JP5156806B2 - Medicaments comprising amide derivatives - Google Patents

Description

The present invention relates to a medicament comprising a novel amide derivative having an action (agonist) action on serotonin 4 receptor (hereinafter sometimes referred to as 5-HT ₄ receptor), which is useful as a gastrointestinal motility promoter or the like.

From the study of the mechanism of action of metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxybenzamide], a gastrointestinal motility promoter or a gastrointestinal function-improving drug widely used in clinical practice, serotonin A 5-HT ₄ receptor, a subtype of receptor, has been found. Then, benzamide such as metoclopramide and cisapride {cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide} prokinetic action of derivatives be caused by stimulating 5-HT ₄ receptor was revealed (see non-Patent documents 1 and 2). Furthermore, tegaserod [2- (5-methoxy-1H-indol-3-ylmethylene) -N-pentylhydrazine carboxyimidamide], which is a 5-HT ₄ receptor agonist, is chronic constipation and constipation type irritable bowel syndrome in the United States and Europe. Has been approved, and the effect of promoting defecation by stimulation of 5-HT ₄ receptor has also been confirmed.
However, metoclopramide has a dopamine D ₂ receptor antagonism that contributes to side effects in addition to the 5-HT ₄ receptor agonistic action, and central suppression based on this action appears, causing a clinical problem. Yes. Further, cisapride was discontinued due to central side-effects based on dopamine D ₂ receptor antagonism and side effects on the heart (serious ventricular arrhythmia, QT prolongation). Tegaserod has also been temporarily withdrawn from the US market due to an increased risk of severe ischemic cardiovascular side effects.
In recent years, the number of patients suffering from gastrointestinal system indefinite complaints tends to increase. Therefore, development of an excellent gastrointestinal motility promoter or gastrointestinal function improving drug with fewer side effects is strongly desired in clinical practice.
As a compound having a morpholine ring or a 1,4-hexahydrooxazepine ring, a morpholine derivative having a benzyl group or the like bonded to the 4-position nitrogen atom selectively has an agonistic action on the 5-HT ₄ receptor. It is known that it is useful as a gastrointestinal motility promoter or a gastrointestinal function improving drug (see Patent Document 1).
In addition, N-carboxyalkylmorpholine derivatives and the like have a gastrointestinal function enhancing action and an antiemetic action, and are known to be useful as a therapeutic agent for digestive system diseases (see Patent Document 2).
Furthermore, it is known that N-substituted morpholine derivatives and the like have gastrointestinal motility stimulation and promote gastric emptying (see Patent Document 3).

  However, no compound has been reported in which a saturated nitrogen-containing heterocycle is bonded to the 4-position nitrogen atom of the morpholine ring or 1,4-hexahydrooxazepine ring via methylene.

J. Pharmacol. Exp. Ther., (1990) 252, p1378 J. Pharmacol. Exp. Ther., (1991) 257, p781

European Patent Application No. 243959 International Publication No. 92/14705 Pamphlet International Publication No. 96/37486 Pamphlet

  The problem to be solved by the present invention is to provide a serotonin 4 receptor agonist useful as a gastrointestinal motility promoter or the like.

As a result of intensive studies, the present inventors have determined that the amine moiety is a morpholine ring or a 1,4-hexahydrooxazepine ring, and a nitrogen-containing heterocycle saturated via a methylene chain at the 4-position of each ring. It has been found that a group of benzamide derivatives possessed by the present invention is useful as a gastrointestinal motility promoting agent or a gastrointestinal function improving agent having an excellent agonist activity with respect to the 5-HT ₄ receptor and a strong defecation promoting action. completed.

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

［式中、Ａｒは下記式（Ａｒ−１）又は式（Ａｒ−２）：

[In the formula, Ar represents the following formula (Ar-1) or formula (Ar-2):

（式中、Ｒ^１は水素原子又はハロゲン原子を意味し、
Ｒ^２は水素原子又はアルキル基を意味し、
Ｒ^３は水素原子、アルキル基又はアルカノイル基を意味し、
Ｒ^４は水素原子、アルキル基、アルケニル基又はアルキニル基を意味し、
Ｘは窒素原子又はＣＨを意味し、
Ｒ^５及びＲ^６は同一又は異なって、水素原子又はアルキル基を意味し、
ｈは１、２又は３を意味する。）
を意味し、
ｌは１、２又は３を意味し、
ｍは１又は２を意味し、
ｎは０、１又は２を意味し、
ｏは０〜３の整数を意味し、但しｎ及びｏは同時に０ではなく、
Ａは以下の（１）〜（６）の基：
（１）水素原子、シアノ基又はホルミル基；
（２）置換されていてもよいアルキル基、置換されていてもよいアルケニル基又は置換されていてもよいアルキニル基；
（３）−ＣＯＲ^７、−ＣＳＲ^７、−ＣＯＯＲ^７、−ＳＯ_２Ｒ^７又は−ＣＯ−ＣＯＲ^７
（Ｒ^７は置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいシクロアルキル基、置換されていてもよいシクロアルケニル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよい単環性もしくは２環性の非芳香族性の不飽和へテロ環基（当該へテロ環基は環上の炭素原子で結合している）、又は置換されていてもよい単環性もしくは２環性の飽和へテロ環基（当該へテロ環基は環上の炭素原子で結合している）を意味する）；
（４）−ＣＯ−ＣＯＯＲ^８
（Ｒ^８はアルキル基を意味する）；
（５）−ＣＯＮＲ^９−ＯＲ^１０
（Ｒ^９及びＲ^１０は同一もしくは異なって水素原子、アルキル基、アルケニル基又はアルキニル基を意味する）；及び
（６）−ＣＯＮＲ^１２Ｒ^１３、−ＣＳＮＲ^１２Ｒ^１３又は−ＳＯ_２ＮＲ^１２Ｒ^１３
（Ｒ^１２は水素原子又は前記Ｒ^７における任意の基を意味し、Ｒ^１３は水素原子、アルキル基、アルケニル基又はアルキニル基を意味するか；或いはＲ^１２及びＲ^１３は結合して、隣接する窒素原子とともに、１〜３個の窒素原子、１個の酸素原子及び１個の硫黄原子から選択される１〜３個のヘテロ原子を含む、置換されていてもよい飽和もしくは不飽和の単環性含窒素ヘテロ環基を形成していてもよい）からなる群から選択される基を意味し；
但し、Ａ又はＲ^７におけるアルキル基、アルケニル基又はアルキニル基が置換されている場合、該アルキル基、アルケニル基及びアルキニル基は以下の（ａ）〜（ｄ）の基：
（ａ）ハロゲン原子、シアノ基、ニトロ基、ヒドロキシ基、カルボキシ基、アミノ基、カルバモイル基又はトリフルオロメチル基；
（ｂ）−ＯＲ^１４、−ＳＲ^１４、−ＣＯＲ^１４、−ＣＯＯＲ^１４、−Ｏ−ＣＯＲ^１４、−ＮＲ^１５−ＣＯＲ^１４、−ＮＲ^１５−ＣＯＯＲ^１４、−ＮＲ^１５−ＳＯ_２Ｒ^１４、−ＮＲ^１５Ｒ^１６又は−ＣＯＮＲ^１５Ｒ^１６
（Ｒ^１４はそれぞれ以下の基：
（ｂ’）ハロゲン原子、ヒドロキシ基、カルボキシ基、アミノ基、カルバモイル基、−ＯＲ^１７、−ＣＯＯＲ^１７、−ＮＲ^１８−ＣＯＲ^１７、−ＮＲ^１８−ＣＯＯＲ^１７、−ＮＲ^１８−ＳＯ_２Ｒ^１７、−ＮＲ^１８Ｒ^１９又は−ＣＯＮＲ^１８Ｒ^１９（ここに、Ｒ^１７はアルキル基、アルケニル基又はアルキニル基を表し、Ｒ^１８は水素原子又はアルキル基を表し、Ｒ^１９はアルキル基、アルケニル基又はアルキニル基を表すか、或いはＲ^１８及びＲ^１９は結合して、隣接する窒素原子とともに、１〜３個の窒素原子、１個の酸素原子及び１個の硫黄原子から選択される１〜３個のヘテロ原子を含む、置換されていてもよい飽和もしくは不飽和の単環性含窒素ヘテロ環基を形成していてもよい）から選択される、同一もしくは異なる１〜５個の置換基で置換されていてもよいアルキル基、アルケニル基又はアルキニル基を表し、
Ｒ^１５はそれぞれ水素原子、又は上記（ｂ’）から選択される同一もしくは異なる１〜５個の置換基で置換されていてもよいアルキル基、アルケニル基又はアルキニル基を表し、
Ｒ^１６はそれぞれ上記（ｂ’）から選択される同一もしくは異なる１〜５個の置換基で置換されていてもよいアルキル基、アルケニル基又はアルキニル基を表すか、或いはＲ^１５及びＲ^１６は結合して、隣接する窒素原子とともに、１〜３個の窒素原子、１個の酸素原子及び１個の硫黄原子から選択される１〜３個のヘテロ原子を含む、置換されていてもよい飽和もしくは不飽和の単環性含窒素ヘテロ環基を形成していてもよい）；
（ｃ）−Ｒ^２０、−ＯＲ^２０又は−ＮＲ^１５−ＣＯＲ^２０
（Ｒ^１５は前記と同義であり、Ｒ^２０は置換されていてもよいシクロアルキル基、置換されていてもよいシクロアルケニル基、置換されていてもよい単環性もしくは２環性の非芳香族性の不飽和へテロ環基、置換されていてもよい単環性もしくは２環性の飽和へテロ環基を表す）；及び
（ｄ）−Ｒ^２１、−ＯＲ^２１、−ＣＯＲ^２１、−ＳＲ^２１、−ＳＯ_２Ｒ^２１又は−ＮＲ^１５−ＣＯＲ^２１
（Ｒ^１５は前記と同義であり、Ｒ^２１は置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表す）
からなる群から選択される、同一もしくは異なる１〜５個の置換基で置換されていてもよく；
シクロアルキル基又はシクロアルケニル基が置換されている場合、該シクロアルキル基及びシクロアルケニル基は以下の（ｅ）の基：
（ｅ）ハロゲン原子、ヒドロキシ基、アルキル基、アルコキシ基又はオキソ基
から選択される、同一もしくは異なる１〜５個の置換基で置換されていてもよく；
単環性もしくは２環性の非芳香族性の不飽和へテロ環基、単環性もしくは２環性の飽和へテロ環基、又は飽和もしくは不飽和の単環性含窒素ヘテロ環基において、環上の炭素原子が置換されている場合、該炭素原子は上記（ｅ）から選択される同一もしくは異なる１〜５個の置換基で置換されていてもよく、
環上の窒素原子が置換されている場合、該窒素原子は以下の（ｆ）の基：
（ｆ）アルキル基、アルカノイル基、アルコキシカルボニル基又はアルキルスルホニル基
で置換されていてもよく；
アリール基又はヘテロアリール基が置換されている場合、該アリール基及びヘテロアリール基は以下の（ｇ）〜（ｉ）の基：
（ｇ）ハロゲン原子、シアノ基、ニトロ基、ヒドロキシ基、カルボキシ基、ハロアルキル基、ハロアルコキシ基、アミノ基、カルバモイル基、−（ＣＨ_２）_２−Ｏ−又は−Ｏ−ＣＨ_２−Ｏ−；
（ｈ）−Ｒ^１４、−ＯＲ^１４、−ＳＲ^１４、−ＣＯＲ^１４、−ＣＯＯＲ^１４、−Ｏ−ＣＯＲ^１４、−ＮＲ^１５−ＣＯＲ^１４、−ＮＲ^１５−ＣＯＯＲ^１４、−ＮＲ^１５−ＳＯ_２Ｒ^１４、−ＮＲ^１５Ｒ^１６又は−ＣＯＮＲ^１５Ｒ^１６
（Ｒ^１４、Ｒ^１５及びＲ^１６は前記と同義である）；及び
（ｉ）フェニル基又はフェノキシ基（ここに、フェニル基及びフェノキシ基はハロゲン原子、ヒドロキシ基、アルキル基及びアルコキシ基からなる群から選択される１〜５個の置換基で置換されていてもよい）
からなる群から選択される、同一もしくは異なる１〜５個の置換基で置換されていてもよい］
で表される化合物又はその薬学上許容される塩からなる医薬。

(Wherein R ¹ represents a hydrogen atom or a halogen atom,
R ² represents a hydrogen atom or an alkyl group,
R ³ represents a hydrogen atom, an alkyl group or an alkanoyl group,
R ⁴ represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group,
X represents a nitrogen atom or CH;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or an alkyl group;
h means 1, 2 or 3. )
Means
l means 1, 2 or 3;
m means 1 or 2,
n means 0, 1 or 2;
o means an integer from 0 to 3, provided that n and o are not 0 at the same time,
A represents the following groups (1) to (6):
(1) hydrogen atom, cyano group or formyl group;
(2) an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group;
^{(3) -COR 7, -CSR 7} , -COOR 7, -SO 2 R 7 or -CO-COR ⁷
(R ⁷ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted cycloalkenyl group. An optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic ring) Group is bonded at a carbon atom on the ring), or an optionally substituted monocyclic or bicyclic saturated heterocyclic group (the heterocyclic group is bonded at a carbon atom on the ring) Means));
(4) -CO-COOR ⁸
(R ⁸ means an alkyl group);
(5) -CONR ⁹ -OR ¹⁰
(R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group); and (6) -CONR ¹² R ¹³ , -CSNR ¹² R ¹³ or -SO ₂ NR ¹² R ¹³
(R ¹² represents a hydrogen atom or an arbitrary group in R ⁷ and R ¹³ represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; or R ¹² and R ¹³ are adjacent to each other. Optionally substituted saturated or unsaturated monocyclic ring containing 1 to 3 heteroatoms selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom together with nitrogen atom A group selected from the group consisting of an optionally nitrogen-containing heterocyclic group);
However, when the alkyl group, alkenyl group or alkynyl group in A or R ⁷ is substituted, the alkyl group, alkenyl group and alkynyl group are the following groups (a) to (d):
(A) a halogen atom, cyano group, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group or trifluoromethyl group;
^{(B) -OR 14, -SR 14} , -COR 14, -COOR 14, -O-COR 14, -NR 15 -COR 14, -NR 15 -COOR 14, -NR 15 -SO 2 R 14, -NR ¹⁵ R ¹⁶ or ^-CONR 15 ^{R 16}
(R ¹⁴ is the following groups:
(B ′) a halogen atom, a hydroxy group, a carboxy group, an amino group, a carbamoyl group, —OR ¹⁷ , —COOR ¹⁷ , —NR ¹⁸ —COR ¹⁷ , —NR ¹⁸ —COOR ¹⁷ , —NR ¹⁸ —SO ₂ R ¹⁷ , —NR ¹⁸ R ¹⁹ or —CONR ¹⁸ R ¹⁹ (wherein R ¹⁷ represents an alkyl group, an alkenyl group, or an alkynyl group, R ¹⁸ represents a hydrogen atom or an alkyl group, and R ¹⁹ represents an alkyl group, an alkenyl group, or an alkynyl group) Represents a group, or R ¹⁸ and R ¹⁹ are bonded together with an adjacent nitrogen atom to 1 to 3 selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. Selected from the group consisting of heteroatoms and optionally substituted saturated or unsaturated monocyclic nitrogen-containing heterocyclic groups), Represents an alkyl group, an alkenyl group or an alkynyl group which may be substituted with different 1 to 5 substituents;
R ¹⁵ represents a hydrogen atom or an alkyl group, an alkenyl group or an alkynyl group which may be substituted with the same or different 1 to 5 substituents selected from the above (b ′);
R ¹⁶ represents an alkyl group, an alkenyl group or an alkynyl group each optionally substituted by the same or different 1 to 5 substituents selected from the above (b ′), or R ¹⁵ and R ¹⁶ are a bond And optionally substituted with 1 to 3 heteroatoms selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom together with adjacent nitrogen atoms, or An unsaturated monocyclic nitrogen-containing heterocyclic group may be formed);
^(C) -R ^{20, -OR} 20 or ^-NR 15 -COR ²⁰
(R ¹⁵ is as defined above, and R ²⁰ is an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted monocyclic or bicyclic non-aromatic group. sexual heterocyclic group unsaturated, monocyclic may be substituted or the bicyclic saturated represents a heterocyclic group); and ^{(d) -R 21, -OR 21} , -COR 21, -SR ²¹ , —SO ₂ R ²¹ or —NR ¹⁵ —COR ²¹
(R ¹⁵ is as defined above, and R ²¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group)
Optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of:
When a cycloalkyl group or a cycloalkenyl group is substituted, the cycloalkyl group and the cycloalkenyl group are the following groups (e):
(E) optionally substituted with 1 to 5 substituents selected from halogen atom, hydroxy group, alkyl group, alkoxy group or oxo group;
In monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, monocyclic or bicyclic saturated heterocyclic group, or saturated or unsaturated monocyclic nitrogen-containing heterocyclic group, When a carbon atom on the ring is substituted, the carbon atom may be substituted with the same or different 1 to 5 substituents selected from (e) above,
When a nitrogen atom on the ring is substituted, the nitrogen atom is a group of the following (f):
(F) optionally substituted with an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group;
When the aryl group or heteroaryl group is substituted, the aryl group and heteroaryl group are the following groups (g) to (i):
(G) a halogen atom, a cyano group, a nitro group, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, — (CH ₂ ) ₂ —O— or —O—CH ₂ —O—;
^{(H) -R 14, -OR 14} , -SR 14, -COR 14, -COOR 14, -O-COR 14, -NR 15 -COR 14, -NR 15 -COOR 14, -NR 15 -SO 2 R ^{14, -NR} 15 ^{R 16} or ^-CONR 15 ^{R 16}
(R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above); and (i) a phenyl group or a phenoxy group (wherein the phenyl group and the phenoxy group are a group consisting of a halogen atom, a hydroxy group, an alkyl group and an alkoxy group) Optionally substituted with 1 to 5 substituents selected from
Which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of
Or a pharmaceutically acceptable salt thereof.

[2] R ¹ is meant chlorine atom, a bromine atom or an iodine atom, R ⁴ is means an alkyl group, R ⁵ and R ⁶ refer to the same or different and each represents a hydrogen atom or a methyl group, [1] Or a pharmaceutically acceptable salt thereof.

[3] A medicament comprising the compound according to [2] or a pharmaceutically acceptable salt thereof, wherein R ⁴ represents a methyl group, an ethyl group, a propyl group or an isopropyl group.

[4] A pharmaceutical comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein R ² represents a hydrogen atom and R ³ represents a hydrogen atom or a methyl group.

[5] A medicament comprising the compound according to [4] or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ represent a hydrogen atom.

[6] Any one of [1] to [5], wherein l represents 1 or 2, m represents 1 or 2, n represents 1 or 2, and o represents 1 or 2. A pharmaceutical comprising the described compound or a pharmaceutically acceptable salt thereof.

[7] R ¹ represents a chlorine atom or a bromine atom, R ² and R ³ represent a hydrogen atom, R ⁴ represents a methyl group or an ethyl group, and R ⁵ and R ⁶ represent a hydrogen atom. H represents 1; l represents 1; m represents 1; n represents 2; o represents 1 or a pharmaceutically acceptable compound thereof A medicine consisting of salt.

[8] A is (1-1) a hydrogen atom, a cyano group or a formyl group; or (2-1) an alkyl group or an alkyl group substituted with a phenyl group (wherein the phenyl group is a halogen atom, a hydroxy group, (It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of alkyl group, alkoxy group, alkanoyl group, haloalkyl group, haloalkoxy group, amino group and carboxy group)
A pharmaceutical comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof.

[9] A is (3-1) -COR ^7a , -COOR ^7a , -SO ₂ R ^7a or -CO-COR ^7a
[Wherein R ^7a is an ^optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, and optionally substituted. A cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, or Means a monocyclic or bicyclic saturated heterocyclic group which may be substituted;
However, when the alkyl group, alkenyl group or alkynyl group in R ^7a is substituted, the alkyl group, alkenyl group and alkynyl group are the following groups (a-1) to (d-1):
(A-1) a halogen atom, a cyano group, a hydroxy group, a carboxy group, an amino group, or a carbamoyl group;
(B-1) -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a , -NR ^15a R ^16a or -CONR ^15a R ^16a
(R ^14a represents an alkyl group, R ^15a represents a hydrogen atom or an alkyl group, R ^16a represents an alkyl group, or R ^15a and R ^16a are bonded together with an adjacent nitrogen atom to form 1 to 3 May form a saturated monocyclic nitrogen-containing heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom on the nitrogen-containing heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group);
(C-1) a cycloalkyl group (the cycloalkyl group may be substituted with 1 to 5 different or different substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group), a single ring Or a bicyclic saturated heterocyclic group (the carbon atom on the saturated heterocyclic group is selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group, and may be the same or different 1 to 5 substituents) And a nitrogen atom on the saturated heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group); and (d-1) -R ^21a or -NR ^15a -COR ^21a
(R ^15a is as defined above, R ^21a represents an aryl group or heteroaryl group, and the aryl group and heteroaryl group are a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, and a carbamoyl group. Group, cyano group, —R ^14a , —OR ^14a , —COR ^14a , —NR ^15a —COR ^14a or —NR ^15a R ^16a (wherein R ^14a , R ^15a and R ^16a are as defined above) Or may be substituted with 1 to 5 different substituents)
Optionally substituted with 1 to 5 substituents selected from the group consisting of:
When the cycloalkyl group or cycloalkenyl group in R ^7a is substituted, the cycloalkyl group and cycloalkenyl group are the following groups (e-1):
(E-1) may be substituted with 1 to 5 substituents which are the same or different selected from a halogen atom, a hydroxy group, an alkyl group or an alkoxy group;
In the ^optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, and optionally substituted monocyclic or bicyclic saturated heterocyclic group In the case where a carbon atom on the ring is substituted, the carbon atom may be substituted with the same or different 1 to 5 substituents selected from the above (e-1), and a nitrogen atom on the ring Is substituted, the nitrogen atom is the following group (f-1):
(F-1) may be substituted with 1 to 5 substituents which are the same or different selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group;
When the aryl group or heteroaryl group in R ^7a is substituted, the aryl group and heteroaryl group are the following groups:
(G-1) a halogen atom, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group, haloalkyl group, haloalkoxy group or cyano group;
(H-1) -R ^14a , -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a or -NR ^15a R ^16a
(R ^14a , R ^15a and R ^16a are as defined above); and (i-1) a phenyl group or a phenoxy group (wherein the phenyl group and the phenoxy group are a halogen atom, a hydroxy group, an alkyl group and an alkoxy group) Optionally substituted with 1 to 5 substituents selected from the group consisting of:
It may be substituted with 1 to 5 substituents which are the same or different selected from the group consisting of]
A pharmaceutical comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof.

[10] A is (3-2) -SO ₂ R ^7b
[Wherein R ^7b means an alkyl group, an alkyl group substituted with an optionally substituted phenyl group, or an optionally substituted phenyl group, provided that when the phenyl group is substituted, The phenyl group is a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, -R ^14b , -OR ^14b , -COR ^14b , -COOR ^14b and -O-COR ^14b (R ^14b is Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
A pharmaceutical comprising the compound according to [9] or a pharmaceutically acceptable salt thereof.

[11] A pharmaceutical comprising the compound according to [10] or a pharmaceutically acceptable salt thereof, wherein R ^7b is an alkyl group having 1 to 3 carbon atoms.

[12] A is (3-3) -COR ^7c or -CO-COR ^7c
[Wherein R ^7c means an ^optionally substituted alkyl group or an optionally substituted alkenyl group;
However, when the alkyl group or alkenyl group in R ^7c is substituted, the alkyl group and alkenyl group are the following groups (a-2) to (d-2):
(A-2) a hydroxy group, a halogen atom, a carbamoyl group or a cyano group;
(B-2) -OR ^14c , -COR ^14c , -COOR ^14c , -O-COR ^14c , -NR ^15c -COR ^14c , -NR ^15c R ^16c or -CONR ^15c R ^16c (here, R ^14c and R ^16c Represent the same or different alkyl groups, and R ^15c represents a hydrogen atom or an alkyl group);
(C-2) a cycloalkyl group or a monocyclic or bicyclic saturated heterocyclic group (wherein the nitrogen atom on the monocyclic or bicyclic saturated heterocyclic group is an alkyl group or an alkanoyl group) Or (d-2) -R ^21c or -NR ^15c -COR ^21c (where R ^15c is as defined above, and R ^21c is an aryl group or heteroaryl. The aryl group and heteroaryl group are a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, a cyano group, -R ^14c , -OR ^14c and -COR ^14c (R ^14c is as defined above) and may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
May be substituted with 1 to 5 substituents selected from the group consisting of]
A pharmaceutical comprising the compound according to [9] or a pharmaceutically acceptable salt thereof.

[13] R ^7c is a group of the following (a-3) and (b-3):
(A-3) hydroxy group, a carbamoyl group or a cyano group; and ^{(b-3) -OR 14d,} -COR 14d, -COOR 14d, -O-COR 14d, -NR 15d -COR 14d, -NR 15d R 16d Or -CONR ^15d R ^16d (wherein R ^14d and R ^16d represent the same or different alkyl groups having 1 to 3 carbon atoms, and R ^15d represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms)
An alkyl group having 1 to 3 carbon atoms which may be substituted with a group selected from the group consisting of: or a group selected from the group consisting of (a-3) and (b-3) A pharmaceutical comprising the compound according to [12] or a pharmaceutically acceptable salt thereof, which is an alkenyl group having 2 to 3 carbon atoms.

[14] A is (3-4) -COR ^7d
[Wherein R ^7d is an ^optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocycle; Means a cyclic group or an optionally substituted monocyclic saturated heterocyclic group;
However, when the carbon atom on the ring of these groups is substituted, the carbon atom is substituted with the same or different 1 to 5 substituents selected from a halogen atom, a hydroxy group, an alkyl group or an alkoxy group. And when the nitrogen atom on the ring of these groups is substituted, the nitrogen atom may be substituted with an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group]
A pharmaceutical comprising the compound according to [9] or a pharmaceutically acceptable salt thereof.

[15] A is (3-5) -COR ^7e
[Wherein R ^7e means an ^optionally substituted aryl group or an optionally substituted heteroaryl group;
However, when the aryl group or heteroaryl group is substituted, the aryl group and heteroaryl group are the following groups (g-2) to (i-2):
(G-2) a halogen atom, an amino group, a carbamoyl group or a cyano group;
(H-2) -R ^14e , -OR ^14e , -O-COR ^14e , -NR ^15e -COR ^14e , -NR ^15e -COOR ^14e or -NR ^15e R ^16e (where R ^14e and R ^16e are the same or R ^15e represents a hydrogen atom or an alkyl group); and (i-2) is substituted with 1 to 5 identical or different substituents selected from the group consisting of a phenyl group or a phenoxy group. May be]
A pharmaceutical comprising the compound according to [9] or a pharmaceutically acceptable salt thereof.

[16] A is (3-6) -COOR ^7f
[Wherein R ^7f means an alkyl group, an alkenyl group or an ^optionally substituted phenyl group;
However, if the phenyl group is substituted, the phenyl group a halogen atom, a nitro group, hydroxy group, a haloalkyl group, means a haloalkoxy ^group, -R ^{14f, -OR 14f} and ^-COR 14f ^{(R 14f} is an alkyl group And may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
A pharmaceutical comprising the compound according to [9] or a pharmaceutically acceptable salt thereof.

[17] A medicament comprising the compound according to [16] or a pharmaceutically acceptable salt thereof, wherein R ^7f is an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 2 to 3 carbon atoms.

[18] A is (6-1) -CONR ^12a R ^13a , -CSNR ^12a R ^13a or -SO ₂ NR ^12a R ^13a
[Wherein R ^12a is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted with an alkoxycarbonyl group having 2 to 3 carbon atoms, This means an alkyl group having 1 to 3 carbon atoms substituted with an optionally substituted phenyl group, or an optionally substituted phenyl group, provided that when the phenyl group is substituted, the phenyl group is a halogen atom. atom, a nitro group, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl ^{group, -R 14a, -OR 14a, -COR} 14a, -COOR 14a and ^{-O-COR 14a (R} 14a is alkyl Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
R ^13a means a hydrogen atom or an alkyl group, or R ^12a and R ^13a are bonded together with adjacent nitrogen atoms, together with 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. A saturated or unsaturated 4- to 6-membered monocyclic nitrogen-containing heterocyclic group optionally containing 1 to 3 heteroatoms selected from the group consisting of The nitrogen atom on the cyclic nitrogen-containing heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group]
A pharmaceutical comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof.

[19] Whether R ^12a and R ^13a represent the same or different alkyl groups having 1 to 3 carbon atoms;
R ^12a is an ^optionally substituted phenyl group (wherein the phenyl group is 1 to 2 halogen atoms, hydroxy group, carboxy group, haloalkyl group, amino group, carbamoyl group, -R ^14a , -OR ^14a ,- COR ^14a , —COOR ^14a or —O—COR ^14a (which may be substituted with R ^14a means an alkyl group), and R ^13a means a hydrogen atom; or R ^12a and R ^13a Are bound to the adjacent nitrogen atom to form a pyrrolidinyl group, piperidinyl group, morpholinyl group or imidazolyl group, and the pharmaceutical comprising the compound according to [18] or a pharmaceutically acceptable salt thereof.

[20] A is (5-1) -CONR ^9a -OR ^10a
[Wherein R ^9a and R ^10a represent the same or different alkyl groups]
A pharmaceutical comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof.

[21] A pharmaceutical comprising the compound according to [1] or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
4-amino-N-[{4-[(1- (1-azetidinecarbonyl) -4-piperidinyl) methyl)]-2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-pyrrolidinecarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (1-pyrrolidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylthiocarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylsulfamoyl-4-piperidinyl) methyl) -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylsulfamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-isopropoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-diethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-diisopropylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
6-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxypyridine-3-carboxamide;
N-[{4-[(1-allylmethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-pyrrolidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan- 7-carboxamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-ethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-phenylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methoxyphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-trifluoromethylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1- (3-acetylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3,5-dimethylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3,4-dichlorophenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-N-[{4-[(1-benzylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methylbenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxybenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (2,4-dichlorobenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-phenethyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
Amino-5-chloro-2-ethoxy-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (1-propoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1-allyloxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-isobutoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-phenoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methoxyphenoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-cyclopentenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (2-cyclopropylvinylcarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-Amino-5-chloro-2-ethoxy-N-[{4-[(1- [2- (furan-2-yl) vinylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-Amino-5-chloro-2-ethoxy-N-[{4-[(1- [2- (thiophen-2-yl) vinylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-amino-N-[{4-[(1- (3-butenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (5-hexenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4-[(1- (1,3-butadienecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (1,5-hexadienecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4-[(1- [1- (1-propyne) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-methoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-N-[{4-[(1-benzoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3-fluorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (3-fluorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (4-chlorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-chlorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-N-[{4-[(1- (3-bromobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (4-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (4-ethylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-N-[{4-[(1- (tert-butylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3-hydroxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-hydroxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
N-[{4-[(1- (2-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
N-[{4-[(1- (2-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
N-[{4-[(1- (3-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
N-[{4-[(1- (4-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (4-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-phenoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (3-dimethylaminobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-dimethylaminobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxycarbonylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-phenylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4- [1 (-(4-amino-3-chlorophenylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (2-furancarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-imidazolecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-Amino-5-chloro-N-[{4-[(1-[(1,2-dihydrobenzofuran-7-yl) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2- Methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-[(5-methylthiophen-2-yl) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-[(S) -2-tetrahydrofurylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-methoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methoxyacetyl-4-piperidinyl) methyl) -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-Amino-5-chloro-2-methoxy-N-[{4-[(1- (4-piperidinylmethylcarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide.
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-N-[{4-[(1-benzoylaminoacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] 5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-cyanoacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-{[4-{[1- (3-methoxypropionyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-N-{[4-{[1-((S) -2-methoxypropionyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (3-tetrahydrofurylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-N-{[4-{[1- (1,2-dioxopropyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (4-oxazolylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (3-triazolylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-N-{[4-{[1- (4-cyanobenzoyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N-{[4-{[1- (3-tetrahydrofurylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2,3-dihydrobenzo [b] furan -7-carboxamide; and 4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] Furan-7-carboxamide.

[22] A pharmaceutical comprising the compound according to [21] or a pharmaceutically acceptable salt thereof, wherein the configuration at the 2-position carbon of the morpholinyl group is S.

[23] The medicament according to any one of [1] to [22], which is used for treatment and prevention of digestive system diseases, digestive system symptoms, neuropsychiatric diseases, or urinary system diseases.

[24] The medicament according to any one of [1] to [22], which is a serotonin 4 receptor agonist.

[25] The medicine according to any one of [1] to [22], which is a gastrointestinal motility promoter or a gastrointestinal function improving drug.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a medicament comprising a novel amide derivative having an action (agonist) action on serotonin 4 receptor, useful as a gastrointestinal motility promoting agent or a gastrointestinal function improving agent having a defecation promoting action or the like. Became.

