acetate solution (3.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the obtained residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified with a silica gel column (hexane only to hexane / ethyl acetate = 1/1). The obtained solid was dissolved in ethyl acetate (3.0 mL), 4N hydrochloric acid ethyl acetate solution (3.0 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.10 g, 45%).
LC / MS 315.0
NMR (DMSO-d ₆ ) δ: 1.17 (9H, s), 1.87-2.18 (1H, m), 3.16-3.77 (4H, m), 4.21 (1H, d, J = 7.6 Hz), 4.39 (1H, dd, J = 15.5, 11.0 Hz), 7.37 (1H, dd, J = 8.7, 2.3 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.73 (1H, d, J = 2.3 Hz), 8.89 ( 1H, d, J = 11.7 Hz), 10.06 (1H, brs).

Example 111
1- (3,4-Dichlorophenyl) -3- (ethoxymethyl) -1,4-diazepan-2-one monohydrochloride

To a solution of tert-butyl 4- (3,4-dichlorophenyl) -2- (ethoxymethyl) -3-oxo-1,4-diazepan-1-carboxylate (0.11 g) in ethyl acetate (3.0 mL), 4N Hydrochloric acid ethyl acetate solution (3.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.07 g, 70%).
LC / MS 317.0
NMR (DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.87-2.23 (2H, m), 3.28-3.52 (2H, m), 3.52-3.63 (2H, m), 3.63- 3.76 (2H, m), 3.82 (1H, dd, J = 10.6, 4.2 Hz), 4.21 (1H, dd, J = 15.7, 10.4 Hz), 4.63 (1H, dd, J = 7.2, 4.2 Hz), 7.34 (1H, dd, J = 8.5, 2.5), 7.68 (1H, d, J = 2.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 8.98 (1H, brs), 10.06 (1H, brs).

Example 112
3-Benzyl-1- (3,4-dichlorophenyl) -1,4-diazepan-2-one monohydrochloride

To a solution of tert-butyl 2-benzyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepan-1-carboxylate (0.54 g) in ethyl acetate (4.0 mL), 4N hydrochloric acid An ethyl solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.44 g, 95%).
LC / MS 349.0
NMR (DMSO-d ₆ ) δ: 1.88-2.13 (2H, m), 3.19-3.33 (2H, m), 3.40-3.52 (2H, m), 3.64-3.76 (1H, m), 4.31 (1H, dd , J = 15.5, 10.1 Hz), 4.82 (1H, dd, J = 8.9, 4.6 Hz), 7.15-7.43 (6H, m), 7.61-7.72 (2H, m), 9.42-10.20 (2H, m).

Example 113
8-Benzyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonane-6-one

tert-Butyl benzyl [(1-{[(bromoacetyl) naphthalen-2-ylamino] methyl} cyclopropyl) methyl] carbamate (0.18 g) in ethyl acetate (2 mL) and 4N aqueous hydrogen chloride in ethyl acetate (2 mL) And stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in DMF (3 mL), cesium carbonate (1.36 g) was added, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water and saturated brine in that order, and dried by adding sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column (hexane / ethyl acetate = 10/1 to 1/1) to give the title compound as a colorless amorphous solid (0.12 g, 100%).
LC / MS 357.2
NMR (CDCl ₃ ) δ: 0.36-0.62 (4H, m), 2.77 (2H, brs), 3.63-3.81 (2H, m), 3.88 (2H, s), 4.02 (2H, s), 7.16-7.55 ( 8H, m), 7.65 (1H, d, J = 2.1 Hz), 7.81 (3H, d, J = 9.6 Hz).

Example 114
5-Naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one

In an ice bath, 1-chloroethyl chlorocarbonate (0.040 mL) was mixed with 8-benzyl-5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one (0.12 g) of acetonitrile. (2 mL) The solution was added dropwise to the solution, stirred for 15 minutes, and then stirred at 75 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted in methanol (5 mL) and heated to reflux for 3 hours. The reaction solution was cooled to room temperature, diluted with 1N aqueous hydrochloric acid solution, and washed with ethyl acetate. The aqueous layer was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried by adding sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column (ethyl acetate / methanol = 1 / 0-4 / 1) to give the title compound as a colorless oil (0.060 g, 68%).
LC / MS 267.0
NMR (CDCl ₃ ) δ: 0.54 (4H, d, J = 4.5 Hz), 2.90 (2H, s), 3.77 (2H, brs), 3.89 (2H, s), 7.34 (1H, dd, J = 8.7, 2.3 Hz), 7.47 (2H, dd, J = 3.0, 1.5 Hz), 7.61 (1H, d, J = 1.9 Hz), 7.73-7.89 (3H, m).

Example 115
5-Naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one monohydrochloride

In an ice bath, 4N hydrogen chloride in ethyl acetate (0.6 mL) was added 5-naphthalen-2-yl-5,8-diazaspiro [2.6] nonan-6-one (0.13 g) in ethyl acetate (1. 0 mL) solution. The reaction solution was stirred at room temperature for 1 hour, and the precipitated white solid was collected by filtration and washed with ethyl acetate to obtain the title compound as a white solid (76 mg, 49%).
LC / MS 267.0
NMR (DMSO-d ₆ ) δ: 0.56-0.76 (4H, m), 3.21 (2H, s), 3.93 (2H, brs), 4.15 (2H, s), 7.44 (1H, dd, J = 8.7, 2.3 Hz), 7.48-7.59 (2H, m), 7.73 (1H, d, J = 1.9 Hz), 7.81-7.99 (3H, m), 10.08 (2H, brs).

Example 116
3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 2-methyl-4-naphthalen-2-yl-3-oxo-1,4-diazepan-1-carboxylate (0.38 g) in ethyl acetate (4.0 mL) solution in 4N hydrochloric acid ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.20 g, 62%).
LC / MS 255.1
NMR (DMSO-d ₆ ) δ: 1.43 (3H, d, J = 6.8 Hz), 2.03-2.21 (2H, m), 3.35-3.49 (2H, m), 3.71-3.88 (1H, m), 4.29 ( 1H, dd, J = 15.3, 10.0 Hz), 4.62 (1H, q, J = 6.2 Hz), 7.47 (1H, dd, J = 8.7, 1.9 Hz), 7.50-7.59 (2H, m), 7.82 (1H , s), 7.88-7.99 (3H, m), 9.67 (2H, brs).

Example 117
3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one

tert-Butyl 2-methyl-4-naphthalen-2-yl-3-oxo-1,4-diazepan-1-carboxylate (1.10 g) in ethyl acetate (5.0 mL) solution in 4N hydrochloric acid ethyl acetate solution (5.0 mL) was added and stirred at room temperature for 5 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column (ethyl acetate / hexane = 1/1 to ethyl acetate only) and recrystallized from ethanol-ethyl acetate to give the title compound as colorless plate crystals (0.58 g, 73%). Got as.
LC / MS 255.1
NMR (DMSO-d ₆ ) δ: 1.14 (3H, d, J = 6.8 Hz), 1.59-1.87 (2H, m), 2.34 (1H, brs), 2.82-2.99 (1H, m), 3.19 (1H, dt, J = 13.1, 3.1 Hz), 3.61-3.81 (2H, m), 4.09-4.23 (1H, m), 7.38 (1H, dd, J = 8.7, 2.1 Hz), 7.44-7.55 (2H, m) , 7.73 (1H, d, J = 1.9Hz), 7.83-7.96 (3H, m).

Example 118
(3S) -3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (low retention time)

Example 119
(3R) -3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (large retention time)

3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (1.51 g) was subjected to supercritical fluid chromatography (instrument: Multigram II (manufactured by METTLER TOLEDO), column: CHIRALPAK OJ-H (20 mm ID × 250 mmL manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100%, C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 /0.4, flow rate: 50 mL / min, column temperature: 35 ° C., sample concentration: 7.5 mg / mL (methanol), injection amount: 1.5 mL). The fraction solution containing the optically active substance having the shorter retention time under the above supercritical fluid chromatography conditions is concentrated to obtain (3S) -3-methyl-1-naphthalen-2-yl-1,4-diazepan -2-one (741 mg,> 99% ee) was obtained.
LC / MS 254.9
The fraction containing the optically active substance having the longer retention time was concentrated to give (3R) -3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (724 mg, 99 .7% ee) was obtained.
LC / MS 254.9
The enantiomeric excess (ee) was determined by supercritical fluid chromatography (column: CHIRALPAK OJ-H (4.6 mm ID × 250 mm L, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100% C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 / 0.4, flow rate: 2.35 mL / min, column temperature: 35 ° C., sample concentration: 0.5 mg / mL ( Methanol), injection amount: 5 μL).

Example 120
(3S) -3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride

To a solution of (3S) -3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (512 mg,> 99% ee) in ethanol (20 mL) was added 4N hydrochloric acid ethyl acetate solution (5.0 mL). ) Was added and stirred for 10 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.43 g, 74%).
LC / MS 255.1
NMR (DMSO-d ₆ ) δ: 1.44 (3H, d, J = 6.8 Hz), 1.96-2.21 (2H, m), 3.36-3.51 (2H, m), 3.72-3.86 (1H, m), 4.30 ( 1H, dd, J = 15.3, 10.2 Hz), 4.63 (1H, q, J = 6.7 Hz), 7.48 (1H, dd, J = 8.7, 2.1 Hz), 7.50-7.59 (2H, m), 7.83 (1H , d, J = 2.1 Hz), 7.88-8.00 (3H, m), 9.76 (2H, brs).

Example 121
(3R) -3-Methyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride

To a solution of (3R) -3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (439 mg, 99.7% ee) in ethanol (20 mL) was added 4N hydrochloric acid ethyl acetate solution (5. 0 mL) was added and stirred for 10 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.36 g, 71%).
LC / MS 255.1
NMR (DMSO-d ₆ ) δ: 1.44 (3H, d, J = 6.6 Hz), 2.00-2.23 (2H, m), 3.35-3.47 (2H, m), 3.73-3.86 (1H, m), 4.30 ( 1H, dd, J = 15.5, 10.1 Hz), 4.62 (1H, q, J = 6.7 Hz), 7.48 (1H, dd, J = 8.7, 2.1 Hz), 7.51-7.58 (2H, m), 7.83 (1H , d, J = 1.9 Hz), 7.89-7.98 (3H, m), 9.76 (2H, brs).

Example 122
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride

tert-Butyl 2-ethyl-4-naphthalen-2-yl-3-oxo-1,4-diazepane-1-carboxylate (1.50 g) in ethyl acetate (10 mL) was added to a 4N hydrochloric acid ethyl acetate solution (10 mL). ) And stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (1.04 g, 83%).
LC / MS 269.1
NMR (DMSO-d ₆ ) δ: 1.02 (3H, t, J = 7.3 Hz), 1.80-2.21 (4H, m), 3.33-3.49 (2H, m), 3.73-3.87 (1H, m), 4.27- 4.50 (2H, m), 7.45-7.60 (3H, m), 7.84 (1H, d, J = 1.9 Hz), 7.88-7.99 (3H, m), 9.76 (2H, brs).

Example 123
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one

A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride (0.85 g), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.73 g, 97%).
LC / MS 269.1
NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.4 Hz), 1.31-1.46 (1H, m), 1.63-1.87 (3H, m), 2.43 (1H, brs), 2.82-2.96 ( 1H, m), 3.19-3.28 (1H, m), 3.46 (1H, t, J = 6.8 Hz), 3.69 (1H, dd, J = 15.1, 3.8 Hz), 4.19 (1H, dd, J = 15.5, 10.6 Hz), 7.39 (1H, dd, J = 8.7, 2.3 Hz), 7.45-7.56 (2H, m), 7.73 (1H, d, J = 1.9 Hz), 7.85-7.95 (3H, m).

Example 124
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (low retention time)
Example 125
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (large retention time)

3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (563 mg) was subjected to supercritical fluid chromatography (instrument: Multigram II (manufactured by METTLER TOLEDO), column: CHIRALPAK OJ-H ( 20 mm ID × 250 mmL manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100%, C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 / 0.4, flow rate: 50 mL / min, column temperature: 35 ° C., sample concentration: 10 mg / mL (methanol), injection amount: 2.0 mL). The fraction containing the optically active substance having a shorter retention time under the above supercritical fluid chromatography conditions is concentrated to give 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (Short retention time) (299 mg,> 99% ee) was obtained.
LC / MS 269.0
Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (large retention time) (324 mg, 99.8% ee) was obtained.
LC / MS 269.0
The enantiomeric excess (ee) was determined by supercritical fluid chromatography (column: CHIRALPAK OJ-H (4.6 mm ID × 250 mm L, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) carbon dioxide 100%, B) methanol = 100% C) monoisopropylamine = 100%, mixing ratio: A / B / C = 600/400 / 0.4, flow rate: 2.35 mL / min, column temperature: 35 ° C., sample concentration: 0.5 mg / mL (Methanol), injection amount: 5 μL).

Example 126
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride (low retention time)

To a solution of the obtained 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (low retention time) (299 mg,> 99% ee) in ethyl acetate (5.0 mL) was added 4N hydrochloric acid. Ethyl acetate solution (5.0 mL) was added and stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.29 g, 85%).
LC / MS 269.1
NMR (DMSO-d ₆ ) δ: 1.01 (3H, t, J = 7.3 Hz), 1.76-2.22 (4H, m), 3.36-3.49 (2H, m), 3.72-3.86 (1H, m), 4.27- 4.49 (2H, m), 7.48 (1H, dd, J = 8.8, 2.2 Hz), 7.51-7.59 (2H, m), 7.83 (1H, d, J = 2.1 Hz), 7.87-7.99 (3H, m) , 9.72 (2H, brs).

Example 127
3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride (large retention time)

To a solution of 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (long retention time) (324 mg, 99.8% ee) in ethyl acetate (5.0 mL) was added 4N ethyl acetate hydrochloride. The solution (5.0 mL) was added and stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.29 g, 79%).
LC / MS 269.1
NMR (DMSO-d ₆ ) δ: 1.01 (3H, t, J = 7.3 Hz), 1.81-2.22 (4H, m), 3.36-3.54 (2H, m), 3.72-3.89 (1H, m), 4.27- 4.48 (2H, m), 7.48 (1H, dd, J = 8.8, 2.2 Hz), 7.50-7.59 (2H, m), 7.83 (1H, d, J = 1.9 Hz), 7.88-8.00 (3H, m) , 9.66 (2H, brs).

Example 128
3- (3,4-Dichlorophenyl) -9-methyl-3,9-diazabicyclo [4.2.1] nonan-4-one

9-methyl-3,9-diazabicyclo [4.2.1] nonan-4-one (synthesized by the method described in J. Med. Chem., 43, 4840-4849 (2000)) (0.60 g), 1 -Bromo-3,4-dichlorobenzene (0.45 mL), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.16 g), tris (dibenzylideneacetone) dipalladium (0) ( 0.085 g) and a 1,4-dioxane mixture of cesium carbonate (1.69 g) were stirred at 105 ° C. for 17 hours under an argon gas atmosphere. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (hexane / ethyl acetate = 3/1 to 1/1) to give the title compound as a yellow solid (0.86 g, 78%).
LC / MS 299.2
NMR (DMSO-d ₆ ) δ: 1.82-1.89 (2H, m), 2.12-2.25 (2H, m), 2.43 (3H, s), 2.74 (1H, dd, J = 15.2, = 7.2 Hz), 2.97 -3.01 (1H, m), 3.26-3.34 (2H, m), 3.39 (1H, dd, J = 15.2, 6.8 Hz), 4.13-4.17 (1H, d, J = 14.4 Hz), 7.06 (1H, dd , J = 2.8, 8.8 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 8.4 Hz).

Example 129
(1S, 5S) -3- (3,4-Dichlorobenzyl) -3,6-diazabicyclo [3.2.1] octan-4-one monohydrochloride

tert-Butyl (1R, 5S) -3- (3,4-dichlorobenzyl) -4-oxo-3,6-diazabicyclo [3.2.1] octane-6-carboxylate (0.10 g) in ethyl acetate A 4N hydrochloric acid 1,4-dioxane solution (0.33 mL) was added to the (5 mL) solution, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was washed with ether to give the title compound as a white solid (0.05 g, 70%).
LC / MS 285.2
NMR (DMSO-d ₆ ) δ: 1.96-2.00 (1H, m), 2.25 (1H, d, J = 12.8 Hz), 2.86 (1H, m), 3.10 (2H, t, J = 12 Hz), 4.06 (1H, d, J = 4.4 Hz), 4.40 and 4.51 (2H, ABq, J = 15.2 Hz), 7.29 (1H, dd, J = 8.4, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz) , 7.60 (1H, d, J = 8.4 Hz), 9.82 (2H, brs).