Terms used in this specification are explained below.
“Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.
Examples of the “alkyl group” include linear or branched alkyl groups having 1 to 10 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like.

  Examples of the “alkenyl group” include linear or branched alkenyl groups having 2 to 10 carbon atoms, and the number of double bonds is not particularly limited, but preferably 1 to 2 double bonds. An alkenyl group containing Specifically, an ethenyl group, 1-propenyl group, 1-methylvinyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2- Methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3 -Butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentenyl group, 2-propyl-2-propenyl group, 1-ethyl -2-methyl-2-propenyl group, 1-methyl-3-methyl-3-butenyl group, 4-methyl-4-pentenyl group, 1,3-butadienyl group, 1,5-hexadienyl group, etc. That.

  Examples of the “alkynyl group” include linear or branched alkynyl groups having 2 to 10 carbon atoms, and the number of triple bonds is not particularly limited, but preferably 1 to 2 triple bonds. Preferably, an alkynyl group containing one triple bond is used. Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 2-butynyl group, 1-pentynyl group, 1-ethyl 2-propynyl group, 4-pentynyl group, 3-pentynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group etc. are mentioned.

Examples of the “alkoxy group” include linear or branched alkoxy groups having 1 to 10 carbon atoms, and specifically include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Group, sec-butoxy group, tert-butoxy group, pentyloxy group and hexyloxy group.
Examples of the “alkanoyl group” include linear or branched alkanoyl groups having 2 to 10 carbon atoms, and specifically include acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group, and pentanoyl. Group, 3-methylbutanoyl group, 2-methylbutanoyl group, hexanoyl group and the like.
Examples of the “alkoxycarbonyl group” include linear or branched alkoxycarbonyl groups having 2 to 10 carbon atoms, and specifically include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group. Group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like.
Examples of the “alkylsulfonyl group” include a linear or branched alkylsulfonyl group having 1 to 10 carbon atoms, and specifically include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group. Butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group and hexylsulfonyl group.
Examples of the “haloalkyl group” include a haloalkyl group substituted with 1 to 5 identical or different halogen atoms having 1 to 3 carbon atoms, specifically, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, Examples include a pentafluoroethyl group, a 2-fluoroethyl group, and a 2,2-difluoroethyl group.
Examples of the “haloalkoxy group” include haloalkoxy groups substituted with the same or different 1 to 5 halogen atoms having 1 to 3 carbon atoms, specifically, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group. Group, pentafluoroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group and the like.

Examples of the “cycloalkyl group” include a 3- to 7-membered cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
Examples of the “cycloalkenyl group” include a 5- to 7-membered cycloalkenyl group. Specifically, the 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group, 3- Examples include a cyclohexenyl group, a 4-cyclohexenyl group, a 1-cycloheptenyl group, a 3-cycloheptenyl group, a 4-cycloheptenyl group, and a 5-cycloheptenyl group.

  Examples of the “aryl group” include 6- to 10-membered monocyclic or bicyclic aryl groups, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  The “heteroaryl group” is a 5- to 10-membered monocyclic group containing 1 to 4 heteroatoms selected from 1 to 4 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom, or 2 And a cyclic heteroaryl group. Specific examples of monocyclic heteroaryl groups include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl Groups and the like. Examples of the bicyclic heteroaryl group include indolyl group, benzofuryl group, benzothienyl group, quinolinyl group, and benzoisoxazolyl group. The bonding position of the heteroaryl group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom.

The “monocyclic or bicyclic non-aromatic unsaturated heterocyclic group” is 1 to 4 selected from 1 to 4 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. 5- to 10-membered monocyclic or bicyclic non-aromatic unsaturated heterocyclic group containing 1 hetero atom.
Monocyclic non-aromatic unsaturated heterocyclic groups include 5-membered containing 1 double bond or 6- or 7-membered non-aromatic unsaturated containing 1 or 2 double bonds. Examples include a terocyclic group, and specific examples include a pyrrolinyl group and a 2,5-dihydrofuryl group.
The bicyclic non-aromatic unsaturated heterocyclic group is an 8- to 10-membered non-cyclic group obtained by substituting one or more double bonds of a bicyclic heteroaryl group with a single bond. An aromatic unsaturated heterocyclic group is exemplified, and specific examples include a 2,3-dihydrobenzofuryl group and a 2,3-dihydrobenzothienyl group.
The bonding position of the non-aromatic unsaturated heterocyclic group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom.

The “monocyclic or bicyclic saturated heterocyclic group” includes 1 to 4 heteroatoms selected from 1 to 4 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. A 5- to 10-membered monocyclic or bicyclic saturated heterocyclic group is exemplified. Examples of monocyclic saturated heterocyclic groups include 4- to 7-membered saturated heterocyclic groups, and specifically include azetidinyl groups, pyrrolidinyl groups, tetrahydrofuryl groups, tetrahydrothienyl groups, piperazinyl groups, piperidinyl groups. , Morpholinyl group, thiomorpholinyl group, tetrahydropyranyl group, hexahydroazepinyl group, 1,4-hexahydrooxazepinyl group, 1,4-hexahydrodiazepinyl group and the like. Examples of the bicyclic saturated heterocyclic group include 8- to 10-membered saturated heterocyclic groups, and specific examples include a quinuclidinyl group.
Any carbon atom on the saturated heterocyclic group may be substituted with an oxo group. Specific examples of the saturated heterocyclic group substituted with the oxo group include a 2-oxopyrrolidinyl group, 2 -Oxotetrahydrofuryl group etc. are mentioned.
The bonding position of the saturated heterocyclic group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom.

R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁸ and R ¹⁹ , R ^12a and R ^13a , and R ^15a and R ^16a are each bonded to form together with the adjacent nitrogen atom “saturated or unsaturated monocyclic The `` nitrogen-containing heterocyclic group '' includes 1 to 3 heteroatoms including at least one nitrogen atom selected from 1 to 3 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom. Examples thereof include a 4- to 7-membered saturated or unsaturated monocyclic nitrogen-containing heterocyclic group. Specific examples of the saturated monocyclic nitrogen-containing heterocyclic group include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, and a perhydroazepinyl group. Specific examples of the unsaturated monocyclic nitrogen-containing heterocyclic group include an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, and the like.

In the present specification, as the substituent in the case where the optionally substituted alkyl group, the optionally substituted alkenyl group and the optionally substituted alkynyl group are substituted, the above-mentioned (a) to ( the group d).
In the above (b), when R ¹⁴ , R ¹⁵ and R ¹⁶ represent an alkyl group, an alkenyl group or an alkynyl group, preferably an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or a carbon number Represents 2-3 alkynyl groups. When the alkyl group, alkenyl group and alkynyl group are substituted, the following groups:
Halogen atom, hydroxy group, carboxy group, an amino group, a carbamoyl ^{group, -OR 17, -COOR 17, -NR} 18 -COR 17, -NR 18 -COOR 17, -NR 18 -SO 2 R 17, -NR 18 R ¹⁹ , -CONR ¹⁸ R ¹⁹
(R ¹⁷ , R ¹⁸ and R ¹⁹ are as described above);
It may be substituted with 1 to 5 substituents selected from The alkyl group, alkenyl group and alkynyl group in R ¹⁷ , R ¹⁸ and R ¹⁹ are preferably an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms and an alkynyl group having 2 to 3 carbon atoms. Can be mentioned.

In the above (c), the cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. In (c), examples of the cycloalkenyl group include a cyclopentenyl group and a cyclohexenyl group, and specific examples include a 1-cyclopentenyl group and a 1-cyclohexenyl group. In (c), examples of the monocyclic or bicyclic non-aromatic unsaturated heterocyclic group include a pyrrolinyl group and a 2,5-dihydrofuryl group. In (c), examples of the monocyclic or bicyclic saturated heterocyclic group include a pyrrolidinyl group and a piperidinyl group, and specific examples include a 4-piperidinyl group.
In the above (d), the aryl group includes a phenyl group. In (d), examples of the heteroaryl group include a thienyl group, a furyl group, and a pyridyl group.

In the present specification, examples of the substituent when the optionally substituted cycloalkyl group and cycloalkenyl group are substituted include the groups described in the above (e).
In the present specification, in the optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group and monocyclic or bicyclic saturated heterocyclic group, When the carbon atom is substituted, examples of the substituent include the group described in the above (e).
In the above (e), the alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, and the alkoxy group is preferably an alkoxy group having 1 to 3 carbon atoms.

In each of the optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group and monocyclic or bicyclic saturated heterocyclic group, the nitrogen atom on the ring is substituted. In this case, examples of the substituent include the group described in the above (f).
In the above (f), the alkyl group is preferably an alkyl group having 1 to 4 carbon atoms. The alkanoyl group is preferably an alkanoyl group having 2 to 4 carbon atoms. The alkoxycarbonyl group is preferably an alkoxycarbonyl group having 2 to 4 carbon atoms. The alkylsulfonyl group is preferably an alkylsulfonyl group having 1 to 4 carbon atoms.

In the present specification, when the optionally substituted aryl group or heteroaryl group is substituted, examples of the substituent include the groups described in the above (g) to (i).
The preferable aspect of R <^14> , R <^15> and R < ¹⁶ > in said (h) is the same as said (b).

R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁸ and R ¹⁹ , R ^12a and R ^13a , and R ^15a and R ^16a are each bonded to form together with the adjacent nitrogen atom “saturated or unsaturated monocyclic Examples of the substituent when the carbon atom on the ring of the “nitrogen-containing heterocyclic group” is substituted include the group described in the above (e), preferably an alkyl group having 1 to 3 carbon atoms, Examples thereof include an alkoxy group having 1 to 3 carbon atoms or an oxo group. Examples of the substituent when the nitrogen atom on the ring of the “saturated or unsaturated monocyclic nitrogen-containing heterocyclic group” is substituted include the groups described in the above (f), preferably Includes an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms, or an alkoxycarbonyl group having 2 to 4 carbon atoms.

Below, the preferable aspect of the compound of Formula (1) is demonstrated in detail.
R ¹ preferably represents a halogen atom, and specifically includes a chlorine atom, a bromine atom or an iodine atom. More preferable R ¹ includes a chlorine atom or a bromine atom. Particularly preferred is a chlorine atom.
R ² preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom.
R ³ preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom or a methyl group. Particularly preferred R ³ is a hydrogen atom.
R ⁴ preferably represents an alkyl group having 1 to 4 carbon atoms, and more preferably represents a methyl group, an ethyl group, or an isopropyl group. Particularly preferred is a methyl group or an ethyl group.
R ⁵ and R ⁶ are preferably the same or different and each represents a hydrogen atom or a methyl group, and more preferably both represent a hydrogen atom.

l preferably represents 1 or 2, more preferably 1.
m preferably represents 1.
As a combination of n and o, specifically, when n is 0 and o is 1 to 3, n is 1 and o is 0 to 3, n is 2 and o is 0 to 3 Is represented. Preferably, when n represents 1 and o represents 0 to 2, n represents 2 and o represents 0 to 2. More preferably, n represents 2 and o represents 1.

Among the compounds of formula (1), R ¹ is a halogen atom in formula (Ar-1), R ² and R ³ are both hydrogen atoms, and R ⁴ has 1 to 3 carbon atoms. The compound which is an alkyl group is mentioned. Alternatively, in the formula (Ar-2), R ¹ is a halogen atom, R ² and R ³ are both hydrogen atoms, R ⁵ is a hydrogen atom, R ⁶ is a hydrogen atom or a methyl group, and h is 1 The compound which is is mentioned.
As a more preferred compound of the formula (1), a compound in which R ¹ is a chlorine atom or a bromine atom and R ⁴ is a methyl group, an ethyl group or an isopropyl group in the formula (Ar-1), or a compound of the formula (Ar— In 2), a compound in which R ¹ is a chlorine atom or a bromine atom, R ⁵ and R ⁶ are hydrogen atoms, and h is 1 is exemplified.

In Formula (1), A is
(1) hydrogen atom, cyano group, formyl group;
Is preferably a hydrogen atom or a cyano group.
In Formula (1), A is
(2) an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group;
In this case, the alkyl group includes an alkyl group having 1 to 4 carbon atoms, the alkenyl group includes an alkenyl group having 2 to 4 carbon atoms, and the alkynyl group includes an alkynyl group having 2 to 4 carbon atoms. . Examples of the substituent when these groups are substituted include the groups described in the above (a) to (d). Preferably an alkyl group having 1 to 4 carbon atoms or a phenyl group (the phenyl group is selected from a halogen atom, a hydroxy group, an alkyl group, an alkoxy group, an alkanoyl group, a haloalkyl group, a haloalkoxy group, an amino group and a carbamoyl group) And an alkyl group having 1 to 4 carbon atoms which may be substituted with the same or different 1 to 5 substituents.

In Formula (1), A is
^{(3) -COR 7, -CSR 7} , -COOR 7, -SO 2 R 7, -CO-COR 7
(R ⁷ is as described above);
If in represented by an alkyl group in R ^7, as preferred alkenyl and alkynyl groups, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, include an alkynyl group having 2 to 3 carbon atoms Examples of the substituent for the alkyl group, alkenyl group and alkynyl group include 1 to 5, preferably 1 to 3 substituents selected from the groups described in (a) to (d) above. It is done.
Of the substituents in (a) above, preferred are:
(A-1) halogen atom, hydroxy group, carboxy group, amino group, carbamoyl group, cyano group;
Can be mentioned.
Of the substituents in (b) above, preferred are:
(B-1) -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a , -NR ^15a R ^16a , -CONR ^15a R ^16a
(R ^14a , R ^15a and R ^16a are as defined above);
Can be mentioned.
Of the substituents in (c) above, preferred are:
(C-1) a cycloalkyl group (the cycloalkyl group may be substituted with 1 to 5 different or different substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group), a single ring Or a bicyclic saturated heterocyclic group (the carbon atom on the saturated heterocyclic group is the same or different from 1 to 5 substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group) A nitrogen atom on the saturated heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group);
Can be mentioned.
Of the substituents in (d) above, preferred are:
(D-1) -R ^21a , -NR ^15a -COR ^21a
(R ^15a is as defined above, and R ^21a represents an aryl group or a heteroaryl group. The groups in this group include a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, and a carbamoyl group. Group, cyano group, —R ^14a , —OR ^14a , —COR ^14a , —NR ^15a —COR ^14a , and —NR ^15a R ^16a (R ^14a , R ^15a and R ^16a are as defined above). Optionally substituted with the same or different 1 to 5 substituents);
Can be mentioned.

Preferred examples of the optionally substituted cycloalkyl group for R ⁷ include an optionally substituted cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group. Preferred examples of the optionally substituted cycloalkenyl group for R ⁷ include an optionally substituted cyclopentenyl group or cyclohexenyl group. Specific examples include a 1-cyclopentenyl group and a 1-cyclohexenyl group. Is mentioned. Examples of the substituent in the case where the cycloalkyl group and the cycloalkenyl group in R ⁷ are substituted include the substituents described in the above (e), preferably a halogen atom, a hydroxy group, an alkyl group, or an alkoxy group. Can be mentioned.
As is optionally Hajime Tamaki may also be monocyclic or bicyclic saturated with substitution at R ⁷ (heterocyclic group such are bonded at a carbon atom on the ring), preferably, a tetrahydrofuryl group, a pyrrolidinyl Group, piperidinyl group and the like. As non-aromatic unsaturated Hajime Tamaki which optionally may also be monocyclic or bicyclic and substituted in R ⁷ (heterocyclic group such are bonded at a carbon atom on the ring), preferably 2,3-dihydrobenzofuryl group or pyrrolinyl group. As the substituent when the monocyclic or bicyclic saturated heterocyclic group and the monocyclic or bicyclic non-aromatic unsaturated heterocyclic group are substituted on a carbon atom, And the substituent described in (e) above, preferably a halogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. When the monocyclic or bicyclic saturated heterocyclic group and the monocyclic or bicyclic non-aromatic unsaturated heterocyclic group are substituted on a nitrogen atom, And the substituent described in the above (f), preferably an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. An alkylsulfonyl group etc. are mentioned.
The aryl group which may be substituted in R ⁷ is preferably a phenyl group. Preferred examples of the heteroaryl group which may be substituted in R ⁷ include a thienyl group, a furyl group, a pyridyl group, and a pyrrolyl group. Examples of the substituent when the aryl group and heteroaryl group in R ⁷ are substituted include 1 to 5 substituents selected from the groups described in the above (g) to (i), Preferably, the following groups:
(G-1) halogen atom, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group, haloalkyl group, haloalkoxy group, cyano group;
(H-1) -R ^14a , -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a , -NR ^15a R ^16a
(R ^14a , R ^15a and R ^16a are as defined above);
(I-1) a phenyl group, a phenoxy group (a group in this group may be substituted with 1 to 5 substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group);
A group selected from:

In Formula (1), A is
When represented by (3-2) -SO ₂ -R ^7b (R ^7b is as defined above), R ^7b is preferably an alkyl group having 1 to 4 carbon atoms and an optionally substituted phenyl group. It represents a substituted alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group. When the phenyl group is substituted, a halogen atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms 1 to 5 substituents selected from a haloalkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a carboxy group, an amino group, and a carbamoyl group, preferably 1 to 3 substituents May be substituted.

In Formula (1), A is
(3-3) -COR ^7c , -CO-COR ^7c (R ^7c is as defined above), and R ^7c represents an optionally substituted alkyl group or an optionally substituted alkenyl group. The alkyl group is preferably an alkyl group having 1 to 3 carbon atoms. The alkenyl group is preferably an alkenyl group having 2 to 3 carbon atoms. Examples of the substituent of the alkyl group or alkenyl group include the following (a-2) to (d-2):
(A-2) hydroxy group, halogen atom, carbamoyl group, cyano group;
(B-2) -OR ^14c , -COR ^14c , -COOR ^14c , -O-COR ^14c , -NR ^15c -COR ^14c , -NR ^15c R ^16c , -CONR ^15c R ^16c
(R ^14c and R ^16c represent the same or different alkyl groups, and R ^15c represents a hydrogen atom or an alkyl group)
(C-2) a cycloalkyl group, a monocyclic or bicyclic saturated heterocyclic group (the nitrogen atom on the monocyclic or bicyclic saturated heterocyclic group is an alkyl group, an alkanoyl group or an alkoxy group) Optionally substituted with a carbonyl group);
(D-2) -R ^21c , -NR ^15c -COR ^21c
(R ^15c has the same meaning as described above, and R ^21c represents an aryl group or heteroaryl group. The groups in this group include a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, and a carbamoyl group. Substituted with 1 to 5 identical or different substituents selected from a group, a cyano group, —R ^14c , —OR ^14c , —COR ^14c , and —COOR ^{14c, where} R ^14c is as defined above. May be);
Can be mentioned.
In (b-2), preferably R ^14c and R ^16c represent the same or different alkyl groups having 1 to 3 carbon atoms, and R ^15c represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
In (c-2), the cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. The monocyclic or bicyclic saturated heterocyclic group is preferably a piperidinyl group or a pyrrolidinyl group, and the nitrogen atom on the monocyclic or bicyclic saturated heterocyclic group is preferably The alkyl group having 1 to 3 carbon atoms, the alkanoyl group having 2 to 3 carbon atoms, or the alkoxycarbonyl group having 2 to 3 carbon atoms may be substituted.
In (d-2), the aryl group includes a phenyl group. The heteroaryl group is preferably a thienyl group, a furyl group, or a pyridyl group. As a substituent of the aryl group or heteroaryl group, preferably a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, an amino group, a carbamoyl group, carbon Examples thereof include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkanoyl group having 2 to 3 carbon atoms, and an alkoxycarbonyl group having 2 to 3 carbon atoms.

When R ^7c represents an optionally substituted alkyl group or an optionally substituted alkenyl group, the alkyl group or the substituent of the alkenyl group is more preferably the following group:
(A-3) a hydroxy group, a carbamoyl group, a cyano group;
(B-3) -OR ^14d , -COR ^14d , -COOR ^14d , -O-COR ^14d , -NR ^15d -COR ^14d , -NR ^15d R ^16d , -CONR ^15d R ^16d
(R ^14d and R ^16d represent the same or different alkyl group having 1 to 3 carbon atoms, and R ^15d represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms);
The group selected from can be mentioned.
As A, R ^7c is particularly preferably an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 2 to 3 carbon atoms, each of which may be substituted with the group (a-3) or (b-3). Specific examples include a methyl group or an ethyl group which may be substituted with the group (a-3) or (b-3).

A is the formula (1), represents -COR ^7c, specific examples of the case where an alkyl group R ^7c is substituted, hydroxymethyl group, 2-hydroxy isopropyl group, an acetoxymethyl group, a methoxymethyl group, ethoxymethyl Group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, carbamoylmethyl group, 2-carbamoylethyl group, dimethylaminomethyl group, diethylaminomethyl group, 2-diethylaminoethyl group, 3-dimethylaminopropyl group, 3- Aminopropyl group, acetaminomethyl group, 3- (tert-butoxycarbonyl) aminopropyl group, 1-piperidinylmethyl group, 2- (1-piperidinyl) ethyl group, 2-carboxyethyl group, 4-piperidinyl Methyl group, cyanomethyl group, 1-cyanoethyl group, - such as a cyanoethyl group, and the like.
A is the formula (1), represents -COR ^7c, specific examples of the case where an alkenyl group ^{which R 7c} is substituted, for example, 2-cyclopropyl-vinyl group, 2-furyl vinyl and 2- (2- Thienyl) vinyl group and the like.

In the formula (1), when A represents -CO-COR ^7c (R ^7c is as defined above), R ^7c is preferably an alkyl group, more preferably an alkyl group having 1 to 3 carbon atoms. .

In Formula (1), A is
(3-4) -COR ^7d (R ^7d is as defined above), and R ^7d is an ^optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted. When it represents a monocyclic or bicyclic non-aromatic unsaturated heterocyclic group or an optionally substituted monocyclic or bicyclic saturated heterocyclic group, the cycloalkyl group is preferably Includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. The cycloalkenyl group is preferably a cyclopentenyl group or a cyclohexenyl group. Examples of the monocyclic non-aromatic unsaturated heterocyclic group include a pyrrolinyl group and a 2,5-dihydrofuryl group. Examples of the bicyclic non-aromatic unsaturated heterocyclic group include a 2,3-dihydrobenzofuryl group. Examples of the monocyclic saturated heterocyclic group include a pyrrolidinyl group, a piperidinyl group, and a tetrahydrofuryl group. Preferred examples of the substituent of the carbon atom on the ring of these groups include a halogen atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms. The substituent of the nitrogen atom on the ring of these groups is preferably an alkyl group having 1 to 3 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, or 1 to 3 carbon atoms. Of the alkylsulfonyl group.

In Formula (1), A is
(3-5) -COR ^7e (R ^7e is as defined above), and when R ^7e represents an optionally substituted aryl group or an optionally substituted heteroaryl group, Preferably a phenyl group is mentioned. The heteroaryl group is preferably a thienyl group, a furyl group, a pyrrolyl group or a pyridyl group. The substituents for these groups are preferably the following groups:
(G-1) halogen atom, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group, haloalkyl group, haloalkoxy group, cyano group;
(H-1) -R ^14a , -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a , -NR ^15a R ^16a
(R ^14a , R ^15a and R ^16a are as defined above);
(I-1) a phenyl group, a phenoxy group (a group in this group may be substituted with 1 to 5 substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group);
A group selected from: More preferably, the following groups:
(G-2) halogen atom, amino group, carbamoyl group, cyano group;
(H-2) -R ^14e , -OR ^14e , -O-COR ^14e , -NR ^15e -COR ^14e , -NR ^15e -COOR ^14e , -NR ^15e R ^16e
(R ^14e , R ^15e and R ^16e are as defined above);
(I-2) phenyl group, phenoxy group;
A group selected from:

A represents -COR ^7e in formula ^(1), specific examples of the case where a phenyl group which may ^{R 7e} is optionally substituted, for example, a phenyl group, 2-, 3- or 4-chlorophenyl group, 2 -, 3- or 4-bromophenyl group, 2-, 3- or 4-fluorophenyl group, 2-, 3- or 4-methylphenyl group, 2-, 3- or 4-cyanophenyl group, 4-ethyl Phenyl group, 4-tbutylphenyl group, 2-, 3- or 4-acetoxyphenyl group, 2-, 3- or 4-acetylaminophenyl group, 2-, 3- or 4-dimethylaminophenyl group, 4- Examples include methoxycarbonylphenyl group, 2-, 3- or 4-phenoxyphenyl group, 2-, 3- or 4-biphenyl group, and 3-chloro-4-aminophenyl group.

In Formula (1), A is
When represented by (3-6) -COOR ^7f (R ^7f is as defined above), R ^7f is preferably an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or substituted. An optionally substituted phenyl group (the phenyl group is preferably a halogen atom, a nitro group, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms, And the same or different 1 to 5, preferably 1 to 3 substituents selected from a haloalkyl group having 1 to 3 carbon atoms and a haloalkyl group having 1 to 3 carbon atoms. More preferably, R ^7f represents an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 2 to 3 carbon atoms.

In formula (1), A is the following group:
(4) -CO-COOR ⁸ (R ⁸ is as defined above);
R ⁸ preferably represents an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 2 carbon atoms.

In formula (1), A is the following group:
(5-1) -CONR ^9a -OR ^10a (R ^9a and R ^10a are as defined above);
R ^9a and R ^10a are preferably the same or different and each represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, or an alkynyl group having 2 to 3 carbon atoms, Preferably R ^9a and R ^10a represent an alkyl group having 1 to 3 carbon atoms.

In formula (1), A is the following group:
(6-1) -CONR ^12a R ^13a , -CSNR ^12a R ^13a , -SO ₂ NR ^12a R ^13a
(R ^12a and R ^13a are as defined above);
R ^12a is preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with an alkoxycarbonyl group having 2 to 3 carbon atoms. It represents an alkyl group, an alkyl group having 1 to 3 carbon atoms substituted with an optionally substituted phenyl group, or an optionally substituted phenyl group. As a substituent of the phenyl group, preferably a halogen atom, a nitro group, a hydroxy group, a carboxy group, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, an amino group, a carbamoyl group, or 1 carbon atom. -3 alkyl groups, C1-C3 alkoxy groups, C2-C4 alkanoyl groups, C2-C4 alkoxycarbonyl groups, C2-C4 alkanoyloxy groups, and the like. R ^13a preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R ^12a and R ^13a bonded together with the adjacent nitrogen atom, and a saturated or unsaturated monocyclic ring which may be substituted A nitrogen-containing heterocycle is formed. Examples of the saturated monocyclic nitrogen-containing heterocycle include pyrrolidine, piperidine, and morpholine. Examples of the unsaturated monocyclic nitrogen-containing heterocycle include imidazole and pyrroline.
R ^12a and R ^13a more preferably represent the same or different alkyl group having 1 to 3 carbon atoms, or R ^12a represents a hydrogen atom and R ^13a represents a phenyl group (the phenyl group has 1 to 2 halogen atoms) , A haloalkyl group having 1 to 3 carbon atoms, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkanoyl group having 2 to 4 carbon atoms, an alkanoyloxy group having 2 to 4 carbon atoms, And may be substituted with an alkoxycarbonyl group having 2 to 4 carbon atoms, a carboxy group, an amino group, or a carbamoyl group. Alternatively, R ^12a and R ^13a are preferably bonded to form a pyrrolidine, piperidine, morpholine or imidazole with the adjacent nitrogen atom.

The compound of the formula (1) is a concept including all tautomers, geometric isomers and stereoisomers depending on the type of substituent, and may be a mixture thereof.
That is, when one or more asymmetric carbon atoms are present in the compound of formula (1), diastereomers and optical isomers exist, but mixtures and isolated isomers of these diastereomers and optical isomers exist. Are also included in the compounds according to the present invention.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate , Propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, lactate, malate, pyruvate, methanesulfonate, benzene Organic acid salts such as sulfonic acid salts and paratoluenesulfonic acid salts can be mentioned. Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. . Moreover, basic amino acid salts or acidic amino acid salts such as arginine salt, aspartate, and glutamate can be exemplified.
In addition, the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may be a hydrate or a solvate such as an ethanol solvate, and these hydrates and / or solvates. Products are also encompassed by the compounds according to the present invention.

  The compound represented by the formula (1) can be produced by the following method. The starting materials not described below can be produced according to the following method, or a method known to those skilled in the art or a method analogous thereto.

(Manufacturing method 1)
The compound of formula (1) can be produced, for example, by the following method.

（式中、Ａ、Ａｒ、ｌ、ｍ、ｎおよびｏは前掲と同じものを意味し、Ｌ^１は脱離基を意味する。）
すなわち、式（１−１）の化合物を、塩基等適当な添加剤の存在下に式（１−２）で表される反応性誘導体と反応させることにより、式（１）の化合物を製造することができる。
Ａが、−ＣＯＲ^７（式中、Ｒ^７は前掲と同じものを意味する）を表す場合、反応性誘導体としては、式（１−３）：
Ｒ^７−ＣＯＯＨ （１−３）
（式中、Ｒ^７は前掲と同じものを意味する）；
で表されるカルボン酸化合物、当該カルボン酸化合物のアルキルエステル（特にメチルエステル）、活性エステル、酸無水物、酸ハライド（特に酸クロリド）を挙げることができる。
式（１−３）の化合物を用いる場合には、１，３−ジシクロヘキシルカルボジイミド、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、Ｎ，Ｎ’−カルボニルジイミダゾール、ベンゾトリアゾール−１−イルオキシトリス（ジメチルアミノ）ホスホニウム・ヘキサフルオロフォスフェート、Ｎ，Ｎ’−カルボニルジコハク酸イミド、１−エトキシカルボニル−２−エトキシ−１，２−ジヒドロキノリン、ジフェニルホスホリルアジド、プロパンホスホン酸無水物のような縮合剤の存在下に反応させることができる。縮合剤として１，３−ジシクロヘキシルカルボジイミド又は塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミドを用いる場合には、Ｎ−ヒドロキシコハク酸イミド、１−ヒドロキシベンゾトリアゾール、３−ヒドロキシ−１，２，３−ベンゾトリアジン−４（３Ｈ）−オン、Ｎ−ヒドロキシ−５−ノルボルネン−２，３−ジカルボキシイミド等を添加して反応させてもよい。
活性エステルの具体例としてはｐ−ニトロフェニルエステル、ペンタクロロフェニルエステル、ペンタフルオロフェニルエステル、Ｎ−ヒドロキシコハク酸イミドエステル、Ｎ−ヒドロキシフタルイミドエステル、１−ヒドロキシベンゾトリアゾールエステル、８−ヒドロキシキノリンエステル、２−ヒドロキシフェニルエステルなどが挙げられる。酸無水物としては、対称酸無水物又は混合酸無水物が用いられ、混合酸無水物の具体例としてはクロル炭酸エチル、クロル炭酸イソブチルのようなクロル炭酸アルキルエステルとの混合酸無水物、クロル炭酸ベンジルのようなクロル炭酸アラルキルエステルとの混合酸無水物、クロル炭酸フェニルのようなクロル炭酸アリールエステルとの混合酸無水物、イソ吉草酸、ピバリン酸のようなアルカン酸との混合酸無水物が挙げられる。
式（１−１）の化合物と式（１−２）の化合物との反応は、溶媒中又は無溶媒下に行われる。使用する溶媒は、原料化合物の種類等に従って適宜選択されるべきであるが、例えばベンゼン、トルエン、キシレンのような芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、シクロペンチルメチルエーテルのようなエーテル類、塩化メチレン、クロロホルムのようなハロゲン化炭化水素類、アセトン、メチルエチルケトンのようなケトン類、酢酸エチル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシドが挙げられ、これらの溶媒はそれぞれ単独で、或いは２種以上混合して用いられる。
本反応は必要に応じて塩基の存在下に行われ、塩基の具体例としては、水酸化ナトリウム、水酸化カリウムのような水酸化アルカリ、炭酸ナトリウム、炭酸カリウムのような炭酸アルカリ、重炭酸ナトリウム、重炭酸カリウムのような重炭酸アルカリ、或いはトリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリンのような有機塩基が挙げられるが、式（１−１）の化合物の過剰量で兼ねることもできる。
反応温度は用いる原料化合物の種類等により異なるが、通常約−３０℃〜約２００℃、好ましくは約−１０℃〜約１５０℃である。

(In the formula, A, Ar, l, m, n and o are the same as described above, and L ¹ is a leaving group.)
That is, a compound of formula (1) is produced by reacting a compound of formula (1-1) with a reactive derivative represented by formula (1-2) in the presence of a suitable additive such as a base. be able to.
When A represents -COR ⁷ (wherein R ⁷ represents the same as described above), the reactive derivative may be represented by formula (1-3):
R ⁷ -COOH (1-3)
(Wherein R ⁷ means the same as above);
And alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides) of the carboxylic acid compounds.
When the compound of formula (1-3) is used, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, benzotriazole-1 -Yloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride Can be reacted in the presence of a condensing agent. When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1, 2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide or the like may be added and reacted.
Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2 -Hydroxyphenyl ester etc. are mentioned. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used, and specific examples of the mixed acid anhydride include mixed acid anhydrides with chlorocarbonic acid alkyl esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate, chloro Mixed anhydrides with chlorocarbonic aralkyl esters such as benzyl carbonate, mixed anhydrides with chlorocarbonic arylesters such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.
The reaction between the compound of formula (1-1) and the compound of formula (1-2) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. A mixture of two or more types is used.
This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, and N-methylmorpholine, but may be combined with an excess of the compound of formula (1-1). .
While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

The compound of the formula (1-1) described in the production method 1 corresponds to a compound (intermediate) in which A represents a hydrogen atom in the formula (1), and is represented by the following production method 2 or production method 3. Can be manufactured.
(Manufacturing method 2)

〔式中、Ａ、Ａｒ、ｌ、ｍ、ｎおよびｏは前掲と同じものを意味し、Ｌ^２、Ｌ^３及びＬ^４は加水分解もしくは加水素分解により脱離し得る保護基を意味し、Ｌ^２及びＬ^３、Ｌ^２及びＬ^４はそれぞれ異なる反応条件で脱保護可能であり、Ｌ^５は−ＣＨ_２−Ｌ^６（Ｌ^６は脱離基を意味する）、ホルミル基、又はカルボキシ基を意味する〕

[Wherein, A, Ar, l, m, n and o represent the same as described above, L ² , L ³ and L ⁴ represent protecting groups which can be eliminated by hydrolysis or hydrogenolysis, and L ² and L ³ , L ² and L ⁴ can be deprotected under different reaction conditions, and L ⁵ represents —CH ₂ —L ⁶ (L ⁶ represents a leaving group), a formyl group, or a carboxy group. means〕

(Manufacturing method 3)

（式中、Ａ、Ａｒ、ｌ、ｍ、ｎ、ｏ、Ｌ^２、Ｌ^３、Ｌ^４及びＬ^５は前掲と同じものを意味する）

(In the formula, A, Ar, l, m, n, o, L ² , L ³ , L ⁴ and L ⁵ are the same as the above)

Hereinafter, Step 1 to Step 10 in the production method 2 or 3 will be described.
1) Deprotection reaction Step 1, step 3, step 5, step 6, step 8, and step 10 are steps for performing a deprotection reaction. Of the protective groups used in L ² , L ³ and L ⁴ in production method 2 and production method 3, examples of the protective group that can be removed by hydrolysis include an ethoxycarbonyl group, a tert-butoxycarbonyl group, and an acetyl group. Benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group, etc., which are eliminated by hydrogenolysis. Examples of the protecting group to be obtained include benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, benzylsulfonyl group and the like.
Deprotection by hydrolysis can be performed according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, isopropanol, acetonitrile, dioxane, water, or a mixture thereof can be used. Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid. It is done. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about 0 ° C to 150 ° C.
Further, deprotection by hydrogenolysis can be carried out according to a conventional method. For example, the reaction is carried out in a suitable solvent in the presence of a catalyst such as palladium carbon or Raney nickel, in the presence of hydrogen or a hydrogen donor such as ammonium formate or cyclohexene. Is done. Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like. The reaction temperature is usually about 0 ° C. to about 80 ° C., and the reaction is carried out at normal pressure or under pressure.
In addition, the protecting group represented by L ² is a protecting group that is deprotected under conditions different from those of L ³ and is similarly deprotected under conditions different from that of L ⁴ . For example, “L ² HN—” represents a phthalimide group, L ³ represents a t-butoxycarbonyl group, and L ⁴ represents an acetyl group.

2) Alkylation reaction When L ⁵ represents -CH ₂ -L ⁶ (L ⁶ represents a leaving group) in the compound of formula (2-3) which is a production intermediate of production method 2 and production method 3, Steps 2 and 9 are alkylation reactions, and are performed in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane. Halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide. These solvents are used alone or in combination of two or more.

  This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but can also be combined with an excess of amine as a substrate for alkylation. is there.

Examples of the leaving group for L ⁶ include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. Halogen atoms, in particular chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy are preferred. When L ⁶ is chlorine or bromine, the reaction proceeds smoothly when an alkali metal iodide such as sodium iodide or potassium iodide is added. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

  The compound of Formula (2-3) is commercially available or can be produced by a known method. That is, the corresponding alcohol derivative of formula (2-3a) can be converted into a leaving group by a conventional method to produce a compound represented by formula (2-3b).

（式中、ｎ、ｏ、Ｌ^４及びＬ^６は前掲と同じものを意味する）
例えば、式（２−３ａ）の化合物を四塩化炭素もしくは四臭化炭素及びトリフェニルホスフィンと反応させることにより、Ｌ^６が塩素原子もしくは臭素原子を表す化合物を製造できる。また、式（２−３ａ）の化合物を塩基の存在下に塩化ベンゼンスルホニル等の塩化スルホニル化合物と反応させることによりＬ^６がアリールスルホニルオキシ基やアルキルスルホニルオキシ基を表す化合物を製造できる。

(In the formula, n, o, L ⁴ and L ⁶ are the same as described above.)
For example, a compound in which L ⁶ represents a chlorine atom or a bromine atom can be produced by reacting the compound of formula (2-3a) with carbon tetrachloride or carbon tetrabromide and triphenylphosphine. Alternatively, a compound in which L ⁶ represents an arylsulfonyloxy group or an alkylsulfonyloxy group can be produced by reacting the compound of formula (2-3a) with a sulfonyl chloride compound such as benzenesulfonyl chloride in the presence of a base.

3) Reductive alkylation reaction When L ⁵ represents a formyl group in the compound of formula (2-3) which is a production intermediate of production method 2 and production method 3, steps 2 and 9 are reductive alkylation reactions. Yes, in the presence of a catalytic amount of acid, catalytic reduction catalyzed by platinum oxide, or in the presence of borane complexes such as pyridine borane, triethyl borane, sodium borohydride, sodium triacetoxyhydroborate or sodium cyanoborohydride To be done. As the solvent to be used, the solvent used in the above 2) is used. As the acid used, p-toluenesulfonic acid or the like is used. The reaction temperature is generally about 0 ° C to about 100 ° C, preferably about 20 ° C to about 80 ° C.

  The compound of the formula (2-3) used here is commercially available or can be produced by a known method. That is, the corresponding alcohol derivative of formula (2-3a) can be oxidized by a conventional method to produce a formyl derivative of formula (2-3c). For example, the compound of formula (2-3a) can be oxidized with phosgene, dimethyl sulfoxide and triethylamine. Alternatively, the compound of formula (2-3c) can also be produced by reducing the corresponding carboxylic acid or ester thereof by a conventional method. For example, the compound of formula (2-3d) can be reduced with DIBAH (diisobutylaluminum hydride).

（式中、ｎ、ｏ、Ｌ^４及びＬ^６は前掲と同じものを意味する）
尚上記工程で用いられる式（２−３ｄ）で表される化合物は、市販されているか、或いは公知の方法により製造することができる。

(In the formula, n, o, L ⁴ and L ⁶ are the same as described above.)
In addition, the compound represented by Formula (2-3d) used at the said process is marketed, or can be manufactured by a well-known method.

4) Amidation reaction When L ⁵ represents a carboxy group in the compound of formula (2-3), which is a production intermediate of production method 2 and production method 3, step 2 is a step of performing a reduction reaction after the amidation reaction It is. The amidation reaction can be performed by the method described in Production Method 1 above. The reduction reaction can be performed by the method described in 5) below.
Moreover, the amidation reaction in the process 4 in the manufacturing method 2 and the process 7 in the manufacturing method 3 can be performed with the following method. That is, the compound of the formula (2-7) can be produced by reacting the compound of the formula (2-5) with the compound of the formula (2-6) or a reactive derivative thereof. The compound of formula (3-2) can be produced by reacting the compound of formula (3-1) with the compound of formula (2-6) or a reactive derivative thereof.
Examples of the reactive derivative of the compound of formula (2-6) include lower alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2 -Hydroxyphenyl ester etc. are mentioned. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used, and specific examples of the mixed acid anhydride include mixed acid anhydrides with chlorocarbonic acid alkyl esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate, chloro Mixed anhydrides with chlorocarbonic aralkyl esters such as benzyl carbonate, mixed anhydrides with chlorocarbonic arylesters such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.
When the carboxylic acid itself represented by the formula (2-6) is used, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N′-carbonyldisuccinic acid imide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide Can be reacted in the presence of a condensing agent such as propanephosphonic anhydride. When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1, 2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide or the like may be added and reacted.
The reaction of the carboxylic acid itself represented by formula (2-6) or a reactive derivative thereof with the compound of formula (2-5) or the compound of formula (3-1) is carried out in a solvent or without solvent. Is called. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. A mixture of the above is used.
This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and the compound of formula (2-5) or formula (3-1) It can also serve as an excess of the compound represented.
While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.
The compound of the formula (2-6) can be produced, for example, by the methods described in JP-A Nos. 11-209347, 11-217372, and 11-228541.

5) Reduction reaction In Step 2 of Production Method 2, the reduction reaction performed following the amidation reaction is performed in a solvent using an appropriate reducing agent. That is, as the reducing agent used in this reaction, for example, diborane, lithium aluminum hydride and its alkoxy complex or transition metal salt, aluminum chloride, boron trifluoride, phosphorus oxychloride or carboxylic acid (for example, acetic acid, trifluoroacetic acid) Sodium borohydride to which is added. This reduction reaction is carried out in a solvent such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, dioxane, diglyme, or a solvent such as toluene, chloroform, methylene chloride, and is appropriately selected depending on the type of reducing agent used. . The reaction temperature varies depending on the type of the reducing agent and the like, but is usually from about 0 ° C to about 160 ° C, preferably from about 10 ° C to 80 ° C.
The raw material compound represented by Formula (2-1) in Production Method 2 and Production Method 3 is commercially available, or can be produced by a known method.

(Manufacturing method 4)
In the formula (1), when A represents —CONR ¹² R ¹³ , —CSNR ¹² R ¹³ or —SO ₂ NR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same as those described above), It can be produced by the same reaction as in production method 1. As the reactive derivative represented by the formula (1-2), a compound in which L ¹ represents a halogen atom can be used. Examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom, and more preferably a chlorine atom.
The reaction between the compound represented by formula (1-1) and the compound represented by formula (1-2) is carried out in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the kind of the raw material compound. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. A mixture of two or more types is used.
This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but can be combined with an excess of the compound of formula (1-1) It is. While the reaction temperature varies depending on the type of raw material compound used, it is generally about −20 ° C. to about 150 ° C., preferably about −10 ° C. to about 80 ° C.
A compound in which A is —CONR ¹² R ¹³ in formula (1) is a chloromethyl carbamate obtained by reacting chloromethyl chlorocarbonate with AH according to the method described in Synth. Commun., 1996, 26 , 4253. It can also be obtained by reacting a compound with the compound represented by formula (1-1) under the same conditions as in the above production method. In this reaction, alcohols such as ethanol can also be used as a solvent.
Here, the compound represented by Formula (1-2) is commercially available, or can be produced by a known method.

(Manufacturing method 5)
When A represents —CONHR ¹² or —CSHRR ¹² (wherein R ¹² represents the same as described above), the compound of formula (1) is the following compound of formula (1-1): Compound of formula (1-5) or compound of formula (1-6):
O = C = N-R ¹² (1-5)
S = C = N-R ¹² (1-6)
(Wherein R ¹² means the same as described above);
It can manufacture by making the compound represented by these react.
The reaction between the compound represented by formula (1-1) and the compound represented by formula (1-5) or (1-6) is carried out in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like. For example, the solvent described in the production method 2 can be used. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 250 ° C, preferably about 25 ° C to about 200 ° C.
The compound represented by the formula (1-5) or (1-6) is commercially available or can be produced by a known method.

(Manufacturing method 6)
When A represents —CONR ¹² R ¹³ or —CSNR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same as those described above), the compound of formula (1) is also prepared by the following method: Method:

（式中、Ｚ^１は−ＣＯ−又は−ＣＳ−を意味し、Ｌ^７は脱離基を意味し、Ａｒ、ｌ、ｍ、ｎおよびｏは前掲と同じものを意味する。）
で製造することができる。
この反応は、溶媒中又は無溶媒下に行われる。使用する溶媒は、原料化合物の種類などに従って適宜選択されるべきであるが、例えば前記製造方法２、２）で述べた溶媒を用いることができる。反応温度は用いる原料化合物の種類などにより異なるが、通常約０℃〜約２５０℃、好ましくは約２５℃〜約２００℃である。
式（１−７）の化合物は、前記式（１−１）で表される化合物に、製造方法２、２）で用いたような塩基の存在下、Ｎ，Ｎ’−カルボニルジイミダゾール、ホスゲン、ジホスゲン、トリホスゲン、チオホスゲン、塩化スルフリル、炭酸ジ（２−ピリジル）、炭酸Ｎ，Ｎ’−ジスクシンイミジル、炭酸ビス（４−ニトロフェニル）、炭酸ビス（トリクロロメチル）、フェノキシカルボニルテトラゾール、クロル炭酸フェニル、クロル炭酸クロロメチル、クロル炭酸２，４，５−トリクロロフェニル、クロル炭酸トリクロロメチル、クロル炭酸１−クロロエチル、クロル炭酸１，２，２，２−テトラクロロエチル、クロル炭酸ノルボルン−５−エン−２，３−ジカルボキシイミジルなどを反応させることにより製造することができ、脱離基Ｌ^７は上記記載の試薬に依存する。例えば、Ｎ，Ｎ’−カルボニルジイミダゾールを用いるならばＬ^７はイミダゾール基であり、ホスゲンを用いるならばＬ^７は塩素原子である。本反応は前記製造方法２、２）で述べた溶媒および反応条件で行うことができる。
式（１−８）の化合物は、市販されているか、或いは公知の方法により製造することができる。

(Wherein Z ¹ represents —CO— or —CS—, L ⁷ represents a leaving group, and Ar, l, m, n, and o represent the same as described above.)
Can be manufactured.
This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like. For example, the solvents described in the above production methods 2, 2) can be used. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 250 ° C, preferably about 25 ° C to about 200 ° C.
The compound of the formula (1-7) is obtained by adding N, N′-carbonyldiimidazole, phosgene to the compound represented by the formula (1-1) in the presence of a base as used in the production method 2, 2). , Diphosgene, triphosgene, thiophosgene, sulfuryl chloride, di (2-pyridyl) carbonate, N, N'-disuccinimidyl carbonate, bis (4-nitrophenyl) carbonate, bis (trichloromethyl) carbonate, phenoxycarbonyltetrazole, chloro Phenyl carbonate, chloromethyl chlorocarbonate, chlorocarbonate 2,4,5-trichlorophenyl, trichloromethyl chlorocarbonate, 1-chloroethyl chlorocarbonate, 1,2,2,2-tetrachloroethyl chlorocarbonate, norborn-5-ene chlorocarbonate above 2,3 and di carboxy succinimidyl can the be prepared by reacting the leaving group L ⁷ is It depends on the reagents described. For example, if N, N′-carbonyldiimidazole is used, L ⁷ is an imidazole group, and if phosgene is used, L ⁷ is a chlorine atom. This reaction can be carried out in the solvent and reaction conditions described in the above production methods 2, 2).
The compound of the formula (1-8) is commercially available or can be produced by a known method.

(Manufacturing method 7)
In the formula (1), a compound in which A is represented by —SO ₂ R ⁷ (R ⁷ is the same as the above) is represented by the following formula (1-9) to the compound represented by the formula (1-1) :
L ¹ —SO ₂ —R ⁷ (1-9)
(Wherein L ¹ and R ⁷ are the same as described above);
It can manufacture by making the compound represented by these react.
The reaction of the compound represented by the formula (1-1) and the compound represented by the formula (1-9) is performed in a solvent or under no solvent. The solvent to be used should be appropriately selected according to the kind of the raw material compound. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. A mixture of two or more types is used.
This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but can be combined with an excess of the compound of formula (1-1) It is. While the reaction temperature varies depending on the type of raw material compound used, it is generally about −20 ° C. to about 150 ° C., preferably about −10 ° C. to about 80 ° C.
The compound represented by the formula (1-9) is commercially available, or can be produced by a known method.

(Manufacturing method 8)
In the formula (1), the compound represented by the alkyl group which may be substituted A, the alkenyl group which may be substituted or the alkynyl group which may be substituted is represented by the above formula (1-2). Or a compound represented by formula (1-10):
OHC-A ² (1-10)
(In the formula, A ² means an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group);
Can be made to react.
The reaction of the compound represented by the formula (1-1) and the compound represented by the formula (1-2) can be performed by the alkylation reaction in the above production method 2, 2). The reaction of the compound represented by the formula (1-1) and the compound represented by the formula (1-10) can be performed by the reductive alkylation reaction in the above production methods 2, 3).
The compound represented by formula (1-2) or formula (1-10) is commercially available, or can be produced by a known method.

(Manufacturing method 9)
In the formula (1), the compound in which A is a cyano group is represented by the following formula (1-11) to the compound represented by the formula (1-1):
L ¹ -CN (1-11)
(Wherein the definition of L ¹ means the same as above);
It can manufacture by making the compound represented by these react.
The reaction between the compound represented by formula (1-1) and the compound represented by formula (1-11) is performed under the same conditions as the alkylation reaction described in the following production method 2, 2). Can do.
The compound represented by the formula (1-11) is commercially available, or can be produced by a known method.

(Manufacturing method 10)
The compound of formula (1) includes a compound of formula (2-6) or a reactive derivative thereof, and formula (10-1):

（式中、Ａ、ｌ、ｍ、ｎおよびｏは前掲と同じものを意味する。）
で表される化合物を反応させることにより製造することもできる。
式（２−６）の化合物の反応性誘導体としては、前記式（１−３）の化合物の反応性誘導体と同じものを例示することができる。また、式（２−６）で表されるカルボン酸化合物又はその反応性誘導体を用いて式（１０−１）の化合物と反応させる場合の反応条件についても、前記式（１−３）の化合物と式（１−１）の化合物の反応と同様の反応条件が挙げられる。

(In the formula, A, l, m, n and o are the same as described above.)
It can also manufacture by making the compound represented by these react.
Examples of the reactive derivative of the compound of formula (2-6) include the same reactive derivatives of the compound of formula (1-3). Moreover, also about the reaction conditions when making it react with the compound of Formula (10-1) using the carboxylic acid compound represented by Formula (2-6), or its reactive derivative, the compound of said Formula (1-3) And reaction conditions similar to those of the compound of formula (1-1).

(Manufacturing method 11)
The compound represented by the formula (10-1) can be produced, for example, by the following production process.

（式中、Ｌ^２、Ｌ^４、Ａ、ｌ、ｍ、ｎおよびｏは前掲と同じものを意味する。）
上記の工程２は、上記の製造方法１〜９のいずれかに記載の方法を用いることができる。また、工程１および工程３は上記製造方法２、１）の脱保護反応を用いて行うことができる。
式（１１−１）及び式（１１−２）の化合物は、下記参考例１２〜１９に記載の方法により製造することもできる。

(In the formula, L ² , L ⁴ , A, l, m, n and o are the same as described above.)
In the step 2, the method described in any one of the production methods 1 to 9 can be used. Steps 1 and 3 can be performed using the deprotection reaction of production method 2, 1).
Compounds of formula (11-1) and formula (11-2) can also be produced by the methods described in Reference Examples 12 to 19 below.

(Manufacturing method 12)
The compound of Formula (1) can also be manufactured with the following manufacturing methods.

（式中、Ａｒ、Ａ、ｌ、ｍ、ｎ、ｏ、Ｌ^５は前記と同義である）
すなわち、前記製造方法３に記載の式（３−３）で表される化合物と、式（１２−１）で表される化合物を反応させることにより式（１）の化合物を製造することができる。反応条件等は、前記製造方法２の工程２及び製造方法３の工程９を参照すればよい。
式（１２−１）で表される化合物は、例えば下記の製造方法で製造することができる。すなわち、式（１２−３）の化合物から上記製造方法２及び３に記載の方法で式（１２−７）の化合物を経由して製造できる。

(In the formula, Ar, A, l, m, n, o, and L ⁵ are as defined above).
That is, the compound of Formula (1) can be produced by reacting the compound represented by Formula (3-3) described in Production Method 3 with the compound represented by Formula (12-1). . For reaction conditions and the like, reference may be made to step 2 of production method 2 and step 9 of production method 3.
The compound represented by the formula (12-1) can be produced, for example, by the following production method. That is, it can be produced from the compound of the formula (12-3) via the compound of the formula (12-7) by the method described in the above production methods 2 and 3.

（式中、Ａ、ｎ、ｏ及びＬ^４は前記と同義であり、Ｌ^８は保護基を表す）
式（１２−３）の化合物は市販されているか、或いは公知の方法により製造することができる。工程１、２及び４の保護・脱保護反応は、上記製造方法２、１）を参照すればよい。但し、保護基Ｌ^２と保護基Ｌ^８とは異なった条件で脱保護される保護基を選ばねばならない。
工程３は、式（１２−５）で表される化合物を上記製造方法１〜９に記載された反応と同様の条件下で反応させることにより式（１２−６）で表される化合物を製造する工程である。
式（１２−７）の化合物は、上記製造方法２及び製造方法３に記載の方法で、式（１２−１）の化合物へ導くことができる。

(Wherein A, n, o and L ⁴ are as defined above, and L ⁸ represents a protecting group)
The compound of the formula (12-3) is commercially available or can be produced by a known method. For the protection and deprotection reactions in Steps 1, 2, and 4, the above production methods 2, 1) may be referred to. However, it must choose a protecting group to be deprotected in different conditions is a protecting group L ² and the protecting group L ^8.
In step 3, the compound represented by the formula (12-6) is produced by reacting the compound represented by the formula (12-5) under the same conditions as the reactions described in the above production methods 1 to 9. It is a process to do.
The compound of the formula (12-7) can be led to the compound of the formula (12-1) by the method described in the above production method 2 and production method 3.

The compound in which A is represented by -CSR ⁷ , -COOR ⁷ or -CO-COR ⁷ in formula (1) can be produced by the same method as Production Method 1.
The compound in which A is represented by —CO—COOR ⁸ in Formula (1) can be produced by the same method as in Production Method 1 or the method described in Production Example 110.
The compound in which A is represented by —CONR ⁹ —OR ¹⁰ in Formula (1) can be produced by the same method as Production Method 1 or the method described in Production Example 205.

  The compound of the formula (1) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, reaction / treatment conditions, and the like. The acid addition salt can be converted to the free base by a conventional method, for example, treatment with a base such as alkali carbonate or alkali hydroxide. On the other hand, the free base can be converted into an acid addition salt by treating with various acids according to a conventional method.

  In addition, when the compound of formula (1) or an intermediate thereof has a functional group such as an amino group, a carboxy group, a hydroxy group, or an oxo group, use protection or deprotection techniques as necessary. Can do. As a suitable protecting group, a protecting method and a deprotecting method, those commonly used in the field of chemistry, particularly in the field of peptide chemistry, can be used in addition to those mentioned in the above production methods 2, 1). For example, it is described in detail in "Protective Groups in Organic Chemistry, T. W. Greene, Wiley-Interscience, New York, 2nd edition, 1991". Also included in the compounds according to the invention are compounds of formula (1) protected with a protecting group or intermediates protected with a protecting group.

The compound of the formula (1) according to the present invention or an intermediate for producing the compound can be purified by methods known to those skilled in the art. For example, it can be isolated and purified by column chromatography (for example, silica gel column chromatography or ion exchange column chromatography), recrystallization or reprecipitation.
In the compound of the formula (1) according to the present invention, when there is one or more asymmetric points, a raw material having the asymmetric point is used according to a usual method, or asymmetry is introduced at an intermediate stage. Can be manufactured. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution at an appropriate stage of the production process. As an optical resolution method, for example, when the compound of formula (1) or an intermediate thereof has a basic group, for example, mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene It can be carried out by a diastereomeric method in which a salt is formed with an optically active acid such as tartaric acid, malic acid, camphor sulfonic acid or bromocamphor sulfonic acid. When the compound of formula (1) or an intermediate thereof has an acidic group, it can also be carried out by forming a salt with an optically active base such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine. The optically resolved salt can be obtained as a compound of the formula (1) by treating with an acid or base by a usual method.

The compound of the formula (1) or a pharmaceutically acceptable salt thereof has an agonistic action on the serotonin 4 receptor and is useful as an active ingredient of a pharmaceutical composition.
Below, the test result about the pharmacological action of the typical compound concerning this invention is shown.

Test Example 1 Serotonin 4 (5-HT ₄ ) Receptor Binding Test The 5-HT ₄ receptor binding test and the preparation of the receptor membrane preparation were performed according to the method of Grossman et al. [British J. Pharmacol., (1993) 109 , 618]].
After decapitation of the Slc-Hartley guinea pig (body weight 300 to 400 g), the brain was immediately removed and the striatum was separated. A 15-fold volume of Hepes buffer (50 mM, pH 7.4, 4 ° C.) is added to the obtained tissue, homogenized with a Teflon (registered trademark) homogenizer, and centrifuged at 48,000 × g (4 ° C.) for 15 minutes. did. A hepes buffer solution was added to the resulting sediment at a ratio of 1 ml to a wet weight of 30 mg of tissue to prepare a receptor membrane preparation.
The assay tube contained 0.1 nM [ ³ H] -GR113808 {chemical name: [1- [2- (methylsulfonylamino) ethyl] -4-piperidinyl] methyl 1-methylindole-3-carboxylate} 1 ml of a Hepes buffer solution (50 mM, pH 7.4, 4 ° C.) containing a receptor membrane preparation and a test compound or 30 μM serotonin was incubated at 37 ° C. for 30 minutes. The reaction was stopped by rapid filtration using a Brandel cell harvester on a Whatman GF / B filter soaked in 0.1% polyethyleneimine for 1 hour, and using 4 ml of ice-cooled 50 mM Tris-HCl (pH 7.7). This was done by washing 3 times. Radioactivity was measured with a liquid scintillation counter after adding an ACS II scintillator to the filtered filter.
A 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound for specific binding obtained by subtracting non-specific binding from the total binding amount of [ ³ H] -GR113808. The results of serotonin 4 (5-HT ₄ ) receptor binding test are shown in Table 1. In the table, “test compound” means the following production example number.

Test Example 2 : Mouse defecation test Slc-ddy male mice (body weight 25-30 g) were used, and food and water were freely consumed until the start of the experiment.
Each group of 25 mice was divided into 5 groups, and each group of 5 mice was transferred to a fasting cage and allowed to acclimate to the new environment for about 1 hour. Thereafter, 3 mg / kg of the test compound suspended in 0.5% tragacanth solution was orally administered, and the weight of the stool of each group was measured after 30, 60 and 120 minutes. The results of the mouse defecation test are shown in Table 2. In the table, “test compound” means the following production example number.
Moreover, the efficacy judgment was processed by the Dunnett test between the control group and the test compound.
-: No effect, +: Moderate promotion (p <0.05), ++: Significant promotion (p <0.01)

Test Example 3 : Guinea pig electrocardiogram test An Slc-Hartley male guinea pig was anesthetized, and an electrocardiogram (induction II) was measured under artificial respiration. The drug solution was continuously infused for 15 minutes at a flow rate of 0.2 ml / kg / min from a cannula placed in the jugular vein. The dose (ED _5% ) that extends QTc by 5% is shown in Table 3. In the table, “test compound” means the following production example number.

As is clear from the above test, the compound according to the present invention represented by the formula (1) or a pharmaceutically acceptable salt thereof shows (1) a strong affinity for the 5-HT ₄ receptor. (2) Since it has a gastrointestinal motility promoting action such as a strong defecation promoting action by oral administration, and (3) there is no influence on the heart (QTc prolongation), as a highly safe 5-HT ₄ receptor agonist, It can be used for the treatment and prevention of diseases or disorders resulting from lack of stimulation of 5-HT ₄ receptors.

Specific examples include the following diseases (i) to (v):
(I) For example, irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, constipation induced by drugs such as morphine and antipsychotics, constipation associated with Parkinson's disease, constipation associated with multiple sclerosis, diabetes Digestive problems such as accompanying constipation, or constipation or defecation disorder (as a pretreatment during endoscopy or barium intestinal X-ray examination);
(Ii) Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-diffuse gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal disorders such as gastric insufficiency, post-gastrectomy syndrome, or pseudo-intestinal obstruction;
(Iii) Gastrointestinal diseases, scleroderma, diabetes mellitus, anorexia in esophagus / biliary tract diseases, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, chest, as described in (i) and (ii) above Gastrointestinal symptoms such as burns or ambiguity;
(Iv) neuropsychiatric diseases such as schizophrenia, Alzheimer's disease, depression, memory impairment, anxiety;
(V) Urinary tract diseases accompanied by urination disorders such as urinary tract obstruction or enlarged prostate.
As described above, the compound according to the present invention can be used for the treatment and prevention of various diseases described above, particularly digestive system diseases, various digestive system abnormalities associated with the treatment of various diseases described above, and the like. That is, since the compound according to the present invention exhibits an excellent motion promoting action on the digestive tract (particularly the lower digestive tract of the colon and rectum), it has a strong defecation promoting action, or a gastrointestinal motility promoting agent or gastrointestinal function. It is particularly useful as an remedy for treating or preventing the diseases described in (i) above.

  In the present specification, the term “prophylactic agent” refers to a drug that is administered to a patient who is not suffering from a disease at the time of administration or whose health condition is not bad, in order to prevent the disease from being affected and the worsening of symptoms. “Prevention” is expected to be particularly appropriate for people who have had symptoms of the disease before and who are considered to be at increased risk of suffering from the disease.

  There is no particular limitation on the administration form of the compound of formula (1) or a pharmaceutically acceptable salt thereof, and any of oral administration, parenteral administration and rectal administration may be used. The dose varies depending on the type of compound, administration method, patient symptom / age, etc., but is usually in the range of 0.01 to 30 mg / kg / day, preferably 0.05 to 10 mg / kg / day. The number of administrations per day is given once or several times a day, for example, 1, 2 or 3 doses each time.

Examples of preparations for oral administration include tablets, capsules, granules, powders, syrups, fine granules, solutions, suspensions, etc. Examples of preparations for parenteral administration include, for example, Injections, infusions, suppositories (rectal administration), nasal preparations, sublingual, transdermal absorption agents [lotions, emulsions, ointments, creams, jellies, gels, patches (tapes) , Transdermal patch preparations, poultices, etc., external powders, etc.].
As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and does not react with the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used. That is, the pharmaceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes an excipient, a binder, a lubricant, a stabilizer, a disintegrant, a buffer, and a solubilizing agent. , Tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, gelling agent, soothing agent, preservative Further, it can contain pharmaceutical carriers such as plasticizers, percutaneous absorption promoters, anti-aging agents, moisturizers, preservatives, and fragrances, and two or more pharmaceutical carriers can be appropriately selected and used.

  Specific examples of the carrier for the preparation include lactose, inositol, glucose, sucrose, fructose, mannitol (mannit), dextran, sorbitol (sorbit), cyclodextrin, starch (potato starch, corn starch, amylopectin, etc.), partial Alpha starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, sodium alginate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropyl Cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydro Cyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, calcium stearate, aluminum stearate, cetostearyl alcohol, wax, paraffin, talc, tragacanth, bentonite, beegum, carboxyvinyl Polymer, titanium oxide, fatty acid ester, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, squalane, silicone oil, vegetable oil (sesame oil, olive oil, soybean oil, cottonseed oil, castor oil Oil), liquid paraffin (liquid paraffin), soft paraffin, white petrolatum, yellow petrolatum, Fin, wool oil, wax (beeswax, carnauba wax, white beeswax, etc.), water, propylene glycol, polyethylene glycol, glycerol, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citrus Acid, lauric acid, myristic acid, stearic acid, oleic acid, benzyl alcohol, glutamic acid, glycine, methyl paraoxybenzoate, propyl paraoxybenzoate, p-hydroxybenzoic acid esters, cholesterol ester, ethylene glycol monoalkyl ester, propylene glycol Monoalkyl ester, glyceryl monostearate, sorbitan fatty acid ester, isopropyl myristate, isopropyl palmitate , Carboxypolymethylene, saccharin, strawberry flavor, peppermint flavor, cocoa butter, polyisobutylene, vinyl acetate copolymer, acrylic copolymer, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, sebacic acid Dibutyl, acetylated monoglyceride, diethylene glycol, dodecylpyrrolidone, urea, ethyl laurate, azone, kaolin, bentonite, zinc oxide, agarose, carrageenan, acacia gum, xanthan gum, potassium laurate, potassium palmitate, potassium myristate, sodium cetyl sulfate , Castor oil sulfate (funnel oil), Span (sorbitan stearate, sorbitan monooleate, sorbitan sesquioleate, triolei Acid sorbitan, etc.), Tween (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene sorbitan fatty acid ester, etc.), polyoxyethylene hydrogenated castor oil (so-called HCO), polyoxyethylene lauryl ether , Polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol monostearate, poloxamer (so-called pluronic), lecithin (including purified phospholipids isolated from lecithin such as phosphatidylcholine and phosphatidylserine) And a hydrogenated product of lecithin.