Example 130
1- (3,4-Dichlorophenyl) -1,5-diazacyclooctan-2-one monohydrochloride

tert-Butyl 5- (3,4-dichlorophenyl) -4-oxo-1,5-diazacyclooctane-1-carboxylate (0.16 g) in dioxane (4.3 mL) and 4N hydrochloric acid 1,4- A dioxane solution (0.43 mL) was added, and the mixture was stirred at room temperature for 12 hours. The precipitated solid was washed with ethyl acetate to give the title compound as a white solid (0.10 g, 74%).
LC / MS 273.2
NMR (DMSO-d ₆ ) δ: 1.87 (2H, m), 2.94 (2H, m), 3.24 (2H, t, J = 5.6 Hz), 3.33 (2H, t, J = 6.0 H), 4.00 (2H , t, J = 5.6 Hz), 7.37 (1H, dd, J = 8.4, 2.4 Hz), 7.69 (1H, d, J = 8.8 Hz), 7.73 (1H, d, J = 2.4 Hz), 9.41 (2H , brs).

Example 131
1-Naphthalen-2-yl-1,5-diazacyclooctane-2-one monohydrochloride

tert-Butyl 5-naphthalen-2-yl-4-oxo-1,5-diazacyclooctane-1-carboxylate (0.28 g) in dioxane (8.0 mL) and 4N hydrochloric acid 1,4-dioxane solution (0.80 mL) was added and stirred at room temperature for 12 hours. The precipitated solid was washed with ethyl acetate to give the title compound as a white solid (0.15 g, 66%).
LC / MS 255.2
NMR (DMSO-d ₆ ) δ: 1.92-1.94 (2H, m), 3.00 (2H, brs), 3.31 (2H, brs), 3.38 (2H, brs), 4.10 (2H, brs), 7.47 (1H, dd, J = 8.8, 2.0 Hz), 7.53-7.55 (2H, m), 7.87-7.95 (4H, m), 9.55 (2H, brs).

Example 132
1- (3,4-Dichlorophenyl) -1,4-diazacyclooctane-2-one

Triethylamine in a solution of N- (4-aminobutyl) -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride (0.43 g) and tetrabutylammonium iodide (0.51 g) in dichloromethane (14 mL) (0.58 mL) was added slowly at room temperature. The reaction mixture was stirred at room temperature for 12 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (dichloromethane / methanol = 20/1) to give the title compound as a yellow solid (0.060 g, 16%).
LC / MS 273.1
NMR (CDCl ₃ ) δ: 1.78-1.82 (4H, m), 3.06 (2H, t, J = 4.2 Hz), 3.75 (2H, s), 4.15 (2H, t, J = 5.6 Hz), 7.10 (1H , dd, J = 8.4, 2.0 Hz), 7.35 (1H, d, J = 2.0 Hz), 7.46 (1H, d, J = 8.4 Hz).

Reference example 1
tert-Butyl 4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

tert-Butyl 3-oxo-1,4-diazepan-1-carboxylate (synthesized by the method described in US 2006/25383) (3.21 g), 4-bromo-1,2-dichlorobenzene (3.39 g), 4 , 5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.65 g), tris (dibenzylideneacetone) dipalladium (0) (0.343 g), cesium carbonate (6.84 g) and toluene (150 mL) ) Was stirred at 100 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 10/1 to 1/2) to give the title compound as a colorless amorphous solid (4.23 g, 78%).
LC / MS 358.9
NMR (DMSO-d ₆ ) δ: 1.49 (9H, s), 1.87-2.02 (2H, m), 3.67 (2H, brs), 3.75-3.82 (2H, m), 4.23 (2H, brs), 7.04 ( 1H, dd, J = 8.7, 2.3 Hz), 7.30 (1H, d, J = 2.3 Hz), 7.44 (1H, d, J = 8.7 Hz).

Reference example 2
N- [3- (Benzylamino) propyl] -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride

2a) N- (3,4-dichlorophenyl) propane-1,3-diamine

A toluene (400 mL) mixture of 1-amino-3-bromopropane monohydrobromide (10.0 g) and 3,4-dichloroaniline (22.2 g) was heated to reflux for 2 hours. After cooling to room temperature, insolubles were removed by filtration, and the filtrate was washed with a 20% aqueous sodium hydroxide solution. The washing solution was extracted with dichloromethane, and the organic layer was washed with saturated brine. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (benzene / methanol = 7/3 to 1/9) to give the title compound as a yellow oil (4.65 g, 47%).
LC / MS 219.1
NMR (CDCl ₃ ) δ: 1.47 (2H, brs), 1.73-1.83 (2H, m), 2.87 (2H, t, J = 6.4 Hz), 3.16 (2H, t, J = 6.4 Hz), 6.43 (1H , dd, J = 8.4, 2.8 Hz), 6.66 (1H, d, J = 2.8 Hz), 7.17 (1H, d, J = 8.8 Hz).

2b) N-benzyl-N '-(3,4-dichlorophenyl) propane-1,3-diamine

Benzaldehyde (2.2 mL) was added to an ethanol (45 mL) solution of N- (3,4-dichlorophenyl) propane-1,3-diamine (12.8 g) at 0 ° C., and the mixture was stirred at 70 ° C. for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Sodium borohydride was added to a methanol (90 mL) / ethanol (45 mL) solution of the obtained residue, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (ethyl acetate / hexane = 1/20 to 1/9) to give the title compound as a colorless oil (5.00 g, 76%).
LC / MS 309.3
NMR (CDCl ₃ ) δ: 1.77-1.83 (2H, m), 2.78 (2H, t, J = 6.4 Hz), 3.16 (2H, t, J = 6.4 Hz), 3.79 (2H, s), 6.39 (1H , dd, J = 8.8, 2.8 Hz), 6.63 (1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m).

2c) tert-butyl benzyl {3-[(3,4-dichlorophenyl) amino] propyl} carbamate

To a solution of N-benzyl-N ′-(3,4-dichlorophenyl) propane-1,3-diamine (3.50 g) in THF (20 mL) was added ditert-butyl dicarbonate (2.6 mL), and at room temperature overnight. Stir. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a yellow oil (4.70 g, 100%).
LC / MS 409.0
NMR (DMSO-d ₆ ) δ: 1.37 (9H, s), 1.70 (2H, quin, J = 7.0 Hz), 2.93 (2H, q, J = 6.7 Hz), 3.21 (2H, brs), 4.37 (2H , s), 6.05 (1H, t, J = 5.3 Hz), 6.49 (1H, dd, J = 9.1, 2.7 Hz), 6.66 (1H, d, J = 2.7 Hz), 7.15-7.42 (6H, m) .

2d) tert-butyl benzyl {3-[(chloroacetyl) (3,4-dichlorophenyl) amino] propyl} carbamate

tert-Butyl benzyl {3-[(3,4-dichlorophenyl) amino] propyl} carbamate (2.00 g) in THF (10 mL) at 0 ° C. with triethylamine (0.68 mL) and chloroacetyl chloride (0.39 mL) ) Was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate only) to give the title compound as a colorless amorphous solid (1.66 g, 70%).
LC / MS 485.0
NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.48-1.67 (2H, m), 3.12 (2H, brs), 3.60 (2H, t, J = 7.4 Hz), 4.04 (2H, s) , 4.33 (2H, s), 7.01-7.46 (6H, m), 7.72 (2H, d, J = 8.7Hz).

2e) N- [3- (benzylamino) propyl] -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride

To a solution of tert-butyl benzyl {3-[(chloroacetyl) (3,4-dichlorophenyl) amino] propyl} carbamate (0.16 g) in ethyl acetate (2.0 mL) was added 4N hydrochloric acid ethyl acetate solution (1.0 mL). In addition, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (0.14 g, 100%).
LC / MS 387.1
NMR (DMSO-d ₆ ) δ: 1.31-1.83 (4H, m), 2.94 (2H, brs), 3.50-4.21 (4H, m), 7.10-7.87 (8H, m), 8.84 (2H, brs).

Reference example 3
tert-Butyl 4- (3,4-dichlorophenyl) -2-methyl-3-oxo-1,4-diazepan-1-carboxylate

3a) tert-butyl {3-[(3,4-dichlorophenyl) amino] propyl} carbamate

To a solution of 4-bromo-1,2-dichlorobenzene (7.3 mL) and tert-butyl (3-aminopropyl) carbamate (10.0 g) in DMSO (30 mL) was added L-proline (1.31 g), phosphoric acid. Tripotassium (24.0 g) and copper iodide (1.09 g) were added, and the mixture was stirred overnight at 90 ° C. under an argon atmosphere. The reaction mixture was cooled to room temperature and then purified by a silica gel column (ethyl acetate / hexane = 1/4 to 1/1) to obtain the title compound as a brown oil (8.59 g, 47%).
LC / MS 319.4
NMR (DMSO-d ₆ ) δ: 1.37 (9H, s), 1.62 (2H, quin, J = 6.9 Hz), 2.88-3.07 (4H, m), 6.05 (1H, t, J = 5.5 Hz), 6.53 (1H, dd, J = 8.9, 2.6 Hz), 6.69 (1H, d, J = 2.8 Hz), 6.86 (1H, t, J = 5.2 Hz), 7.23 (1H, d, J = 8.9 Hz).

3b) tert-butyl {3-[(2-bromopropanoyl) (3,4-dichlorophenyl) amino] propyl}
Carbamate

tert-Butyl benzyl {3-[(3,4-dichlorophenyl) amino] propyl} carbamate (1.88 g) in THF (12 mL) was added at 0 ° C. with triethylamine (0.90 mL) and 2-bromopropanoyl chloride ( 0.66 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (2.48 g, 93%).
LC / MS 455.2
NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.61-1.72 (1H, m), 1.74 (3H, d, J = 6.8 Hz), 1.82-1.91 (1H, m), 3.06-3.31 (2H, m), 3.58-3.72 (1H, m), 3.79-3.91 (1H, m), 4.07-4.19 (1H, m), 5.22 (1H, brs), 7.12-7.21 (1H, m), 7.41 (1H, brs), 7.55 (1H, d, J = 8.3 Hz).

3c) tert-butyl 4- (3,4-dichlorophenyl) -2-methyl-3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl {3-[(2-bromopropanoyl) (3,4-dichlorophenyl) amino] propyl} carbamate (2.48 g) in DMF (11 mL) at room temperature with sodium hydride (0.44 g, (60% oily) was added and stirred at 60 ° C. overnight. After cooling to room temperature, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/2 to ethyl acetate alone) to give the title compound as a brown oil (0.75 g, 37%).
LC / MS 316.9 ([M + H] ⁺ -tBu)
NMR (CDCl ₃ ) δ: 1.44-1.54 (13H, m), 1.96 (1H, brs), 2.96-3.60 (2H, m), 3.80-4.02 (2H, m), 4.73 (1H, brs), 7.05 ( 1H, dd, J = 8.7, 2.4 Hz), 7.31 (1H, d, J = 2.4 Hz), 7.44 (1H, d, J = 8.5 Hz).

Reference example 4
tert-butyl {3-[(2-bromobutanoyl) (3,4-dichlorophenyl) amino] propyl} carbamate

tert-Butyl {3-[(3,4-dichlorophenyl) amino] propyl} carbamate (1.60 g) in THF (20 mL) at 0 ° C. with triethylamine (0.77 mL) and 2-bromobutanoyl bromide (0 .60 mL) was added, and the mixture was warmed to room temperature and stirred for 7 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.95 g, 83%).
LC / MS 369.3 ([M + H] ⁺ -Boc), 491.4 ([M + H] ⁺ + Na)
NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.44 (9H, s), 1.58-1.78 (1H, m), 1.89-2.02 (1H, m), 2.07-2.22 (1H, m), 3.06-3.39 (2H, m), 3.60-3.73 (2H, m), 3.79-3.93 (2H, m), 5.26 (1H, brs), 7.10-7.19 (1H, m), 7.40 (1H, brs), 7.55 (1H, d, J = 8.7 Hz).

Reference Example 5
tert-Butyl 4- (3,4-dichlorophenyl) -7-methyl-3-oxo-1,4-diazepan-1-carboxylate

5a) tert-butyl {3-[(3,4-dichlorophenyl) amino] -1-methyl-3-oxopropyl} carbamate

To a solution of 3,4-dichloroaniline (1.07 g) in EtOH (33 mL) was added 3-[(tert-butoxycarbonyl) amino] butanoic acid (J. Org. Chem., 66, 6541-6544 (2001)). Synthesized by the method) (1.34 g) and DMT-MM (1.82 g) were added and stirred for 3 days. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane only to ethyl acetate only) to give the title compound as a white solid (1.59 g, 69%).
LC / MS 247.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 6.8 Hz), 1.44 (9H, s), 2.57-2.65 (2H, m), 4.00-4.16 (1H, m), 4.85 (1H, d, J = 7.5 Hz), 7.32-7.41 (2H, m), 7.84 (1H, d, J = 2.1 Hz), 8.47 (1H, brs).

5b) 3-Amino-N- (3,4-dichlorophenyl) butanamide

tert-butyl {3-[(3,4-dichlorophenyl) amino] -1-methyl-3-oxopropyl} carbamate (1.59 g) in ethyl acetate (10 mL) / EtOH (2.0 mL) in 4N hydrochloric acid Ethyl solution (4.0 mL) was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.98 g, 86%).
LC / MS 247.0
NMR (DMSO-d ₆ ) δ: 1.03 (3H, d, J = 6.4 Hz), 2.19-2.40 (2H, m), 3.10-3.48 (2H, m), 7.46 (1H, dd, J = 8.7, 2.3 Hz), 7.55 (1H, d, J = 8.7 Hz), 8.01 (1H, d, J = 2.3 Hz).

5c) N ^1- (3,4-dichlorophenyl) butane-1,3-diamine

To a solution of 3-amino-N- (3,4-dichlorophenyl) butanamide (0.98 g) in THF (8.0 mL) was added 1M borane THF complex THF solution (16 mL), and the mixture was stirred at 60 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. A solution of the concentrated concentrated hydrochloric acid (4.0 mL) was stirred at 100 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate. 8N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale brown oil (0.88 g, 95%).
LC / MS 233.2
NMR (DMSO-d ₆ ) δ: 1.01 (3H, d, J = 6.4 Hz), 1.39-1.61 (2H, m), 1.99 (2H, s), 2.80-2.94 (1H, m), 2.97-3.08 ( 2H, m), 6.09 (1H, t, J = 5.1 Hz), 6.53 (1H, dd, J = 8.7, 2.7 Hz), 6.71 (1H, d, J = 2.7 Hz), 7.22 (1H, d, J = 8.7 Hz).

5d) tert-butyl {3-[(3,4-dichlorophenyl) amino] -1-methylpropyl} carbamate

Di-tert-butyl dicarbonate (0.96 mL) was added to a THF (10 mL) solution of N ^1- (3,4-dichlorophenyl) butane-1,3-diamine (0.88 g), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a white solid (1.27 g, 100%).
LC / MS 233.1 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 1.04 (3H, dd, J = 6.3, 1.6 Hz), 1.37 (9H, s), 1.51-1.67 (2H, m), 2.89-3.02 (2H, m), 3.52- 3.65 (1H, m), 6.03 (1H, t, J = 5.4 Hz), 6.52 (1H, dd, J = 8.9, 2.8 Hz), 6.68 (1H, d, J = 2.8 Hz), 6.76 (1H, d , J = 8.1 Hz), 7.22 (1H, d, J = 8.9 Hz).