  When the compound of the formula (1) or a pharmaceutically acceptable salt thereof is used for pharmaceutical use as described above, it is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier, and the preparation is prepared according to a usual method. Is done. For example, 0.01 to 99% by weight, preferably 0.05 to 80% by weight, more preferably 0.1 to 70% by weight, using the compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, More preferably, it can be a pharmaceutical composition containing 0.1 to 50% by weight. These formulations may also contain other therapeutically valuable ingredients.

A compound of formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them may be used sequentially or simultaneously for the treatment of the diseases described herein in one or more of the following other Includes combination therapy administered in combination with drugs.
Specifically, in the case of digestive system diseases accompanied by constipation, for example, salt laxatives such as magnesium sulfate, magnesium oxide and magnesium citrate, for example, invasiveness such as dioctylsodium, sulfosuccinate, and cassanthranol Laxatives, for example, expansive laxatives such as carmellose, for example, colonic stimulating laxatives such as bisacodyl, picosulfer, senna, sennoside, for example, small intestinal stimulating laxatives such as castor oil, for example, intestinal cleansing agents such as magcorol, Niflec, etc. It is done.
Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, non-diffuse gastroesophageal reflux disease, diabetic gastric palsy, gastric ulcer, duodenal ulcer, NSAID ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus In gastrointestinal disorders such as post-gastrectomy syndrome or pseudo-intestinal obstruction, proton pump inhibitors such as omeprazole, rabeprazole, lansoprozole, and histamine H ₂ receptor inhibitors such as cimetidine, ranitidine, famotidine, etc. And the like, for example, gastrointestinal function regulators such as mosapride and domperidone, gastric mucosa protective agents, intestinal regulating agents and the like. In depression / anxiety, for example, selective serotonin reuptake inhibitors (SSRI) such as paroxetine and sertraline, for example, serotonin-norepinephrine reuptake inhibitors (SNRI) such as venlafaxine and duloxetine, such as amitriptyline and imipramine And antidepressant and anxiolytic agents such as tetracyclic antidepressants such as mianserin and maprotiline. Examples of memory disorders include cholinesterase inhibitors such as donepezil and rivastigmine, and cognitive impairment improving drugs such as memantine. Examples of dysuria associated with benign prostatic hyperplasia include drugs for treating dysuria such as tamsulosin and terazosin.

The present invention will be described more specifically with reference examples and production examples below, but the present invention is not limited to these production examples. Compound identification is performed using elemental analysis values, mass spectrum, IR spectrum, liquid chromatograph mass spectrometry (LC-MS), hydrogen nuclear magnetic resonance absorption spectrum ( ¹ H-NMR spectrum), powder X-ray diffraction measurement (XRD), etc. I went there. The powder X-ray diffractometer is a CuKα1 line (wavelength 1.54060 angstrom), an X-ray tube current 40 mA, voltage using X'Pert Pro (Expert Pro) manufactured by Spectris Co. The measurement was performed under the conditions of 45 kilovolts, step 0.01700 degrees, and measurement time 101.41770 seconds / step.
In the following reference examples and production examples, the following abbreviations may be used for the sake of simplicity.

Me: methyl, Et: ethyl, Pr: propyl, ⁱ Pr: isopropyl, Bu: butyl, ⁱ Bu: isobutyl, ^t Bu: tert-butyl, Ph: phenyl, Ac: acetyl, Boc: tert-butoxycarbonyl, THF: Tetrahydrofuran, E: ethanol, M: methanol, IP: isopropanol, A: acetone, H: hexane, DE: diethyl ether, EA: ethyl acetate, DIP: diisopropyl ether, AN: acetonitrile, DMF: N, N-dimethylformamide, TEA: triethylamine, s: single line, d: double line, t: triple line, q: quadruple line, quint: quintet line, dd: two double lines, td: three double lines, ddd: four double lines, sex: hexagonal line, m: multiple line, brs: wide single line, br d: wide Doublet, br t: broad triplet, br q: broad quartet, brdd: broad two doublets, J: coupling constant.

Reference example 1:
Production of 1- (tert-butoxycarbonyl) -3-[(p-toluenesulfonyloxy) methyl] azetidine:

（１）１−ジフェニルメチル−３−ヒドロキシアゼチジン１．０ｇおよびＴＥＡ１．１１ｍｌの塩化メチレン５ｍｌ溶液に塩化メタンスルホニル０．７２ｇの塩化メチレン５ｍｌ溶液を氷冷却下、２０分かけて滴下した。終了後、反応液の内温を室温に昇温し、２時間攪拌した。反応液に水を加え、クロロホルムで抽出し、抽出液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘキサン〜ヘキサン／酢酸エチル＝７／３）で精製し、１−ジフェニルメチル−３−メタンスルホニルオキシアゼチジン１．０ｇを白色粉状物として得た。
¹H-NMR (CDCl₃, δppm); 2.98 (3H, s), 3.14-3.25 (2H, m), 3.59-3.68 (2H, m), 4.40 (1H, s), 5.10 (1H, quint, J = 5.9 Hz), 7.15-7.3, 7.3-7.4 (10H, m). LC-MS, m/z; 318 (MH⁺).
（２）上記生成物０．７７ｇ、シアン化ナトリウム０．１８ｇおよびＤＭＦ７ｍｌの混合物を攪拌下、７０℃で７時間加温した。反応液に氷水を加え、析出した固体を減圧濾取、水洗後、乾燥し、３−シアノ−１−ジフェニルメチルアゼチジン０．４８ｇを黄色粉状物として得た。
¹H-NMR (CDCl₃, δppm); 3.2-3.33 (3H, m), 3.42-3.53 (2H, m), 4.36 (1H, s), 7.15-7.3, 7.3-7.45 (10H, m). LC-MS, m/z; 249 (MH⁺).
（３）上記生成物５．７９ｇ、水酸化ナトリウム２．５７ｇおよび５０％含水エタノール５０ｍｌの混合物を攪拌下、６時間加熱還流した。０℃に冷却後、濃塩酸でｐＨ３に調節し、クロロホルムで抽出した。抽出液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、１−ジフェニルメチルアゼチジン−３−カルボン酸約６．５ｇを黄色アモルファス状固体として得た。この固体は精製することなく次の工程に用いた。
（４）上記生成物約６．５ｇのメタノール６０ｍｌ溶液に濃硫酸６ｍｌを加え、撹拌下、１時間加熱還流した。室温に冷却後、溶媒を減圧留去し、残渣をクロロホルムに溶解した。この溶液を水、５％炭酸水素ナトリウム水溶液、水、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、１−ジフェニルメチルアゼチジン−３−カルボン酸メチルエステル４．９ｇを茶色粉状物として得た。
¹H-NMR (CDCl₃, δppm); 3.2-3.4, 3.4-3.5 (5H, m), 3.69 (3H, s), 4.39 (1H, s), 7.2-7.3, 7.3-7.45 (10H, m). LC-MS, m/z; 282 (MH⁺).
（５）水素化リチウムアルミニウム１．３２ｇの無水ＴＨＦ５０ｍｌ懸濁液に上記生成物４．９ｇの無水ＴＨＦ２０ｍｌ溶液を内温０℃で１５分かけて滴下した。同温度で３０分間攪拌した後、反応液に飽和酒石酸カリウムナトリウム水溶液を少量ずつ滴下して過剰の水素化リチウムアルミニウムを分解した。上澄みのＴＨＦを濾過し、不溶物をＴＨＦで洗浄後、合わせたＴＨＦを無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９７／３）で精製し、１−ジフェニルメチル−３−アゼチジンメタノール３．５６ｇを黄色油状物として得た。この油状物は精製することなく次の工程に用いた。
（６）上記生成物３．７４ｇのエタノール７０ｍｌ溶液に１０％パラジウム炭素１．１ｇを加え、常圧下、５０℃で水素添加した。理論量の水素吸収後、反応液を室温に冷却、セライトに通すことで触媒を除き、濾液に二炭酸ジ−ｔｅｒｔ−ブチル３．５６ｇを加えて、室温で２時間攪拌した。反応液を減圧乾固し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９６／４）で精製し、１−（ｔｅｒｔ−ブトキシカルボニル）−３−アゼチジンメタノール２．６６ｇを白色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.44 (9H, s), 1.7 (1H, br s), 2.70 (1H, m), 3.69 (2H, dd, J = 5.1, 8.6 Hz), 3.78 (2H, br t, J = 5.1 Hz), 3.99 (2H, dd, J = 8.6, 8.6 Hz). LC-MS, m/z; 188 (MH⁺).
（７）上記生成物２．６６ｇ、塩化ｐ−トルエンスルホニル２．４０ｇ、ＴＥＡ２．９８ｍｌ、４−ジメチルアミノピリジン０．１７ｇおよび塩化メチレン２７ｍｌの混合物を室温下、１日攪拌した。反応液を減圧乾固し、残渣に酢酸エチルを加えた後、水、３０％炭酸水素ナトリウム水溶液、３０％クエン酸水溶液、水、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、標記化合物３．９９ｇを黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.42 (9H, s), 2.46 (3H, s), 2.85 (1H, m), 3.59 (2H, br dd, J = 5.3, 8.7 Hz), 3.96 (2H, dd, J = 8.7, 8.7 Hz), 4.14 (2H, d, J = 7.0 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz). LC-MS, m/z; 242.

(1) To a solution of 1.0 g of 1-diphenylmethyl-3-hydroxyazetidine and 1.11 ml of TEA in 5 ml of methylene chloride was added dropwise a solution of 0.72 g of methanesulfonyl chloride in 5 ml of methylene chloride over 20 minutes under ice cooling. After completion, the internal temperature of the reaction solution was raised to room temperature and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane to hexane / ethyl acetate = 7/3) to obtain 1.0 g of 1-diphenylmethyl-3-methanesulfonyloxyazetidine as a white powder.
¹ H-NMR (CDCl ₃ , δppm); 2.98 (3H, s), 3.14-3.25 (2H, m), 3.59-3.68 (2H, m), 4.40 (1H, s), 5.10 (1H, quint, J = 5.9 Hz), 7.15-7.3, 7.3-7.4 (10H, m). LC-MS, m / z; 318 (MH ⁺ ).
(2) A mixture of 0.77 g of the above product, 0.18 g of sodium cyanide and 7 ml of DMF was heated at 70 ° C. for 7 hours with stirring. Ice water was added to the reaction solution, and the precipitated solid was collected by filtration under reduced pressure, washed with water, and dried to obtain 0.48 g of 3-cyano-1-diphenylmethylazetidine as a yellow powder.
¹ H-NMR (CDCl ₃ , δppm); 3.2-3.33 (3H, m), 3.42-3.53 (2H, m), 4.36 (1H, s), 7.15-7.3, 7.3-7.45 (10H, m). LC -MS, m / z; 249 (MH ⁺ ).
(3) A mixture of 5.79 g of the above product, 2.57 g of sodium hydroxide and 50 ml of 50% aqueous ethanol was heated to reflux with stirring for 6 hours. After cooling to 0 ° C., the mixture was adjusted to pH 3 with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain about 6.5 g of 1-diphenylmethylazetidine-3-carboxylic acid as a yellow amorphous solid. . This solid was used in the next step without purification.
(4) 6 ml of concentrated sulfuric acid was added to a solution of about 6.5 g of the above product in 60 ml of methanol, and the mixture was heated to reflux for 1 hour with stirring. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. This solution was washed with water, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-diphenylmethylazetidine-3-carboxylic acid methyl ester 4 .9 g was obtained as a brown powder.
¹ H-NMR (CDCl ₃ , δppm); 3.2-3.4, 3.4-3.5 (5H, m), 3.69 (3H, s), 4.39 (1H, s), 7.2-7.3, 7.3-7.45 (10H, m) LC-MS, m / z; 282 (MH ⁺ ).
(5) A solution of 4.9 g of the above product in 20 ml of anhydrous THF was added dropwise to a suspension of 1.32 g of lithium aluminum hydride in 50 ml of anhydrous THF at an internal temperature of 0 ° C. over 15 minutes. After stirring for 30 minutes at the same temperature, a saturated potassium sodium tartrate aqueous solution was added dropwise to the reaction solution little by little to decompose excess lithium aluminum hydride. The supernatant THF was filtered, the insoluble matter was washed with THF, the combined THF was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 97/3) to obtain 3.56 g of 1-diphenylmethyl-3-azetidinemethanol as a yellow oil. This oil was used in the next step without purification.
(6) 1.1 g of 10% palladium carbon was added to a solution of 3.74 g of the above product in 70 ml of ethanol, and hydrogenated at 50 ° C. under normal pressure. After absorbing the theoretical amount of hydrogen, the reaction solution was cooled to room temperature and passed through Celite to remove the catalyst, and 3.56 g of di-tert-butyl dicarbonate was added to the filtrate, followed by stirring at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 96/4) to give 2.66 g of 1- (tert-butoxycarbonyl) -3-azetidinemethanol as a white oil. Obtained as a thing.
¹ H-NMR (CDCl ₃ , δppm); 1.44 (9H, s), 1.7 (1H, br s), 2.70 (1H, m), 3.69 (2H, dd, J = 5.1, 8.6 Hz), 3.78 (2H , br t, J = 5.1 Hz), 3.99 (2H, dd, J = 8.6, 8.6 Hz). LC-MS, m / z; 188 (MH ⁺ ).
(7) A mixture of the above product 2.66 g, p-toluenesulfonyl chloride 2.40 g, TEA 2.98 ml, 4-dimethylaminopyridine 0.17 g and methylene chloride 27 ml was stirred at room temperature for 1 day. The reaction solution was evaporated to dryness, ethyl acetate was added to the residue, washed with water, 30% aqueous sodium hydrogen carbonate solution, 30% aqueous citric acid solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. Was distilled off under reduced pressure to obtain 3.99 g of the title compound as a yellow oily substance.
¹ H-NMR (CDCl ₃ , δppm); 1.42 (9H, s), 2.46 (3H, s), 2.85 (1H, m), 3.59 (2H, br dd, J = 5.3, 8.7 Hz), 3.96 (2H , dd, J = 8.7, 8.7 Hz), 4.14 (2H, d, J = 7.0 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz). LC-MS , m / z; 242.

Reference example 2:
Preparation of 4-amino-5-chloro-2-methoxy-N- (2-morpholinylmethyl) benzamide:

（１）Ｎ−［（４−ベンジル−２−モルホリニル）メチル］フタルイミド（S. Kato, et al., J. Med. Chem., (1990) 33, 1406-1413）２．０ｇの３Ｎ塩酸４８ｍｌ、水１０ｍｌおよびエタノール１５ｍｌの懸濁液に１０％パラジウム炭素０．３ｇを加え、室温で４ｋｇｆ／ｃｍ^２下、１８時間水素添加した。原料の消失を確認後、反応液をセライトに通すことで触媒を除き、濾液に過剰の粉末炭酸カリウムを加えてアルカリ性にした後、クロロホルムで抽出した。抽出液を無水硫酸マグネシウムで乾燥、溶媒を減圧留去してＮ−（２−モルホリニルメチル）フタルイミド１．４５ｇを固体として得た。
¹H-NMR (CDCl₃, δppm); 2.66 (1H, dd, J = 9.5, 12.1 Hz), 2.77 (1H, br d, J = 12.3 Hz), 2.86 (1H, dd, J = 3.3, 14.1 Hz), 2.96 (1H, dd, J = 2.0, 12.5 Hz), 3.52 (1H, td, J = 2.9, 13.9 Hz), 3.63 (1H, dd, J = 3.9, 16.8 Hz), 3.73-3.88 (4H, m), 7.68-7.78 (2H, m), 7.82-7.92 (2H, m). LC-MS, m/z; 247 （ＭＨ^＋）．
（２）上記生成物１．０ｇおよびＴＥＡ０．４１ｇのメタノール１０ｍｌ溶液に二炭酸ジ−ｔｅｒｔ−ブチル０．９８ｇのメタノール５ｍｌ溶液を少量ずつ加え、終了後、室温で４時間攪拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解後、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製してＮ−〔｛４−（ｔｅｒｔ−ブトキシカルボニル）−２−モルホリニル｝メチル〕フタルイミド１．４ｇを白色粉状物として得た。
¹H-NMR (CDCl₃, δppm); 1.46 (9H, s), 2.75 (1H, br d like), 3.0 (1H, br t like), 3.45 (1H, m), 3.6-4.1 (6H, m), 7.7-7.85 (2H, m), 7.85-8.0 (2H, m). LC-MS, m/z; 247.
（３）上記生成物１．４ｇおよびヒドラジン・一水和物０．１８ｇのエタノール１０ｍｌ溶液を撹拌下、１．５時間加熱還流した。室温に冷却後、溶媒を減圧留去し、残渣に３０％クエン酸水溶液を加えて不溶物を減圧濾去した。濾液をクロロホルムで洗浄、２Ｎ水酸化ナトリウム水溶液でｐＨ１０にした後、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、２−アミノメチル−４−（ｔｅｒｔ−ブトキシカルボニル）モルホリン０．３４ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.46 (9H, s), 1.8 (2H, br s), 2.55-2.85 (3H, m), 2.93 (1H, br d like), 3.37 (1H, m), 3.53 (1H, td, J = 2.8, 14.4 Hz), 3.7-3.95 (3H, m). LC-MS, m/z; 217 (MH⁺), 117.
（４）４−アミノ−５−クロロ−２−メトキシ安息香酸０．３２ｇおよびＮ，Ｎ’−カルボニルジイミダゾール０．３０ｇのＴＨＦ１０ｍｌ懸濁液に上記生成物０．３４ｇのＴＨＦ２ｍｌ溶液を加え、室温で３日間撹拌した。反応液に水を加え、減圧濃縮して析出した不溶物を減圧濾取した後、水洗、乾燥して４−アミノ−Ｎ−［｛４−（ｔｅｒｔ−ブトキシカルボニル）−２−モルホリニル｝メチル］−５−クロロ−２−メトキシベンズアミド０．５ｇを白色粉状物として得た。 LC-MS, m/z; 400 (MH⁺), 300.
（５）上記生成物８．０ｇのエタノール４０ｍｌ溶液に濃塩酸４０ｍｌを加え、室温で１時間撹拌した。反応液を減圧濃縮し、氷冷却下、２Ｎ水酸化ナトリウム水溶液でｐＨ １０にした後、クロロホルムで抽出した。抽出液を水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して標記化合物６．０ｇを白色粉状物として得た。 LC-MS, m/z; 300 (MH⁺).

(1) N-[(4-benzyl-2-morpholinyl) methyl] phthalimide (S. Kato, et al., J. Med. Chem., (1990) 33 , 1406-1413) 48 g of 3N hydrochloric acid 48 ml Then, 0.3 g of 10% palladium carbon was added to a suspension of 10 ml of water and 15 ml of ethanol, and hydrogenated at room temperature under 4 kgf / cm ² for 18 hours. After confirming disappearance of the raw materials, the catalyst was removed by passing the reaction solution through Celite, and the filtrate was made alkaline by adding excess powdered potassium carbonate, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.45 g of N- (2-morpholinylmethyl) phthalimide as a solid.
¹ H-NMR (CDCl ₃ , δppm); 2.66 (1H, dd, J = 9.5, 12.1 Hz), 2.77 (1H, br d, J = 12.3 Hz), 2.86 (1H, dd, J = 3.3, 14.1 Hz ), 2.96 (1H, dd, J = 2.0, 12.5 Hz), 3.52 (1H, td, J = 2.9, 13.9 Hz), 3.63 (1H, dd, J = 3.9, 16.8 Hz), 3.73-3.88 (4H, m), 7.68-7.78 (2H, m), 7.82-7.92 (2H, m). LC-MS, m / z; 247 (MH ⁺ ).
(2) To a solution of 1.0 g of the above product and 0.41 g of TEA in 10 ml of methanol, a solution of 0.98 g of di-tert-butyl dicarbonate in 5 ml of methanol was added little by little. The reaction solution was evaporated to dryness, the residue was dissolved in chloroform, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to give N-[{4- (tert-butoxycarbonyl) -2-morpholinyl} methyl] phthalimide 1 0.4 g was obtained as a white powder.
¹ H-NMR (CDCl ₃ , δppm); 1.46 (9H, s), 2.75 (1H, br d like), 3.0 (1H, br t like), 3.45 (1H, m), 3.6-4.1 (6H, m ), 7.7-7.85 (2H, m), 7.85-8.0 (2H, m). LC-MS, m / z; 247.
(3) A solution of 1.4 g of the above product and 0.18 g of hydrazine monohydrate in 10 ml of ethanol was heated to reflux with stirring for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, 30% aqueous citric acid solution was added to the residue, and the insoluble material was filtered off under reduced pressure. The filtrate was washed with chloroform, adjusted to pH 10 with 2N aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 0.34 g of 2-aminomethyl-4- (tert-butoxycarbonyl) morpholine as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.46 (9H, s), 1.8 (2H, br s), 2.55-2.85 (3H, m), 2.93 (1H, br d like), 3.37 (1H, m) , 3.53 (1H, td, J = 2.8, 14.4 Hz), 3.7-3.95 (3H, m). LC-MS, m / z; 217 (MH ⁺ ), 117.
(4) To a suspension of 0.32 g of 4-amino-5-chloro-2-methoxybenzoic acid and 0.30 g of N, N′-carbonyldiimidazole in 10 ml of THF was added a solution of 0.34 g of the above product in 2 ml of THF, and room temperature. For 3 days. Water was added to the reaction solution, and the insoluble matter precipitated by vacuum concentration was collected by filtration, washed with water and dried to give 4-amino-N-[{4- (tert-butoxycarbonyl) -2-morpholinyl} methyl]. 0.5 g of -5-chloro-2-methoxybenzamide was obtained as a white powder. LC-MS, m / z; 400 (MH ⁺ ), 300.
(5) To a solution of 8.0 g of the above product in 40 ml of ethanol, 40 ml of concentrated hydrochloric acid was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, adjusted to pH 10 with 2N aqueous sodium hydroxide solution under ice cooling, and extracted with chloroform. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 6.0 g of the title compound as a white powder. LC-MS, m / z; 300 (MH ⁺ ).

Reference Example 3:
Preparation of 4-amino-5-chloro-N-[(1,4-hexahydrooxazepin-2-yl) methyl] -2-methoxybenzamide:

（１）２−アミノメチル−４−ベンジル−１，４−ヘキサヒドロオキサゼピン（H. Harada, et al., Chem. Pharm, Bull., (1995) 43, 1364-1378）１．７５ｇおよび炭酸水素ナトリウム２．０ｇの塩化メチレン１０ｍｌおよび水１０ｍｌ混合溶液に０℃で塩化アセチル１．７３ｍｌを滴下した。終了後、同温度で０．５時間攪拌した。有機層を分取し、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９５／５）で精製して２−アセチルアミノメチル−４−ベンジル−１，４−ヘキサヒドロオキサゼピン１．６６ｇを黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.75-2.0 (2H, m), 1.94 (3H, s), 2.44 (1H, dd, J = 5.9, 13.6 Hz), 2.55-2.8 (3H, m), 3.0 (1H, m), 3.45 (1H, m), 3.64 (2H, dd like), 3.65-3.85 (2H, m), 3.9 (1H, m), 5.75 (1H, br s), 7.2-7.45 (5H, m). LC-MS, m/z; 263 (MH⁺).
（２）上記生成物１．６６ｇのエタノール２０ｍｌおよび酢酸３ｍｌ混合溶液に１０％パラジウム炭素０．５ｇを加え、５０℃で常圧下、水素添加した。理論量の水素を吸収した後（約２時間）、反応液をセライトに通すことで触媒を除き、濾液にＴＥＡ５ｍｌおよび二炭酸ジ−ｔｅｒｔ−ブチル１．６０ｇを加え、溶液を室温で１日間攪拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解した後、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、２−アセチルアミノメチル−４−（ｔｅｒｔ−ブトキシカルボニル）−１，４−ヘキサヒドロオキサゼピン１．６８ｇを黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.47 (9H, s), 1.75 (1H, m), 1.8-2.0 (2H, m), 2.00 (3H, s), 2.9-3.7 (6H, m), 3.76 (1H, dd, J = 3.0, 14.4 Hz), 4.05 (1H, m), 5.85, 6.00 (1H, br s). LC-MS, m/z; 173.
（３）上記生成物１．６８ｇおよび粒状の水酸化ナトリウム２．２３ｇの５０％含水エタノール１６ｍｌ溶液を攪拌下、４時間加熱還流した。室温に冷却後、反応溶液を減圧乾固し、残渣をクロロホルムに溶解し、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、２−アミノメチル−４−（ｔｅｒｔ−ブトキシカルボニル）−１，４−ヘキサヒドロオキサゼピン１．１８ｇを黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.47 (9H, s), 1.7-2.1 (3H, m), 2.7 (1H, m), 2.95 (1H, m), 3.3 (1H, m), 3.45 (2H, m), 3.7 (2H, m), 4.1 (1H, m). LC-MS, m/z; 231 (MH⁺), 131.
（４）上記生成物１．１８ｇ、４−アミノ−５−クロロ−２−メトキシ安息香酸１．０３ｇ、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド１．２８ｇおよび塩化メチレン１０ｍｌの混合物を室温で終夜攪拌した。反応液を水、１Ｎ水酸化ナトリウム水溶液、水、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９９／１）で精製し、４−アミノ−Ｎ−［〔４−（ｔｅｒｔ−ブトキシカルボニル）−１，４−ヘキサヒドロオキサゼピン−２−イル〕メチル］−５−クロロ−２−メトキシベンズアミド１．２４ｇを白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.45 (9H, s), 1.75-2.05 (2H, m), 3.05 (1H, m), 3.1-3.5, 3.5-4.0 (7H, m), 3.90 (3H, s), 4.1 (1H, m), 4.40 (2H, br s), 6.29 (1H, s), 8.05 (1H, br s like), 8.10 (1H, s). LC-MS, m/z; 414 (MH⁺), 314.
（５）参考例２（５）の４−アミノ−Ｎ−［｛４−（ｔｅｒｔ−ブトキシカルボニル）−２−モルホリニル｝メチル］−５−クロロ−２−メトキシベンズアミドの代わりに上記生成物を用い、参考例２（５）と同様に反応・処理して標記化合物を白色粉状物として得た。
¹H-NMR (DMSO-d₆, δppm); 1.7-1.8 (2H, m), 2.7 (1H, m), 2.75-3.0 (1H, m), 3.10 (1H, m), 3.35 (1H, m), 3.5-3.7 (2H, m), 3.8-4.0 (2H, m), 3.83 (3H, s), 5.94 (2H, s), 6.48 (1H, s), 7.70 (1H, s), 8.05 (1H, t like, J = 5.2 Hz). LC-MS, m/z; 314 (MH⁺).

(1) 1.75 g of 2-aminomethyl-4-benzyl-1,4-hexahydrooxazepine (H. Harada, et al., Chem. Pharm, Bull., (1995) 43 , 1364-1378) and To a mixed solution of 2.0 g of sodium bicarbonate in 10 ml of methylene chloride and 10 ml of water, 1.73 ml of acetyl chloride was added dropwise at 0 ° C. After completion, the mixture was stirred at the same temperature for 0.5 hour. The organic layer was separated, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 95/5) to give 1.66 g of 2-acetylaminomethyl-4-benzyl-1,4-hexahydrooxazepine as a yellow oil. It was.
¹ H-NMR (CDCl ₃ , δppm); 1.75-2.0 (2H, m), 1.94 (3H, s), 2.44 (1H, dd, J = 5.9, 13.6 Hz), 2.55-2.8 (3H, m), 3.0 (1H, m), 3.45 (1H, m), 3.64 (2H, dd like), 3.65-3.85 (2H, m), 3.9 (1H, m), 5.75 (1H, br s), 7.2-7.45 ( 5H, m). LC-MS, m / z; 263 (MH ⁺ ).
(2) 0.5% of 10% palladium carbon was added to a mixed solution of 1.66 g of the above product in 20 ml of ethanol and 3 ml of acetic acid, and hydrogenated at 50 ° C. under normal pressure. After absorbing the theoretical amount of hydrogen (about 2 hours), the catalyst was removed by passing the reaction through Celite, 5 ml of TEA and 1.60 g of di-tert-butyl dicarbonate were added to the filtrate, and the solution was stirred at room temperature for 1 day. did. The reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.68 g of 2-acetylaminomethyl-4- (tert-butoxycarbonyl) -1,4-hexahydrooxazepine as a yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.47 (9H, s), 1.75 (1H, m), 1.8-2.0 (2H, m), 2.00 (3H, s), 2.9-3.7 (6H, m), 3.76 (1H, dd, J = 3.0, 14.4 Hz), 4.05 (1H, m), 5.85, 6.00 (1H, br s). LC-MS, m / z; 173.
(3) A solution of 1.68 g of the product and 2.23 g of granular sodium hydroxide in 16 ml of 50% aqueous ethanol was heated to reflux with stirring for 4 hours. After cooling to room temperature, the reaction solution was dried under reduced pressure, the residue was dissolved in chloroform, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.18 g of 2-aminomethyl-4- (tert-butoxycarbonyl) -1,4-hexahydrooxazepine as a yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.47 (9H, s), 1.7-2.1 (3H, m), 2.7 (1H, m), 2.95 (1H, m), 3.3 (1H, m), 3.45 ( 2H, m), 3.7 (2H, m), 4.1 (1H, m). LC-MS, m / z; 231 (MH ⁺ ), 131.
(4) 1.18 g of the above product, 1.03 g of 4-amino-5-chloro-2-methoxybenzoic acid, 1.28 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 10 ml of methylene chloride. The mixture was stirred at room temperature overnight. The reaction solution was washed with water, 1N aqueous sodium hydroxide solution, water and saturated brine in that order, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 99/1) to give 4-amino-N-[[4- (tert-butoxycarbonyl) -1,4-hexahydrooxazepine-2. There was obtained 1.24 g of -yl] methyl] -5-chloro-2-methoxybenzamide as a white amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 1.45 (9H, s), 1.75-2.05 (2H, m), 3.05 (1H, m), 3.1-3.5, 3.5-4.0 (7H, m), 3.90 (3H , s), 4.1 (1H, m), 4.40 (2H, br s), 6.29 (1H, s), 8.05 (1H, br s like), 8.10 (1H, s). LC-MS, m / z; 414 (MH ⁺ ), 314.
(5) The above product was used instead of 4-amino-N-[{4- (tert-butoxycarbonyl) -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide of Reference Example 2 (5). The title compound was obtained as a white powder by reaction and treatment in the same manner as in Reference Example 2 (5).
¹ H-NMR (DMSO-d ₆ , δppm); 1.7-1.8 (2H, m), 2.7 (1H, m), 2.75-3.0 (1H, m), 3.10 (1H, m), 3.35 (1H, m ), 3.5-3.7 (2H, m), 3.8-4.0 (2H, m), 3.83 (3H, s), 5.94 (2H, s), 6.48 (1H, s), 7.70 (1H, s), 8.05 ( 1H, t like, J = 5.2 Hz) .LC-MS, m / z; 314 (MH ⁺ ).

  The compounds of Reference Examples 4 to 9 below were produced in the same manner as in Reference Example 2. All of the products were white powder.