5e) tert-butyl 4- (3,4-dichlorophenyl) -7-methyl-3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl {3-[(3,4-dichlorophenyl) amino] -1-methylpropyl} carbamate (1.27 g) in THF (8 mL) at 0 ° C. at 0 ° C. with triethylamine (0.59 mL) and chloroacetyl chloride (0 .33 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a DMF (10 mL) solution of the residue was added sodium hydride (0.19 g, 60% oil) at 0 ° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate only) to give the title compound as a yellow oil (0.59 g, 42%).
LC / MS 373.4
NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 6.6 Hz), 1.37-1.44 (1H, m), 1.50 (9H, s), 1.77-1.99 (1H, m), 2.17-2.32 (1H, m), 3.44-3.69 (2H, m), 4.45 (2H, brs), 7.02 (1H, dd, J = 8.6, 2.4 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.44 (1H, d , J = 8.5 Hz).

Reference Example 6
tert-Butyl 4- (3,4-Dichlorophenyl) -6-methyl-3-oxo-1,4-diazepan-1-carboxylate

6a) tert-butyl {3-[(3,4-dichlorophenyl) amino] -2-methylpropyl} carbamate

1-bromo-3,4-dichlorobenzene (0.75 mL), tert-butyl (3-amino-2-methylpropyl) carbamate (1.10 g), L-proline (0.13 g) and tripotassium phosphate ( To a suspension of 2.46 g) in DMSO (3.0 mL) was added copper iodide (0.11 g), and the mixture was stirred at 90 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column (ethyl acetate / hexane = 1/5) to obtain the title compound as a light brown oil (1.17 g, 61%).
LC / MS 333.1
NMR (DMSO-d ₆ ) δ: 0.86 (3H, d, J = 6.8 Hz), 1.38 (9H, s), 1.64-1.91 (1H, m), 2.61-3.09 (4H, m), 6.08 (1H, t, J = 5.5 Hz), 6.53 (1H, dd, J = 8.7, 2.7 Hz), 6.70 (1H, d, J = 2.7 Hz), 6.89 (1H, t, J = 5.7 Hz), 7.22 (1H, d, J = 8.7 Hz).

6b) tert-butyl 4- (3,4-dichlorophenyl) -6-methyl-3-oxo-1,4-diazepane-1-carboxylate

tert-Butyl {3-[(3,4-Dichlorophenyl) amino] -2-methylpropyl} carbamate (1.17 g) in THF (7.0 mL) at 0 ° C. at 0 ° C. with triethylamine (0.54 mL) and chloroacetyl chloride (0.31 mL) was added, and the mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a DMF (18 mL) solution of the residue, sodium hydride (0.15 g, 60% oil) was added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow oil (0.46 g, 35%).
LC / MS 373.0
NMR (DMSO-d ₆ ) δ: 0.81-0.90 (3H, m), 1.40 (9H, brs), 1.95-2.09 (2H, m), 3.54-3.88 (3H, m), 4.12 (1H, d, J = 15.5 Hz), 4.20 (1H, d, J = 15.5 Hz), 7.16 (1H, dd, J = 8.5, 2.5 Hz), 7.45 (1H, d, J = 2.3 Hz), 7.65 (1H, d, J = 8.3 Hz).

Reference Example 7
tert-Butyl 4- (3,4-dichlorophenyl) -6,6-dimethyl-3-oxo-1,4-diazepane-1-carboxylate

7a) tert-butyl 6,6-dimethyl-3-oxo-1,4-diazepan-1-carboxylate

6,6-Dimethyl-1,4-diazepan-2-one (synthesized by the method described in Polish Journal of Chemistry, 52, 1023-1028 (1978)) (7.26 g) in a solution of ditert- Butyl dicarbonate (11.7 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (10.1 g, 81%).
LC / MS 243.2
NMR (DMSO-d ₆ ) δ: 0.76-0.88 (6H, m), 1.38 (9H, s), 2.81-2.91 (2H, m), 3.21 (2H, brs), 3.87 (2H, s), 7.45 ( 1H, brs).

7b) tert-butyl 4- (3,4-dichlorophenyl) -6,6-dimethyl-3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl 6,6-Dimethyl-3-oxo-1,4-diazepan-1-carboxylate (0.73 g), 1-bromo-3,4-dichlorobenzene (0.32 mL), 4,5-bis 1,4-dioxane (2) of (diphenylphosphino) -9,9-dimethylxanthene (0.11 g), tris (dibenzylideneacetone) dipalladium (0) (0.06 g) and cesium carbonate (1.14 g) 0.5 mL) The suspension was stirred at 110 ° C. under a nitrogen gas atmosphere for 7.5 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous solid (0.46 g, 48%).
LC / MS 287.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 0.96 (6H, s), 1.50 (9H, s), 3.36 (2H, brs), 3.55 (2H, brs), 4.20 (2H, brs), 6.97-7.08 (1H, m) , 7.25-7.31 (1H, m), 7.43 (1H, d, J = 8.3 Hz).

Reference Example 8
tert-Butyl 4- (3,4-Dichlorophenyl) -6,6-difluoro-3-oxo-1,4-diazepane-1-carboxylate

8a) 3-[(3,4-Dichlorophenyl) amino] -2,2-difluoropropanoic acid

3-amino-2,2-difluoropropanoic acid (synthesized by the method described in Tetrahedron Lett., 44, 2375-2378 (2003)) (2.42 g), 1-bromo-3,4-dichlorobenzene (1.9 mL) ), L-proline (0.35 g) and tripotassium phosphate (6.37 g) in DMSO (15 mL) suspension was added copper iodide (0.29 g) and stirred overnight at 90 ° C. under an argon gas atmosphere. did. The reaction mixture was cooled to room temperature and purified by silica gel column (ethyl acetate only to ethanol / ethyl acetate = 1/1) to obtain the title compound as a brown oil (0.57 g, 14%).
LC / MS 270.0
NMR (DMSO-d ₆ ) δ: 3.38-3.62 (2H, m), 6.27 (1H, t, J = 6.5 Hz), 6.63 (1H, dd, J = 8.9, 2.8 Hz), 6.84 (1H, d, J = 2.8 Hz), 7.22 (1H, d, J = 8.9 Hz), 8.55 (1H, brs).

8b) 3-[(3,4-Dichlorophenyl) amino] -2,2-difluoropropanamide

3-[(3,4-Dichlorophenyl) amino] -2,2-difluoropropanoic acid (1.10 g), N-hydroxybenzotriazole ammonium salt (synthesized by the method described in WO2006 / 100119) (0.91 g) and triethylamine WSC (1.15 g) was added to a DMF (12 mL) solution of (0.84 mL), and the mixture was stirred at room temperature for 3 days. After the solvent was distilled off under reduced pressure, the obtained residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a light brown solid (0.55 g, 51%).
LC / MS 269.0
NMR (DMSO-d ₆ ) δ: 3.73 (2H, td, J = 14.8, 6.8 Hz), 6.45 (1H, t, J = 6.8 Hz), 6.69 (1H, dd, J = 8.7, 2.7 Hz), 6.91 (1H, d, J = 3.0 Hz), 7.26 (1H, d, J = 9.1 Hz), 7.97 (1H, brs), 8.18 (1H, brs).

8c) N- (3,4-dichlorophenyl) -2,2-difluoropropane-1,3-diamine

To a solution of 3-[(3,4-dichlorophenyl) amino] -2,2-difluoropropanamide (0.55 g) in THF (20 mL) was added 1.2 M borane THF complex THF solution (4.2 mL) at 0 ° C. In addition, the temperature was raised to 60 ° C., and the mixture was stirred overnight under an argon gas atmosphere. After cooling to room temperature, water (2.0 mL) and 6N aqueous hydrochloric acid (2.0 mL) were added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hr. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only-ethyl acetate only-methanol / ethyl acetate = 1/1) to give the title compound as a colorless oil (0.15 g, 29%). 8N aqueous sodium hydroxide solution was added to the previous aqueous layer to adjust the pH to about 9, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.15 g, 29%).
LC / MS 255.0
NMR (DMSO-d ₆ ) δ: 1.69 (2H, brs), 2.89 (2H, t, J = 14.4 Hz), 3.57 (2H, td, J = 14.7, 6.7 Hz), 6.37 (1H, t, J = 6.4 Hz), 6.68 (1H, dd, J = 8.9, 2.8 Hz), 6.89 (1H, d, J = 2.6 Hz), 7.26 (1H, d, J = 8.9 Hz).

8d) tert-butyl {3-[(3,4-dichlorophenyl) amino] -2,2-difluoropropyl} carbamate

Di-tert-butyl dicarbonate (0.28 mL) was added to a THF (12 mL) solution of N- (3,4-dichlorophenyl) -2,2-difluoropropane-1,3-diamine (0.30 g) at room temperature. Stir overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.35 g, 83%).
LC / MS 255.1 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 3.36-3.64 (4H, m), 6.34 (1H, t, J = 6.6 Hz), 6.66 (1H, dd, J = 8.7, 2.7 Hz) , 6.87 (1H, d, J = 2.7 Hz), 7.14-7.33 (2H, m).

8e) tert-butyl {3-[(bromoacetyl) (3,4-dichlorophenyl) amino] -2,2-difluoropropyl} carbamate

To a solution of tert-butyl {3-[(3,4-dichlorophenyl) amino] -2,2-difluoropropyl} carbamate (0.32 g) in toluene (9.0 mL) was added bromoacetyl bromide (0.09 mL). The mixture was stirred at 100 ° C. for 1 hour in a nitrogen gas atmosphere. After cooling to room temperature, water (2.0 mL) and 6N aqueous hydrochloric acid (2.0 mL) were added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hr. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow oil (0.13 g, 31%).
LC / MS 376.9
NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 3.42 (2H, td, J = 14.7, 6.6 Hz), 3.94 (2H, brs), 4.18 (2H, t, J = 14.8 Hz), 7.19 (1H, brs), 7.49 (1H, d, J = 7.6 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.84 (1H, brs).

8f) tert-butyl 4- (3,4-dichlorophenyl) -6,6-difluoro-3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl {3-[(Bromoacetyl) (3,4-dichlorophenyl) amino] -2,2-difluoropropyl} carbamate (0.13 g) in DMF (3.0 mL) solution at 0 ° C. Sodium (0.01 g, 60% oil) was added and stirred at room temperature for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate only) to give the title compound as a colorless amorphous solid (0.07 g, 64%).
LC / MS 339.0 ([M + H] ⁺ -tBu)
NMR (DMSO-d ₆ ) δ: 1.41 (9H, brs), 3.94-4.12 (2H, m), 4.22-4.34 (4H, m), 7.16 (1H, dd, J = 8.7, 2.1 Hz), 7.45 ( 1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 8.3 Hz).

Reference Example 9
tert-Butyl 8- (3,4-dichlorophenyl) -7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

9a) 1-cyano-N- (3,4-dichlorophenyl) cyclopropanecarboxamide

To a solution of 3,4-dichloroaniline (5.02 g) in EtOH (60 mL), a method described in 1-cyanocyclopropanecarboxylic acid (3.12 g) (J. Fluorine Chem., 104, 297-302 (2000)). Synthesis) and DMT-MM (9.75 g) were added and stirred for 3 days. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/5) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as a white solid (4.17 g, 58%).
LC / MS 255.1
NMR (CDCl ₃ ) δ: 1.60-1.67 (2H, m), 1.77-1.85 (2H, m), 7.32 (1H, dd, J = 8.7, 2.3Hz), 7.42 (1H, d, J = 8.7 Hz) , 7.78 (1H, d, J = 2.3 Hz), 8.03 (1H, brs).

9b) N-{[1- (aminomethyl) cyclopropyl] methyl} -3,4-dichloroaniline

To a solution of 1-cyano-N- (3,4-dichlorophenyl) cyclopropanecarboxamide (18.4 g) in THF (180 mL) was added 1.0 M borane / THF complex THF solution (180 mL) at 0 ° C., and the temperature was raised to 60 ° C. Warmed and stirred overnight. A 6N aqueous hydrochloric acid solution (40 mL) was carefully added to the reaction mixture, and the mixture was stirred at 60 ° C. for 0.5 hr. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was diluted with water and washed with ethyl acetate. 8N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (19.2 g, 100%).
LC / MS 246.0
NMR (CDCl ₃ ) δ: 0.37-0.54 (4H, m), 2.71 (2H, s), 3.03 (2H, s), 6.42 (1H, dd, J = 8.7, 2.7 Hz), 6.65 (1H, d, J = 2.7 Hz), 7.15 (1H, d, J = 8.7 Hz).

9c) tert-butyl [(1-{[(3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl]
Carbamate

To a solution of N-{[1- (aminomethyl) cyclopropyl] methyl} -3,4-dichloroaniline (2.0 g) in THF (16 mL) was added ditert-butyl dicarbonate (1.76 mL) at room temperature. Stir overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a pale red oil (2.76 g, 97%).
LC / MS 345.0
NMR (CDCl ₃ ) δ: 0.46-0.55 (4H, m), 1.40-1.45 (9H, m), 3.00 (2H, brs), 3.12 (2H, d, J = 6.4 Hz), 4.34 (1H, brs) , 4.74 (1H, brs), 6.46 (1H, dd, J = 8.8, 2.7 Hz), 6.68 (1H, d, J = 2.8 Hz), 7.16 (1H, d, J = 8.7 Hz).

9d) tert-butyl [(1-{[(chloroacetyl) (3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate

tert-Butyl [(1-{[(3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate (2.16 g) in THF (6 mL) at room temperature with triethylamine (0.96 mL) and chloro Acetyl chloride (0.55 mL) was added and stirred for 4 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a colorless oil (1.11 g, 42%).
LC / MS 322.0 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 0.02-0.08 (2H, m), 0.49-0.58 (2H, m), 1.45 (9H, s), 3.05 (2H, d, J = 6.4 Hz), 3.65 (2H, brs) , 3.84 (2H, s), 5.67 (1H, brs), 7.16 (1H, dd, J = 8.5, 2.5 Hz), 7.40 (1H, d, J = 2.3 Hz), 7.54 (1H, d, J = 8.7 Hz).

9e) tert-butyl 8- (3,4-dichlorophenyl) -7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

tert-Butyl [(1-{[(Chloroacetyl) (3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate (0.42 g) in DMF (5.0 mL) at 0 ° C. with hydrogen Sodium chloride (0.04 g, 60% oil) was added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale brown oil (0.28 g, 72%).
LC / MS 385.0
NMR (CDCl ₃ ) δ: 0.54-0.61 (2H, m), 0.64-0.78 (2H, m), 1.50 (9H, s), 3.46 (2H, s), 3.54 (2H, s), 4.24-4.37 ( 2H, m), 6.99 (1H, d, J = 8.1 Hz), 7.23 (1H, brs), 7.43 (1H, d, J = 8.5 Hz).

Reference Example 10
tert-Butyl 8- (3,4-dichlorophenyl) -6-methyl-7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

10a) tert-butyl [(1-{[(2-chloropropanoyl) (3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate

tert-Butyl [(1-{[(3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate (3.80 g) in THF (11 mL) at room temperature with triethylamine (1.83 mL) and 2 -Chloropropanoyl chloride (1.28 mL) was added and stirred for 5 hours. Ethanol (2.0 mL) was added to the reaction mixture, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a light brown amorphous solid (4.20 g, 88%).
LC / MS 337.0 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: -0.03-0.13 (2H, m), 0.47-0.64 (2H, m), 1.45 (9H, s), 1.60 (3H, d, J = 6.4 Hz), 2.93-3.97 (4H , m), 4.19 (1H, q, J = 6.2 Hz), 5.73 (1H, t, J = 5.9 Hz), 7.09-7.25 (1H, m), 7.34-7.48 (1H, m), 7.54 (1H, d, J = 8.3 Hz).

10b) tert-butyl 8- (3,4-dichlorophenyl) -6-methyl-7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

tert-Butyl [(1-{[(2-chloropropanoyl) (3,4-dichlorophenyl) amino] methyl} cyclopropyl) methyl] carbamate (4.20 g) in DMF (50 mL) at 0 ° C. Sodium hydride (0.42 g, 60% oily) was added, and the mixture was stirred at 0 ° C for 2 hours, at room temperature for 7 hours, and then at 60 ° C overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/5) to give the title compound as a colorless oil (1.85 g, 48%).
LC / MS 399.3
NMR (CDCl ₃ ) δ: 0.31-0.77 (4H, m), 1.38-1.46 (3H, m), 1.49-1.53 (9H, m), 2.66-3.25 (2H, m), 3.35-3.47 (2H, m ), 4.50-5.01 (1H, m), 6.70-7.53 (3H, m).

Reference Example 11
tert-Butyl benzyl {3-[(chloroacetyl) (3,4-dichlorophenyl) amino] butyl} carbamate

11a) 3-[(3,4-Dichlorophenyl) amino] butanoic acid

1,2-dichloro-4-iodobenzene (5.46 g), 3-aminobutanoic acid (2.06 g), 1,1′-bi-2-naphthol (1.15 g) and tripotassium phosphate (12.7 g) ) Was added to a DMF (20 mL) suspension, and copper bromide (0.57 g) was added thereto, followed by stirring at 40 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. A 1N hydrochloric acid aqueous solution was added to the separated aqueous layer to adjust the pH to about 4, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (5.50 g, 100%).
LC / MS 248.0
NMR (DMSO-d ₆ ) δ: 1.14 (3H, d, J = 6.1 Hz), 2.28 (1H, dd, J = 15.1, 6.8 Hz), 2.46 (1H, dd, J = 15.5, 6.4 Hz), 3.64 -3.81 (1H, m), 5.98 (1H, brs), 6.54 (1H, dd, J = 9.1, 2.7 Hz), 6.73 (1H, d, J = 2.7 Hz), 7.25 (1H, d, J = 8.7 Hz), 12.14 (1H, brs).

11b) N-benzyl-3-[(3,4-dichlorophenyl) amino] butanamide

To a solution of 3-[(3,4-dichlorophenyl) amino] butanoic acid (5.50 g), benzylamine (2.62 mL), HOBt (3.68 g) and triethylamine (3.35 mL) in DMF (40 mL) was added WSC. (4.60 g) was added, and the mixture was stirred at room temperature for 3 days. After the solvent was distilled off under reduced pressure, the obtained residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow solid (3.77 g, 56%).
LC / MS 337.0
NMR (DMSO-d ₆ ) δ: 1.13 (3H, d, J = 6.4 Hz), 2.19 (1H, dd, J = 14.0, 7.6 Hz), 2.42 (1H, dd, J = 13.8, 5.5 Hz), 3.70 -3.85 (1H, m), 4.27 (2H, d, J = 6.1 Hz), 5.98 (1H, d, J = 8.7 Hz), 6.56 (1H, dd, J = 9.1, 2.7 Hz), 6.75 (1H, d, J = 2.7 Hz), 7.17-7.30 (6H, m), 8.40 (1H, t, J = 5.9 Hz).

11c) N ¹ -benzyl-N ^3- (3,4-dichlorophenyl) butane-1,3-diamine

To a solution of N-benzyl-3-[(3,4-dichlorophenyl) amino] butanamide (2.04 g) in THF (30 mL) was added 1.2 M borane THF complex THF solution (13 mL), and the mixture was stirred at 60 ° C. overnight. . After cooling to room temperature, water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. A solution of the residue in concentrated hydrochloric acid (20 mL) was stirred at 100 ° C. for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water, 8N aqueous sodium hydroxide solution was added to adjust the pH to about 9, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column (hexane only to ethyl acetate only) to give the title compound as a colorless amorphous solid (0.36 g, 19%).
LC / MS 323.1
NMR (DMSO-d ₆ ) δ: 1.05 (3H, d, J = 5.8 Hz), 2.52-2.61 (2H, m), 3.24-3.56 (4H, m), 3.59-3.74 (2H, m), 4.26- 4.51 (1H, m), 6.41-7.51 (8H, m).

11d) tert-butyl benzyl {3-[(3,4-dichlorophenyl) amino] butyl} carbamate

Di tert-butyl dicarbonate (1.0 mL) was added to a THF (20 mL) solution of N ¹ -benzyl-N ^3- (3,4-dichlorophenyl) butane-1,3-diamine (1.40 g) at room temperature. Stir overnight. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane only to ethyl acetate / hexane = 1/1) to obtain the title compound as a colorless oil (1.49 g, 82%).
LC / MS 422.9
NMR (DMSO-d ₆ ) δ: 1.05 (3H, d, J = 6.4 Hz), 1.36 (9H, s), 1.52-1.66 (2H, m), 3.18 (2H, brs), 3.28-3.38 (1H, m), 4.24-4.51 (2H, m), 5.89 (1H, d, J = 8.3 Hz), 6.48 (1H, dd, J = 8.7, 2.7 Hz), 6.66 (1H, d, J = 2.3 Hz), 7.14-7.37 (6H, m).

11e) tert-butyl benzyl {3-[(chloroacetyl) (3,4-dichlorophenyl) amino] butyl} carbamate

tert-Butyl benzyl {3-[(3,4-dichlorophenyl) amino] butyl} carbamate (1.49 g) in THF (7 mL) at 0 ° C. with triethylamine (0.49 mL) and chloroacetyl chloride (0. 28 mL) was added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.72 g, 41%).
LC / MS 400.9 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 0.88-1.04 (3H, m), 1.39 (9H, brs), 1.59 (2H, brs), 2.94-3.40 (2H, m), 3.75-3.94 (2H, m), 4.19-4.74 (3H, m), 7.01-7.92 (8H, m).

Reference Example 12
tert-butyl 4-naphthalen-2-yl-3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl 3-oxo-1,4-diazepan-1-carboxylate (0.52 g), 2-bromonaphthalene (0.52 g), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene A mixture of (0.11 g), tris (dibenzylideneacetone) dipalladium (0) (0.06 g), cesium carbonate (1.14 g) and toluene (25 mL) was stirred at 100 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was purified with a silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a yellow amorphous solid (0.79 g, 93%). It was.
LC / MS 341.2
NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.97-2.14 (2H, m), 3.62-3.78 (2H, m), 3.84-3.98 (2H, m), 4.30 (2H, brs), 7.27- 7.39 (1H, m), 7.42-7.52 (2H, m), 7.62 (1H, s), 7.74-7.92 (3H, m).

Reference Example 13
tert-Butyl 4- (3,4-dichlorophenyl) -5-oxo-1,4-diazepan-1-carboxylate

tert-Butyl 5-oxo-1,4-diazepan-1-carboxylate (synthesized by the method described in Bioorg. Med. Chem. Lett., 14, 5907-5912 (2004)) (0.64 g), 4-bromo -1,2-dichlorobenzene (0.32 mL), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.11 g), tris (dibenzylideneacetone) dipalladium (0) (0. 06 g), cesium carbonate (1.14 g) and 1,4-dioxane (2.5 mL) were stirred at 110 ° C. for 7.5 hours under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a white solid (0.28 g, 31%).
LC / MS 259.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.76-2.88 (2H, m), 3.66-3.83 (6H, m), 7.06 (1H, dd, J = 8.5, 2.5 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.45 (1H, d, J = 8.3 Hz).

Reference Example 14
tert-Butyl 8- (3,4-dichlorophenyl) -9-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

14a) 1- (Aminomethyl) -N- (3,4-dichlorophenyl) cyclopropanecarboxamide monohydrochloride

Concentrated hydrochloric acid (7.0 mL) and platinum oxide (0.80 g) were added to a solution of 1-cyano-N- (3,4-dichlorophenyl) cyclopropanecarboxamide (8.0 g) in methanol (160 mL), and a hydrogen gas atmosphere The mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with water, washed with ethyl acetate, 1N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), and 4N hydrochloric acid ethyl acetate solution (20 mL) was added. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous solid (5.51 g, 59%).
LC / MS 258.9
NMR (DMSO-d ₆ ) δ: 1.02-1.74 (6H, m), 7.53-7.70 (2H, m), 7.87-8.13 (4H, m), 9.57 (1H, brs).

14b) tert-butyl (2-chloroethyl) ({1-[(3,4-dichlorophenyl) carbamoyl] cyclopropyl} methyl) carbamate

1- (Aminomethyl) -N- (3,4-dichlorophenyl) cyclopropanecarboxamide monohydrochloride (1.00 g), 45% aqueous chloroacetaldehyde (1.19 g) and acetic acid (0.39 mL) in THF (10 mL) Sodium triacetoxyborohydride (1.44 g) was added to the mixture and stirred at room temperature for 4 hours. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (10 mL), ditert-butyl dicarbonate (0.73 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane only to ethyl acetate only) to obtain the title compound as a colorless oil (0.57 g, 40%).
LC / MS 323.0 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 0.77-0.84 (2H, m), 0.93-1.03 (1H, m), 1.42-1.47 (1H, m), 1.49 (9H, s), 3.54-3.62 (4H, m), 3.70 (2H, s), 7.32 (1H, d, J = 9.1 Hz), 7.52 (1H, dd, J = 8.9, 2.5 Hz), 7.93 (1H, d, J = 2.3 Hz), 9.85 (1H, brs ).

14c) tert-butyl 8- (3,4-dichlorophenyl) -9-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

To a solution of tert-butyl (2-chloroethyl) ({1-[(3,4-dichlorophenyl) carbamoyl] cyclopropyl} methyl) carbamate (0.57 g) and sodium iodide (0.22 g) in DMF (4 mL), Sodium hydride (0.06 g, 60% oil) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a white solid (0.24 g, 45%).
LC / MS 385.3
NMR (CDCl ₃ ) δ: 0.91 (2H, brs), 1.20-1.32 (2H, m), 1.48 (9H, s), 3.57 (2H, brs), 3.73-3.79 (2H, m), 3.86-3.98 ( 2H, m), 7.04 (1H, dd, J = 8.5, 2.5 Hz), 7.30 (1H, d, J = 2.7 Hz), 7.43 (1H, d, J = 8.7 Hz).

Reference Example 15
tert-Butyl 7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

15a) N-benzyl-1-cyanocyclopropanecarboxamide

1-cyanocyclopropanecarboxylic acid (synthesized by the method described in J. Fluorine Chem., 104, 297-302 (2000)) (33.6 g), benzylamine (36.4 mL), HOBt (45.0 g) and triethylamine WSC (63.8 g) was added to a solution of (46.2 mL) in DMF (333 mL), and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/4 to ethyl acetate alone) to give the title compound as a yellow oil (49.0 g, 81%).
LC / MS 201.2
NMR (CDCl ₃ ) δ: 1.44-1.56 (2H, m), 1.63-1.76 (2H, m), 4.47 (2H, d, J = 5.7 Hz), 6.74 (1H, brs), 7.12-7.57 (5H, m).

15b) 1- [1- (Aminomethyl) cyclopropyl] -N-benzylmethanamine

To a solution of N-benzyl-1-cyanocyclopropanecarboxamide (23.5 g) in THF (350 mL) was added 1 M borane THF complex THF solution (470 mL) at 0 ° C., 1.5 hours at room temperature, then 60 ° C. And stirred overnight. After cooling to room temperature, water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. A concentrated hydrochloric acid (300 mL) solution of the residue was stirred for 2.5 hours with heating under reflux. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate. 8N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (23.1 g, 100%).
LC / MS 191.3
NMR (CDCl ₃ ) δ: 0.29-0.42 (4H, m), 1.64 (3H, s), 2.58 (2H, s), 2.66 (2H, s), 3.79 (2H, s), 7.21-7.27 (1H, m), 7.29-7.35 (4H, m).

15c) tert-butyl 8-benzyl-7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

Di-tert-butyl dicarbonate (11 mL) was added to a solution of 1- [1- (aminomethyl) cyclopropyl] -N-benzylmethanamine (10.0 g) in THF (530 mL) and stirred at room temperature for 3 days. The solvent was removed under reduced pressure. Triethylamine (8.1 mL) and chloroacetyl chloride (4.6 mL) were added to a THF (100 mL) solution of the obtained residue at room temperature, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in DMF (250 mL) was added sodium hydride (2.32 g, 60% oil) at 0 ° C., and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a white solid (5.27 g, 30%).
LC / MS 331.2
NMR (CDCl ₃ ) δ: 0.14-0.37 (2H, m), 0.40-0.69 (2H, m), 1.39-1.52 (9H, m), 2.84-2.99 (2H, m), 3.21-3.41 (2H, m ), 4.18-4.37 (2H, m), 4.48-4.67 (2H, m), 6.97-7.48 (5H, m).

15d) tert-butyl 7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate

To a solution of metallic sodium (2.12 g) in liquid ammonia (140 mL) at −78 ° C., tert-butyl 8-benzyl-7-oxo-5,8-diazaspiro [2.6] nonane-5-carboxylate (4 .35 g) in THF (25 mL) and tert-butanol (1.0 mL) were added dropwise and stirred for 15 minutes. Saturated aqueous ammonium chloride solution was carefully added to the reaction mixture, and the mixture was warmed to room temperature and concentrated under reduced pressure. The obtained suspension was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as a white solid (0.90 g, 28%). The mother liquor was concentrated, and the obtained residue was purified by silica gel column (ethyl acetate only to methanol / ethyl acetate = 1/10) to give the title compound as a white solid (0.47 g, 15%).
LC / MS 241.2
NMR (DMSO-d ₆ ) δ: 0.41-0.57 (4H, m), 1.38 (9H, s), 2.92 (2H, d, J = 4.2 Hz), 3.32 (2H, s), 3.95 (2H, s) , 7.47 (1H, t, J = 4.7 Hz).

Reference Example 16
tert-Butyl 4- (3,4-dichlorobenzyl) -3-oxo-1,4-diazepane-1-carboxylate

To a solution of tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.30 g) in DMF (4.0 mL) at 0 ° C. was added sodium hydride (0.06 g, 60% oil). Stir for 0.5 hour. 4- (Bromomethyl) -1,2-dichlorobenzene (0.20 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 5 hours. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (0.40 g, 77%).
LC / MS 273.0 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.72-1.82 (2H, m), 3.32-3.37 (2H, m), 3.49-3.56 (2H, m), 4.12-4.25 (2H, m), 4.52 (2H, s), 7.09 (1H, dd, J = 8.1, 1.9 Hz), 7.34 (1H, d, J = 1.9 Hz), 7.38 (1H, d, J = 8.3 Hz).

Reference Example 17
tert-Butyl 4- (4-Bromo-3-chlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

1-bromo-2-chloro-4-iodobenzene (0.63 g), tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.43 g), 4,5-bis (diphenylphosphino) ) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) under an argon gas atmosphere And stirred at 100 ° C. overnight. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 4/1 to 0/1) to give the title compound as a colorless amorphous solid (0.22 g, 27%).
LC / MS 304.8 ([M + H] ⁺ -Boc)
_{NMR (CDCl 3) δ: 1.49} (9H, s), 1.99 (2H, brs), 3.67 (2H, brs), 3.73-3.86 (2H, m), 4.23 (2H, brs), 6.97 (1H, d, J = 6.6 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.5 Hz).

Reference Example 18
tert-Butyl 4- (1-benzofuran-5-yl) -3-oxo-1,4-diazepane-1-carboxylate

5-Bromo-1-benzofuran (0.48 g), tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.35 g), 4,5-bis (diphenylphosphino) -9,9 A mixture of dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) at 100 ° C. overnight under an argon gas atmosphere. Stir. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 4/1 to 0/1) to give the title compound as a colorless oil (0.092 g, 17%).
LC / MS 231.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.77 (2H, dd, J = 7.5, 6.1 Hz), 2.66 (2H, t, J = 6.1 Hz), 3.29 (2H, d, J = 7.5 Hz ), 3.57 (1H, t, J = 6.1 Hz), 3.67 (1H, t, J = 6.1 Hz), 7.29-7.52 (3H, m), 7.64 (2H, dd, J = 7.7, 1.7 Hz).

Reference Example 19
tert-Butyl 4- (4,5-dichloro-2-fluorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

19a) 1,2-dichloro-4-fluoro-5-iodobenzene

Ice (30 g) and concentrated sulfuric acid (24 mL) were added to a 300 mL three-necked flask and cooled to 0 ° C. A solution of 4,5-dichloro-2-fluoroaniline (2.60 g) in acetonitrile (24 mL) was added dropwise at 0 ° C. and stirred for 30 minutes. While maintaining the temperature of the solution close to 0 ° C., an aqueous solution (24 mL) of sodium nitrite (1.82 g) was added dropwise to the reaction solution. After stirring at 0 ° C. for 30 minutes, the reaction solution was poured into an aqueous solution (24 mL) of potassium iodide (7.17 g) and stirred at 60 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution, saturated aqueous sodium thiosulfate solution and saturated brine in that order, and dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1 / 0-4 / 1) to give the title compound as a yellow oil (3.06 g, 73%).
_{NMR (CDCl 3) δ: 7.19} (1H, d, J = 7.2 Hz), 7.83 (1H, d, J = 6.1 Hz).