Reference Example 9 (Alternative method):
Preparation of 4-amino-5-bromo-2-methoxy-N- (2-morpholinylmethyl) benzamide:

（１）４−アミノ−Ｎ−［（４−ベンジル−２−モルホリニル）メチル］−５−クロロ−２−メトキシベンズアミド（S. Kato, et al., J. Med. Chem., (1990) 33, 1406-1413）４５．０ｇをエタノール６５０ｍｌ、酢酸１００ｍｌおよび水５０ｍｌの混合溶媒に溶解した後、１０％パラジウム炭素４ｇを加え、常圧下、約５０℃で水素添加した。理論量の水素吸収後（約３時間）、反応液を室温に冷却し、反応液をセライトに通すことで触媒を除いた。濾液を減圧濃縮し、３０％水酸化カリウム水溶液でアルカリ性にした後、析出した粉状物を減圧濾取、水洗、乾燥して４−アミノ−２−メトキシ−Ｎ−（２−モルホリニルメチル）ベンズアミド２３．２ｇを得た。 LC-MS, m/z; 266 (MH⁺).
（２）上記生成物４８．５ｇのメタノール４００ｍｌ懸濁液に無水酢酸５２．８ｇを加え、室温で３時間撹拌した。溶媒を減圧留去、残渣を水に溶解し、氷冷却下、３０％水酸化カリウム水溶液でアルカリ性にした後、クロロホルムで抽出した。抽出液を水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去してＮ−〔（４−アセチル−２−モルホリニル）メチル〕−４−アセチルアミノ−２−メトキシベンズアミド５０．０ｇを淡褐色アモルファス状固体として得た。 LC-MS, m/z; 350 (MH⁺).
（３）上記生成物５０．０ｇおよびＮ−ブロモコハク酸イミド２４．４ｇのＤＭＦ３００ｍｌ溶液を７０℃で１時間攪拌した。室温に冷却後、反応溶液を減圧乾固し、残渣に水を加え、析出した結晶を減圧濾取して白色のＮ−〔（４−アセチル−２−モルホリニル）メチル〕−４−アセチルアミノ−５−ブロモ−２−メトキシベンズアミドを得た。この結晶は乾燥することなく次の工程に進んだ。 LC-MS, m/z; 430 (MH⁺).
（４）上記化合物に１０％塩酸３６０ｍｌを加え、その懸濁液を攪拌下、３時間加熱還流した。反応液を氷冷却後、３０％水酸化カリウム水溶液でアルカリ性にし、クロロホルムで抽出した。抽出液を水、続いて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して標記化合物２５．０ｇを白色粉状物として得た。

(1) 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-methoxybenzamide (S. Kato, et al., J. Med. Chem., (1990) 33 , 1406-1413) 45.0 g was dissolved in a mixed solvent of 650 ml of ethanol, 100 ml of acetic acid and 50 ml of water, 4 g of 10% palladium carbon was added, and hydrogenated at about 50 ° C. under normal pressure. After absorbing the theoretical amount of hydrogen (about 3 hours), the reaction solution was cooled to room temperature, and the catalyst was removed by passing the reaction solution through Celite. The filtrate was concentrated under reduced pressure, made alkaline with a 30% aqueous potassium hydroxide solution, and the precipitated powder was collected by filtration under reduced pressure, washed with water and dried to give 4-amino-2-methoxy-N- (2-morpholinylmethyl). ) 23.2 g of benzamide were obtained. LC-MS, m / z; 266 (MH ⁺ ).
(2) To a suspension of 48.5 g of the above product in 400 ml of methanol was added 52.8 g of acetic anhydride, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, made alkaline with 30% aqueous potassium hydroxide under ice cooling, and extracted with chloroform. The extract was washed with water and then with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to remove N-[(4-acetyl-2-morpholinyl) methyl] -4-acetylamino-2-methoxy. Benzamide 50.0 g was obtained as a light brown amorphous solid. LC-MS, m / z; 350 (MH ⁺ ).
(3) A solution of 50.0 g of the above product and 24.4 g of N-bromosuccinimide in 300 ml of DMF was stirred at 70 ° C. for 1 hour. After cooling to room temperature, the reaction solution was evaporated to dryness, water was added to the residue, and the precipitated crystals were collected by filtration under reduced pressure to give white N-[(4-acetyl-2-morpholinyl) methyl] -4-acetylamino- 5-Bromo-2-methoxybenzamide was obtained. The crystals proceeded to the next step without drying. LC-MS, m / z; 430 (MH ⁺ ).
(4) To the above compound was added 360 ml of 10% hydrochloric acid, and the suspension was heated to reflux with stirring for 3 hours. The reaction mixture was cooled with ice, made alkaline with 30% aqueous potassium hydroxide, and extracted with chloroform. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 25.0 g of the title compound as a white powder.

  The following compounds of Reference Examples 10 to 11 were produced in the same manner as in Reference Example 9 (another method). All of the products were white powder.

Reference Example 12:
Preparation of 2-aminomethyl-4- [1- (tert-butoxycarbonyl) -4-piperidinylmethyl] morpholine:

（１）２−アセチルアミノメチル−４−ベンジルモルホリン（S. Kato, et al., J. Med. Chem., (1990) 33, 1406-1413）５６．２ｇのエタノール８００ｍｌ、酢酸８０ｍｌおよび水２０ｍｌの溶液に１０％パラジウム炭素６ｇを加え、約５０℃で常圧下、水素添加した。理論量の水素吸収後、室温に冷却した反応液をセライトに通すことで触媒を除き、濾液を減圧留去した。２−アセチルアミノメチルモルホリンを含む無色油状の残渣に１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジン８３．７ｇ、無水炭酸カリウム１５６．６ｇ、ヨウ化カリウム５ｇおよびアセトニトリル１５００ｍｌを加え、混合物を攪拌下、１日間加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣をクロロホルムに溶解した。水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル〜酢酸エチル／メタノール＝９／１）で精製して２−アセチルアミノメチル−４−〔｛１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニル｝メチル〕モルホリン５８．５ｇを淡黄褐色油状物として得た。 LC-MS, m/z; 356 (MH⁺).
（２） 上記生成物４６．８ｇのエタノール３００ｍｌ溶液に水酸化カリウム水溶液（水酸化カリウム７３．３ｇ／水５００ｍｌ）を加え、攪拌下、６２時間加熱還流した。室温に冷却後、溶媒を減圧留去し、残渣をクロロホルムに溶解した。水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して標記化合物３９．３ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 0.95-1.25 (3H, m), 1.46 (9H, s), 1.5-1.8 (5H, m), 2.0-2.2 (3H, m), 2.6-2.8 (6H,m), 3.45 (1H, m), 3.65 (1H, td, J = 2.4, 13.7 Hz), 3.86 (1H, d like, J = 9.7 Hz), 4.07 (2H, br d). LC-MS, m/z; 314 (MH⁺).

(1) 2-acetylaminomethyl-4-benzylmorpholine (S. Kato, et al., J. Med. Chem., (1990) 33 , 1406-1413) 56.2 g of ethanol 800 ml, acetic acid 80 ml and water 20 ml To this solution, 6 g of 10% palladium carbon was added, and hydrogenated at about 50 ° C. under normal pressure. After absorbing the theoretical amount of hydrogen, the reaction solution cooled to room temperature was passed through Celite to remove the catalyst, and the filtrate was distilled off under reduced pressure. To a colorless oily residue containing 2-acetylaminomethylmorpholine, 83.7 g of 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine, 156.6 g of anhydrous potassium carbonate, 5 g of potassium iodide And 1500 ml of acetonitrile were added and the mixture was heated to reflux with stirring for 1 day. After cooling to room temperature, the reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform. The extract was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethyl acetate / methanol = 9/1) to give 2-acetylaminomethyl-4-[{1- (tert-butoxycarbonyl). ) -4-piperidinyl} methyl] morpholine was obtained as a pale tan oil. LC-MS, m / z; 356 (MH ⁺ ).
(2) A potassium hydroxide aqueous solution (73.3 g of potassium hydroxide / 500 ml of water) was added to a solution of 46.8 g of the above product in 300 ml of ethanol, and the mixture was heated to reflux for 62 hours with stirring. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The extract was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 39.3 g of the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 0.95-1.25 (3H, m), 1.46 (9H, s), 1.5-1.8 (5H, m), 2.0-2.2 (3H, m), 2.6-2.8 (6H , m), 3.45 (1H, m), 3.65 (1H, td, J = 2.4, 13.7 Hz), 3.86 (1H, d like, J = 9.7 Hz), 4.07 (2H, br d). LC-MS, m / z; 314 (MH ⁺ ).

Reference Example 12 (Alternative Method 1):
Preparation of 2-aminomethyl-4-[{1- (tert-butoxycarbonyl) -4-piperidinyl} methyl] morpholine:

（１）Ｎ−（２−モルホリニルメチル）フタルイミド（参考例２（２））１．５ｇ、１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジン２．１５ｇ、無水炭酸カリウム２．５２ｇ、ヨウ化カリウム０．９１ｇおよびアセトニトリル３５ｍｌの混合物を攪拌下、終夜加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣を酢酸エチルに溶解した。水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去してＮ−［｛４−〔（１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニル）メチル〕−２−モルホリニル｝メチル］フタルイミド１．７５ｇ白色固体として得た。
¹H-NMR (CDCl₃, δppm); 0.9-1.15 (2H, m), 1.45 (9H, s), 1.5-1.8 (3H, m), 1.98 (1H, t, J = 10.1 Hz), 2.16 (3H, d like, J = 6.8 Hz), 2.5-2.85 (4H, m), 3.5-3.8 (2H,m), 3.8-4.9 (3H, m), 4.1 (2H, br s), 7.6-7.8 (2H, m), 7.8-7.9 (2H, m). LC-MS, m/z; 444 (MH⁺).
（２）参考例２（３）のＮ−〔｛４−（ｔｅｒｔ−ブトキシカルボニル）−２−モルホリニル｝メチル〕フタルイミドの代わりに上記生成物を用い、参考例２（３）と同様に反応・処理して標記化合物を淡黄色油状物として得た。

(1) 1.5 g of N- (2-morpholinylmethyl) phthalimide (Reference Example 2 (2)), 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine A mixture of 15 g, anhydrous potassium carbonate 2.52 g, potassium iodide 0.91 g and acetonitrile 35 ml was heated to reflux overnight with stirring. After cooling to room temperature, the reaction solution was dried under reduced pressure, and the residue was dissolved in ethyl acetate. The extract was washed with water and then with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2. -Morpholinyl} methyl] phthalimide 1.75 g was obtained as a white solid.
¹ H-NMR (CDCl ₃ , δppm); 0.9-1.15 (2H, m), 1.45 (9H, s), 1.5-1.8 (3H, m), 1.98 (1H, t, J = 10.1 Hz), 2.16 ( 3H, d like, J = 6.8 Hz), 2.5-2.85 (4H, m), 3.5-3.8 (2H, m), 3.8-4.9 (3H, m), 4.1 (2H, br s), 7.6-7.8 ( 2H, m), 7.8-7.9 (2H, m). LC-MS, m / z; 444 (MH ⁺ ).
(2) The above product was used in place of N-[{4- (tert-butoxycarbonyl) -2-morpholinyl} methyl] phthalimide in Reference Example 2 (3), and the reaction was conducted in the same manner as in Reference Example 2 (3). Treatment gave the title compound as a pale yellow oil.

Reference Example 12 (Alternative Method 2):
Preparation of 2-aminomethyl-4-[{1- (tert-butoxycarbonyl) -4-piperidinyl} methyl] morpholine:

（１）激しく攪拌している２−アミノメチル−４−（４−フルオロベンジル）モルホリン（S. Kato, et al., J. Med. Chem., (1991) 34, 616-624）２２．９ｇのクロロホルム２００ｍｌおよび１Ｎ水酸化ナトリウム水溶液１００ｍｌの混合溶液中に氷冷却下、クロロギ酸ベンジル１８．７ｇのクロロホルム２０ｍｌ溶液を滴下した。終了後、反応液の内温を室温に昇温し、更に２時間攪拌した。有機層を分取し、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して２−ベンジルオキシカルボニルアミノメチル−４−（４−フルオロベンジル）モルホリン３４．０ｇを淡褐色アモルファス状固体として得た。 LC-MS, m/z; 359 (MH⁺).
（２）上記生成物６５．１ｇの塩化メチレン５００ｍｌ溶液に９８％クロロギ酸α−クロロエチル３．４ｇを加え、室温で４時間撹拌した。溶媒を減圧留去し、残渣をメタノール５００ｍｌに溶解した後、撹拌下、１時間加熱還流した。室温に冷却後、再度溶媒を減圧留去した。残渣を氷水に溶解し、冷水溶液を酢酸エチルで３回洗浄、３０％水酸化カリウム水溶液でアルカリ性にした後、クロロホルムで抽出した。抽出液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して２−ベンジルオキシカルボニルアミノメチルモルホリン４３．６ｇを淡黄色油状物として得た。この油状物は精製することなく次の工程に用いた。 LC-MS, m/z; 251 (MH⁺).
（３）上記生成物４３．６ｇ、１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジン６４．４ｇ、無水炭酸カリウム４８．２ｇ、ヨウ化カリウム２ｇおよびアセトニトリル５００ｍｌの混合物を攪拌下、終夜加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣をクロロホルムに溶解した。水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１〜酢酸エチル）で精製して２−ベンジルオキシカルボニルアミノメチル−４−〔｛１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニル｝メチル〕モルホリン４５．７ｇを淡黄色油状物として得た。 LC-MS, m/z; 448 (MH⁺).
（４）上記生成物５．０ｇのエタノール１００ｍｌ溶液に含水１０％パラジウム炭素１．５ｇを加え常圧下、室温で水素添加した。理論量の水素を吸収した後、反応液をセライトに通すことで触媒を除き、濾液を減圧乾固した。残渣をクロロホルムに溶解し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して標記化合物約３．８ｇを淡黄色油状物として得た。LC-MS, m/z; 314 (MH⁺).

(1) 22.9 g of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (S. Kato, et al., J. Med. Chem., (1991) 34 , 616-624) with vigorous stirring A solution of 18.7 g of benzyl chloroformate in 20 ml of chloroform was added dropwise to a mixed solution of 200 ml of chloroform and 100 ml of 1N aqueous sodium hydroxide solution while cooling with ice. After completion, the internal temperature of the reaction solution was raised to room temperature and further stirred for 2 hours. The organic layer was separated, washed with water and then with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-benzyloxycarbonylaminomethyl-4- (4-fluorobenzyl) morpholine. 0 g was obtained as a light brown amorphous solid. LC-MS, m / z; 359 (MH ⁺ ).
(2) To a solution of 65.1 g of the above product in 500 ml of methylene chloride was added 3.4 g of 98% α-chloroethyl chloroformate and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 500 ml of methanol, and then heated under reflux for 1 hour with stirring. After cooling to room temperature, the solvent was distilled off again under reduced pressure. The residue was dissolved in ice water, and the cold aqueous solution was washed three times with ethyl acetate, made alkaline with 30% aqueous potassium hydroxide solution, and extracted with chloroform. The extract was washed with water and then with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 43.6 g of 2-benzyloxycarbonylaminomethylmorpholine as a pale yellow oil. This oil was used in the next step without purification. LC-MS, m / z; 251 (MH ⁺ ).
(3) 43.6 g of the above product, 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine 64.4 g, anhydrous potassium carbonate 48.2 g, potassium iodide 2 g and acetonitrile 500 ml The mixture was heated to reflux overnight with stirring. After cooling to room temperature, the reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform. The extract was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1 to ethyl acetate) to give 2-benzyloxycarbonylaminomethyl-4-[{1- (tert-butoxycarbonyl) -4-piperidinyl. } Methyl] morpholine (45.7 g) was obtained as a pale yellow oil. LC-MS, m / z; 448 (MH ⁺ ).
(4) To a solution of 5.0 g of the above product in 100 ml of ethanol, 1.5 g of water-containing 10% palladium carbon was added and hydrogenated at room temperature under normal pressure. After absorbing a theoretical amount of hydrogen, the catalyst was removed by passing the reaction solution through Celite, and the filtrate was dried under reduced pressure. The residue was dissolved in chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give about 3.8 g of the title compound as a pale yellow oil. LC-MS, m / z; 314 (MH ⁺ ).

In the same manner as in Reference Example 12 (Alternative Method 2), an optically active compound (T. Morie, et al., Heterocycles, (1994) 38 , 1033-1040) was used as a raw material. The compound was prepared. All products were pale yellow oils.

Reference Example 15:
Preparation of 4-[(1-acetyl-4-piperidinyl) methyl] -2- (tert-butoxycarbonyl) aminomethylmorpholine:

（１）２−アミノメチル−４−ベンジルモルホリン（S. Kato, et al., J. Med. Chem., (1990) 33, 1406-1413）１．０ｇの塩化メチレン１０ｍｌ溶液に二炭酸ジ−ｔｅｒｔ−ブチル１．０８ｇを加え、室温で終夜撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製し、４−ベンジル−２−（ｔｅｒｔ−ブトキシカルボニル）アミノメチルモルホリン１．４ｇを黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.42 (9H, s), 1.90 (1H, t, J = 10.5 Hz), 2.15 (1H, td, J = 3.4, 14.7 Hz), 2.68 (2H, dd, J = 11.3, 33.3 Hz), 3.05 (1H, m), 3.28 (1H, m), 3.49 (2H, s), 3.5-3.7 (2H,m), 3.83 (1H, m), 4.86 (1H, br s), 7.2-7.35 (5H, m). LC-MS, m/z; 307 (MH⁺).
（２）上記生成物１．４ｇのエタノール１５ｍｌ溶液に１０％パラジウム炭素０．３ｇを加え、常圧下、室温で水素添加した。理論量の水素を吸収した後、反応液をセライトに通すことで触媒を除き、濾液を減圧乾固した。２−（ｔｅｒｔ−ブトキシカルボニル）アミノメチルモルホリンを含む残渣に１−アセチル−４−（ｐ−トルエンスルホニルオキシ）メチルピペリジン１．７１ｇ、無水炭酸カリウム１．８９ｇ、ヨウ化ナトリウム０．６８ｇおよびアセトニトリル３０ｍｌを加え、撹拌下、終夜加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣を酢酸エチルに溶解、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製して標記化合物１．４３ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 0.95-1.15 (2H, m), 1.45 (9H, s), 1.52-1.9 (4H, m), 2.08 (3H, s), 2.16 (3H, d like, J = 6.8 Hz), 2.45-2.75 (3H, m), 2.95-3.13 (2H, m), 3.3 (1H, m), 3.5-3.7 (2H, m), 3.82 (2H, t like, J = 12.1 Hz), 4.59 (1H, br d, J = 13.4 Hz), 4.88 (1H, br s). LC-MS, m/z; 356 (MH⁺).

(1) 2-aminomethyl-4-benzylmorpholine (S. Kato, et al., J. Med. Chem., (1990) 33 , 1406-1413) 1.08 g of tert-butyl was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to give 1.4 g of 4-benzyl-2- (tert-butoxycarbonyl) aminomethylmorpholine as a yellow oil. Obtained as a thing.
¹ H-NMR (CDCl ₃ , δppm); 1.42 (9H, s), 1.90 (1H, t, J = 10.5 Hz), 2.15 (1H, td, J = 3.4, 14.7 Hz), 2.68 (2H, dd, J = 11.3, 33.3 Hz), 3.05 (1H, m), 3.28 (1H, m), 3.49 (2H, s), 3.5-3.7 (2H, m), 3.83 (1H, m), 4.86 (1H, br s), 7.2-7.35 (5H, m) .LC-MS, m / z; 307 (MH ⁺ ).
(2) 0.3 g of 10% palladium carbon was added to a solution of 1.4 g of the above product in 15 ml of ethanol, and hydrogenated at room temperature under normal pressure. After absorbing a theoretical amount of hydrogen, the catalyst was removed by passing the reaction solution through Celite, and the filtrate was dried under reduced pressure. To the residue containing 2- (tert-butoxycarbonyl) aminomethylmorpholine, 1.71 g of 1-acetyl-4- (p-toluenesulfonyloxy) methylpiperidine, 1.89 g of anhydrous potassium carbonate, 0.68 g of sodium iodide and 30 ml of acetonitrile And heated to reflux overnight with stirring. After cooling to room temperature, the reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate, washed with water, then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to obtain 1.43 g of the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 0.95-1.15 (2H, m), 1.45 (9H, s), 1.52-1.9 (4H, m), 2.08 (3H, s), 2.16 (3H, d like, J = 6.8 Hz), 2.45-2.75 (3H, m), 2.95-3.13 (2H, m), 3.3 (1H, m), 3.5-3.7 (2H, m), 3.82 (2H, t like, J = 12.1 Hz), 4.59 (1H, br d, J = 13.4 Hz), 4.88 (1H, br s). LC-MS, m / z; 356 (MH ⁺ ).

Reference Example 16:
Preparation of 2-aminomethyl-4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] morpholine:

（１）２−ベンジルオキシカルボニルアミノメチル−４−〔｛１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニル｝メチル〕モルホリン（参考例１２（別法２）（３））２５．０ｇのメタノール５０ｍｌ溶液に６Ｎ塩酸１００ｍｌを加え、室温で３時間撹拌した。反応液の内温を０℃以下にした後、粒状の水酸化ナトリウムでアルカリ性にし、クロロホルムで抽出した。抽出液を少量の飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して２−ベンジルオキシカルボニルアミノメチル−４−（４−ピペリジニルメチル）モルホリン１８．６ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.0-1.2 (2H, m), 1.5-1.8 (5H, m), 2.0-2.2 (3H, m), 2.5-2.75 (4H, m), 3.0-3.25 (3H, m), 3.35 (1H, m), 3.5-3.7 (2H, m), 3.73 (1H, d like), 5.1 (1H, m), 5.11 (2H, s), 7.25-7.9 (5H, m). LC-MS, m/z; 348 (MH⁺).
（２）上記生成物５．０ｇおよびＴＥＡ３．０ｍｌの塩化メチレン７５ｍｌ溶液に氷冷却下、塩化ジメチルカルバモイル１．６ｍｌを滴下した。終了後、反応液の内温を室温まで昇温し、終夜攪拌した。反応液を水で２回、１０％クエン酸水溶液、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝４０／１）で精製し、２−ベンジルオキシカルボニルアミノメチル−４−［（１−ジメチルカルバモイル−４−ピペリジニル）メチル］モルホリン４．１ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.0-1.25 (2H, m), 1.65-1.9 (4H, m), 2.0-2.25 (3H, m), 2.5-2.8 (4H, m), 2.81 (6H, s), 3.15 (1H, m), 3.4 (1H, m), 3.5-3.8 (4H, m), 3.83 (1H, d like, J = 9.7 Hz), 5.1 (1H, m), 5.11 (2H, s), 7.25-7.5 (5H, m). LC-MS, m/z; 419 (MH⁺).
（３）上記生成物１０．７ｇのエタノール１００ｍｌ溶液に１０％パラジウム炭素２．０ｇを加え、室温で４ｋｇｆ／ｃｍ^２下、水素添加した。理論量の水素を吸収した後、反応液をセライトに通すことで触媒を除き、濾液を減圧乾固した。残渣をクロロホルムに溶解し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して標記化合物約７．３ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.0-1.25 (2H, m), 1.55-1.7 (3H, m), 1.91 (1H, t, J = 10.4 Hz), 2.19 (3H, d like, J = 6.8 Hz), 2.55-2.7 (5H, m), 2.81 (6H, s), 2.85-3.15 (3H, m), 3.52 (2H, br s), 3.5-4.0 (3H, m). LC-MS, m/z; 285 (MH⁺).

(1) 2-benzyloxycarbonylaminomethyl-4-[{1- (tert-butoxycarbonyl) -4-piperidinyl} methyl] morpholine (Reference Example 12 (Alternative Method 2) (3)) 25.0 g of methanol 50 ml To the solution, 100 ml of 6N hydrochloric acid was added and stirred at room temperature for 3 hours. After the internal temperature of the reaction solution was reduced to 0 ° C. or lower, it was made alkaline with granular sodium hydroxide and extracted with chloroform. The extract was washed with a small amount of saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 18.6 g of 2-benzyloxycarbonylaminomethyl-4- (4-piperidinylmethyl) morpholine was pale yellow. Obtained as an oil.
¹ H-NMR (CDCl ₃ , δppm); 1.0-1.2 (2H, m), 1.5-1.8 (5H, m), 2.0-2.2 (3H, m), 2.5-2.75 (4H, m), 3.0-3.25 (3H, m), 3.35 (1H, m), 3.5-3.7 (2H, m), 3.73 (1H, d like), 5.1 (1H, m), 5.11 (2H, s), 7.25-7.9 (5H, m). LC-MS, m / z; 348 (MH ⁺ ).
(2) 1.6 ml of dimethylcarbamoyl chloride was added dropwise to a solution of 5.0 g of the above product and 3.0 ml of TEA in 75 ml of methylene chloride under ice cooling. After completion, the internal temperature of the reaction solution was raised to room temperature and stirred overnight. The reaction mixture was washed twice with water in that order, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to give 4.1 g of 2-benzyloxycarbonylaminomethyl-4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] morpholine. Obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.0-1.25 (2H, m), 1.65-1.9 (4H, m), 2.0-2.25 (3H, m), 2.5-2.8 (4H, m), 2.81 (6H , s), 3.15 (1H, m), 3.4 (1H, m), 3.5-3.8 (4H, m), 3.83 (1H, d like, J = 9.7 Hz), 5.1 (1H, m), 5.11 (2H , s), 7.25-7.5 (5H, m). LC-MS, m / z; 419 (MH ⁺ ).
(3) 2.0 g of 10% palladium carbon was added to a solution of 10.7 g of the above product in 100 ml of ethanol, and hydrogenated at 4 kgf / cm ² at room temperature. After absorbing a theoretical amount of hydrogen, the catalyst was removed by passing the reaction solution through Celite, and the filtrate was dried under reduced pressure. The residue was dissolved in chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give about 7.3 g of the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.0-1.25 (2H, m), 1.55-1.7 (3H, m), 1.91 (1H, t, J = 10.4 Hz), 2.19 (3H, d like, J = 6.8 Hz), 2.55-2.7 (5H, m), 2.81 (6H, s), 2.85-3.15 (3H, m), 3.52 (2H, br s), 3.5-4.0 (3H, m). LC-MS, m / z; 285 (MH ⁺ ).

  In the same manner as in Reference Example 16, the optically active compound (S) -2-benzyloxycarbonylaminomethyl-4-[{1- (tert-butoxycarbonyl) -4-piperidinyl} methyl] morpholine (Reference Example 13) was used as the starting material. The compound of Reference Example 17 below was prepared using The raw material was produced with reference to the method described in (1) to (3) of Reference Example 12 (Alternative Method 2).

Reference Example 18:
Preparation of 2-aminomethyl-4-[(1-methylcarbamoyl-4-piperidinyl) methyl] morpholine:

（１）クロロギ酸トリクロロメチル０．３５ｍｌの塩化メチレン１０ｍｌ溶液に氷冷却下、２−ベンジルオキシカルボニルアミノメチル−４−（４−ピペリジニルメチル）モルホリン（参考例１６（１））２．０ｇの塩化メチレン２０ｍｌ溶液を２０分かけて滴下した。反応液の内温を室温に昇温した後、１．５時間攪拌した。反応液を再び氷冷却した後、２ＮメチルアミンＴＨＦ溶液１１．６ｍｌおよびＴＥＡ３．２ｍｌの塩化メチレン１０ｍｌ溶液を１５分かけて滴下した。終了後、反応液の内温を室温に昇温した。終夜攪拌した反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製し、２−ベンジルオキシカルボニルアミノメチル−４−［（１−メチルカルバモイル−４−ピペリジニル）メチル］モルホリン２．３ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.0-1.2 (2H, m), 1.55-1.8 (4H, m), 2.0-2.2 (3H, m), 2.55-2.8 (4H, m), 2.81 (3H, d like, J = 4.3 Hz), 3.15 (1H, m), 3.38 (1H, m), 3.5-3.7 (2H, m), 3.25-4.0 (3H, m), 4.4 (1H, d like), 5.10 (2H, s), 5.1 (1H, m), 7.25-7.4 (5H, m). LC-MS, m/z; 405 (MH⁺).
（２）参考例１６（３）の２−ベンジルオキシカルボニルアミノメチル−４−［（１−ジメチルカルバモイル−４−ピペリジニル）メチル］モルホリンの代わりに上記生成物を用い、参考例１６（３）と同様に反応・処理して標記化合物を淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.1-1.3 (2H, m), 1.94 (2H, br t, J = 14.6 Hz), 2.16 (1H, br s), 2.77 (3H, s), 2.7-2.9 (2H, m), 2.9-3.3 (10H, m), 3.7 (1H, m), 3.99 (2H, br d, J = 13.0 Hz), 4.10 (1H, br d, J = 11.5 Hz), 4.31 (1H, br t, J = 12.2 Hz), 4.49 (1H, br s). LC-MS, m/z; 271 (MH⁺).

(1) 2.0 g of 2-benzyloxycarbonylaminomethyl-4- (4-piperidinylmethyl) morpholine (Reference Example 16 (1)) under cooling with ice in a solution of 0.35 ml of trichloromethyl chloroformate in 10 ml of methylene chloride Was added dropwise over 20 minutes. After raising the internal temperature of the reaction solution to room temperature, the reaction solution was stirred for 1.5 hours. The reaction solution was ice-cooled again, and 11.6 ml of 2N methylamine THF solution and 3.2 ml of TEA in 10 ml of methylene chloride were added dropwise over 15 minutes. After completion, the internal temperature of the reaction solution was raised to room temperature. The reaction solution stirred overnight was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to obtain 2.3 g of 2-benzyloxycarbonylaminomethyl-4-[(1-methylcarbamoyl-4-piperidinyl) methyl] morpholine. Obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.0-1.2 (2H, m), 1.55-1.8 (4H, m), 2.0-2.2 (3H, m), 2.55-2.8 (4H, m), 2.81 (3H , d like, J = 4.3 Hz), 3.15 (1H, m), 3.38 (1H, m), 3.5-3.7 (2H, m), 3.25-4.0 (3H, m), 4.4 (1H, d like), 5.10 (2H, s), 5.1 (1H, m), 7.25-7.4 (5H, m). LC-MS, m / z; 405 (MH ⁺ ).
(2) The above product was used in place of 2-benzyloxycarbonylaminomethyl-4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] morpholine in Reference Example 16 (3), and Reference Example 16 (3) and Reaction and treatment in the same manner gave the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.1-1.3 (2H, m), 1.94 (2H, br t, J = 14.6 Hz), 2.16 (1H, br s), 2.77 (3H, s), 2.7- 2.9 (2H, m), 2.9-3.3 (10H, m), 3.7 (1H, m), 3.99 (2H, br d, J = 13.0 Hz), 4.10 (1H, br d, J = 11.5 Hz), 4.31 (1H, br t, J = 12.2 Hz), 4.49 (1H, br s). LC-MS, m / z; 271 (MH ⁺ ).

Reference Example 19:
Preparation of 2-aminomethyl-4-[(1-carbamoyl-4-piperidinyl) methyl] morpholine:

（１）２−ベンジルオキシカルボニルアミノメチル−４−（４−ピペリジニルメチル）モルホリン（参考例１６（１））１．０ｇの塩化メチレン１０ｍｌ溶液に室温下、トリメチルシリルイソシアネート０．４０ｇを加え、終夜攪拌した。反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製し、２−ベンジルオキシカルボニルアミノメチル−４−［（１−カルバモイル−４−ピペリジニル）メチル］モルホリン０．７５ｇを淡黄色油状物として得た。
¹H-NMR (CDCl₃, δppm); 1.12 (2H, ddd, J = 3.9, 16.1, 40.2 Hz), 1.55-1.8 (4H, m), 2.05-2.2 (3H, m), 2.62 (1H, dd, J = 10.9, 35.5 Hz), 2.80 (2H, t, J = 12.2 Hz), 3.15 (1H, m), 3.4 (1H, m), 3.5-3.7 (2H,m), 3.83 (1H, d like, J = 11.4 Hz), 3.92 (2H, br d, J = 12.1 Hz), 4.45 (2H, s), 5.11 (2H, s), 5.15 (1H, m), 7.25-7.4 (5H,m). LC-MS, m/z; 391 (MH⁺).
（２）参考例１６（３）の２−ベンジルオキシカルボニルアミノメチル−４−［（１−ジメチルカルバモイル−４−ピペリジニル）メチル］モルホリンの代わりに上記生成物を用い、参考例１６（３）と同様に反応・処理して標記化合物を淡黄色油状物として得た。 LC-MS, m/z; 257 (MH⁺).

(1) To a solution of 1.0 g of 2-benzyloxycarbonylaminomethyl-4- (4-piperidinylmethyl) morpholine (Reference Example 16 (1)) in 10 ml of methylene chloride at room temperature was added 0.40 g of trimethylsilyl isocyanate. Stir overnight. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1), and 0.75 g of 2-benzyloxycarbonylaminomethyl-4-[(1-carbamoyl-4-piperidinyl) methyl] morpholine was palely added. Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ , δppm); 1.12 (2H, ddd, J = 3.9, 16.1, 40.2 Hz), 1.55-1.8 (4H, m), 2.05-2.2 (3H, m), 2.62 (1H, dd , J = 10.9, 35.5 Hz), 2.80 (2H, t, J = 12.2 Hz), 3.15 (1H, m), 3.4 (1H, m), 3.5-3.7 (2H, m), 3.83 (1H, d like , J = 11.4 Hz), 3.92 (2H, br d, J = 12.1 Hz), 4.45 (2H, s), 5.11 (2H, s), 5.15 (1H, m), 7.25-7.4 (5H, m). LC-MS, m / z; 391 (MH ⁺ ).
(2) The above product was used in place of 2-benzyloxycarbonylaminomethyl-4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] morpholine in Reference Example 16 (3), and Reference Example 16 (3) and Reaction and treatment in the same manner gave the title compound as a pale yellow oil. LC-MS, m / z; 257 (MH ⁺ ).

Production Example 1:
Preparation of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide:

４−アミノ−５−クロロ−２−メトキシ安息香酸２７．６ｇのクロロホルム２００ｍｌ懸濁液にＴＥＡ１６．６ｇを攪拌下、室温で滴下した。反応液の内温を氷冷却後、クロロギ酸エチル１６．３ｇを内温が５℃以上にならないようゆっくり滴下した。終了後、内温０〜５℃で１時間攪拌した。この反応液に、２−アミノメチル−４−〔１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニルメチル〕モルホリン（参考例１２）４２．９ｇのクロロホルム５０ｍｌ溶液を内温が５℃以上に上がらないようゆっくり滴下し、終了後、氷浴をはずして一晩攪拌した。反応液を水、５％水酸化カリウム水溶液、水、５％クエン酸水溶液、水、飽和食塩水の順で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製して標記化合物３２．４ｇをアモルファス状固体として得た。
¹H-NMR (DMSO-d₆, δppm); 0.8-1.0 (2H, br q, J = 11.6 Hz), 1.38 (9H, s), 1.65 (2H, br d, J = 11.3 Hz), 1.74 (1H, t, J = 10.6 Hz), 1.95 (1H, m), 2.10 (2H, d, J = 7.7 Hz), 2.55-2.8 (4H, m), 3.2-3.6 (5H,m), 3.83 (3H, s), 3.75-4.0 (3H,m), 5.96 (2H, s), 6.48 (1H, s), 7.68 (1H, s), 7.97 (1H, br t, J = 5.6 Hz). LC-MS, m/z; 497 (MH⁺).

To a suspension of 27.6 g of 4-amino-5-chloro-2-methoxybenzoic acid in 200 ml of chloroform, 16.6 g of TEA was added dropwise at room temperature with stirring. After cooling the internal temperature of the reaction solution with ice, 16.3 g of ethyl chloroformate was slowly added dropwise so that the internal temperature did not exceed 5 ° C. After completion, the mixture was stirred at an internal temperature of 0 to 5 ° C. for 1 hour. To this reaction solution, a solution of 42.9 g of 2-aminomethyl-4- [1- (tert-butoxycarbonyl) -4-piperidinylmethyl] morpholine (Reference Example 12) in 50 ml of chloroform was brought to an internal temperature of 5 ° C. or higher. The solution was slowly added dropwise so as not to rise, and after completion, the ice bath was removed and the mixture was stirred overnight. The reaction solution was washed with water, 5% aqueous potassium hydroxide solution, water, 5% aqueous citric acid solution, water and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 32.4 g of the title compound as an amorphous solid.
¹ H-NMR (DMSO-d ₆ , δppm); 0.8-1.0 (2H, br q, J = 11.6 Hz), 1.38 (9H, s), 1.65 (2H, br d, J = 11.3 Hz), 1.74 ( 1H, t, J = 10.6 Hz), 1.95 (1H, m), 2.10 (2H, d, J = 7.7 Hz), 2.55-2.8 (4H, m), 3.2-3.6 (5H, m), 3.83 (3H , s), 3.75-4.0 (3H, m), 5.96 (2H, s), 6.48 (1H, s), 7.68 (1H, s), 7.97 (1H, br t, J = 5.6 Hz). LC-MS , m / z; 497 (MH ⁺ ).

Production Example 1 (Alternative method):

４−アミノ−５−クロロ−２−メトキシ−Ｎ−（２−モルホリニルメチル）ベンズアミド（参考例２）１６．２ｇ、１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジン２８．５ｇ、無水炭酸カリウム２２．４ｇ、ヨウ化ナトリウム１２．２ｇおよびアセトニトリル２２０ｍｌの混合物を撹拌下、終夜加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、標記化合物２７．０ｇをアモルファス状固体として得た。

4-Amino-5-chloro-2-methoxy-N- (2-morpholinylmethyl) benzamide (Reference Example 2) 16.2 g, 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) ) A mixture of 28.5 g of methyl] piperidine, 22.4 g of anhydrous potassium carbonate, 12.2 g of sodium iodide and 220 ml of acetonitrile was heated to reflux with stirring overnight. After cooling to room temperature, the reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 27.0 g of the title compound as an amorphous solid.

  In the same manner as in Production Example 1, the compounds of Production Examples 2 to 3 below were produced using optically active compounds (Reference Example 13 and Reference Example 14) as raw materials.

Production Example 4:
1.5 Preparation of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide :

製造例１の４−アミノ−５−クロロ−２−メトキシ安息香酸の代わりに４−アミノ−５−クロロ−２−エトキシ安息香酸を用い、製造例１と同様に反応・処理して得たアモルファス状固体をフマル酸で処理して標記化合物を粉状物として得た。融点１６７−１６９℃（Ｅ／ＤＥから再結晶）
¹H-NMR (DMSO-d₆, δppm); 0.8-1.0 (2H, br q, J = 10.4 Hz), 1.3-1.5 (4H, m), 1.37 (9H, s), 1.40 (3H, t, J = 7.0 Hz), 1.65 (2H, br d, J = 10.6 Hz), 1.81 (1H, t, J = 10.6 Hz), 2.02 (1H, t like, J = 10.6 Hz), 2.13 (2H, d, J = 6.0 Hz), 2.5-2.75 (4H, m), 3.2 (1H,m), 3.35-3.6 (3H,m), 3.80 (1H, d, J = 11.3 Hz), 3.89 (2H, d like, J = 12.1 Hz), 4.06 (2H, q, J = 7.0 Hz), 5.93 (2H, s), 6.46 (1H, s), 6.61 (3H, s), 7.70 (1H, s), 8.06 (1H, t like, J = 4.8 Hz). LC-MS, m/z; 511 (MH⁺).

4-amino-5-chloro-2-ethoxybenzoic acid was used in place of 4-amino-5-chloro-2-methoxybenzoic acid of Production Example 1 and the amorphous was obtained by reacting and treating in the same manner as in Production Example 1. The solid was treated with fumaric acid to give the title compound as a powder. Melting point 167-169 ° C. (recrystallized from E / DE)
¹ H-NMR (DMSO-d ₆ , δppm); 0.8-1.0 (2H, br q, J = 10.4 Hz), 1.3-1.5 (4H, m), 1.37 (9H, s), 1.40 (3H, t, J = 7.0 Hz), 1.65 (2H, br d, J = 10.6 Hz), 1.81 (1H, t, J = 10.6 Hz), 2.02 (1H, t like, J = 10.6 Hz), 2.13 (2H, d, J = 6.0 Hz), 2.5-2.75 (4H, m), 3.2 (1H, m), 3.35-3.6 (3H, m), 3.80 (1H, d, J = 11.3 Hz), 3.89 (2H, d like, J = 12.1 Hz), 4.06 (2H, q, J = 7.0 Hz), 5.93 (2H, s), 6.46 (1H, s), 6.61 (3H, s), 7.70 (1H, s), 8.06 (1H, t like, J = 4.8 Hz). LC-MS, m / z; 511 (MH ⁺ ).

  In the same manner as in Production Example 4, the following compounds of Production Examples 5 to 6 were produced using optically active compounds (Reference Example 13 and Reference Example 14) as raw materials.

Production Example 7:
4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2,3-dihydrobenzo [b] furan- Production of 7-carboxamide:

製造例１の４−アミノ−５−クロロ−２−メトキシ安息香酸の代わりに４−アミノ−５−クロロ−２，３−ジヒドロベンゾ［ｂ］フラン−７−カルボン酸を用い、製造例１と同様に反応・処理して標記化合物をアモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 0.92-1.13 (2H, m), 1.45 (9H, s), 1.5-1.8 (4H, m), 1.87 (1H, d, J = 10.3 Hz), 2.05-2.2 (3H, m), 2.55-2.85 (4H,m), 3.06 (2H, t, J = 8.8 Hz), 3.35 (1H, m), 3.6-3.75 (3H, m), 3.87 (1H, br d, J = 9.7 Hz), 3.95-4.2 (2H, br d), 4.2 (1H, m), 4.78 (2H, t, J = 8.8 Hz), 7.61 (1H, br t, J = 5.9 Hz), 7.86 (1H, s). LC-MS, m/z; 509 (MH⁺).

4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid was used in place of 4-amino-5-chloro-2-methoxybenzoic acid in Production Example 1, and The same reaction and treatment were performed to obtain the title compound as an amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 0.92-1.13 (2H, m), 1.45 (9H, s), 1.5-1.8 (4H, m), 1.87 (1H, d, J = 10.3 Hz), 2.05- 2.2 (3H, m), 2.55-2.85 (4H, m), 3.06 (2H, t, J = 8.8 Hz), 3.35 (1H, m), 3.6-3.75 (3H, m), 3.87 (1H, br d , J = 9.7 Hz), 3.95-4.2 (2H, br d), 4.2 (1H, m), 4.78 (2H, t, J = 8.8 Hz), 7.61 (1H, br t, J = 5.9 Hz), 7.86 (1H, s). LC-MS, m / z; 509 (MH ⁺ ).

Production Example 7 (Alternative method):
4-amino-5-chloro-N- (2-morpholinyl) instead of 4-amino-5-chloro-2-methoxy-N- (2-morpholinylmethyl) benzamide of Preparation Example 1 (alternative method) Methyl) -2,3-dihydrobenzo [b] furan-7-carboxamide (Reference Example 6) was used for the reaction and treatment in the same manner as in Production Example 1 (another method) to obtain the title compound as an amorphous solid.

  In the same manner as in Production Example 7, the following compounds of Production Examples 8 to 9 were produced using optically active compounds (Reference Example 13 and Reference Example 14) as raw materials.

  The following compounds of Production Example 10 and Production Examples 12 to 17 were produced in the same manner as in Production Example 1 and Production Example 1 (another method). All of the products are amorphous solids.

Production Example 11:
1.5 Preparation of 4-fumaric acid 4-amino-5-bromo-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide :

製造例１の４−アミノ−５−クロロ−２−メトキシ安息香酸の代わりに４−アミノ−５−ブロモ−２−エトキシ安息香酸を用い、製造例１と同様に反応・処理して得たアモルファス状固体をフマル酸で処理して標記化合物を粉状物として得た。融点１７１−１７２℃（Ｅから再結晶）
¹H-NMR (DMSO-d₆, δppm); 0.8-1.0 (2H, m), 1.37 (9H, s), 1.40 (3H, t, J = 7.1 Hz), 1.65 (3H, br d, J = 10.8 Hz), 1.81 (1H, t, J = 10.5 Hz), 2.01 (1H, br t), 2.12 (2H, d like, J = 6.4 Hz), 2.70 (4H, dd, J = 11.4, 29.3 Hz), 3.2 (1H,m), 3.4-3.6 (3H,m), 3.80 (1H, d, J = 10.6 Hz), 3.89 (2H, br d, J = 12.3 Hz), 4.06 (2H, q, J = 7.1 Hz), 5.87 (2H, s), 6.47 (1H, s), 6.61 (3H, s), 7.85 (1H, s), 8.04 (1H, t like). LC-MS, m/z; 557 (MH⁺).

An amorphous substance obtained by reacting and treating in the same manner as in Production Example 1 using 4-amino-5-bromo-2-ethoxybenzoic acid instead of 4-amino-5-chloro-2-methoxybenzoic acid in Production Example 1. The solid was treated with fumaric acid to give the title compound as a powder. Melting point 171-172 ° C. (recrystallization from E)
¹ H-NMR (DMSO-d ₆ , δppm); 0.8-1.0 (2H, m), 1.37 (9H, s), 1.40 (3H, t, J = 7.1 Hz), 1.65 (3H, br d, J = 10.8 Hz), 1.81 (1H, t, J = 10.5 Hz), 2.01 (1H, br t), 2.12 (2H, d like, J = 6.4 Hz), 2.70 (4H, dd, J = 11.4, 29.3 Hz) , 3.2 (1H, m), 3.4-3.6 (3H, m), 3.80 (1H, d, J = 10.6 Hz), 3.89 (2H, br d, J = 12.3 Hz), 4.06 (2H, q, J = 7.1 Hz), 5.87 (2H, s), 6.47 (1H, s), 6.61 (3H, s), 7.85 (1H, s), 8.04 (1H, t like) .LC-MS, m / z; 557 ( MH ⁺ ).

Production Example 18:
4-Amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -1,4-hexahydrooxazepin-2-yl} methyl] -5-chloro-2 -Preparation of methoxybenzamide:

製造例１（別法）の４−アミノ−５−クロロ−２−メトキシ−Ｎ−（２−モルホリニルメチル）ベンズアミドの代わりに４−アミノ−５−クロロ−Ｎ−〔（１，４−ヘキサヒドロオキサゼピン−２−イル）メチル〕−２−メトキシベンズアミド（参考例３）を用い、製造例１（別法）と同様に反応・処理して標記化合物をアモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 0.95-1.1 (2H, m), 1.44 (9H, s), 1.5-2.0 (5H, m), 2.32 (2H, d, J = 7.1 Hz), 2.45 (1H, m), 2.55-2.85 (5H, m), 3.15 (1H, m), 3.65-3.8 (3H, m), 3.89 (3H, s), 3.9 (1H, m), 4.0-4.15 (2H, m), 4.37 (2H, s), 6.29 (1H, s), 8.04 (1H, br t like), 8.10 (1H, s). LC-MS, m/z; 511 (MH⁺), 411.

Instead of 4-amino-5-chloro-2-methoxy-N- (2-morpholinylmethyl) benzamide of Production Example 1 (alternative method), 4-amino-5-chloro-N-[(1,4- Hexahydrooxazepin-2-yl) methyl] -2-methoxybenzamide (Reference Example 3) was used for the reaction and treatment in the same manner as in Production Example 1 (alternative method) to obtain the title compound as an amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 0.95-1.1 (2H, m), 1.44 (9H, s), 1.5-2.0 (5H, m), 2.32 (2H, d, J = 7.1 Hz), 2.45 ( 1H, m), 2.55-2.85 (5H, m), 3.15 (1H, m), 3.65-3.8 (3H, m), 3.89 (3H, s), 3.9 (1H, m), 4.0-4.15 (2H, m), 4.37 (2H, s), 6.29 (1H, s), 8.04 (1H, br t like), 8.10 (1H, s) .LC-MS, m / z; 511 (MH ⁺ ), 411.

Production Example 19:
Preparation of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -3-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide:

製造例１（別法）における１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジンの代わりに１−（ｔｅｒｔ−ブトキシカルボニル）−３−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジンを用い、製造例１（別法）と同様に反応・処理して標記化合物を白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.1 (1H, m), 1.45 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.5-2.2 (8H, m), 2.6-2.8 (4H, m), 3.35 (1H, m), 3.6-3.75 (3H, m), 3.8-4.0 (3H, m), 4.08 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 6.27 (1H,s), 8.11 (1H, s), 8.22 (1H, t like). LC-MS, m/z; 511 (MH⁺).

Instead of 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine in Production Example 1 (alternative method), 1- (tert-butoxycarbonyl) -3-[(p-toluenesulfonyl) The title compound was obtained as a white amorphous solid by reaction and treatment in the same manner as in Production Example 1 (alternative method) using [oxy) methyl] piperidine.
¹ H-NMR (CDCl ₃ , δppm); 1.1 (1H, m), 1.45 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.5-2.2 (8H, m), 2.6-2.8 ( 4H, m), 3.35 (1H, m), 3.6-3.75 (3H, m), 3.8-4.0 (3H, m), 4.08 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.22 (1H, t like). LC-MS, m / z; 511 (MH ⁺ ).

Production Example 20:
Preparation of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -3-azetidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide:

製造例１（別法）における１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジンの代わりに１−（ｔｅｒｔ−ブトキシカルボニル）−３−〔（ｐ−トルエンスルホニルオキシ）メチル〕アゼチジン（参考例１）を用い、製造例１（別法）と同様に反応・処理し、標記化合物を白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.43 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.97 (1H, br t, J = 10.5 Hz), 2.17 (1H, td, J = 3.3, 11.2 Hz), 2.5-2.65, 2.65-2.8 (5H, m), 3.2-3.4 (2H, m), 3.5-3.75 (6H, m), 3.87 (1H, m), 4.09 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 6.27 (1H,s), 8.11 (1H, s), 8.21 (1H, t like). LC-MS, m/z; 314.

Instead of 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine in Production Example 1 (alternative method), 1- (tert-butoxycarbonyl) -3-[(p-toluenesulfonyl) Oxy) methyl] azetidine (Reference Example 1) was used for the reaction and treatment in the same manner as in Production Example 1 (Alternative Method) to obtain the title compound as a white amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 1.43 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.97 (1H, br t, J = 10.5 Hz), 2.17 (1H, td, J = 3.3, 11.2 Hz), 2.5-2.65, 2.65-2.8 (5H, m), 3.2-3.4 (2H, m), 3.5-3.75 (6H, m), 3.87 (1H, m), 4.09 (2H, q , J = 7.0 Hz), 4.35 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.21 (1H, t like). LC-MS, m / z; 314.

Production Example 21:
Preparation of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -3-pyrrolidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide:

製造例１（別法）における１−（ｔｅｒｔ−ブトキシカルボニル）−４−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピペリジンの代わりに１−（ｔｅｒｔ−ブトキシカルボニル）−３−〔（ｐ−トルエンスルホニルオキシ）メチル〕ピロリジンを用い、製造例１（別法）と同様に反応・処理して標記化合物を白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.46 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.8-2.0 (2H, m), 2.15 (1H, m), 2.2-2.45 (3H, m), 2.65-2.8 (2H, m), 3.0 (1H, m), 3.1-3.55 (5H, m), 3.67 (3H, br s), 3.86 (1H, br d, J = 10.3 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.34 (2H, s), 6.27 (1H,s), 8.11 (1H, s), 8.21 (1H, t like). LC-MS, m/z; 497 (MH⁺), 397.

Instead of 1- (tert-butoxycarbonyl) -4-[(p-toluenesulfonyloxy) methyl] piperidine in Production Example 1 (alternative method), 1- (tert-butoxycarbonyl) -3-[(p-toluenesulfonyl) The title compound was obtained as a white amorphous solid by reaction and treatment in the same manner as in Production Example 1 (alternative method) using [oxy) methyl] pyrrolidine.
¹ H-NMR (CDCl ₃ , δppm); 1.46 (9H, s), 1.50 (3H, t, J = 7.0 Hz), 1.8-2.0 (2H, m), 2.15 (1H, m), 2.2-2.45 ( 3H, m), 2.65-2.8 (2H, m), 3.0 (1H, m), 3.1-3.55 (5H, m), 3.67 (3H, br s), 3.86 (1H, br d, J = 10.3 Hz) , 4.09 (2H, q, J = 7.0 Hz), 4.34 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.21 (1H, t like). LC-MS, m / z; 497 (MH ⁺ ), 397.

Production Example 22:
Preparation of 2-fumaric acid 4-amino-5-chloro-2-ethoxy-N-[[4- (4-piperidinylmethyl) -2-morpholinyl] methyl] benzamide:

４−アミノ−Ｎ−［｛４−〔（１−（ｔｅｒｔ−ブトキシカルボニル）−４−ピペリジニル）メチル〕−２−モルホリニル｝メチル］−５−クロロ−２−エトキシベンズアミド（製造例４）４３．０ｇのメタノール２０ｍｌ溶液に、氷冷下、６Ｎ塩酸１００ｍｌを加えた後、室温で終夜撹拌した。氷冷却下、反応液に粒状の水酸化ナトリウムを加えてアルカリ性にした後、氷水で希釈した。析出した固体を減圧濾取し、水洗した後、乾燥して標記化合物の塩基３５．６ｇを得た。この固体をフマル酸で処理して標記化合物を固体として得た。融点１３８−１４０℃（Ｅから再結晶）
¹H-NMR (DMSO-d₆, δppm); 1.23 (2H, br q, J = 11.7 Hz), 1.41 (3H, t, J = 6.9 Hz), 1.7-1.95 (4H, br d), 2.01 (1H, br t, J = 9.8 Hz), 2.13 (2H, br d, J = 6.2 Hz), 2.65 (1H, d like, J = 11.2 Hz), 2.78 (3H, br q, J = 10.8 Hz), 3.23 (3H, br d, J = 12.3 Hz), 3.35-3.65 (3H, m), 3.81 (1H,br d, J = 11.2 Hz), 4.07 (2H, q, J = 6.9 Hz), 5.96 (2H, s), 6.47 (1H, s), 6.54 (4H, s), 7.71 (1H, s), 8.08 (1H, t like, J = 4.7 Hz). LC-MS, m/z; 411 (MH⁺).

4-Amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide (Production Example 4) 43. To a solution of 0 g of methanol in 20 ml, 6N hydrochloric acid (100 ml) was added under ice cooling, followed by stirring at room temperature overnight. Under ice cooling, the reaction solution was made alkaline by adding granular sodium hydroxide, and then diluted with ice water. The precipitated solid was collected by filtration under reduced pressure, washed with water, and dried to obtain 35.6 g of the base of the title compound. This solid was treated with fumaric acid to give the title compound as a solid. Melting point 138-140 ° C (recrystallized from E)
¹ H-NMR (DMSO-d ₆ , δppm); 1.23 (2H, br q, J = 11.7 Hz), 1.41 (3H, t, J = 6.9 Hz), 1.7-1.95 (4H, br d), 2.01 ( 1H, br t, J = 9.8 Hz), 2.13 (2H, br d, J = 6.2 Hz), 2.65 (1H, d like, J = 11.2 Hz), 2.78 (3H, br q, J = 10.8 Hz), 3.23 (3H, br d, J = 12.3 Hz), 3.35-3.65 (3H, m), 3.81 (1H, br d, J = 11.2 Hz), 4.07 (2H, q, J = 6.9 Hz), 5.96 (2H , s), 6.47 (1H, s), 6.54 (4H, s), 7.71 (1H, s), 8.08 (1H, t like, J = 4.7 Hz). LC-MS, m / z; 411 (MH ⁺ ).

Production Examples 23-42:
Instead of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide in Production Example 22 Using the corresponding amide compound, the reaction and treatment were conducted in the same manner as in Production Example 22 to obtain the following compounds of Production Examples 23-42 as powdery or amorphous solids.

１）立体配置表記を表す
２）Ｆは、フマル酸を表す。製造例２３の化合物の融点は、１０４−１０７℃（再結晶溶媒：Ｅ）

1) Representation of configurational configuration 2) F represents fumaric acid. The melting point of the compound of Production Example 23 is 104-107 ° C. (recrystallization solvent: E)

Production Example 43:
Preparation of 4-amino-N-[{4-((1-carbamoyl-4-piperidinyl) methyl) -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide:

４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２２）１．０ｇの塩化メチレン１５ｍｌ溶液に室温下、トリメチルシリルイソシアネート０．３４ｇ加え、２．５時間攪拌した。溶媒を減圧留去後、残渣に水を加え、析出固体を減圧濾取した。含水エタノールで洗浄、乾燥して標記化合物１．０ｇを白色固体として得た。融点２０１−２０７℃（Ｅ／Ｈから再結晶）
¹H-NMR (CDCl₃, δppm); 1.12 (2H, ddd, J = 3.7, 12.0, 20.4 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.64 (2H, s), 1.62-1.82 (2H, m), 1.92 (1H, t, J = 10.5 Hz), 2.08-2.22 (3H, m), 2.62 (1H, d like, J = 9.9 Hz), 2.78 (3H, br q, J = 12.2 Hz), 3.38 (1H, m), 3.58-3.77 (3H,m), 3.8-4.0 (3H, m), 4.05 (2H, q, J = 7.0 Hz), 4.24-4.44 (3H, m), 6.27 (1H, s), 8.11 (1H, s), 8.23 (1H, t like). LC-MS, m/z; 454 (MH⁺).

4-Amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 22) In a solution of 1.0 g of methylene chloride at room temperature. Then, 0.34 g of trimethylsilyl isocyanate was added and stirred for 2.5 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the precipitated solid was collected by filtration under reduced pressure. Washing with aqueous ethanol and drying gave 1.0 g of the title compound as a white solid. Melting point 201-207 ° C (recrystallized from E / H)
¹ H-NMR (CDCl ₃ , δppm); 1.12 (2H, ddd, J = 3.7, 12.0, 20.4 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.64 (2H, s), 1.62-1.82 ( 2H, m), 1.92 (1H, t, J = 10.5 Hz), 2.08-2.22 (3H, m), 2.62 (1H, d like, J = 9.9 Hz), 2.78 (3H, br q, J = 12.2 Hz ), 3.38 (1H, m), 3.58-3.77 (3H, m), 3.8-4.0 (3H, m), 4.05 (2H, q, J = 7.0 Hz), 4.24-4.44 (3H, m), 6.27 ( 1H, s), 8.11 (1H, s), 8.23 (1H, t like). LC-MS, m / z; 454 (MH ⁺ ).

Production Example 43 (alternative method):

４−アミノ−５−クロロ−２−エトキシ安息香酸０．３６ｇおよびＮ，Ｎ’−カルボニルジイミダゾール０．３０ｇのＤＭＦ１５ｍｌ溶液を室温下、１時間撹拌した。この反応液に２−アミノメチル−４−（１−カルバモイル−４−ピペリジニルメチル）モルホリン（参考例１９）０．４９ｇを加え、室温で終夜撹拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解、水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製して標記化合物０．４５ｇを白色固体として得た。

A solution of 0.36 g of 4-amino-5-chloro-2-ethoxybenzoic acid and 0.30 g of N, N′-carbonyldiimidazole in 15 ml of DMF was stirred at room temperature for 1 hour. To this reaction solution, 0.49 g of 2-aminomethyl-4- (1-carbamoyl-4-piperidinylmethyl) morpholine (Reference Example 19) was added and stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to obtain 0.45 g of the title compound as a white solid.

Production Examples 44-66:
Instead of 4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide in Production Example 43, the corresponding amide compound and the corresponding isocyanate were used. Using and reacting in the same manner as in Production Example 43, the following compounds in Table 13 were obtained as an amorphous solid or powder. Some amorphous solids were salted by treatment with fumaric acid.

１）立体配置表記を表す。
２）製造例４５の化合物の融点は、１５５−１５６℃（再結晶溶媒：ＥＡ／ＤＥ）。
３）製造例４６−１の化合物の融点は、１６１−１６２℃（再結晶溶媒：ＥＡ）。
４）Ｆは、フマル酸を表す。製造例５０の化合物の融点は、１７６−１７８℃（再結晶溶媒：Ｅ／ＤＥ）。
５）製造例６４の化合物の融点は、１３５−１３７℃（再結晶溶媒：Ｅ／ＥＡ）。
６）製造例６５の化合物の融点は、４７−１４９℃（再結晶溶媒：Ｅ／ＥＡ）。
７）製造例６６の化合物の融点は、１６０−１６２℃（再結晶溶媒：Ｅ／ＥＡ）。

1) Represents a configurational notation.
2) Melting | fusing point of the compound of manufacture example 45 is 155-156 degreeC (recrystallization solvent: EA / DE).
3) Melting | fusing point of the compound of manufacture example 46-1 was 161-162 degreeC (recrystallization solvent: EA).
4) F represents fumaric acid. The melting point of the compound of Production Example 50 is 176 to 178 ° C. (recrystallization solvent: E / DE).
5) Melting | fusing point of the compound of manufacture example 64 is 135-137 degreeC (recrystallization solvent: E / EA).
6) Melting | fusing point of the compound of manufacture example 65 is 47-149 degreeC (recrystallization solvent: E / EA).
7) Melting | fusing point of the compound of manufacture example 66 is 160-162 degreeC (recrystallization solvent: E / EA).

Production Example 46 (alternative method):
Preparation of 4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:
2-aminomethyl-4-[(1-methylcarbamoyl-4-piperidinyl) methyl instead of 2-aminomethyl-4- (1-carbamoyl-4-piperidinylmethyl) morpholine in Production Example 43 (alternative method) Using morpholine (Reference Example 18), the reaction and treatment were conducted in the same manner as in Production Example 43 (Alternative method) to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ , δppm); 0.8-1.2 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.5-1.8 (3H, m), 1.91 (1H, t, J = 10.4 Hz), 2.0-2.3 (3H, m), 2.3-3.0 (4H, m), 2.81 (3H, d, J = 4.6 Hz), 3.35 (1H, m), 3.5-3.8 (3H, m), 3.75 -4.1 (3H, m), 4.09 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 4.4 (1H, m), 6.27 (1H, s), 8.11 (1H, s), 8.22 ( 1H, t like).

Production Example 67:
Preparation of 4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide:

４−アミノ−５−クロロ−２−メトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２３）１．０ｇおよびＴＥＡ０．５３ｍｌの塩化メチレン２０ｍｌ溶液に氷冷却下、塩化ジメチルカルバモイル０．３０ｇを滴下した。終了後、内温を室温まで昇温させて３時間攪拌した。反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製して標記化合物を１．１ｇ白色固体として得た。融点１７９−１８０℃（ＥＡから再結晶）
¹H-NMR (CDCl₃, δppm); 1.0-1.2 (2H, m), 1.55-1.8 (3H, m), 1.89 (1H, t, J = 10.4 Hz), 2.05-2.2 (3H, m), 2.55-2.8 (4H,m), 2.81 (6H, s), 3.33 (1H, m), 3.55-3.75 (5H, m), 3.86 (1H, m), 3.89 (3H, s), 4.37 (2H, br s), 6.29 (1H, s), 8.00 (1H, br t), 8.09 (1H, s). LC-MS, m/z; 468 (MH⁺).

4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 23) 1.0 g and TEA 0.53 ml methylene chloride 20 ml To the solution, 0.30 g of dimethylcarbamoyl chloride was added dropwise under ice cooling. After completion, the internal temperature was raised to room temperature and stirred for 3 hours. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to obtain 1.1 g of the title compound as a white solid. Melting point 179-180 ° C (recrystallized from EA)
¹ H-NMR (CDCl ₃ , δppm); 1.0-1.2 (2H, m), 1.55-1.8 (3H, m), 1.89 (1H, t, J = 10.4 Hz), 2.05-2.2 (3H, m), 2.55-2.8 (4H, m), 2.81 (6H, s), 3.33 (1H, m), 3.55-3.75 (5H, m), 3.86 (1H, m), 3.89 (3H, s), 4.37 (2H, br s), 6.29 (1H, s), 8.00 (1H, br t), 8.09 (1H, s). LC-MS, m / z; 468 (MH ⁺ ).

Production Example 68-133:
Instead of 4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide in Preparation Example 67, the corresponding amide compound and the corresponding acidification The product was reacted and treated in the same manner as in Production Example 67 to obtain the compounds shown in Tables 14 to 16 as an amorphous solid or powder. Some amorphous solids were salted by treatment with fumaric acid or hydrochloric acid.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。
３）分解温度を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.
3) Represents the decomposition temperature.

Production Examples 134-141:
Racemic or optically active 4-amino instead of 4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide in Production Example 67 Using -5-chloro-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide and the corresponding acid chloride, The reaction and treatment were conducted in the same manner as in Production Example 67 to obtain the compounds shown in Table 17 as amorphous or solid. Some amorphous solids were salted by treatment with fumaric acid.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.

  The compounds of Production Example 70, Production Example 71, Production Example 82, Production Example 83, Production Example 84, Production Example 85, and Production Example 86 are produced by another method (the method described in Production Example 43 (Another Method)). A solid was obtained. Table 18 shows the data.

Production Example 90 (Alternative method):
1.5 Preparation of fumaric acid 4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (1-pyrrolidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide :

（１）無水ＴＨＦ１５００ｍｌに塩化カルシウム１１０．９ｇ、水素化ホウ素ナトリウム７５．６ｇ、続いてエチル１−フェノキシカルボニル−４−ピペリジンカルボン酸３００ｇを加えた後、内温を１０℃以下に冷却した。エタノール１０００ｍｌをゆっくりと滴下し、終了後、氷冷却下、約２０時間撹拌した。室温まで発熱した反応液を再度氷冷却し、冷却した１８％塩酸を反応液に少しずつ滴下した。酸性溶液になり、不溶物が析出した反応液をセライトに通すことで不溶物を濾去した後、溶媒を減圧留去した。残渣に水を加え、クロロホルムで抽出し、抽出液を水、２Ｎ水酸化ナトリウム水溶液、水、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して１−フェノキシカルボニル−４−ピペリジンメタノール２３２ｇを淡黄色油状物として得た。この油状物は精製することなく次の工程に使用した。 LC-MS, m/z; 236 (MH⁺).
（２）上記生成物２３２ｇとピロリジン１２００ｍｌの混合物を撹拌下、６時間加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣をクロロホルムに溶解、水、２Ｎ塩酸、２Ｎ水酸化ナトリウム水溶液、水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して１−ピロリジンカルボニル−４−ピペリジンメタノール１８３．５ｇを淡褐色油状物として得た。この油状物は精製することなく次の工程に使用した。 LC-MS, m/z; 213 (MH⁺).
（３）上記生成物１８３．５ｇ、４−ジメチルアミノピリジン２．１ｇおよびＴＥＡ１３１．１ｇの塩化メチレン１０００ｍｌ溶液に塩化ｐ−トルエンスルホニル１９８ｇを室温で少しずつ加え、終了後、２日間撹拌した。反応液を水、２Ｎ塩酸、２Ｎ水酸化ナトリウム水溶液、水、飽和食塩水の順で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して１−ピロリジンカルボニル−４−（ｐ−トルエンスルホニルオキシメチル）ピペリジン２１５ｇを淡褐色固体として得た。LC-MS, m/z; 367 (MH⁺).
（４）上記生成物２．３４ｇ、４−アミノ−５−クロロ−２−エトキシ−Ｎ−（２−モルホリニルメチル）ベンズアミド（S. Kato, et al., Chem. Pharm, Bull., (1995) 43, 699-702）２．０ｇ、無水炭酸カリウム１．３ｇ、ヨウ化カリウム０．１ｇおよびアセトニトリル８０ｍｌの混合物を撹拌下、２３時間加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣に水を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１９／１〜９／１）で精製して得たアモルファス状固体をフマル酸で処理して標記化合物０．７ｇを粉状物として得た。
¹H-NMR (DMSO-d₆, δppm); 0.96-1.08 (2H, m), 1.41 (3H, t, J = 6.9 Hz), 1.6-1.8 (7H, m), 1.8 (1H, t, J = 10.5 Hz), 2.04 (1H, t like), 2.16 (2H, d like, J = 6.4 Hz), 2.64-2.85 (4H, m), 3.2-3.3 (5H, m), 3.4-3.65 (5H, m), 3.81 (1H, d, J = 11 Hz), 4.07 (2H, q, J = 6.9 Hz), 5.95 (2H, s), 6.47 (1H, s), 6.62 (3H,s), 7.71 (1H, s), 8.07 (1H, t, J = 5.1 Hz).