19b) tert-butyl 4- (4,5-dichloro-2-fluorophenyl) -3-oxo-1,4-diazepan-1-carboxylate

1,2-dichloro-4-fluoro-5-iodobenzene (0.582 g), tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.43 g), 4,5-bis ( A mixture of diphenylphosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL). The mixture was stirred at 100 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 8/1 to 1/1) to give the title compound as a colorless oil (0.11 g, 14%).
LC / MS 276.9 ([M + H] ⁺ -Boc)
_{NMR (CDCl 3) δ: 1.49} (9H, s), 2.00 (2H, brs), 3.6 2-3.77 (4H, m), 4.22 (2H, brs), 7.27-7.32 (2H, m).

Reference Example 20
tert-Butyl 4- (3,4-Dichloro-2-fluorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

20a) 1,2-dichloro-3-fluoro-4-iodobenzene

Ice (30 g) and concentrated sulfuric acid (30 mL) were added to a 300 mL three-necked flask and cooled to 0 ° C. A solution of 3,4-dichloro-2-fluoroaniline (3.60 g) in acetonitrile (30 mL) was added dropwise at 0 ° C. and stirred for 30 minutes. While maintaining the temperature of the solution near 0 ° C., an aqueous solution (30 mL) of sodium nitrite (2.52 g) was added dropwise to the reaction solution. After stirring at 0 ° C. for 30 minutes, the reaction solution was poured into an aqueous solution (30 mL) of potassium iodide (9.96 g) and stirred at 60 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution, saturated aqueous sodium thiosulfate solution and saturated brine in that order, and dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1 / 0-2 / 1) to give the title compound as an orange oil (5.07 g, 87%).
NMR (CDCl ₃ ) δ: 7.05 (1H, dd, J = 8.7, 1.5 Hz), 7.58 (1H, dd, J = 8.7, 6.1 Hz).

20b) tert-butyl 4- (3,4-dichloro-2-fluorophenyl) -3-oxo-1,4-diazepan-1-carboxylate

1,2-dichloro-3-fluoro-4-iodobenzene (0.582 g), tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.43 g), 4,5-bis (diphenyl) A mixture of phosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) was added with argon gas. The mixture was stirred at 100 ° C. overnight under an atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 8/1 to 1/1) to give the title compound as a colorless oil (0.021 g, 2.8%).
LC / MS 276.9 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.01 (2H, brs), 3.60-3.77 (4H, m), 4.23 (2H, brs), 7.05 (1H, t, J = 8.0 Hz), 7.29 (1H, t, J = 2.7 Hz).

Reference Example 21
tert-Butyl 4- (1-benzofuran-5-yl) -3-oxo-1,4-diazepane-1-carboxylate

tert-butyl 5-bromo-1H-indole-1-carboxylate (0.59 g), tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (0.43 g), 4,5-bis ( A mixture of diphenylphosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) was added to argon. The mixture was stirred at 100 ° C. overnight under a gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 4/1 to 0/1) to give the title compound as a colorless oil (0.075 g, 8.7%).
LC / MS 230.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.56 (9H, s), 2.00 (2H, brs), 3.67 (2H, brs), 3.76-3.87 (2H, m), 4.25 (2H, brs) , 7.17 (1H, d, J = 7.5 Hz), 7.21-7.31 (2H, m), 7.38
(2H, t, J = 7.4 Hz).

Reference Example 22
tert-Butyl 4- (1-benzofuran-3-yl) -3-oxo-1,4-diazepane-1-carboxylate

3-Bromo-1-benzofuran (0.55 g), tert-butyl 3-oxo-1,4-diazepan-1-carboxylate (0.43 g), 4,5-bis (diphenylphosphino) -9,9 A mixture of dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) at 100 ° C. overnight under an argon gas atmosphere. Stir. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 4/1 to 0/1) to give the title compound as a colorless oil (0.057 g, 8.6%).
NMR (DMSO-d ₆ ) δ: 1.41 (9H, brs), 1.82 (2H, brs), 3.56 (2H, t, J = 5.3 Hz), 3.80 (2H, dd, J = 4.9, 4.0 Hz), 4.16 (2H, s), 7.14 (2H, dd, J = 8.4, 1.2 Hz), 7.24 (1H, dt, J = 7.4, 1.6 Hz), 7.32-7.43 (2H, m).

Reference Example 23
tert-Butyl benzyl [(1-{[(2-bromopropanoyl) naphthalen-2-ylamino] methyl} cyclopropyl) methyl] carbamate

23a) N, N-dibenzyl-1-cyanocyclopropanecarboxamide

To a solution of 1-cyanocyclopropanecarboxylic acid (11.1 g), dibenzylamine (21.0 mL), HOBt (16.9 g) and triethylamine (16.5 mL) in DMF (110 mL) was added WSC (21.1 g). In addition, the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/2) to give the title compound as a pale yellow solid (9.94 g, 34%).
LC / MS 291.4
NMR (CDCl ₃ ) δ: 1.47-1.54 (2H, m), 1.63-1.70 (2H, m), 4.45-4.94 (4H, m), 7.12-7.22 (4H, m), 7.28-7.45 (6H, m ).

23b) tert-butyl ({1-[(dibenzylamino) methyl] cyclopropyl} methyl) carbamate

To a solution of N, N-dibenzyl-1-cyanocyclopropanecarboxamide (9.93 g) in THF (100 mL) was added 1M borane / THF complex THF solution (137 mL) at 0 ° C., 1 hour at room temperature, then 60 ° C. And stirred overnight. After cooling to 0 ° C., water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. A solution of the concentrated concentrated hydrochloric acid (100 mL) was stirred with heating under reflux for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate. To the aqueous layer was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (100 mL), di-tert-butyl dicarbonate (9.4 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (7.86 g, 60%).
LC / MS 381.5
NMR (DMSO-d ₆ ) δ: 0.15-0.23 (2H, m), 0.35-0.44 (2H, m), 1.37 (9H, s), 2.30 (2H, s), 3.08 (2H, d, J = 5.8 Hz), 3.50 (4H, s), 6.45 (1H, t, J = 5.6 Hz), 7.17-7.42 (10H, m).

23c) 1- [1- (Aminomethyl) cyclopropyl] -N, N-dibenzylmethanamine dihydrochloride

To a solution of tert-butyl ({1-[(dibenzylamino) methyl] cyclopropyl} methyl) carbamate (3.02 g) in ethyl acetate (20 mL) was added 4N hydrochloric acid ethyl acetate solution (20 mL), and the mixture was stirred at room temperature for 5 days. did. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound as a white solid (2.56 g, 90%).
LC / MS 281.4
NMR (DMSO-d ₆ ) δ: 0.36-0.88 (4H, m), 2.69-3.19 (4H, m), 4.19 (2H, dd, J = 13.1, 5.9 Hz), 4.48 (2H, dd, J = 13.1 , 4.4 Hz), 7.24-7.49 (8H, m), 7.59-7.70 (3H, m), 8.05 (3H, brs).

23d) N-({1-[(dibenzylamino) methyl] cyclopropyl} methyl) naphthalen-2-amine

2-bromonaphthalene (4.40 g), 1- [1- (aminomethyl) cyclopropyl] -N, N-dibenzylmethanamine dihydrochloride (5.79 g), copper iodide (0.33 g), L A mixture of proline (0.41 g), tripotassium phosphate (7.51 g) and DMSO (30 mL) was stirred at 110 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column (hexane / ethyl acetate = 1/0 to 4/1) to give the title compound as a brown oil (1.48 g, 21%).
LC / MS 407.1
NMR (CDCl ₃ ) δ: 0.29-0.44 (2H, m), 0.53-0.59 (2H, m), 2.43 (2H, s), 3.15-3.27 (2H, m), 3.62 (4H, s), 4.33 ( 1H, brs), 7.06-7.77 (17H, m).

23e) N-({1-[(benzylamino) methyl] cyclopropyl} methyl) naphthalen-2-amine

To a solution of N-({1-[(dibenzylamino) methyl] cyclopropyl} methyl) naphthalen-2-amine (1.48 g) and 6N aqueous hydrochloric acid (1.21 mL) in methanol (60 mL) was added palladium hydroxide (0 .15 g) was added. The reaction solution was stirred at room temperature for 1 day under an atmosphere of hydrogen gas (1 kg / cm ² ). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried by adding sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (0.87 g, 76%).
LC / MS 317.1
NMR (DMSO-d ₆ ) δ: 0.66-0.82 (4H, m), 2.84-3.45 (4H, m), 3.81-4.28 (4H, m), 7.01-7.86 (12H, m).

23f) tert-butyl benzyl ({1-[(naphthalen-2-ylamino) methyl] cyclopropyl} methyl) carbamate

N-({1-[(benzylamino) methyl] cyclopropyl} methyl) naphthalen-2-amine (0.87 g) is dissolved in THF (30 mL), and di-tert-butyl dicarbonate (0.66 g) is added. And stirred overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column (hexane / ethyl acetate = 1 / 0-4 / 1) to give the title compound as a colorless oil (0.82 g, 72%). .
LC / MS 317.1 ([M + H] ⁺ -Boc), 361.1 ([M + H] ⁺ -tBu)
NMR (CDCl ₃ ) δ: 0.34-0.67 (4H, m), 1.43 (9H, d, J = 8.7 Hz), 2.97 (1H, s), 3.06-3.17 (2H, m), 3.31 (2H, s) , 4.56 (2H, brs), 7.10-7.43 (10H, m), 7.51-7.72 (2H, m).

23 g) tert-butyl benzyl [(1-{[(2-bromopropanoyl) naphthalen-2-ylamino] methyl} cyclopropyl) methyl] carbamate

tert-Butyl benzyl ({1-[(naphthalen-2-ylamino) methyl] cyclopropyl} methyl) carbamate (0.50 g) in N, N-dimethylacetamide (5 mL) solution with 2-bromopropanoyl chloride (0. 135 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried by adding magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1 / 0-0 / 1) to give the title compound as a colorless oil (0.31 g, 47%).
LC / MS 452.8 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 0.08-0.43 (4H, m), 1.42 (9H, s), 2.56-3.15 (2H, m), 3.28-3.90 (3H, m), 4.10-4.37 (2H, m), 4.36-4.50 (2H, m), 4.53-4.67 (1H, m), 7.26 (10H, m), 7.89 (2H, s).

Reference Example 24
tert-Butyl 4- (3,4-Dichlorophenyl) -3-oxo-2-propyl-1,4-diazepane-1-carboxylate

24a) tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] butyl} carbamate

A solution of N- (tert-butoxycarbonyl) norvaline (3.52 g), 3,4-dichloroaniline (2.43 g), HOBt (2.03 g) and triethylamine (2.1 mL) in DMF (45 mL) was added to WSC (45 mL). 2.88 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/3) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (2.98 g, 55%).
LC / MS 361.0
NMR (DMSO-d ₆ ) δ: 0.87 (3H, t, J = 7.4 Hz), 1.22-1.35 (2H, m), 1.38 (9H, s), 1.51-1.66 (2H, m), 3.89-4.08 ( 1H, m), 7.10 (1H, d, J = 7.6 Hz), 7.47-7.59 (2H, m), 8.00 (1H, d, J = 2.3 Hz), 10.26 (1H, s).

24b) N- (3,4-dichlorophenyl) norvaline amide monohydrochloride

To a solution of tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] butyl} carbamate (2.98 g) in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as white crystals (2.44 g, 100%).
LC / MS 261.0
NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.24-1.47 (2H, m), 1.79 (2H, q, J = 7.2 Hz), 3.99 (1H, t, J = 6.6 Hz), 7.51-7.68 (2H, m), 8.00 (1H, d, J = 2.3 Hz), 8.31 (3H, brs), 11.11 (1H, brs).

24c) N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) norvaline amide

To a suspension of N- (3,4-dichlorophenyl) norvalineamide monohydrochloride (2.44 g) in THF (32 mL), acetic acid (0.47 mL), 3-[(tert-butyldiphenylsilyl) oxy] pro Panal (synthesized by the method described in Org. Lett. 9, 1951-1954 (2007)) (2.56 g) and sodium triacetoxyborohydride (5.49 g) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a white solid (2.97 g, 65%).
LC / MS 557.1
NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J = 7.4 Hz), 0.94 (9H, s), 1.23-1.75 (7H, m), 2.53-2.67 (2H, m), 3.12 (1H, t, J = 6.6 Hz), 3.70 (2H, t, J = 6.1 Hz), 7.34-7.48 (6H, m), 7.52-7.63 (6H, m), 8.05 (1H, s), 10.11 (1H, brs ).

24d) tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] butyl} (3-hydroxypropyl) carbamate

Di-tert-butyl dicarbonate in a solution of N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) norvaline amide (2.97 g) in THF (20 mL) (1.22 mL) was added, and the mixture was stirred at room temperature for 4 hours and then at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M tetrabutylammonium fluoride in THF (6.4 mL) was added and stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.40 g, 63%).
LC / MS 418.9
NMR (DMSO-d ₆ ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.22-1.49 (11H, m), 1.57-1.92 (4H, m), 3.22 (2H, brs), 3.42 (2H, brs), 4.13-4.84 (2H, m), 7.46-7.66 (2H, m), 7.99 (1H, d, J = 1.5 Hz), 10.28 (1H, brs).

24e) tert-butyl 4- (3,4-dichlorophenyl) -3-oxo-2-propyl-1,4-diazepane-1-carboxylate

tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] butyl} (3-hydroxypropyl) carbamate (1.40 g) in THF (15 mL) in triethylamine (0.56 mL) and methanesulfonyl chloride (0. 31 mL) was added and stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.89 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a white solid (1.05 g, 80%).
LC / MS 401.0
NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.22-1.36 (2H, m), 1.40 (9H, s), 1.66-1.92 (4H, m), 3.40-3.71 ( 3H, m), 3.92 (1H, brs), 4.46 (1H, brs), 7.18 (1H, dd, J = 8.7, 2.3 Hz), 7.47 (1H, d, J = 2.3 Hz), 7.65 (1H, d , J = 8.3 Hz).

Reference Example 25
tert-Butyl 4- (3,4-dichlorophenyl) -2- (1-methylethyl) -3-oxo-1,4-diazepane-1-carboxylate

25a) tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] -2-methylpropyl} carbamate

N- (tert-butoxycarbonyl) valine (3.26 g), 3,4-dichloroaniline (2.43 g), HOBt (2.03 g) and triethylamine (2.1 mL) in DMF (45 mL) were added to WSC (45 mL). 2.88 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/3) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (1.83 g, 34%).
LC / MS 361.0
NMR (DMSO-d ₆ ) δ: 0.83-0.93 (6H, m), 1.38 (9H, s), 1.90-2.07 (1H, m), 3.87 (1H, t, J = 8.0 Hz), 7.00 (1H, d, J = 8.3 Hz), 7.46-7.61 (2H, m), 8.01 (1H, d, J = 2.3 Hz), 10.30 (1H, s).

25b) N- (3,4-dichlorophenyl) valinamide monohydrochloride

To a solution of tert-butyl {1-[(3,4-dichlorophenyl) carbamoyl] -2-methylpropyl} carbamate (1.83 g) in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (15 mL), and 3% at room temperature. Stir for hours. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (1.51 g, 100%).
LC / MS 261.0
NMR (DMSO-d ₆ ) δ: 0.95-1.06 (6H, m), 2.12-2.30 (1H, m), 3.85 (1H, t, J = 5.1 Hz), 7.55-7.67 (2H, m), 8.02 ( 1H, d, J = 1.9 Hz), 8.33 (3H, brs), 11.20 (1H, s).

25c) N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) valine amide

To a suspension of N- (3,4-dichlorophenyl) norvalineamide monohydrochloride (1.51 g) in THF (20 mL), acetic acid (0.29 mL), 3-[(tert-butyldiphenylsilyl) oxy] pro Panal (1.59 g) and sodium triacetoxyborohydride (3.41 g) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.59 g, 56%).
LC / MS 557.0
NMR (DMSO-d ₆ ) δ: 0.90 (6H, t, J = 7.2 Hz), 0.95 (9H, s), 1.62-1.73 (2H, m), 1.76-1.88 (1H, m), 2.46-2.55 ( 2H, m), 2.58-2.73 (1H, m), 2.85 (1H, d, J = 6.8 Hz), 3.71 (2H, t, J = 6.1 Hz), 7.36-7.48 (6H, m), 7.53-7.64 (6H, m), 8.07 (1H, s), 10.16 (1H, brs).

25d) tert-butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2-methylpropyl) (3-hydroxypropyl) carbamate

To a solution of N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) valinamide (1.59 g) in THF (10 mL) was added ditert-butyl dicarbonate (0 .66 mL) was added, and the mixture was stirred at room temperature for 4 hours and then at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M tetrabutylammonium fluoride in THF (3.4 mL) was added and stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.66 g, 55%).
LC / MS 319.0 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 0.77-0.92 (6H, m), 1.41 (9H, s), 1.55-1.72 (2H, m), 2.20 (1H, brs), 3.18 (1H, brs), 3.29- 3.43 (3H, m), 4.25-4.55 (2H, m), 7.46-7.61 (2H, m), 8.02 (1H, s), 10.49 (1H, brs).

25e) tert-butyl 4- (3,4-dichlorophenyl) -2- (1-methylethyl) -3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2-methylpropyl) (3-hydroxypropyl) carbamate (0.66 g) in THF (8 mL) in triethylamine (0.26 mL) And methanesulfonyl chloride (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.42 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.43 g, 55%).
LC / MS 401.0
NMR (DMSO-d ₆ ) δ: 0.87 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.4 Hz), 1.39 (9H, brs), 1.74 (2H, brs), 2.55-2.75 (1H, m), 3.48-4.28 (5H, m), 7.17 (1H, dd, J = 8.6, 2.5 Hz), 7.44 (1H, d, J = 2.3 Hz), 7.65 (1H, d, J = 8.7 Hz).

Reference Example 26
tert-butyl 2-butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

26a) N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) norleucinamide

A solution of N- (tert-butoxycarbonyl) norleucine (3.83 g), 3,4-dichloroaniline (2.43 g), HOBt (2.03 g) and triethylamine (2.1 mL) in DMF (45 mL) was added to WSC (45 mL). 2.88 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/3) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (2.69 g, 48%).
LC / MS 375.0
NMR (DMSO-d ₆ ) δ: 0.75-0.92 (3H, m), 1.16-1.34 (4H, m), 1.38 (9H, s), 1.49-1.76 (2H, m), 3.92-4.08 (1H, m ), 7.10 (1H, d, J = 7.5 Hz), 7.44-7.63 (2H, m), 8.00 (1H, d, J = 2.3 Hz), 10.26 (1H, s).

26b) N- (3,4-dichlorophenyl) norleucinamide monohydrochloride

To a solution of N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) norleucinamide (2.69 g) in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 3 hours. Stir. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (2.23 g, 100%).
LC / MS 275.0
NMR (DMSO-d ₆ ) δ: 0.80-0.92 (3H, m), 1.27-1.39 (4H, m), 1.76-1.85 (2H, m), 3.97-4.08 (1H, m), 7.47-7.73 (2H , m), 8.02 (1H, d, J = 1.9 Hz), 8.38 (3H, brs), 11.24 (1H, brs).

26c) N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) norleucinamide

To a solution of N- (3,4-dichlorophenyl) norleucinamide monohydrochloride (2.23 g) in THF (30 mL), acetic acid (0.41 mL), 3-[(tert-butyldiphenylsilyl) oxy] propanal ( 2.25 g) and sodium triacetoxyborohydride (4.82 g) were added and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (2.51 g, 61%).
LC / MS 571.1
NMR (DMSO-d ₆ ) δ: 0.81-0.87 (3H, m), 0.94 (9H, s), 1.21-1.82 (9H, m), 2.53-2.72 (2H, m), 3.10 (1H, t, J = 6.8 Hz), 3.70 (2H, t, J = 6.1 Hz), 7.34-7.48 (6H, m), 7.53-7.66 (6H, m), 8.06 (1H, d, J = 1.5 Hz), 10.10 (1H , brs).

26d) N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) -N ^2- (3-hydroxypropyl) norleucinamide

N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) norleucinamide (2.51 g) in THF (20 mL) in ditert-butyl dicarbonate (1.01 mL) was added, and the mixture was stirred at room temperature for 4 hours and then at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M tetrabutylammonium fluoride in THF (5.3 mL) was added and stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.25 g, 66%).
LC / MS 433.0
NMR (DMSO-d ₆ ) δ: 0.88 (3H, t, J = 6.8 Hz), 1.21-1.50 (13H, m), 1.54-1.93 (4H, m), 3.03-3.57 (4H, m), 4.11- 4.88 (2H, m), 7.36-7.66 (2H, m), 7.99 (1H, s), 10.29 (1H, brs).

26e) tert-butyl 2-butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

Triethylamine (0.48 mL) was added to a solution of N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) -N ^2- (3-hydroxypropyl) norleucinamide (1.25 g) in THF (15 mL). And methanesulfonyl chloride (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.78 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.94 g, 79%).
LC / MS 415.0
NMR (DMSO-d ₆ ) δ: 0.88 (3H, t, J = 6.8 Hz), 1.22-1.35 (4H, m), 1.40 (9H, s), 1.72-1.95 (4H, m), 3.42-3.72 ( 3H, m), 3.91 (1H, brs), 4.45 (1H, brs), 7.18 (1H, dd,
J = 8.5, 2.5 Hz), 7.47 (1H, d, J = 2.3 Hz), 7.64 (1H, d, J = 8.3 Hz).

Reference Example 27
tert-Butyl 4- (3,4-dichlorophenyl) -2- (2-methylpropyl) -3-oxo-1,4-diazepane-1-carboxylate

27a) N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) leucinamide

A solution of N- (tert-butoxycarbonyl) leucine (3.74 g), 3,4-dichloroaniline (2.43 g), HOBt (2.03 g) and triethylamine (2.1 mL) in DMF (45 mL) was added to WSC (45 mL). 2.88 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/3) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (1.68 g, 30%).
LC / MS 375.0
NMR (DMSO-d ₆ ) δ: 0.81-0.93 (6H, m), 1.24-1.34 (1H, m), 1.38 (9H, s), 1.44-1.73 (2H, m), 3.99-4.14 (1H, m ), 7.12 (1H, d, J = 7.7 Hz), 7.44-7.67 (2H, m), 8.00 (1H, d, J = 2.1 Hz), 10.27 (1H, s).

27b) N- (3,4-dichlorophenyl) leucinamide monohydrochloride

N ² - (tert-butoxycarbonyl)-N-(3,4-dichlorophenyl) 4N hydrochloric ethyl acetate solution (15 mL) was added to ethyl acetate (10 mL) solution of leucine amide (1.68 g), stirred for 3 hours at room temperature did. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as white crystals (1.40 g, 100%).
LC / MS 275.0
NMR (DMSO-d ₆ ) δ: 0.88-1.00 (7H, m), 1.54-1.78 (3H, m), 4.02 (1H, t, J = 6.2 Hz), 7.48-7.74 (2H, m), 8.36 ( 3H, brs), 11.25 (1H, brs).

27c) N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) leucinamide

To a solution of N- (3,4-dichlorophenyl) leucinamide monohydrochloride (1.40 g) in THF (20 mL), acetic acid (0.26 mL), 3-[(tert-butyldiphenylsilyl) oxy] propanal ( 1.41 g) and sodium triacetoxyborohydride (3.01 g) were added and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.57 g, 61%).
LC / MS 571.1
NMR (DMSO-d ₆ ) δ: 0.81-0.91 (7H, m), 0.94 (9H, s), 1.33-1.45 (2H, m), 1.60-1.78 (3H, m), 2.52-2.68 (2H, m ), 3.17 (1H, t, J = 7.2 Hz), 3.70 (2H, t, J = 6.1 Hz), 7.36-7.48 (6H, m), 7.51-7.62 (6H, m), 8.06 (1H, d, J = 1.5 Hz), 10.15 (1H, brs).

27d) N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) -N ^2- (3-hydroxypropyl) leucinamide

To a solution of N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) leucinamide (1.57 g) in THF (10 mL) was added ditert-butyl dicarbonate ( 0.63 mL) was added, and the mixture was stirred at room temperature for 4 hours and then at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M tetrabutylammonium fluoride THF solution (3.3 mL) was added, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.95 g, 80%).
LC / MS 433.0
NMR (DMSO-d ₆ ) δ: 0.93 (6H, d, J = 6.4 Hz), 1.39 (9H, brs), 1.49-1.80 (5H, m), 3.12-3.48 (4H, m), 4.19-4.75 ( 2H, m), 7.51-7.61 (2H, m), 8.00 (1H, s), 10.30 (1H, brs).

27e) tert-butyl 4- (3,4-dichlorophenyl) -2- (2-methylpropyl) -3-oxo-1,4-diazepan-1-carboxylate

To a solution of N ^2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) -N ^2- (3-hydroxypropyl) leucinamide (0.95 g) in THF (10 mL) and triethylamine (0.37 mL) and Methanesulfonyl chloride (0.21 mL) was added and stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.59 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (0.65 g, 71%).
LC / MS 415.0
NMR (DMSO-d ₆ ) δ: 0.84-1.00 (6H, m), 1.40 (9H, s), 1.50-1.85 (4H, m), 3.36-3.68 (3H, m), 3.85-4.07 (2H, m ), 4.45 (1H, brs), 7.17 (1H, dd, J = 8.7, 2.3 Hz), 7.45 (1H, s), 7.64 (1H, d, J = 8.3 Hz).

Reference Example 28
tert-butyl 2-tert-butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate

28a) tert-butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2,2-dimethylpropyl) carbamate

To a DMF (40 mL) solution of N- (tert-butoxycarbonyl) -3-methylvaline (3.12 g), 3,4-dichloroaniline (2.19 g), HOBt (1.82 g) and triethylamine (1.9 mL). , WSC (2.59 g) was added and stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature, ethyl acetate and saturated brine were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/3) to give the title compound as a white solid (0.67 g, 13%).
LC / MS 375.0
NMR (DMSO-d ₆ ) δ: 0.95 (9H, s), 1.39 (9H, brs), 4.00 (1H, d, J = 8.7 Hz), 6.79 (1H, d, J = 8.0 Hz), 7.46-7.61 (2H, m), 8.01 (1H, d, J = 2.3 Hz), 10.31 (1H, brs).

28b) N- (3,4-dichlorophenyl) -3-methylvalinamide monohydrochloride

tert-Butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2,2-dimethylpropyl) carbamate (0.67 g) in ethyl acetate (5.0 mL) solution in 4N hydrochloric acid ethyl acetate solution (5 .0 mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as white crystals (0.56 g, 100%).
LC / MS 275.0
NMR (DMSO-d ₆ ) δ: 1.05 (9H, s), 3.77-3.89 (1H, m), 7.47-7.76 (2H, m), 8.03 (1H, d, J = 1.9 Hz), 8.32 (3H, brs), 11.23 (1H, s).

28c) N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) -3-methylvaline amide

To a suspension of N- (3,4-dichlorophenyl) -3-methylvalinamide monohydrochloride (0.82 g) in THF (13 mL), acetic acid (0.15 mL), 3-[(tert-butyldiphenylsilyl) Oxy] propanal (0.81 g) and sodium triacetoxyborohydride (1.76 g) were added and stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous solid (0.85 g, 57%).
LC / MS 572.9
NMR (DMSO-d ₆ ) δ: 0.93 (9H, s), 0.95 (9H, s), 0.96-1.00 (2H, m), 1.61-1.74 (2H, m), 2.60-2.73 (1H, m), 2.85 (1H, s), 3.62-3.78 (2H, m), 7.33-7.65 (12H, m), 8.07 (1H, d, J = 2.1 Hz), 10.18 (1H, s).

28d) N ^2- (tert-butoxycarbonyl) -N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) -3-methylvaline amide

To a THF (7.5 mL) solution of N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) -3-methylvalinamide (0.85 g) Di tert-butyl dicarbonate (0.38 mL) was added, and the mixture was stirred at 60 ° C. overnight. Di tert-butyl dicarbonate (1.50 mL) was added to the reaction mixture, and the mixture was stirred at 60 ° C. overnight. Di tert-butyl dicarbonate (1.50 mL) was further added to the reaction mixture, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/4) to give the title compound as a colorless amorphous solid (0.89 g, 88%).
LC / MS 570.9 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 0.97 (9H, s), 1.00 (9H, s), 1.39 (9H, s), 1.49-1.68 (1H, m), 1.70-1.89 (1H, m), 3.40- 3.73 (4H, m), 4.63 (1H, brs), 7.32-7.49 (6H, m), 7.52-7.64 (6H, m), 8.06 (1H, s), 10.56 (1H, brs).

28e) tert-butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2,2-dimethylpropyl) (3-hydroxypropyl) carbamate

N ^2- (tert-butoxycarbonyl) -N ^2- (3-{[tert-butyl (diphenyl) silyl] oxy} propyl) -N- (3,4-dichlorophenyl) -3-methylvalinamide (0.89 g ) In THF (10 mL) was added 1M tetrabutylammonium fluoride in THF (1.58 mL) and stirred overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to obtain the title compound as a colorless amorphous solid (0.46 g, 80%). .
LC / MS 333.0 ([M + H] ⁺ -Boc)
NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 1.37-1.54 (10H, m), 1.68 (1H, brs), 3.21-3.59 (4H, m), 4.25-4.72 (2H, m), 7.44-7.62 (2H, m), 8.02 (1H, s), 10.55 (1H, brs).

28f) tert-butyl 2-tert-butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepan-1-carboxylate

tert-Butyl (1-{[(3,4-dichlorophenyl) amino] carbonyl} -2,2-dimethylpropyl) (3-hydroxypropyl) carbamate (0.46 g) in THF (5 mL) in triethylamine (0. 18 mL) and methanesulfonyl chloride (0.10 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.29 g), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane only to ethyl acetate / hexane = 1/1) to obtain the title compound as a white solid (0.30 g, 68%).
LC / MS 414.9
NMR (DMSO-d ₆ ) δ: 1.06 (9H, s), 1.11-1.22 (2H, m), 1.42 (9H, s), 1.76-1.94 (2H, m), 3.35-3.50 (2H, m), 4.69 (1H, brs), 7.16-7.29 (1H, m), 7.51-7.60 (1H, m), 7.64 (1H, d, J = 8.7 Hz).

Reference Example 29
tert-Butyl 4- (3,4-dichlorophenyl) -2- (ethoxymethyl) -3-oxo-1,4-diazepane-1-carboxylate

29a) Methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -O-methyl serinate

Methyl 2-amino-3-methoxypropionate monohydrochloride (synthesized by the method described in Eur. J. Med. Chem. Chim. Ther., 11, 283-286 (1976)) (2.04 g) of THF ( 50 mL) suspension was added acetic acid (0.69 mL), benzyl (3-oxopropyl) carbamate (2.49 g) and sodium triacetoxyborohydride (8.03 g), and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate only to methanol / ethyl acetate = 1/10) to obtain the title compound as a colorless oil (1.68 g, 43%).
LC / MS 325.0
NMR (DMSO-d ₆ ) δ: 1.50 (2H, quin, J = 6.9 Hz), 2.34-2.45 (1H, m), 2.52-2.60 (1H, m), 3.01 (2H, q, J = 6.7 Hz) , 3.21 (3H, s), 3.33-3.54 (3H, m), 3.59-3.67 (4H, m), 5.00 (2H, s), 7.22 (1H, t, J = 5.5 Hz), 7.27-7.41 (5H , m).

29b) Methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -N- (tert-butoxycarbonyl) -O-methyl serinate

To a solution of methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -O-methyl serinate (1.68 g) in THF (15 mL) was added ditert-butyl dicarbonate (1.31 mL). Stir overnight at ° C. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.90 g, 86%).
LC / MS 425.0
NMR (DMSO-d ₆ ) δ: 1.29-1.42 (9H, m), 1.52-1.77 (2H, m), 2.89-3.14 (3H, m), 3.18-3.44 (4H, m), 3.56-3.89 (5H , m), 4.19-4.54 (1H, m), 5.00 (2H, s), 7.12-7.41 (6H, m).