(1) 11500 g of calcium chloride, 75.6 g of sodium borohydride, and then 300 g of ethyl 1-phenoxycarbonyl-4-piperidinecarboxylic acid were added to 1500 ml of anhydrous THF, and the internal temperature was cooled to 10 ° C. or lower. 1000 ml of ethanol was slowly added dropwise, and after completion, the mixture was stirred for about 20 hours under ice cooling. The reaction solution that exothermed to room temperature was ice-cooled again, and cooled 18% hydrochloric acid was added dropwise to the reaction solution little by little. The reaction solution, which became an acidic solution and precipitated insoluble matter, was passed through Celite to remove the insoluble matter, and then the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The extract was washed with water, 2N aqueous sodium hydroxide solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 232 g of 1-phenoxycarbonyl-4-piperidinemethanol as a pale yellow oil. This oil was used in the next step without purification. LC-MS, m / z; 236 (MH ⁺ ).
(2) A mixture of 232 g of the product and 1200 ml of pyrrolidine was heated to reflux for 6 hours with stirring. After cooling to room temperature, the reaction mixture was evaporated to dryness, the residue was dissolved in chloroform, washed with water, 2N hydrochloric acid, 2N aqueous sodium hydroxide, water, and then saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 183.5 g of 1-pyrrolidinecarbonyl-4-piperidinemethanol as a light brown oil. This oil was used in the next step without purification. LC-MS, m / z; 213 (MH ⁺ ).
(3) To a solution of 183.5 g of the above product, 2.1 g of 4-dimethylaminopyridine and 131.1 g of TEA in 1000 ml of methylene chloride, 198 g of p-toluenesulfonyl chloride was added little by little at room temperature, and stirred for 2 days after completion. The reaction solution was washed with water, 2N hydrochloric acid, 2N aqueous sodium hydroxide solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 215 g of 1-pyrrolidinecarbonyl-4- (p-toluenesulfonyloxymethyl) piperidine as a light brown solid. LC-MS, m / z; 367 (MH ⁺ ).
(4) 2.34 g of the above product, 4-amino-5-chloro-2-ethoxy-N- (2-morpholinylmethyl) benzamide (S. Kato, et al., Chem. Pharm, Bull., ( 1995) 43 , 699-702) 2.0 g, anhydrous potassium carbonate 1.3 g, potassium iodide 0.1 g and acetonitrile 80 ml were heated to reflux with stirring for 23 hours. After cooling to room temperature, the reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 19/1 to 9/1) and the amorphous solid obtained was treated with fumaric acid to obtain 0.7 g of the title compound as a powder. .
¹ H-NMR (DMSO-d ₆ , δppm); 0.96-1.08 (2H, m), 1.41 (3H, t, J = 6.9 Hz), 1.6-1.8 (7H, m), 1.8 (1H, t, J = 10.5 Hz), 2.04 (1H, t like), 2.16 (2H, d like, J = 6.4 Hz), 2.64-2.85 (4H, m), 3.2-3.3 (5H, m), 3.4-3.65 (5H, m), 3.81 (1H, d, J = 11 Hz), 4.07 (2H, q, J = 6.9 Hz), 5.95 (2H, s), 6.47 (1H, s), 6.62 (3H, s), 7.71 ( 1H, s), 8.07 (1H, t, J = 5.1 Hz).

  The compound of Production Example 135 was produced by another method (the method described in Production Example 43 (Alternative Method)) to obtain a solid. The data is shown in Table 19 below.

Production Example 139 (Alternative Method) :
Preparation of N-[{4- (1-acetyl-4-piperidinylmethyl) -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide :

４−（１−アセチル−４−ピペリジニルメチル）−２−（ｔｅｒｔ−ブトキシカルボニル）アミノメチルモルホリン（参考例１５）０．７０ｇの塩化メチレン５ｍｌ溶液にトリフルオロ酢酸５ｍｌを加え、室温で２時間撹拌した。反応液を減圧乾固し、残渣をトルエンに溶解後、再度減圧乾固した。残渣に水を加え、２Ｎ水酸化ナトリウムでアルカリ性にし、クロロホルム抽出した。抽出液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。４−（１−アセチル−４−ピペリジニルメチル）−２−アミノメチルモルホリンを含む油状残渣のＤＭＦ５ｍｌ溶液を４−アミノ−５−クロロ−２，３−ジヒドロベンゾ［ｂ］フラン−７−カルボン酸０．４２ｇおよびＮ，Ｎ’−カルボニルジイミダゾール０．３５ｇのＤＭＦ１０ｍｌ溶液を室温で１時間撹拌した後の反応液に加え、この混合物を室温で更に終夜撹拌した。反応液に水を加え、クロロホルムで抽出した後、抽出液を飽和炭酸水素ナトリウム、水、飽和食塩水の順で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１）で精製して標記化合物０．８５ｇを白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 0.95-1.2 (2H, m), 1.6-2.0 (5H, m), 2.08 (3H, s), 2.16 (2H, d, J = 6.8 Hz), 2.45-2.7 (2H, m), 2.75 (1H, m), 3.0 (1H, m), 3.06 (2H, t, J = 8.8 Hz), 3.35 (1H, m), 3.55-3.75 (3H, m), 3.79 (1H, br d, J = 13.5 Hz), 3.87 (1H,br d, J = 10.4 Hz), 4.29 (2H, s), 4.58 (1H, br d, J = 13.0 Hz), 4.78 (2H, t, J = 8.8 Hz), 7.62 (1H, br t like), 7.85 (1H, s).

4- (1-acetyl-4-piperidinylmethyl) -2- (tert-butoxycarbonyl) aminomethylmorpholine (Reference Example 15) To a solution of 0.70 g in 5 ml of methylene chloride was added 5 ml of trifluoroacetic acid, and 2% at room temperature. Stir for hours. The reaction solution was dried under reduced pressure, the residue was dissolved in toluene, and then again dried under reduced pressure. Water was added to the residue, and the mixture was made alkaline with 2N sodium hydroxide and extracted with chloroform. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A solution of 4- (1-acetyl-4-piperidinylmethyl) -2-aminomethylmorpholine in DMF (5 ml) was added to 4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carvone. A solution of 0.42 g of acid and 0.35 g of N, N′-carbonyldiimidazole in 10 ml of DMF was added to the reaction solution after stirring at room temperature for 1 hour, and the mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to obtain 0.85 g of the title compound as a white amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 0.95-1.2 (2H, m), 1.6-2.0 (5H, m), 2.08 (3H, s), 2.16 (2H, d, J = 6.8 Hz), 2.45- 2.7 (2H, m), 2.75 (1H, m), 3.0 (1H, m), 3.06 (2H, t, J = 8.8 Hz), 3.35 (1H, m), 3.55-3.75 (3H, m), 3.79 (1H, br d, J = 13.5 Hz), 3.87 (1H, br d, J = 10.4 Hz), 4.29 (2H, s), 4.58 (1H, br d, J = 13.0 Hz), 4.78 (2H, t , J = 8.8 Hz), 7.62 (1H, br t like), 7.85 (1H, s).

Production Example 142:
1.5 Preparation of 4-amino-5-chloro-2-ethoxy-N-[{4-[(1-ethoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:

４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２２）１．０ｇ、エトキシ酢酸０．２５ｇおよび塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド０．５６ｇの塩化メチレン１０ｍｌ溶液を室温で１時間攪拌した。反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物の塩基１．０５ｇを白色アモルファス状固体として得た。この固体をフマル酸で処理して標記化合物を粉状物として得た。融点１４９℃（分解、Ｅ／ＥＡから再結晶）
¹H-NMR (DMSO-d₆, δppm); 0.8-1.2 (2H, m), 1.11 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 6.9 Hz), 1.6-1.8 (4H, m), 2.03 (1H, dd, J = 8.2, 11.4 Hz), 2.14 (2H, d like, J = 6.6 Hz), 2.67 (1H, d, J = 10.9 Hz), 2.77 (1H, d, J = 10.9 Hz), 2.93 (1H, t like, J = 12.4 Hz), 3.25 (1H, m), 3.35-3.65 (6H, m), 3.80 (2H, br t, J = 11.8 Hz), 3.95-4.2 (4H,m), 4.29 (1H, br t, J = 11.2 Hz), 5.94 (2H, s), 6.47 (1H, s), 6.63 (3H, s), 7.71 (1H, s), 8.07 (1H, t like, J = 5.0 Hz). LC-MS, m/z; 497 (MH⁺).

4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 22) 1.0 g, ethoxyacetic acid 0.25 g and hydrochloric acid A solution of 0.56 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide in 10 ml of methylene chloride was stirred at room temperature for 1 hour. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 1.05 g of the base of the title compound as a white amorphous solid. This solid was treated with fumaric acid to give the title compound as a powder. Melting point 149 ° C (decomposition, recrystallization from E / EA)
¹ H-NMR (DMSO-d ₆ , δppm); 0.8-1.2 (2H, m), 1.11 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 6.9 Hz), 1.6-1.8 ( 4H, m), 2.03 (1H, dd, J = 8.2, 11.4 Hz), 2.14 (2H, d like, J = 6.6 Hz), 2.67 (1H, d, J = 10.9 Hz), 2.77 (1H, d, J = 10.9 Hz), 2.93 (1H, t like, J = 12.4 Hz), 3.25 (1H, m), 3.35-3.65 (6H, m), 3.80 (2H, br t, J = 11.8 Hz), 3.95- 4.2 (4H, m), 4.29 (1H, br t, J = 11.2 Hz), 5.94 (2H, s), 6.47 (1H, s), 6.63 (3H, s), 7.71 (1H, s), 8.07 ( 1H, t like, J = 5.0 Hz) .LC-MS, m / z; 497 (MH ⁺ ).

Production Example 143-189:
Instead of 4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide in Production Example 142, instead of the corresponding starting compound and ethoxyacetic acid The compounds shown in Tables 20 to 23 were obtained as amorphous solids or powders by reacting and treating in the same manner as in Production Example 142 using the carboxylic acid corresponding to the above. Some amorphous solids were salted by treatment with fumaric acid.

１）立体配置表記を表す。

1) Represents a configurational notation.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。
３）分解点を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.
3) Represents the decomposition point.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。
３）分解点を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.
3) Represents the decomposition point.

１）立体配置表記を表す。

1) Represents a configurational notation.

Production Examples 190-195:
Instead of 4-amino-N-[{4-[(1- (tert-butoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide in Preparation Example 22. Using the corresponding raw material compounds, the compounds shown in Table 24 below were obtained as an amorphous solid by the same reaction as in Production Example 22.

Production Example 196:
Preparation of fumaric acid 4-amino-5-chloro-2-ethoxy-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:

Ｎ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２−エトキシベンズアミド（製造例１２８）１．０ｇのメタノール１０ｍｌ溶液に２８％ナトリウムメトキシドメタノール溶液０．１９ｍｌを室温で加え、室温下、３時間攪拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解させた後、水、続いて飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物の塩基０．８２ｇを白色アモルファス状固体として得た。この固体をフマル酸で処理して標記化合物を粉状物として得た。融点１９５℃（分解、Eから再結晶)
¹H-NMR (DMSO-d₆, δppm); 0.8-1.2 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.6-1.8 (4H, m), 2.01 (1H, td, J = 8.3, 2.9 Hz), 2.13 (2H, br d, J = 6.8 Hz), 2.64 (1H, br t, J = 13.0 Hz), 2.76 (1H, br d, J = 11.5 Hz), 2.90 (2H, br t, J = 12.5 Hz), 3.2 (1H, m), 3.35-3.7 (4H, m), 3.81 (1H, br d, J = 11.5 Hz), 3.95-4.1 (4H,m), 4.31 (1H, br d, J = 12.6 Hz), 4.4 (1H, br s), 5.94 (2H, s), 6.47 (1H, s), 6.63 (2H, s), 7.71 (1H, s), 8.07 (1H, t like, J = 5.1 Hz). LC-MS, m/z; 469 (MH⁺).

N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide (Production Example 128) 1.0 g of methanol 10 ml To the solution, 0.19 ml of 28% sodium methoxide methanol solution was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was dried under reduced pressure, the residue was dissolved in chloroform, and then washed with water and then with saturated saline. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 0.82 g of the base of the title compound as a white amorphous solid. . This solid was treated with fumaric acid to give the title compound as a powder. Melting point 195 ° C (decomposition, recrystallized from E)
¹ H-NMR (DMSO-d ₆ , δppm); 0.8-1.2 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.6-1.8 (4H, m), 2.01 (1H, td, J = 8.3, 2.9 Hz), 2.13 (2H, br d, J = 6.8 Hz), 2.64 (1H, br t, J = 13.0 Hz), 2.76 (1H, br d, J = 11.5 Hz), 2.90 (2H, br t, J = 12.5 Hz), 3.2 (1H, m), 3.35-3.7 (4H, m), 3.81 (1H, br d, J = 11.5 Hz), 3.95-4.1 (4H, m), 4.31 (1H , br d, J = 12.6 Hz), 4.4 (1H, br s), 5.94 (2H, s), 6.47 (1H, s), 6.63 (2H, s), 7.71 (1H, s), 8.07 (1H, t like, J = 5.1 Hz) .LC-MS, m / z; 469 (MH ⁺ ).

Production Examples 197-202:
The corresponding starting material compound instead of N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide in Production Example 196 Was used in the same manner as in Production Example 196 to obtain the compounds shown in Table 25 as an amorphous solid. Some amorphous solids were salted by treatment with hydrochloric acid or fumaric acid.

１）立体配置表記を表す。
２）Ｆはフマル酸を表す。

1) Represents a configurational notation.
2) F represents fumaric acid.

Production Example 198 (alternative method):
Preparation of 4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide hydrochloride:

Ｎ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２−メトキシベンズアミド（製造例１２７）６．６ｇのメタノール２５ｍｌ溶液に２Ｎ水酸化ナトリウム水溶液６．７ｍｌを室温で加え、室温下、３０分間攪拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解させた後、飽和炭酸水素ナトリウム水溶液、続いて水で洗浄した。無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物の塩基５．１ｇを白色アモルファス状固体として得た。この固体を４Ｎ ＨＣｌ 酢酸エチルで処理して標記化合物を粉状物として得た。融点１６４−１６７℃（分解）
¹H-NMR (DMSO-d₆, δppm); 0.97-1.20 (2H, m), 2.01 (2H, m), 2.13 (1H, m), 2.63 (1H, br t, J = 12.0 Hz), 2.77 (1H, br q, J = 11.2 Hz), 2.90-3.10 (4H, m), 3.27-3.62 (6H, m), 3.62 (1H, br d, J = 13.2 Hz), 3.84 (3H, s), 3.84-4.12 (3H,m), 4.06 (2H, d, J = 7.1 Hz), 4.31 (1H, br d, J = 11.5 Hz), 6.02 (2H, s), 6.49 (1H, s), 7.70 (1H, s), 8.09 (1H, t like, J = 7.7 Hz). LC-MS, m/z; 455 (MH⁺).

N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide (Production Example 127) 6.6 g of methanol 25 ml To the solution was added 6.7 ml of 2N aqueous sodium hydroxide solution at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated to dryness, the residue was dissolved in chloroform, and then washed with a saturated aqueous sodium hydrogen carbonate solution and then with water. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 5.1 g of the base of the title compound as a white amorphous solid. . This solid was treated with 4N HCl ethyl acetate to give the title compound as a powder. Melting point 164-167 ° C. (decomposition)
¹ H-NMR (DMSO-d ₆ , δppm); 0.97-1.20 (2H, m), 2.01 (2H, m), 2.13 (1H, m), 2.63 (1H, br t, J = 12.0 Hz), 2.77 (1H, br q, J = 11.2 Hz), 2.90-3.10 (4H, m), 3.27-3.62 (6H, m), 3.62 (1H, br d, J = 13.2 Hz), 3.84 (3H, s), 3.84-4.12 (3H, m), 4.06 (2H, d, J = 7.1 Hz), 4.31 (1H, br d, J = 11.5 Hz), 6.02 (2H, s), 6.49 (1H, s), 7.70 ( 1H, s), 8.09 (1H, t like, J = 7.7 Hz) .LC-MS, m / z; 455 (MH ⁺ ).

Production Example 203:
4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide Manufacturing:

製造例１９６におけるＮ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２−エトキシベンズアミドの代わりにＮ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２，３−ジヒドロベンゾ［ｂ］フラン−７−カルボキサミド（製造例１４１）を用い、製造例１９６と同様に反応・処理して標記化合物をアモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 0.9-1.2 (2H, m), 1.55-2.0 (4H, m), 2.18 (3H, br d, J = 6.6 Hz), 2.55-2.85 (3H, m), 2.94 (1H, br d, J = 11.6 Hz), 3.04 (2H, t, J = 8.7 Hz), 3.35 (1H, m), 3.47 (1H, br d, J = 13.4 Hz), 3.5-3.8 (4H, m), 3.88 (1H, br d, J = 11.0 Hz), 4.13 (2H, s), 4.43 (2H, s), 4.54 (1H, br d, J = 13.2 Hz), 4.76 (2H, t, J = 8.7 Hz), 7.61 (1H, t like), 7.80 (1H, s). LC-MS, m/z; 467 (MH⁺).

Instead of N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide in Preparation Example 196, N-[{ 4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide (Production Example 141) The title compound was obtained as an amorphous solid by reaction and treatment in the same manner as in Production Example 196.
¹ H-NMR (CDCl ₃ , δppm); 0.9-1.2 (2H, m), 1.55-2.0 (4H, m), 2.18 (3H, br d, J = 6.6 Hz), 2.55-2.85 (3H, m) , 2.94 (1H, br d, J = 11.6 Hz), 3.04 (2H, t, J = 8.7 Hz), 3.35 (1H, m), 3.47 (1H, br d, J = 13.4 Hz), 3.5-3.8 ( 4H, m), 3.88 (1H, br d, J = 11.0 Hz), 4.13 (2H, s), 4.43 (2H, s), 4.54 (1H, br d, J = 13.2 Hz), 4.76 (2H, t , J = 8.7 Hz), 7.61 (1H, t like), 7.80 (1H, s). LC-MS, m / z; 467 (MH ⁺ ).

Production Example 204:
1.5 fumaric acid N-[{4-[(1- (N-allyl-N-methylcarbamoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2- Production of ethoxybenzamide:

クロロギ酸トリクロロメチル０．２９ｇの塩化メチレン３ｍｌ溶液に氷冷却下、Ｎ−メチルアリルアミン０．２１ｇの塩化メチレン２ｍｌ溶液を滴下した。氷冷却下、１０分間攪拌した後、４−アミノ−５−クロロ−２−エトキシ−Ｎ−［〔４−（４−ピペリジニルメチル）−２−モルホリニル〕メチル］ベンズアミド（製造例２２）１．０ｇおよびＴＥＡ０．４４ｍｌの塩化メチレン５ｍｌ溶液を滴下した。終了後、同温度で３時間攪拌した。反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９９／１〜９５／１）で精製して標記化合物の塩基０．４７ｇを白色アモルファス状固体として得た。この固体をフマル酸で処理して標記化合物を粉状物として得た。融点１７０℃（Ｅから再結晶）
¹H-NMR (DMSO-d₆, δppm); 0.95-1.0 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.67 (3H, d like, J = 9.9 Hz), 1.82 (1H, t, J = 10.4 Hz), 2.03 (1H, t like, J = 9.7 Hz), 2.15 (2H, d like, J = 6.1 Hz), 2.55-2.75 (2H, m), 2.66 (3H, s), 2.76 (1H, br d, J = 11.0 Hz), 3.2 (1H, m), 3.35-3.65 (6H,m), 3.66 (2H, d like, J = 5.5 Hz), 3.81 (1H, br d, J = 11.0 Hz), 4.07 (2H, q, J = 7.0 Hz), 5.14 (1H, s like), 5.18 (1H, d like, J = 5.3 Hz), 5.82 (1H, m), 5.94 (2H, s), 6.47 (1H, s), 6.63 (3H, s), 7.71 (1H, s), 8.09 (1H, t, J = 5.2 Hz). LC-MS, m/z; 508 (MH⁺).

A solution of 0.21 g of trichloromethyl chloroformate in 3 ml of methylene chloride was added dropwise with 2 ml of methylene chloride in 0.21 g of N-methylallylamine under ice-cooling. After stirring for 10 minutes under ice cooling, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-piperidinylmethyl) -2-morpholinyl] methyl] benzamide (Production Example 22) 1 0.05 g and 0.44 ml of TEA in 5 ml of methylene chloride were added dropwise. After completion, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 99/1 to 95/1) to obtain 0.47 g of the base of the title compound as a white amorphous solid. This solid was treated with fumaric acid to give the title compound as a powder. Melting point 170 ° C (recrystallized from E)
¹ H-NMR (DMSO-d ₆ , δppm); 0.95-1.0 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.67 (3H, d like, J = 9.9 Hz), 1.82 (1H , t, J = 10.4 Hz), 2.03 (1H, t like, J = 9.7 Hz), 2.15 (2H, d like, J = 6.1 Hz), 2.55-2.75 (2H, m), 2.66 (3H, s) , 2.76 (1H, br d, J = 11.0 Hz), 3.2 (1H, m), 3.35-3.65 (6H, m), 3.66 (2H, d like, J = 5.5 Hz), 3.81 (1H, br d, J = 11.0 Hz), 4.07 (2H, q, J = 7.0 Hz), 5.14 (1H, s like), 5.18 (1H, d like, J = 5.3 Hz), 5.82 (1H, m), 5.94 (2H, s), 6.47 (1H, s), 6.63 (3H, s), 7.71 (1H, s), 8.09 (1H, t, J = 5.2 Hz). LC-MS, m / z; 508 (MH ⁺ ).

Production Example 205:
(S) -4-Amino-5-chloro-2-ethoxy-N-[{4-[(1- (N-methoxy-N-methylcarbamoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] Production of benzamide:

室温下、クロロギ酸トリクロロメチル０．１５ｍｌおよび塩酸О，Ｎ−ジメチルヒドロキシアミン０．２４ｇの塩化メチレン１０ｍｌ懸濁液にＴＥＡ１．０２ｍｌを加え、１時間攪拌した。この懸濁液を氷冷却下、（Ｓ）−４−アミノ−５−クロロ−２−エトキシ−Ｎ−［〔４−（４−ピペリジニルメチル）−２−モルホリニル〕メチル］ベンズアミド（製造例２６）１．０ｇの塩化メチレン１０ｍｌ溶液に滴下した。終了後、反応液の内温を室温に昇温し、２時間攪拌した。反応液を水、続いて飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物０．８ｇを白色固体として得た。融点１２７−１２９℃（ＥＡ／Ｈから再結晶）
¹H-NMR (CDCl₃, δppm); 1.01-1.22 (2H, m), 1.51 (3H, t, J = 7.0 Hz), 1.62-1.85 (3H, m), 1.92 (1H, br t, J = 10.4 Hz), 2.05-2.25 (3H, m), 2.62 (1H, br d, J = 11.3 Hz), 2.78 (3H,br q, J = 11.7 Hz), 2.84 (3H, s), 3.37 (1H, m), 3.58 (3H, s), 3.61-3.76 (3H, m), 3.87 (1H, br d, J = 10.1 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.0-4.3 (2H, m), 4.33 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.22 (1H, br t). LC-MS, m/z; 498 (MH⁺).

At room temperature, 1.02 ml of TEA was added to a suspension of 0.15 ml of trichloromethyl chloroformate and 0.24 g of O, N-dimethylhydroxyamine hydrochloride in 10 ml of methylene chloride, and the mixture was stirred for 1 hour. (S) -4-Amino-5-chloro-2-ethoxy-N-[[4- (4-piperidinylmethyl) -2-morpholinyl] methyl] benzamide (Production Example) 26) The solution was added dropwise to a solution of 1.0 g of methylene chloride in 10 ml. After completion, the internal temperature of the reaction solution was raised to room temperature and stirred for 2 hours. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 0.8 g of the title compound as a white solid. Melting point 127-129 ° C (recrystallized from EA / H)
¹ H-NMR (CDCl ₃ , δppm); 1.01-1.22 (2H, m), 1.51 (3H, t, J = 7.0 Hz), 1.62-1.85 (3H, m), 1.92 (1H, br t, J = 10.4 Hz), 2.05-2.25 (3H, m), 2.62 (1H, br d, J = 11.3 Hz), 2.78 (3H, br q, J = 11.7 Hz), 2.84 (3H, s), 3.37 (1H, m), 3.58 (3H, s), 3.61-3.76 (3H, m), 3.87 (1H, br d, J = 10.1 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.0-4.3 (2H, m), 4.33 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.22 (1H, br t). LC-MS, m / z; 498 (MH ⁺ ).

Production Example 206:
Preparation of (S) -4-amino-5-chloro-2-ethoxy-N-[{4-[(1-imidazolecarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:

（Ｓ）−４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２６）１．０ｇおよびＮ，Ｎ’−カルボニルジイミダゾール０．４３ｇのＤＭＦ１５ｍｌ溶液を室温で１時間攪拌した。溶媒を減圧留去し、残渣をクロロホルムに溶解させた後、水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物１．０７ｇをアモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.1-1.3 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.7-2.0 (3H, m), 2.1-2.3 (4H, m), 2.62 (1H, br d, J = 10.6 Hz), 2.74 (1H, br d, J = 11.2 Hz), 3.02 (2H, t like, J = 11.9 Hz), 3.4 (1H, m), 3.6-3.8 (3H, m), 3.87 (1H, br d, J = 9.7 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.0-4.25 (2H, m), 4.36 (2H, s), 6.27 (1H, s), 7.09 (1H, s), 7.19 (1H, s), 7.85 (1H, s), 8.11 (1H, s), 8.22 (1H, t like). LC-MS, m/z; 505 (MH⁺).

(S) -4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 26) 1.0 g and N, N A solution of 0.43 g of '-carbonyldiimidazole in 15 ml of DMF was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 1.07 g of the title compound as an amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 1.1-1.3 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.7-2.0 (3H, m), 2.1-2.3 (4H, m), 2.62 (1H, br d, J = 10.6 Hz), 2.74 (1H, br d, J = 11.2 Hz), 3.02 (2H, t like, J = 11.9 Hz), 3.4 (1H, m), 3.6-3.8 ( 3H, m), 3.87 (1H, br d, J = 9.7 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.0-4.25 (2H, m), 4.36 (2H, s), 6.27 (1H, s), 7.09 (1H, s), 7.19 (1H, s), 7.85 (1H, s), 8.11 (1H, s), 8.22 (1H, t like) .LC-MS, m / z; 505 (MH ⁺ ).

Production Example 207:
Preparation of (S) -4-amino-5-chloro-N-[{4-[(1-imidazolecarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide:

（Ｓ）−４−アミノ−５−クロロ−２−メトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２４）を用い、製造例２０６と同様に反応・処理して標記化合物をアモルファス状固体として得た。 LC-MS, m/z; 491 (MH⁺).

Using (S) -4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 24), Production Example 206 and The same reaction and treatment were performed to obtain the title compound as an amorphous solid. LC-MS, m / z; 491 (MH ⁺ ).

Production Example 208:
Preparation of (S) -4-amino-N-[{4-[(1- (1-azetidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide :

（Ｓ）−４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−［（１−イミダゾールカルボニル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］ベンズアミド（製造例２０６）１．０７ｇおよびアゼチジン０．２５ｇのＴＨＦ１５ｍｌ溶液を攪拌下、１９時間加熱還流した。室温に冷却後、反応液を減圧乾固し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物０．４３ｇを白色固体として得た。融点１６６−１６８℃（ＥＡ／Ｈから再結晶）
¹H-NMR (CDCl₃, δppm); 0.98-1.17 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.57-1.8 (3H, m), 1.91 (1H, br t, J = 10.4 Hz), 2.2-2.3 (3H, m), 2.21 (2H, t, J = 7.7 Hz), 2.57-2.7 (2H, m), 2.73 (2H,br d, J = 12.6 Hz), 3.35 (1H, m), 3.58-3.78 (3H, m), 3.78-3.92 (3H, m), 3.98 (4H, t, J = 7.7 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.34 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.22 (1H, t like). LC-MS, m/z; 494 (MH⁺).

(S) -4-Amino-5-chloro-2-ethoxy-N-[{4-[(1-imidazolecarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide (Production Example 206) A solution of 07 g and azetidine 0.25 g in THF 15 ml was heated to reflux with stirring for 19 hours. After cooling to room temperature, the reaction solution was dried under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 0.43 g of the title compound as a white solid. Melting point: 166-168 ° C. (recrystallized from EA / H)
¹ H-NMR (CDCl ₃ , δppm); 0.98-1.17 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.57-1.8 (3H, m), 1.91 (1H, br t, J = 10.4 Hz), 2.2-2.3 (3H, m), 2.21 (2H, t, J = 7.7 Hz), 2.57-2.7 (2H, m), 2.73 (2H, br d, J = 12.6 Hz), 3.35 (1H , m), 3.58-3.78 (3H, m), 3.78-3.92 (3H, m), 3.98 (4H, t, J = 7.7 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.34 (2H, s), 6.27 (1H, s), 8.11 (1H, s), 8.22 (1H, t like). LC-MS, m / z; 494 (MH ⁺ ).

Production Example 209:
Preparation of 4-amino-5-chloro-2-ethoxy-N-[{4-[(1-ethyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:

４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２２）１．０ｇおよびＴＥＡ０．４９ｇのメタノール１０ｍｌ溶液に氷冷却下、アセトアルデヒド０．２１ｇを加えた。同温度で２時間攪拌後、水素化ホウ素ナトリウム９２ ｍｇを少しずつ加えた。終了後、同温度で１時間、更に室温に昇温して終夜攪拌した。反応液を減圧乾固し、残渣をクロロホルムに溶解した。水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物１．２ｇを白色アモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.09 (3H, t, J = 7.2 Hz), 1.27 (2H, br q, J = 11.5 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.5 (1H, m), 1.6-2.3 (9H, m), 2.43 (2H, q, J = 7.2 Hz), 2.62 (1H, br d, J = 10.8 Hz), 2.74 (1H, br d, J = 10.8 Hz), 2.98 (2H, br d, J = 11.0 Hz), 3.3 (1H, m), 3.6-3.75 (3H, m), 3.86 (1H, br d, J = 11.3 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.33 (1H, br d, J = 6.8 Hz), 6.27 (1H, s), 8.11 (1H, s), 8.23 (1H, br t). LC-MS, m/z; 439 (MH⁺), 314.

4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 22) 1.0 g and TEA 0.49 g in 10 ml of methanol To the solution, 0.21 g of acetaldehyde was added under ice cooling. After stirring at the same temperature for 2 hours, 92 mg of sodium borohydride was added little by little. After completion, the mixture was stirred at the same temperature for 1 hour, further warmed to room temperature and stirred overnight. The reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform. After washing with water and then with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 1.2 g of the title compound as a white amorphous solid.
¹ H-NMR (CDCl ₃ , δppm); 1.09 (3H, t, J = 7.2 Hz), 1.27 (2H, br q, J = 11.5 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.5 ( 1H, m), 1.6-2.3 (9H, m), 2.43 (2H, q, J = 7.2 Hz), 2.62 (1H, br d, J = 10.8 Hz), 2.74 (1H, br d, J = 10.8 Hz) ), 2.98 (2H, br d, J = 11.0 Hz), 3.3 (1H, m), 3.6-3.75 (3H, m), 3.86 (1H, br d, J = 11.3 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.33 (1H, br d, J = 6.8 Hz), 6.27 (1H, s), 8.11 (1H, s), 8.23 (1H, br t). LC-MS, m / z; 439 (MH ⁺ ), 314.