29c) Methyl N- (3-aminopropyl) -N- (tert-butoxycarbonyl) -O-methyl serinate

Methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -N- (tert-butoxycarbonyl) -O-methyl serinate (1.90 g) in ethanol (25 mL) in 10% palladium on carbon ( 0.19 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.20 g, 92%).
NMR (DMSO-d ₆ ) δ: 1.29-1.46 (9H, m), 1.47-1.71 (2H, m), 1.94-2.60 (4H, m), 2.98-3.47 (5H, m), 3.56-3.87 (5H , m), 4.14-4.51 (1H, m).

29d) tert-butyl 4- (3,4-dichlorophenyl) -2- (ethoxymethyl) -3-oxo-1,4-diazepan-1-carboxylate

To a solution of methyl N- (3-aminopropyl) -N- (tert-butoxycarbonyl) -O-methyl serinate (1.20 g) in ethanol (41 mL) was added 28% sodium methoxide MeOH solution (1.15 mL). And stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature, 6N aqueous hydrochloric acid solution (1.03 mL) was added, and the mixture was concentrated under reduced pressure. The obtained residue was purified with a basic silica gel column (ethyl acetate only to ethanol / ethyl acetate = 1/3) to obtain a mixture as a pale yellow oil (540 mg). This was dissolved in toluene (21 mL), 4-bromo-1,2-dichlorobenzene (0.27 mL), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.09 g), carbonic acid Cesium (0.96 g) and tris (dibenzylideneacetone) dipalladium (0) (0.05 g) were added, and the mixture was stirred at 90 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1/1) to give the title compound as a yellow oil (0.11 g, 13%).
LC / MS 416.9
NMR (DMSO-d ₆ ) δ: 1.09 (3H, t, J = 7.0 Hz), 1.33-1.53 (9H, m), 1.77 (2H, brs), 3.39-3.69 (4H, m), 3.84 (2H, brs), 3.92-4.19 (2H, m), 4.60 (1H, brs), 7.19 (1H, dd, J = 8.7, 2.4 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.66 (1H, d , J = 8.7 Hz).

Reference Example 30
tert-Butyl 2-benzyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepan-1-carboxylate

30a) Methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) phenylalaninate

To a suspension of methyl phenylalaninate monohydrochloride (2.16 g) in THF (30 mL) was added acetic acid (0.57 mL), benzyl (3-oxopropyl) carbamate (2.07 g) and sodium triacetoxyborohydride (6 .36 g) was added and stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate only to methanol / ethyl acetate = 1/10) to obtain the title compound as a colorless oil (2.69 g, 73%).
LC / MS 371.1
NMR (DMSO-d ₆ ) δ: 1.40-1.59 (2H, m), 2.29-2.44 (1H, m), 2.61-3.08 (5H, m), 3.36-3.46 (1H, m), 3.48-3.61 (3H , m), 4.90-5.07 (2H, m), 7.06-7.49 (11H, m).

30b) Methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -N- (tert-butoxycarbonyl) phenylalaninate

Di-tert-butyl dicarbonate (1.67 mL) was added to a solution of methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) phenylalaninate (2.69 g) in THF (20 mL) at 60 ° C. Stir overnight. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.60 g, 47%).
LC / MS 493.1 ([M + H] ⁺ + Na)
NMR (DMSO-d ₆ ) δ: 1.27-1.50 (11H, m), 2.34-2.67 (1H, m), 2.77-3.24 (5H, m), 3.56-3.72 (3H, m), 4.21-4.36 (1H , m), 4.98 (2H, s), 6.93-7.55 (11H, m).

30c) Methyl N- (3-aminopropyl) -N- (tert-butoxycarbonyl) phenylalaninate

To a solution of methyl N- (3-{[(benzyloxy) carbonyl] amino} propyl) -N- (tert-butoxycarbonyl) phenylalaninate (1.60 g) in ethanol (34 mL) was added 10% palladium carbon (0.34 g). ) And stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (1.13 g, 99%).
LC / MS 337.1
NMR (DMSO-d ₆ ) δ: 1.19-1.30 (2H, m), 1.36 (9H, s), 1.57 (2H, brs), 2.32 (2H, t, J = 6.6 Hz), 2.92-3.31 (4H, m), 3.58-3.74 (3H, m), 4.18-4.35 (1H, m), 7.08-7.37 (5H, m).

30d) tert-butyl 2-benzyl-3-oxo-1,4-diazepan-1-carboxylate

To a solution of methyl N- (3-aminopropyl) -N- (tert-butoxycarbonyl) phenylalaninate (0.63 g) in ethanol (10 mL) was added 2N aqueous sodium hydroxide solution (1.87 mL), and at room temperature overnight. Stir. To the reaction mixture were added 6N aqueous hydrochloric acid (0.63 mL) and DMT-MM (0.57 g), and the mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give the title compound as a white solid (0.68 g, 100%).
LC / MS 305.1
NMR (DMSO-d ₆ ) δ: 1.19-1.40 (9H, m), 1.52-1.81 (2H, m), 2.88-3.53 (6H, m), 4.66 (1H, brs), 7.06-7.36 (5H, m ), 7.62 (1H, brs).

30e) tert-butyl 2-benzyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepan-1-carboxylate

To a solution of tert-butyl 2-benzyl-3-oxo-1,4-diazepan-1-carboxylate (0.45 g) in toluene (10 mL) was added 4-bromo-1,2-dichlorobenzene (0.19 mL), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.064 g), cesium carbonate (0.67 g) and tris (dibenzylideneacetone) dipalladium (0) (0.034 g) were added, The mixture was stirred at 90 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a colorless amorphous solid (0.54 g, 82%).
LC / MS 448.8
NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.72 (2H, brs), 3.02-3.37 (4H, m), 3.47-3.75 (1H, m), 3.87-4.18 (1H, m), 4.77 (1H, brs), 7.08-7.35 (6H, m), 7.47 (1H, brs), 7.66 (1H, d, J = 8.7 Hz).

Reference Example 31
tert-Butyl benzyl [(1-{[(bromoacetyl) naphthalen-2-ylamino] methyl} cyclopropyl) methyl] carbamate

Bromoacetyl chloride (0.072 mL) was added to a solution of tert-butyl benzyl ({1-[(naphthalen-2-ylamino) methyl] cyclopropyl} methyl) carbamate (0.32 g) in N, N-dimethylacetamide (3 mL). It added at 0 degreeC and stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried by adding magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 1 / 0-0 / 1) to give the title compound as a colorless oil (0.18 g, 44%).
LCMS 437.1 ([M + H] ⁺ -Boc)
NMR (CDCl ₃ ) δ: 0.04-0.26 (4H, m), 1.45 (9H, s), 3.34 (2H, s), 3.87 (4H, brs), 4.54 (2H, brs), 7.10-7.33 (5H, m), 7.37-7.48 (1H, m), 7.56 (2H, dd, J = 6.2, 3.2 Hz), 7.78-7.96 (4H, m).

Reference Example 32
tert-butyl 2-methyl-4-naphthalen-2-yl-3-oxo-1,4-diazepane-1-carboxylate

32a) tert-butyl [3- (naphthalen-2-ylamino) propyl] carbamate

2-bromonaphthalene (3.83 g), tert-butyl (3-aminopropyl) carbamate (3.23 g), 1,1′-bi-2-naphthol (1.06 g) and tripotassium phosphate (11.8 g) ) In DMF (40 mL) suspension was added copper iodide (0.71 g) and stirred at 90 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a pale yellow solid (0.62 g, 11%).
LC / MS 245.1 ([M + H] ⁺ -tBu)
NMR (DMSO-d ₆ ) δ: 1.38 (9H, s), 1.67-1.79 (2H, m), 2.97-3.15 (4H, m), 5.87 (1H, t, J = 5.5 Hz), 6.67 (1H, d, J = 2.1 Hz), 6.84-7.34 (3H, m), 7.49-7.67 (3H, m), 7.79-7.88 (1H, m).

32b) tert-butyl 2-methyl-4-naphthalen-2-yl-3-oxo-1,4-diazepane-1-carboxylate

tert-Butyl [3- (Naphthalen-2-ylamino) propyl] carbamate (0.62 g) in THF (10 mL) at 0 ° C. with triethylamine (0.32 mL) and 2-bromopropanoyl chloride (0.24 mL) The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in DMF (6.0 mL), sodium hydride (0.092 g, 60% oil) was added at 0 ° C., and the mixture was stirred at 80 ° C. overnight. After cooling to room temperature, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a white solid (0.38 g, 51%).
LC / MS 355.1
NMR (DMSO-d ₆ ) δ: 1.29-1.49 (13H, m), 1.74-1.93 (2H, m), 3.59-3.75 (2H, m), 3.88-4.07 (1H, m), 4.73 (1H, brs ), 7.34 (1H, dd, J = 8.7, 1.9 Hz), 7.46-7.56 (2H, m), 7.73 (1H, s), 7.83-7.96 (3H, m).

Reference Example 33
tert-butyl 2-ethyl-4-naphthalen-2-yl-3-oxo-1,4-diazepane-1-carboxylate

tert-Butyl [3- (Naphthalen-2-ylamino) propyl] carbamate (3.13 g) in THF (30 mL) at 0 ° C. with triethylamine (1.45 mL) and 2-bromobutanoyl bromide (1.26 mL) The mixture was heated to room temperature and stirred for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a DMF (30 mL) solution of the obtained residue was added sodium hydride (0.46 g, 60% oil) at 0 ° C., and the mixture was stirred at 80 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow amorphous solid (1.50 g, 39%).
LC / MS 369.1
NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.73-2.06 (4H, m), 3.40-4.12 (4H, m), 4.48 (1H, brs), 7.31 (1H, d, J = 8.7 Hz), 7.46-7.58 (2H, m), 7.70 (1H, s), 7.77-7.95 (3H, m).

Reference Example 34
tert-Butyl (1R, 5S) -3- (3,4-Dichlorobenzyl) -4-oxo-3,6-diazabicyclo [3.2.1] octane-6-carboxylate

34a) tert-butyl (1R, 5S) -4-oxo-3,6-diazabicyclo [3.2.1] octane-6-carboxylate

1-tert-Butyl-2-methyl (2S, 4R) -4- (aminomethyl) pyrrolidine-1,2-dicarboxylate (synthesized by the method described in US5821261) (3.25 g) in methanol (75 mL) Then, potassium carbonate (2.61 g) was added, and the mixture was heated to reflux for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (dichloromethane / ethyl acetate = 1/2) to give the title compound as a white solid (0.57 g, 20%).
NMR (DMSO-d ₆ ) δ: 1.48 (9H, s), 2.01-2.05 (2H, m), 2.72 (1H, d, J = 4.0 Hz), 3.26-3.39 (2H, m), 3.48-3.61 ( 2H, m), 4.27 (0.6H, d, J = 4.0 Hz), 4.41 (0.4H, brs), 5.66-6.16 (1H, m).

34b) tert-butyl (1R, 5S) -3- (3,4-dichlorobenzyl) -4-oxo-3,6-diazabicyclo [3.2.1] octane-6-carboxylate

tert-Butyl (1R, 5S) -4-oxo-3,6-diazabicyclo [3.2.1] octane-6-carboxylate (0.12 g) in DMF (3.0 mL) was added to sodium hydride ( 15 mg) (95%) was added at room temperature and stirred for 1 hour. 3,4-Dichlorobenzyl bromide (136 mg) was added to the obtained reaction mixture, and the mixture was stirred at 120 ° C. for 12 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane / ethyl acetate = 1/1) to give the title compound as a white solid (0.11 g, 59%).
NMR (DMSO-d ₆ ) δ: 1.49 (9H, s), 1.96 (1H, d, J = 11.2 Hz), 2.00-2.16 (1H, m), 2.70 (1H, m), 3.10-3.12 (1H, m), 3.28-3.37 (2H, m), 3.53-3.57 (1H, m), 4.35-4.56 (3H, m), 7.02 (1H, d, J = 8.0 Hz), 7.28 (1H, s), 7.37 (1H, d, J = 8.0 Hz).

Reference Example 35
tert-Butyl 5- (3,4-Dichlorophenyl) -4-oxo-1,5-diazacyclooctane-1-carboxylate

35a) methyl 3-[(3-{[(benzyloxy) carbonyl] amino} propyl) amino] propanoate

To a solution of benzyl (3-aminopropyl) carbamate monohydrochloride (2.5 g) and diisopropylethylamine (3.6 mL) in DMF (35 mL) at 0 ° C. was added methyl 3-bromopropanoate (1.2 mL). The mixture was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere and then at room temperature for 11 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound. The obtained compound was used in the next reaction without further purification.
NMR (CDCl ₃ ) δ: 1.54 (1H, brs), 1.64-1.70 (2H, m), 2.50 (2H, t, J = 6.4 Hz), 2.70 (2H, t, J = 6.4 Hz), 2.86 (2H , t, J = 6.4 Hz), 3.29 (2H, td, J = 6.4, 6.4 Hz), 3.66 (3H, s), 5.09 (2H, s), 5.52 (1H, brs), 7.30-7.37 (5H, m).

35b) Methyl 3-[(3-{[(benzyloxy) carbonyl] amino} propyl) (tert-butoxycarbonyl) amino] propanoate

Triethylamine (2.2 mL) and ditert-butyl dicarbonate were added to a solution of methyl 3-[(3-{[(benzyloxy) carbonyl] amino} propyl) amino] propanoic acid obtained in Reference Example 35a) in dichloromethane (51 mL). (2.7 g) was added and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified with a silica gel column (hexane / ethyl acetate = 4/1) to give the title compound as a colorless oil (1.8 g, 44% (two-stage yield)). Got as.
NMR (CDCl ₃ ) δ: 1.43 and 1.45 (9H, each s), 1.65 (2H, brs), 2.56 (2H, brs), 3.17 (2H, brs), 3.30 (2H, brs), 3.42 (2H, brs ), 3.68 (3H, s), 5.10 (2H, s), 5.68 (1H, brs), 7.31-7.36 (5H, m).

35c) methyl 3-[(3-aminopropyl) (tert-butoxycarbonyl) amino] propanoate

Add Pd / C (0.4 g) to a solution of methyl 3-[(3-{[(benzyloxy) carbonyl] amino} propyl) (tert-butoxycarbonyl) amino] propanoate (1.8 g) in methanol (45 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.0 g, 86%).
NMR (CDCl ₃ ) δ: 1.44-1.46 (9H, m), 1.50 (2H, brs), 1.60-1.68 (2H, m), 2.57 (2H, brs), 2.69-2.77 (2H, m), 3.30 ( 2H, brs), 3.47 (2H, brs), 3.68 (3H, s).

35d) tert-butyl 4-oxo-1,5-diazacyclooctane-1-carboxylate

To a solution of methyl 3-[(3-aminopropyl) (tert-butoxycarbonyl) amino] propanoate (0.48 g) in methanol (18 mL) was added 30% sodium methoxide in methanol (0.69 mL) and heated for 2 days. Refluxed. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and washed successively with 2N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (0.21 g, 50%).
NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.79-1.91 (2H, m), 2.52-2.57 (2H, m), 3.25-3.34 (4H, m), 3.61-3.69 (2H, m), 5.76 (1H, brs).

35e) tert-butyl 5- (3,4-dichlorophenyl) -4-oxo-1,5-diazacyclooctane-1-carboxylate

tert-Butyl 4-oxo-1,5-diazacyclooctane-1-carboxylate (0.20 g), tris (dibenzylideneacetone) dipalladium (0) (0.020 g), 4,5-bis (diphenyl) To a suspension of phosphino) -9,9-dimethylxanthene (0.038 g) and cesium carbonate (0.40 g) in 1,4-dioxane (2.0 mL) was added 4-bromo-1,2-dichlorobenzene ( 0.20 g) was added, and the mixture was stirred at 110 ° C. for 12 hours under a nitrogen gas atmosphere. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with dichloromethane, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (ethyl acetate alone to ethyl acetate / methanol = 20/1) to give the title compound as a yellow oil (0.16 g, 50%).
NMR (CDCl ₃ ) δ: 1.48-1.50 (9H, m), 1.82-1.93 (2H, m), 2.79 (2H, brs), 3.42 (2H, brs), 3.76 (4H, brs), 7.05-7.09 ( 1H, m), 7.32-7.33 (1H, m), 7.46-7.49 (1H, m).

Reference Example 36
tert-Butyl 5-Naphthalen-2-yl-4-oxo-1,5-diazacyclooctane-1-carboxylate

tert-Butyl 4-oxo-1,5-diazacyclooctane-1-carboxylate (0.21 g), tris (dibenzylideneacetone) dipalladium (0) (0.021 g), 4,5-bis (diphenyl) To a suspension of phosphino) -9,9-dimethylxanthene (0.040 g) and cesium carbonate (0.42 g) in 1,4-dioxane (2.0 mL) was added 2-bromonaphthalene (0.21 g). The mixture was stirred at 110 ° C. for 12 hours in a nitrogen gas atmosphere. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with dichloromethane, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (ethyl acetate alone to ethyl acetate / methanol = 20/1) to give the title compound as a yellow oil (0.28 g, 87%).
NMR (CDCl ₃ ) δ: 1.49-1.52 (9H, m), 1.80-2.00 (2H, m), 2.85 (2H, brs), 3.51 (2H, brs), 3.79-3.87 (4H, m), 7.31- 7.33 (1H, m), 7.48-7.50 (2H, m), 7.66 (1H, s), 7.80-7.89 (3H, m).

Reference Example 37
N- (4-aminobutyl) -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride

37a) tert-butyl {4-[(3,4-dichlorophenyl) amino] butyl} carbamate

Copper iodide (0.051 g), cesium carbonate (1.7 g), tert-butyl (4-aminobutyl) carbamate (0.50 g) and 4-bromo-1,2-dichlorobenzene (0.34 mL) in dimethyl 2- (2-Methylpropanoyl) cyclohexanone (0.038 g) was added to a suspension of formamide (1.3 mL), and the mixture was stirred at 90 ° C. for 48 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 7/1) to give the title compound as a yellow oil (0.72 g, 81%).
NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.53-1.61 (4H, m), 3.04 (2H, t, J = 6.4 Hz), 3.12-3.15 (2H, m), 4.11 (1H, brs) , 4.66 (1H, brs), 6.38 (1H, dd, J = 8.4, 2.4 Hz), 6.61 (1H, d, J = 2.4 Hz), 7.13 (1H, d, J = 8.4 Hz).

37b) tert-butyl {4-[(chloroacetyl) (3,4-dichlorophenyl) amino] butyl} carbamate

tert-Butyl {4-[(3,4-Dichlorophenyl) amino] butyl} carbamate (716 mg) in 1,4-dioxane (17 mL) in 10% aqueous sodium carbonate (11 mL) and chloroacetyl chloride (0.43 mL) And stirred at 0 ° C. for 30 minutes. Chloroacetyl chloride (0.43 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 30 min. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column (hexane / ethyl acetate = 2/1) to give the title compound as a yellow oil (0.77 g, 87%).
NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.47-1.58 (4H, m), 3.11 (2H, q, J = 6.4 Hz), 3.71 (2H, t, J = 7.2 Hz), 3.81 (2H , s), 4.66 (1H, brs), 7.12 (1H, dd, J = 8.4, 2.4 Hz), 7.38 (1H, d, J = 2.4 Hz), 7.55 (1H, d, J = 8.4 Hz).

37c) N- (4-aminobutyl) -2-chloro-N- (3,4-dichlorophenyl) acetamide monohydrochloride

tert-Butyl {4-[(Chloroacetyl) (3,4-dichlorophenyl) amino] butyl} carbamate (0.77 g) in dioxane (1.9 mL) and 4N hydrochloric acid 1,4-dioxane solution (0.94 mL) Was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from dichloromethane-ether to give the title compound as a yellow solid (0.46 g, 80%).
NMR (Methanol-d ₄ ) δ: 1.57-1.71 (4H, m), 2.94 (2H, t, J = 6.8 Hz), 3.77 (2H, t, J = 6.8 Hz), 3.97 (2H, s), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.65 (1H, d, J = 1.6 Hz), 7.68 (1H, d, J = 8.8 Hz).

Test example 1
(1) Construction of human dopamine transporter expression plasmid The SRα promoter contained in pTB1411 described in JP-A-5-076385 was cleaved with a restriction enzyme HindIII (manufactured by Takara Bio Inc.), blunt-ended, and further subjected to a restriction enzyme. It was cut and fragmented with EcoRI (Takara Bio Inc.). On the other hand, the pCI vector was cleaved with a restriction enzyme BglII (Takara Bio Inc.), blunt-ended with T4 DNA polymerase, and further cleaved with a restriction enzyme EcoRI (Takara Bio Inc.). The SRα promoter fragment was inserted into this site to prepare pCI-SRa. Next, pCI-SRa was cleaved with restriction enzyme ClaI (Takara Bio Inc.) and then blunt-ended, and pGFP-C1 (Toyobo Co., Ltd.) was added to restriction enzyme Bsu36I (Daiichi Chemical Co., Ltd.). After cutting, the 1.63 Kb fragment blunt-ended was inserted to prepare pMSRα neo. Human dopamine transporter cDNA was amplified by PCR from a human substantia nigra cDNA library and inserted into a pCRII vector (Invitrogen Corporation). After confirming and correcting the base sequence, it was subcloned into pMSRα neo to construct a human dopamine transporter expression plasmid.

(2) Production of human monoamine-expressing cells Human serotonin transporter cDNA was amplified by PCR from a human brain cDNA library and inserted into a pCRII-TOPO vector (Invitrogen Corporation). After confirming and correcting the base sequence, it was subcloned into a pcDNA3.1 vector (manufactured by Invitrogen Corporation) to construct a human serotonin transporter expression plasmid. Human norepinephrine transporter cDNA was purchased from Invitrogen, and after confirming and correcting the base sequence, it was subcloned into pcDNA3.1 vector to construct a human norepinephrine transporter expression plasmid.
These produced monoamine transporter expression plasmids were introduced into CHO-K1 cells using FuGENE6 (manufactured by Roche Diagnostics) according to the attached protocol, and the respective expression cells were established.

(3) Inhibitory effect on human serotonin transporter For the measurement of human serotonin transporter inhibitory activity, CHO cells stably expressing human serotonin transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
The cells cultured until almost confluent were rinsed with PBS (Invitrogen), peeled off with Trypsin / EDTA (Invitrogen), and collected by centrifugation. The number of cells obtained was measured, diluted to contain 3 × 10 ⁵ cells per mL of medium, dispensed 100 μL per well into 96 well white plate (Corning), and then in a CO ₂ incubator. Cultured overnight.
Next, an assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH ₂ PO ₄ , 1.26 mM MgSO ₄ , 10 mM HEPES, 2.32 mM CaCl ₂ , 5.52 mM Glucose, 0.5% BSA) is prepared. After removing the cell plate medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into a cell plate. [3H] -5-hydroxytryptamine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. After 20 minutes from the addition of [3H] -5-hydroxytryptamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti 20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM Paroxetine (a serotonin transporter inhibitor) as 100%. The results are shown in Table 2.

Test Example 2 Inhibitory action on human noradrenaline transporter For the measurement of human noradrenaline transporter inhibitory activity, CHO cells stably expressing human noradrenaline transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
The cells cultured until almost confluent were rinsed with PBS (Invitrogen), peeled off with Trypsin / EDTA (Invitrogen), and collected by centrifugation. The number of cells obtained was measured, diluted to contain 3 × 10 ⁵ cells per mL of medium, dispensed 100 μL per well into 96 well white plate (Corning), and then in a CO ₂ incubator. Cultured overnight.
Next, an assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH ₂ PO ₄ , 1.26 mM MgSO ₄ , 10 mM HEPES, 2.32 mM CaCl ₂ , 5.52 mM Glucose, 0.5% BSA) is prepared. After removing the cell plate medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into a cell plate. [3H] -Noradrenaline (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. 45 minutes after the addition of [3 H] -noradrenaline, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti 20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM DMI (noradrenaline transporter inhibitor) as 100%. The results are shown in Table 3.

Test Example 3 Inhibitory Action on Human Dopamine Transporter For the measurement of human dopamine transporter inhibitory activity, CHO cells stably expressing human dopamine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
On the day before the assay, the cells cultured until they became almost confluent were rinsed with PBS (Invitrogen), peeled off with Trypsin / EDTA (Invitrogen), and collected by centrifugation. The number of cells obtained was measured, diluted to contain 3 × 10 ⁵ cells per mL of medium, dispensed 100 μL per well into 96 well white plate (Corning), and then in a CO ₂ incubator. Cultured overnight.
Prepare assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH ₂ PO ₄ , 1.26 mM MgSO ₄ , 10 mM HEPES, 2.32 mM CaCl ₂ , 5.52 mM Glucose, 0.5% BSA) on the day of the test After removing the cell plate medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into a cell plate. [3H] -Dopamine (GE Healthcare) was diluted to 200 nM with assay buffer, and cold dopamine was diluted to 10 μM. 10 μL was dispensed onto the cell plate. When 60 minutes had elapsed since the addition of [3 H] -dopamine, the assay buffer was removed by suction, and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti 20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 100 μM Nomifensine (dopamine transporter inhibitor) as 100%. The results are shown in Table 4.

Formulation Example 1
A medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
1. Capsule (1) 40 mg of the compound obtained in Example 1
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.

2. Tablet (1) Compound obtained in Example 1 40 mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation Example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 ml of JP distilled water for injection, JP distilled water for injection is added to make 100 ml. The solution is filtered under sterile conditions, then 1 ml of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Since the compound of the present invention or a salt thereof or a prodrug thereof has an excellent monoamine neurotransmitter uptake inhibitory effect, all monoamine neurotransmitter-related diseases such as psychiatric disorders (depression / anxiety or attention deficit hyperactivity) Sexual disorder) It is useful as a preventive / therapeutic, dysuria, or pain.

This application is based on Japanese Patent Application No. 2008-076799 filed in Japan, the contents of which are included in the present invention.

Claims

Formula (I):

[Where,
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a group and thiazolyl having a substituent);
L is
(1) a bond, or (2) an optionally substituted C 1-3 (poly) methylene;
R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 3 represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 4 represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 5 represents a hydrogen atom or an optionally substituted hydrocarbon group;
m + n = 2 or 3 (where m and n are each an integer of 0 to 3);
Ring A is a 7- or 8-membered ring which may have a substituent other than R 1 to R 5 (the substituents on the ring A are bonded to each other, together with the ring atom to which the substituent is bonded) A ring which may have a group may be formed)
Indicates. ]
[Wherein the following formula:

Or the salt thereof.
2. The compound according to claim 1, wherein L is a bond.
The compound according to claim 1, wherein ring A is a 7-membered ring (m = 2, n = 0).
The compound according to claim 1, wherein ring A is a 7-membered ring (m = 2, n = 0) and L is a bond.
Formula (I-II)

[Where,
R 1a to R 5a are the same or different and each represents (1) a hydrogen atom, or (2) an optionally substituted C 1-6 alkyl group,
R 6a to R 9a are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted C 1-6 alkyl group,
Any combination of R 1a and R 4a , R 4a and R 6a and R 8a and R 9a is bonded to each other to form — (CH 2 ) n′— (where n ′ is an integer of 1 to 3). May be formed)
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of Claim 1 represented by this.
Formula (I-III)

[Where,
R 1a ′ represents (1) a hydrogen atom or (2) a C 1-6 alkyl group which may be substituted with a phenyl group,
R 4a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group which may be substituted with a C 1-3 alkoxy group,
R 6a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group,
R 8a ′ and R 9a ′ are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-6 alkyl group,
Any combination of R 1a ′ and R 4a ′ , R 4a ′ and R 6a ′ and R 8a ′ and R 9a ′ is bonded to each other to form — (CH 2 ) n′— (where n ′ Represents an integer of 1 to 3).
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of Claim 5 represented by these.
Ar is (1) phenyl having a substituent,
(2) indanyl which may have a substituent,
(3) an indolyl optionally having a substituent,
6. The compound according to claim 5, which is (4) benzofuranyl which may have a substituent, or (5) naphthyl which may have a substituent.
Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl;
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
6. The compound according to claim 5, which is (4) benzofuranyl or (5) naphthyl optionally substituted with a C1-3 alkoxy group.
R 1a ′ represents (1) a hydrogen atom or (2) a C 1-6 alkyl group which may be substituted with a phenyl group,
R 4a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group which may be substituted with a C 1-3 alkoxy group,
R 6a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group,
R 8a ′ and R 9a ′ are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-6 alkyl group,
Any combination of R 1a ′ and R 4a ′ , R 4a ′ and R 6a ′ and R 8a ′ and R 9a ′ is bonded to each other to form — (CH 2 ) n′— (where n ′ Represents an integer of 1 to 3).
Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Methoxy and (f) phenyl having 1 or 2 substituents selected from phenyl,
(2) indanyl optionally substituted with an oxo group,
(3) In-drill,
7. The compound according to claim 6, which is (4) benzofuranyl or (5) naphthyl optionally substituted with a C1-3 alkoxy group.
Ring A is a 7-membered ring (m = 1, n = 1)
Ar is
(1) (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) C 6-10 aryl Phenyl having 1 or 2 substituents selected from
(2) indanyl which may have a substituent, or (3) naphthyl which may have a substituent, and
The compound according to claim 1, wherein L is a bond.
Formula (I-IV)

[Where,
R 1b to R 9b are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group,
R 6b and R 7b may combine with each other to form — (CH 2 ) n′— (where n ′ represents an integer of 1 to 3);
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of Claim 1 represented by this.
Formula (IV)

[Where,
R 6b ′ and R 7b ′ are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group,
R 6b ′ and R 7b ′ may combine with each other to form — (CH 2 ) n′— (wherein n ′ represents an integer of 1 to 3);
Ar is
(1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed),
(2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent)
Indicates. The compound of Claim 11 represented by these.
Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
The compound according to claim 11, which is (2) indanyl which may have a substituent, or (3) naphthyl which may have a substituent.
R 6b ′ and R 7b ′ are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group,
R 6b ′ and R 7b ′ may combine with each other to form — (CH 2 ) n′— (wherein n ′ represents an integer of 1 to 3);
Ar is
(1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups,
13. The compound according to claim 12, which is (2) indanyl optionally substituted with an oxo group, or (3) naphthyl.
Ring A is an 8-membered ring (m = 2, n = 1)
Ar is (1) phenyl substituted with a halogen atom, or (2) naphthyl which may have a substituent, and
The compound according to claim 1, wherein L is a bond.
Ring A is an 8-membered ring (m = 3, n = 0),
Ar is phenyl substituted with a halogen atom, and
The compound according to claim 1, wherein L is a bond.
1- (3,4-dichlorophenyl) -1,4-diazepan-2-one,
1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one,
1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one,
1- (3,4-dichlorophenyl) -3-propyl-1,4-diazepan-2-one,
1-naphthalen-2-yl-1,4-diazepan-2-one,
3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one,
3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one, or a salt thereof.
A prodrug of the compound according to claim 1.
A pharmaceutical comprising the compound according to claim 1 or a salt thereof or a prodrug thereof.
The medicament according to claim 19, which is a serotonin reuptake inhibitor and / or a norepinephrine reuptake inhibitor and / or a dopamine reuptake inhibitor.
The medicament according to claim 19, which is a prophylactic or therapeutic drug for diseases caused by serotonin, norepinephrine, or dopamine.
The medicament according to claim 19, which is a prophylactic or therapeutic agent for depression, anxiety, attention deficit hyperactivity disorder, or stress urinary incontinence.
A serotonin reuptake inhibition method and / or a norepinephrine reuptake inhibition method and / or a dopamine reuptake inhibition, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof or a prodrug thereof to a mammal. Method.
A method for preventing or treating a disease caused by serotonin, norepinephrine, or dopamine, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof or a prodrug thereof to a mammal.
A depression, anxiety, attention deficit hyperactivity disorder or stress urine in the mammal, characterized by administering an effective amount of the compound according to claim 1 or a salt thereof or a prodrug thereof to the mammal. How to prevent or treat incontinence.
Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a serotonin reuptake inhibitor and / or a norepinephrine reuptake inhibitor and / or a dopamine reuptake inhibitor.
Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a prophylactic or therapeutic agent for a disease caused by serotonin, norepinephrine or dopamine.
Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for the manufacture of a prophylactic or therapeutic drug for depression, anxiety, attention deficit hyperactivity disorder or stress urinary incontinence.