Production Example 210:
Preparation of 4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (3-fluorobenzyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide:

４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２２）０．７５ｇおよび４−フルオロベンズアルデヒド０．２７ｇのメタノール２０ｍｌ溶液に室温下、トリアセトキシヒドロホウ酸ナトリウム０．７７ｇを少しずつ加え、終了後、終夜攪拌した。水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝３０／１〜１０／１）で精製して標記化合物０．３ｇを白色固体として得た。融点１７２−１７４℃（Ｅ／ＤＥから再結晶）
¹H-NMR (CDCl₃, δppm); 1.12-1.33 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.55-1.85 (4H, m), 1.85-2.04 (3H, m), 2.05-2.2 (3H, m), 2.62 (1H, br d, J = 11.7 Hz), 2.74 (1H, br d, J = 11.3 Hz), 2.85 (2H, br d, J = 11.5 Hz), 3.35 (1H, m), 3.48 (2H, s), 3.6-3.75 (3H, m), 3.85 (1H,m), 4.08 (2H, q, J = 7.0 Hz), 4.32 (1H, br d, J = 6.8 Hz), 6.26 (1H, s), 6.92 (1H, m), 7.02-7.12 (2H, m), 7.26 (1H, m), 8.11 (1H, s), 8.23 (1H, t like). LC-MS, m/z; ５１９ （ＭＨ^＋）．

4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 22) 0.75 g and 4-fluorobenzaldehyde 0.27 g To a 20 ml methanol solution, 0.77 g sodium triacetoxyhydroborate was added little by little at room temperature, and after completion, the mixture was stirred overnight. After washing with water and then with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1 to 10/1) to obtain 0.3 g of the title compound as a white solid. Melting point 172-174 ° C (recrystallized from E / DE)
¹ H-NMR (CDCl ₃ , δppm); 1.12-1.33 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.55-1.85 (4H, m), 1.85-2.04 (3H, m), 2.05-2.2 (3H, m), 2.62 (1H, br d, J = 11.7 Hz), 2.74 (1H, br d, J = 11.3 Hz), 2.85 (2H, br d, J = 11.5 Hz), 3.35 ( 1H, m), 3.48 (2H, s), 3.6-3.75 (3H, m), 3.85 (1H, m), 4.08 (2H, q, J = 7.0 Hz), 4.32 (1H, br d, J = 6.8 Hz), 6.26 (1H, s), 6.92 (1H, m), 7.02-7.12 (2H, m), 7.26 (1H, m), 8.11 (1H, s), 8.23 (1H, t like). LC- MS, m / z; 519 (MH ^<+> ).

Production Example 211:
Preparation of 4-amino-5-chloro-N-[{4-[(1-cyano-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide:

４−アミノ−５−クロロ−２−エトキシ−Ｎ−［｛４−（４−ピペリジニルメチル）−２−モルホリニル｝メチル］ベンズアミド（製造例２２）１．０ｇおよびＴＥＡ０．４１ｍｌの塩化メチレン１０ｍｌ溶液に室温下、ブロモシアン０．２７ｇを加えた後、４時間攪拌した。水、続いて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製して標記化合物０．７ｇを白色固体として得た。融点１９７℃（分解、Ｅから再結晶）
¹H-NMR (CDCl₃, δppm); 1.15-1.4 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.6 (1H, m), 1.78 (2H, t, J = 16.1 Hz), 1.91 (1H, t, J = 10.5 Hz), 2.0-2.2 (3H, m), 2.59 (1H, d, J = 11.2 Hz), 2.71 (1H, d, J = 11.0 Hz), 2.99 (2H, td, J = 2.8, 12.5 Hz), 3.25-3.5 (3H, m), 3.58-3.76 (3H, m), 3.86 (1H, d like, J = 6.4 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.37 (2H, s), 6.27 (1H, s), 8.10 (1H, s), 8.22 (1H, t like). LC-MS, m/z; 436 (MH⁺).

4-amino-5-chloro-2-ethoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide (Production Example 22) 1.0 g and TEA 0.41 ml methylene chloride 10 ml Bromocyan 0.27g was added to the solution at room temperature, followed by stirring for 4 hours. After washing with water and then with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain 0.7 g of the title compound as a white solid. Melting point 197 ° C (decomposition, recrystallization from E)
¹ H-NMR (CDCl ₃ , δppm); 1.15-1.4 (2H, m), 1.50 (3H, t, J = 7.0 Hz), 1.6 (1H, m), 1.78 (2H, t, J = 16.1 Hz) , 1.91 (1H, t, J = 10.5 Hz), 2.0-2.2 (3H, m), 2.59 (1H, d, J = 11.2 Hz), 2.71 (1H, d, J = 11.0 Hz), 2.99 (2H, td, J = 2.8, 12.5 Hz), 3.25-3.5 (3H, m), 3.58-3.76 (3H, m), 3.86 (1H, d like, J = 6.4 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.37 (2H, s), 6.27 (1H, s), 8.10 (1H, s), 8.22 (1H, t like). LC-MS, m / z; 436 (MH ⁺ ).

Production Examples 212-219:
Instead of 4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide in Production Example 142, instead of the corresponding starting compound and ethoxyacetic acid The compounds shown in Table 26 and Table 27 were obtained as amorphous solids or powders by reacting and treating in the same manner as in Production Example 142 using the carboxylic acid corresponding to.

製造例２２０：
臭化水素酸 （Ｓ）−４−アミノ−５−クロロ−Ｎ−［｛４−［（１−ヒドロキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−２−メトキシベンズアミド ２水和物の製造：

Production Example 220:
Hydrobromic acid (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide dihydrate Manufacturing of goods:

製造例１９８（別法）におけるＮ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２−メトキシベンズアミドの代わりに（Ｓ）−Ｎ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２−メトキシベンズアミドを用い、同様の製造方法で標記化合物のフリー体を白色アモルファス状固体として得た。この固体を含水アセトンに溶解し、１当量のＨＢｒ水を滴下後、種結晶を接種して室温で撹拌することにより標記化合物（ＨＢｒ塩）を白色固体として得た（用いた種結晶は標記化合物のフリー体を臭化水素酸で処理することによって得られる塩を、９３％調湿下で静置することによって得た）。融点；２１５−２１６℃（分解）
¹H-NMR (DMSO-d₆, δppm); 0.95-1.22 (2H, m), 1.67-1.80 (2H, m), 2.07 (1H, m), 2.63 (1H, br t, J = 12.7 Hz), 2.81 (1H, m), 2.90-3.12 (4H, m), 3.25-3.55 (6H, m), 3.64-3.82 (2H, m), 3.84 (3H,s), 3.93 (1H, m), 4.00-4.13 (3H, m), 4.33 (1H, d, J = 11.7 Hz), 6.02 (2H, br s), 6.49 (1H, s), 7.70 (1H, s), 8.10 (1H, t like, J = 6.0 Hz), 9.37 (1H, br s). LC-MS, m/z; 455 (MH⁺). XRD ; 2θ=9.5、17.7、20.4、24.4、25.5°．

Instead of N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide in Preparation Example 198 (alternative method) (S) -N-[{4-[(1-Acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide Gave the free form of the title compound as a white amorphous solid. This solid was dissolved in water-containing acetone, 1 equivalent of HBr water was added dropwise, and seed crystals were inoculated and stirred at room temperature to obtain the title compound (HBr salt) as a white solid (the seed crystals used were the title compound). The salt obtained by treating the free form of <RTIgt; of </ RTI> with hydrobromic acid was obtained by standing at 93% humidity). Melting point: 215-216 ° C (decomposition)
¹ H-NMR (DMSO-d ₆ , δppm); 0.95-1.22 (2H, m), 1.67-1.80 (2H, m), 2.07 (1H, m), 2.63 (1H, br t, J = 12.7 Hz) , 2.81 (1H, m), 2.90-3.12 (4H, m), 3.25-3.55 (6H, m), 3.64-3.82 (2H, m), 3.84 (3H, s), 3.93 (1H, m), 4.00 -4.13 (3H, m), 4.33 (1H, d, J = 11.7 Hz), 6.02 (2H, br s), 6.49 (1H, s), 7.70 (1H, s), 8.10 (1H, t like, J = 6.0 Hz), 9.37 (1H, br s). LC-MS, m / z; 455 (MH ⁺ ). XRD; 2θ = 9.5, 17.7, 20.4, 24.4, 25.5 °.

Production Example 221-230:
Production Example 142 using (S) -4-amino-5-chloro-2-methoxy-N-[{4- (4-piperidinylmethyl) -2-morpholinyl} methyl] benzamide and the corresponding carboxylic acid compound The compound of Table 28 was obtained as an amorphous solid or powder by the same production method.

Production Examples 231-232:
Using (S) -4-amino-5-chloro-N-[{4- (4-piperidinylmethyl) -2,3-dihydrobenzo [b] furan-7-carboxamide and the corresponding carboxylic acid compound, The compound of Table 29 was obtained as an amorphous solid or powder by the same production method as in Production Example 142.

製造例２３３：
（Ｓ）−４−アミノ−５−クロロ−Ｎ−［｛４−［（１−ヒドロキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−２，３−ジヒドロベンゾ［ｂ］フラン−７−カルボキサミドの製造：

Production Example 233:
(S) -4-Amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan- Production of 7-carboxamide:

製造例２０３におけるＮ−［｛４−［（１−アセトキシアセチル−４−ピペリジニル）メチル］−２−モルホリニル｝メチル］−４−アミノ−５−クロロ−２，３−ジヒドロベンゾ［ｂ］フラン−７−カルボキサミドの代わりに、対応する光学活性な原料化合物を用い、製造例２０３と同様に反応・処理して標記化合物をアモルファス状固体として得た。
¹H-NMR (CDCl₃, δppm); 1.00-1.15 (2H, m), 1.70-1.92 (4H, m), 2.08-2.21 (3H, m), 2.55-2.83 (3H, m), 2.94 (1H, m), 3.06 (2H, t, J = 8.8 Hz), 3.34 (1H, m), 3.47 (1H, br d, J = 13.4 Hz), 3.62-3.76 (4H, m), 3.87 (1H, br d, J = 11.7 Hz), 4.13-4.20 (2H, m), 4.27 (2H, s), 4.57 (1H, br d, J = 13.2 Hz), 4.78 (2H, t, J = 9.0 Hz), 7.62 (1H, br s), 7.86 (1H, s).

N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan- in Production Example 203 The title compound was obtained as an amorphous solid by reacting and treating in the same manner as in Production Example 203 using the corresponding optically active starting material compound instead of 7-carboxamide.
¹ H-NMR (CDCl ₃ , δppm); 1.00-1.15 (2H, m), 1.70-1.92 (4H, m), 2.08-2.21 (3H, m), 2.55-2.83 (3H, m), 2.94 (1H , m), 3.06 (2H, t, J = 8.8 Hz), 3.34 (1H, m), 3.47 (1H, br d, J = 13.4 Hz), 3.62-3.76 (4H, m), 3.87 (1H, br d, J = 11.7 Hz), 4.13-4.20 (2H, m), 4.27 (2H, s), 4.57 (1H, br d, J = 13.2 Hz), 4.78 (2H, t, J = 9.0 Hz), 7.62 (1H, br s), 7.86 (1H, s).

Formulation Example 1 : Preparation of tablets 4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide (5 g), Lactose (80 g), corn starch (30 g), crystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) are mixed and granulated by a conventional method. Tablets are made at 145 mg per tablet, producing 1000 tablets.

Formulation Example 2 : Preparation of powder 4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide (10 g), Lactose (960 g), hydroxypropylcellulose (25 g) and light anhydrous silicic acid (5 g) are mixed by a conventional method and then made into a powder.

The compounds according to the present invention show a strong affinity for 5-HT ₄ receptors, such as digestive system diseases (irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, morphine, antipsychotics, etc. Drug-induced constipation, contrast media constipation or defecation, functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, post-gastrectomy Syndrome, digestive disorders such as pseudo-intestinal obstruction), neuropsychiatric disorders (schizophrenia, Alzheimer's disease, depression, memory impairment, anxiety, etc.) It can be used for the treatment and prevention of various diseases such as dysuria and various gastrointestinal dysfunctions (for example, loss of appetite, nausea, vomiting, abdominal bloating etc.) It is useful as a drug for promoting gastrointestinal movement or a drug for improving gastrointestinal function.

Claims (30)

Formula (1):

[In the formula, Ar represents the following formula (Ar-1) or formula (Ar-2):

(Wherein R ¹ represents a hydrogen atom or a halogen atom,
R ² represents a hydrogen atom or an alkyl group,
R ³ represents a hydrogen atom, an alkyl group or an alkanoyl group,
R ⁴ represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group,
X represents a nitrogen atom or CH;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or an alkyl group;
h means 1, 2 or 3. )
Means
l means 1, 2 or 3;
m means 1 or 2,
n means 0, 1 or 2;
o means an integer from 0 to 3, provided that n and o are not 0 at the same time,
A represents the following groups (1) to (6):
(1) hydrogen atom, cyano group or formyl group;
(2) an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group;
^{(3) -COR 7, -CSR 7} , -COOR 7, -SO 2 R 7 or -CO-COR ⁷
(R ⁷ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted cycloalkenyl group. An optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic ring) Group is bonded at a carbon atom on the ring), or an optionally substituted monocyclic or bicyclic saturated heterocyclic group (the heterocyclic group is bonded at a carbon atom on the ring) Means));
(4) -CO-COOR ⁸
(R ⁸ means an alkyl group);
(5) -CONR ⁹ -OR ¹⁰
(R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group); and (6) -CONR ¹² R ¹³ , -CSNR ¹² R ¹³ or -SO ₂ NR ¹² R ¹³
(R ¹² represents a hydrogen atom or an arbitrary group in R ⁷ and R ¹³ represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; or R ¹² and R ¹³ are adjacent to each other. Optionally substituted saturated or unsaturated monocyclic ring containing 1 to 3 heteroatoms selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom together with nitrogen atom A group selected from the group consisting of an optionally nitrogen-containing heterocyclic group);
However, when the alkyl group, alkenyl group or alkynyl group in A or R ⁷ is substituted, the alkyl group, alkenyl group and alkynyl group are the following groups (a) to (d):
(A) a halogen atom, cyano group, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group or trifluoromethyl group;
^{(B) -OR 14, -SR 14} , -COR 14, -COOR 14, -O-COR 14, -NR 15 -COR 14, -NR 15 -COOR 14, -NR 15 -SO 2 R 14, -NR ¹⁵ R ¹⁶ or ^-CONR 15 ^{R 16}
(R ¹⁴ is the following groups:
(B ′) a halogen atom, a hydroxy group, a carboxy group, an amino group, a carbamoyl group, —OR ¹⁷ , —COOR ¹⁷ , —NR ¹⁸ —COR ¹⁷ , —NR ¹⁸ —COOR ¹⁷ , —NR ¹⁸ —SO ₂ R ¹⁷ , —NR ¹⁸ R ¹⁹ or —CONR ¹⁸ R ¹⁹ (wherein R ¹⁷ represents an alkyl group, an alkenyl group, or an alkynyl group, R ¹⁸ represents a hydrogen atom or an alkyl group, and R ¹⁹ represents an alkyl group, an alkenyl group, or an alkynyl group) Represents a group, or R ¹⁸ and R ¹⁹ are bonded together with an adjacent nitrogen atom to 1 to 3 selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. Selected from the group consisting of heteroatoms and optionally substituted saturated or unsaturated monocyclic nitrogen-containing heterocyclic groups), Represents an alkyl group, an alkenyl group or an alkynyl group which may be substituted with different 1 to 5 substituents;
R ¹⁵ represents a hydrogen atom or an alkyl group, an alkenyl group or an alkynyl group which may be substituted with the same or different 1 to 5 substituents selected from the above (b ′);
R ¹⁶ represents an alkyl group, an alkenyl group or an alkynyl group each optionally substituted by the same or different 1 to 5 substituents selected from the above (b ′), or R ¹⁵ and R ¹⁶ are a bond And optionally substituted with 1 to 3 heteroatoms selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom together with adjacent nitrogen atoms, or An unsaturated monocyclic nitrogen-containing heterocyclic group may be formed);
^(C) -R ^{20, -OR} 20 or ^-NR 15 -COR ²⁰
(R ¹⁵ is as defined above, and R ²⁰ is an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted monocyclic or bicyclic non-aromatic group. sexual heterocyclic group unsaturated, monocyclic may be substituted or the bicyclic saturated represents a heterocyclic group); and ^{(d) -R 21, -OR 21} , -COR 21, -SR ²¹ , —SO ₂ R ²¹ or —NR ¹⁵ —COR ²¹
(R ¹⁵ is as defined above, and R ²¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group)
Optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of:
When a cycloalkyl group or a cycloalkenyl group is substituted, the cycloalkyl group and the cycloalkenyl group are the following groups (e):
(E) optionally substituted with 1 to 5 substituents selected from halogen atom, hydroxy group, alkyl group, alkoxy group or oxo group;
In monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, monocyclic or bicyclic saturated heterocyclic group, or saturated or unsaturated monocyclic nitrogen-containing heterocyclic group, When a carbon atom on the ring is substituted, the carbon atom may be substituted with the same or different 1 to 5 substituents selected from (e) above,
When a nitrogen atom on the ring is substituted, the nitrogen atom is a group of the following (f):
(F) optionally substituted with an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group;
When the aryl group or heteroaryl group is substituted, the aryl group and heteroaryl group are the following groups (g) to (i):
(G) a halogen atom, a cyano group, a nitro group, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, — (CH ₂ ) ₂ —O— or —O—CH ₂ —O—;
^{(H) -R 14, -OR 14} , -SR 14, -COR 14, -COOR 14, -O-COR 14, -NR 15 -COR 14, -NR 15 -COOR 14, -NR 15 -SO 2 R ^{14, -NR} 15 ^{R 16} or ^-CONR 15 ^{R 16}
(R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above); and (i) a phenyl group or a phenoxy group (wherein the phenyl group and the phenoxy group are a group consisting of a halogen atom, a hydroxy group, an alkyl group and an alkoxy group) Optionally substituted with 1 to 5 substituents selected from
Which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of
Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ¹ represents a chlorine atom, a bromine atom or an iodine atom, R ⁴ represents an alkyl group, and R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a methyl group. A pharmaceutical comprising a pharmaceutically acceptable salt thereof. A medicament comprising the compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ⁴ represents a methyl group, an ethyl group, a propyl group or an isopropyl group. The pharmaceutical consisting of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to ³ , wherein R ² represents a hydrogen atom and R ³ represents a hydrogen atom or a methyl group. A pharmaceutical comprising the compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ represent a hydrogen atom.   The compound according to any one of claims 1 to 5, wherein l means 1 or 2, m means 1 or 2, n means 1 or 2, and o means 1 or 2. A pharmaceutical comprising a pharmaceutically acceptable salt. R ¹ represents a chlorine atom or a bromine atom, R ² and R ³ represent a hydrogen atom, R ⁴ represents a methyl group or an ethyl group, R ⁵ and R ⁶ represent a hydrogen atom, and h represents 1 means 1, l means 1, m means 1, n means 2, and o means 1 or consists of the compound or pharmaceutically acceptable salt thereof according to claim 1 Medicine. A is (1-1) a hydrogen atom, a cyano group or a formyl group; (It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of alkoxy group, alkanoyl group, haloalkyl group, haloalkoxy group, amino group and carboxy group)
A pharmaceutical comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A is (3-1) -COR ^7a , -COOR ^7a , -SO ₂ R ^7a or -CO-COR ^7a
[Wherein R ^7a is an ^optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, and optionally substituted. A cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, or Means a monocyclic or bicyclic saturated heterocyclic group which may be substituted;
However, when the alkyl group, alkenyl group or alkynyl group in R ^7a is substituted, the alkyl group, alkenyl group and alkynyl group are the following groups (a-1) to (d-1):
(A-1) a halogen atom, a cyano group, a hydroxy group, a carboxy group, an amino group, or a carbamoyl group;
(B-1) -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a , -NR ^15a R ^16a or -CONR ^15a R ^16a
(R ^14a represents an alkyl group, R ^15a represents a hydrogen atom or an alkyl group, R ^16a represents an alkyl group, or R ^15a and R ^16a are bonded together with an adjacent nitrogen atom to form 1 to 3 May form a saturated monocyclic nitrogen-containing heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom on the nitrogen-containing heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group);
(C-1) a cycloalkyl group (the cycloalkyl group may be substituted with 1 to 5 different or different substituents selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group), a single ring Or a bicyclic saturated heterocyclic group (the carbon atom on the saturated heterocyclic group is selected from a halogen atom, a hydroxy group, an alkyl group and an alkoxy group, and may be the same or different 1 to 5 substituents) And a nitrogen atom on the saturated heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group); and (d-1) -R ^21a or -NR ^15a -COR ^21a
(R ^15a is as defined above, R ^21a represents an aryl group or heteroaryl group, and the aryl group and heteroaryl group are a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, and a carbamoyl group. Group, cyano group, —R ^14a , —OR ^14a , —COR ^14a , —NR ^15a —COR ^14a or —NR ^15a R ^16a (wherein R ^14a , R ^15a and R ^16a are as defined above) Or may be substituted with 1 to 5 different substituents)
Optionally substituted with 1 to 5 substituents selected from the group consisting of:
When the cycloalkyl group or cycloalkenyl group in R ^7a is substituted, the cycloalkyl group and cycloalkenyl group are the following groups (e-1):
(E-1) may be substituted with 1 to 5 substituents which are the same or different selected from a halogen atom, a hydroxy group, an alkyl group or an alkoxy group;
In the ^optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocyclic group, and optionally substituted monocyclic or bicyclic saturated heterocyclic group In the case where a carbon atom on the ring is substituted, the carbon atom may be substituted with the same or different 1 to 5 substituents selected from the above (e-1), and a nitrogen atom on the ring Is substituted, the nitrogen atom is the following group (f-1):
(F-1) may be substituted with 1 to 5 substituents which are the same or different selected from an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group;
When the aryl group or heteroaryl group in R ^7a is substituted, the aryl group and heteroaryl group are the following groups:
(G-1) a halogen atom, nitro group, hydroxy group, carboxy group, amino group, carbamoyl group, haloalkyl group, haloalkoxy group or cyano group;
(H-1) -R ^14a , -OR ^14a , -COR ^14a , -COOR ^14a , -O-COR ^14a , -NR ^15a -COR ^14a , -NR ^15a -COOR ^14a or -NR ^15a R ^16a
(R ^14a , R ^15a and R ^16a are as defined above); and (i-1) a phenyl group or a phenoxy group (wherein the phenyl group and the phenoxy group are a halogen atom, a hydroxy group, an alkyl group and an alkoxy group) Optionally substituted with 1 to 5 substituents selected from the group consisting of:
It may be substituted with 1 to 5 substituents which are the same or different selected from the group consisting of]
A pharmaceutical comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A is (3-2) -SO ₂ R ^7b
[Wherein R ^7b means an alkyl group, an alkyl group substituted with an optionally substituted phenyl group, or an optionally substituted phenyl group, provided that when the phenyl group is substituted, The phenyl group is a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, -R ^14b , -OR ^14b , -COR ^14b , -COOR ^14b and -O-COR ^14b (R ^14b is Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
A medicament comprising the compound according to claim 9 or a pharmaceutically acceptable salt thereof. The pharmaceutical consisting of the compound of Claim 10 whose R ^<7b> is a C1-C3 alkyl group, or its pharmaceutically acceptable salt. A is (3-3) -COR ^7c or -CO-COR ^7c
[Wherein R ^7c means an ^optionally substituted alkyl group or an optionally substituted alkenyl group;
However, when the alkyl group or alkenyl group in R ^7c is substituted, the alkyl group and alkenyl group are the following groups (a-2) to (d-2):
(A-2) a hydroxy group, a halogen atom, a carbamoyl group or a cyano group;
(B-2) -OR ^14c , -COR ^14c , -COOR ^14c , -O-COR ^14c , -NR ^15c -COR ^14c , -NR ^15c R ^16c or -CONR ^15c R ^16c (here, R ^14c and R ^16c Represent the same or different alkyl groups, and R ^15c represents a hydrogen atom or an alkyl group);
(C-2) a cycloalkyl group or a monocyclic or bicyclic saturated heterocyclic group (wherein the nitrogen atom on the monocyclic or bicyclic saturated heterocyclic group is an alkyl group or an alkanoyl group) Or (d-2) -R ^21c or -NR ^15c -COR ^21c (where R ^15c is as defined above, and R ^21c is an aryl group or heteroaryl. The aryl group and heteroaryl group are a halogen atom, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl group, a cyano group, -R ^14c , -OR ^14c and -COR ^14c (R ^14c is as defined above) and may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
May be substituted with 1 to 5 substituents selected from the group consisting of]
A medicament comprising the compound according to claim 9 or a pharmaceutically acceptable salt thereof. R ^7c is a group of the following (a-3) and (b-3):
(A-3) hydroxy group, a carbamoyl group or a cyano group; and ^{(b-3) -OR 14d,} -COR 14d, -COOR 14d, -O-COR 14d, -NR 15d -COR 14d, -NR 15d R 16d Or -CONR ^15d R ^16d (wherein R ^14d and R ^16d represent the same or different alkyl groups having 1 to 3 carbon atoms, and R ^15d represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms)
An alkyl group having 1 to 3 carbon atoms which may be substituted with a group selected from the group consisting of: or a group selected from the group consisting of (a-3) and (b-3) A medicament comprising the compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is an alkenyl group having 2 to 3 carbon atoms. A is (3-4) -COR ^7d
[Wherein R ^7d is an ^optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted monocyclic or bicyclic non-aromatic unsaturated heterocycle; Means a cyclic group or an optionally substituted monocyclic saturated heterocyclic group;
However, when the carbon atom on the ring of these groups is substituted, the carbon atom is substituted with the same or different 1 to 5 substituents selected from a halogen atom, a hydroxy group, an alkyl group or an alkoxy group. And when the nitrogen atom on the ring of these groups is substituted, the nitrogen atom may be substituted with an alkyl group, an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group]
A medicament comprising the compound according to claim 9 or a pharmaceutically acceptable salt thereof. A is (3-5) -COR ^7e
[Wherein R ^7e means an ^optionally substituted aryl group or an optionally substituted heteroaryl group;
However, when the aryl group or heteroaryl group is substituted, the aryl group and heteroaryl group are the following groups (g-2) to (i-2):
(G-2) a halogen atom, an amino group, a carbamoyl group or a cyano group;
(H-2) -R ^14e , -OR ^14e , -O-COR ^14e , -NR ^15e -COR ^14e , -NR ^15e -COOR ^14e or -NR ^15e R ^16e (where R ^14e and R ^16e are the same or R ^15e represents a hydrogen atom or an alkyl group); and (i-2) is substituted with 1 to 5 identical or different substituents selected from the group consisting of a phenyl group or a phenoxy group. May be]
A medicament comprising the compound according to claim 9 or a pharmaceutically acceptable salt thereof. A is (3-6) -COOR ^7f
[Wherein R ^7f means an alkyl group, an alkenyl group or an ^optionally substituted phenyl group;
However, if the phenyl group is substituted, the phenyl group a halogen atom, a nitro group, hydroxy group, a haloalkyl group, means a haloalkoxy ^group, -R ^{14f, -OR 14f} and ^-COR 14f ^{(R 14f} is an alkyl group And may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
A medicament comprising the compound according to claim 9 or a pharmaceutically acceptable salt thereof. The pharmaceutical consisting of the compound of Claim 16, or its pharmaceutically acceptable salt, wherein R ^7f is an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 2 to 3 carbon atoms. A is (6-1) -CONR ^12a R ^13a , -CSNR ^12a R ^13a or -SO ₂ NR ^12a R ^13a
[Wherein R ^12a is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted with an alkoxycarbonyl group having 2 to 3 carbon atoms, This means an alkyl group having 1 to 3 carbon atoms substituted with an optionally substituted phenyl group, or an optionally substituted phenyl group, provided that when the phenyl group is substituted, the phenyl group is a halogen atom. atom, a nitro group, a hydroxy group, a carboxy group, a haloalkyl group, a haloalkoxy group, an amino group, a carbamoyl ^{group, -R 14a, -OR 14a, -COR} 14a, -COOR 14a and ^{-O-COR 14a (R} 14a is alkyl Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
R ^13a means a hydrogen atom or an alkyl group, or R ^12a and R ^13a are bonded together with adjacent nitrogen atoms, together with 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. A saturated or unsaturated 4- to 6-membered monocyclic nitrogen-containing heterocyclic group optionally containing 1 to 3 heteroatoms selected from the group consisting of The nitrogen atom on the cyclic nitrogen-containing heterocyclic group may be substituted with an alkyl group, an alkanoyl group or an alkoxycarbonyl group]
A pharmaceutical comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. Whether R ^12a and R ^13a represent the same or different alkyl groups having 1 to 3 carbon atoms;
R ^12a is an ^optionally substituted phenyl group (wherein the phenyl group is 1 to 2 halogen atoms, hydroxy group, carboxy group, haloalkyl group, amino group, carbamoyl group, -R ^14a , -OR ^14a ,- COR ^14a , —COOR ^14a or —O—COR ^14a (which may be substituted with R ^14a means an alkyl group), and R ^13a means a hydrogen atom; or R ^12a and R ^13a And a pyrrolidinyl group, piperidinyl group, morpholinyl group or imidazolyl group together with an adjacent nitrogen atom, to form a pharmaceutical comprising the compound or a pharmaceutically acceptable salt thereof. A is (5-1) -CONR ^9a -OR ^10a
[Wherein R ^9a and R ^10a represent the same or different alkyl groups]
A pharmaceutical comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
4-amino-N-[{4-[(1- (1-azetidinecarbonyl) -4-piperidinyl) methyl)]-2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-pyrrolidinecarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (1-pyrrolidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylthiocarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylsulfamoyl-4-piperidinyl) methyl) -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylsulfamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-isopropoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-diethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-diisopropylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
6-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxypyridine-3-carboxamide;
N-[{4-[(1-allylmethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-pyrrolidinecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan- 7-carboxamide;
4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-ethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-phenylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methoxyphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-trifluoromethylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1- (3-acetylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3,5-dimethylphenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3,4-dichlorophenyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-N-[{4-[(1-benzylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methylbenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxybenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (2,4-dichlorobenzyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-phenethyl) carbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
Amino-5-chloro-2-ethoxy-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (1-propoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1-allyloxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-isobutoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-phenoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methoxyphenoxycarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
N-[{4-[(1-acetoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-cyclopentenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (2-cyclopropylvinylcarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-Amino-5-chloro-2-ethoxy-N-[{4-[(1- [2- (furan-2-yl) vinylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-Amino-5-chloro-2-ethoxy-N-[{4-[(1- [2- (thiophen-2-yl) vinylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-amino-N-[{4-[(1- (3-butenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (5-hexenecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4-[(1- (1,3-butadienecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (1,5-hexadienecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4-[(1- [1- (1-propyne) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-methoxycarbonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-N-[{4-[(1-benzoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-ethoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3-fluorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (3-fluorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (4-chlorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-chlorobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide;
4-amino-N-[{4-[(1- (3-bromobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (4-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (4-ethylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-N-[{4-[(1- (tert-butylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (3-hydroxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-hydroxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
N-[{4-[(1- (2-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
N-[{4-[(1- (2-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-ethoxybenzamide;
N-[{4-[(1- (3-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
N-[{4-[(1- (4-acetoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (3-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (4-methoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (2-phenoxybenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1- (3-dimethylaminobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (4-dimethylaminobenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-methoxycarbonylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1- (4-phenylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-N-[{4- [1 (-(4-amino-3-chlorophenylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (2-furancarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1- (1-imidazolecarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-Amino-5-chloro-N-[{4-[(1-[(1,2-dihydrobenzofuran-7-yl) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] -2- Methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-[(5-methylthiophen-2-yl) carbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide ;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-[(S) -2-tetrahydrofurylcarbonyl] -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-methoxy-N-[{4-[(1-methoxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-methoxyacetyl-4-piperidinyl) methyl) -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-2-ethoxy-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide;
4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-Amino-5-chloro-2-methoxy-N-[{4-[(1- (4-piperidinylmethylcarbonyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide.
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2-methoxybenzamide;
4-amino-N-[{4-[(1-benzoylaminoacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] 5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[{4-[(1-cyanoacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide;
4-amino-5-chloro-N-{[4-{[1- (3-methoxypropionyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-N-{[4-{[1-((S) -2-methoxypropionyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (3-tetrahydrofurylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-N-{[4-{[1- (1,2-dioxopropyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (4-oxazolylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-2-methoxy-N-{[4-{[1- (3-triazolylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} benzamide;
4-amino-5-chloro-N-{[4-{[1- (4-cyanobenzoyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxybenzamide;
N-[{4-[(1-acetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -4-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N-{[4-{[1- (3-tetrahydrofurylcarbonyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2,3-dihydrobenzo [b] furan -7-carboxamide; and 4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2,3-dihydrobenzo [b] Furan-7-carboxamide.   The medicament comprising the compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein the configuration of carbon at the 2-position of the morpholinyl group is S.   A pharmaceutical comprising (S) -4-amino-5-chloro-N-[{4-[(1-dimethylcarbamoyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-ethoxybenzamide.   A pharmaceutical comprising (S) -4-amino-5-chloro-N-[{4-[(1-methanesulfonyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide.   (S) -4-amino-5-chloro-2-ethoxy-N-[{4-[(1- (4-methylbenzoyl) -4-piperidinyl) methyl] -2-morpholinyl} methyl] benzamide .   Hydrobromic acid (S) -4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl} methyl] -2-methoxybenzamide dihydrate Medicine consisting of things.   (S) -4-amino-5-chloro-N-{[4-{[1-((S) -2-methoxypropionyl) -4-piperidinyl] methyl} -2-morpholinyl] methyl} -2-methoxy A pharmaceutical consisting of benzamide.   The medicament according to any one of claims 1 to 27, which is used for treatment and prevention of digestive system diseases, digestive system symptoms, neuropsychiatric diseases, or urinary system diseases.   It is a serotonin 4 receptor agonist, The pharmaceutical as described in any one of Claims 1-27.   The medicament according to any one of claims 1 to 27, which is a gastrointestinal motility promoter or a gastrointestinal function improving drug.