JP2021042126A - Aryloxy compound - Google Patents

Abstract

To provide a compound that has β2-adrenergic receptor antagonist activity and carbonic anhydrase-inhibitory activity and that exhibits excellent ocular antihypertensive activity.SOLUTION: Provided is an aryloxy compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [In the formula, A represents a substituted/unsubstituted phenyl group, or a 5- or 6-membered heteroaryl group. R1 and R2 each independently represent H or a lower alkyl group. X1 represents a single bond or a lower alkylene group. X2 represents a single bond, O, S, a sulfenyl group, a sulfonyl group, N(RN), N(RN)CO, CON(RN) or the like; B represents a divalent substituted/unsubstituted benzene ring, pyridine ring, oxazole ring, thiazole ring, furan ring or thiophene ring].SELECTED DRAWING: None

Description

The present invention relates to aryloxy compounds. More specifically, the present invention relates to an aryloxy compound useful for the prevention and treatment of diseases associated with intraocular pressure such as glaucoma, and a pharmaceutical composition containing the compound.

Glaucoma is an irreversible eye disease characterized by impaired optic nerve, resulting in impaired visual function such as visual field loss and decreased visual acuity. These visual dysfunctions are known to be associated with persistently high intraocular pressure. Therefore, as a treatment method for glaucoma, it is a reliable treatment method to lower the intraocular pressure (Non-Patent Document 1).
Ocular hypertension is a condition in which the intraocular pressure is higher than normal but there is no visual impairment. Ocular hypertension may develop into glaucoma due to persistent high intraocular pressure, so treatment to reduce intraocular pressure may be given.

Treatment methods for lowering intraocular pressure include, for example, drug therapy, laser treatment, and surgical treatment.
Drug therapy includes sympathetic stimulants (eg, receptor non-selective stimulants, α ₂ receptor selective stimulants, etc.), sympathetic blockers (eg, β-receptor blockers, αβ receptor blockers, α). ₁ Receptor-selective blockers, etc.), parasympathetic nerve stimulants, prostaglandin-related drugs, carbonate dehydration enzyme inhibitors, Rho kinase (ROCK) inhibitors, and other drugs are used. Among these, prostaglandin-related drugs are widely used as first-line drugs because of their excellent intraocular pressure-lowering effect.
Prostaglandin-related drugs are effective in many patients with glaucoma and ocular hypertension, but there are patients who show no effect or are inadequately effective. Furthermore, long-term use may be inappropriate due to side effects. In such cases, changes to drugs with different mechanisms of action are made. Examples of such a drug include a β-receptor blocker, a carbonic anhydrase inhibitor, and the like.
The β receptor (adrenergic β ₂ receptor) is expressed in the ciliary pigment epithelium of the eye, and when an agonist (adrenergic or the like) binds to the receptor, the intraocular pressure increases. Beta-receptor blockers suppress the production of aqueous humor by antagonizing the adrenergic β-receptor expressed in the hairy body of the eye, mainly the adrenergic β ₂ receptor, thereby eliminating or attenuating its function. It is known to reduce intraocular pressure. As such a drug, for example, timolol, carteolol and the like are known.
Carbonic anhydrase inhibitors delay the formation of bicarbonate ions by inhibiting carbonic anhydrase II (CA-II) expressed in the ciliary process of the eye and reduce the subsequent transport of sodium and secretions. This suppresses the production of aqueous humor. As a result, it is known to lower the intraocular pressure, and examples of such agents include dorzolamide, brinzolamide, acetazolamide and the like.

If necessary, so-called combination therapy, in which two or more drugs having different mechanisms of action are used in combination, is also performed. In the case of combination therapy, patients often instill two or more combinations of drugs, respectively. In order to instill multiple drugs, each drug needs to be instilled at intervals. In addition, some drugs are effective for administration twice a day, and some drugs are effective for administration three times a day. This is inconvenient for the patient.
As a drug for concomitant therapy, a single preparation containing two drugs having different mechanisms of action, that is, a combination eye drop (hereinafter referred to as "combination drug") is known. The combination drug overcomes the above-mentioned problems and is a drug that is beneficial to the patient. As the combination drug, for example, a combination drug containing a prostaglandin-related drug and a β-blocker, a combination drug containing a β-receptor blocker and a carbonic anhydrase inhibitor, and the like are known.
Examples of the combination drug containing a β-receptor blocker and a carbonic anhydrase inhibitor include a combination drug containing timolol and dorzolamide (Patent Document 1) and a combination drug containing timolol and brinzolamide (Patent Document 2). is there.

In the above-mentioned eye drops used for the treatment of glaucoma and ocular hypertension, the compound lowers the intraocular pressure by penetrating the cornea and acting at each site of action. It is known that the corneal permeability of a compound is greatly affected by the physical characteristics of the compound, but is also affected by the pH of the preparation and additives. For example, Non-Patent Document 2 describes that timolol, which is a β-blocker, exhibits different corneal permeability depending on the pH of the preparation and the additive.
The stability of the compound also differs depending on the formulation. Since the combination drug combines two compounds having different physical characteristics into a single preparation, it is difficult to prepare a preparation optimized for each of the two compounds.

By the way, a compound in which two or more distinct modes of action are imparted to a single compound is known. By having two or more distinct modes of action despite being a single molecule, the disadvantages of the above-mentioned combination drug can be eliminated. Furthermore, the single molecule is beneficial to the patient because it makes it easier to prescribe a combination of treatments with three or more modes of action along with other therapeutic agents.

Patent Document 3 discloses a compound of the following general formula as an active substance in a pharmaceutical preparation for the treatment of obesity and / or diabetes.

Patent Document 4 discloses a compound having the following general formula as _{a β 3 adrenergic agonist.}

Patent Document 5 discloses a compound having the following general formula as _{a β 3 adrenergic agonist.}

Patent Document 6 discloses a compound having the following general formula as _{a β 3 adrenergic agonist.}

Patent Document 7 discloses a compound having the following general formula as _{a β 3 adrenergic agonist.}

Non-Patent Document 3 discloses, for example, a compound having the following formula as a compound having a prostaglandin F receptor (FP) agonist action and a carbonic anhydrase inhibitory action.

Non-Patent Document 4 discloses, for example, a compound having the following formula as a compound having an antioxidant effect.

Japanese Patent Publication, Japanese Patent Application Laid-Open No. 5-117167 Japanese Patent Publication Special Table 7-504899 Japanese Patent Publication Japanese Patent Application Laid-Open No. 60-105647 International Publication No. 97/10822 Pamphlet International Publication No. 97/10825 Pamphlet International Publication No. 98/09625 Pamphlet International Publication No. 2002/006276 Pamphlet

Japan Glaucoma Society, Glaucoma Practice Guidelines 3rd Edition Fukuda, M. et al. et al. , J. Occul. Pharmacol. the. 2015, 31, 57-60 Long, D.D. D. et al. , Bioorg. Med. Chem. Lett. 2013, 23, 939-943 Sichrovska, L. et al. et al. , Dhaka Univ. J. Pharm. Sci. 2013, 12, 23-28

However, no compound has been known that has different modes of action in a single molecule, that is, a β-receptor blocking action and a carbonic anhydrase inhibitory action, and exhibits an excellent intraocular pressure lowering action.

［式中、
Ａは、フェニル基、又は５若しくは６員環ヘテロアリール基を表し（該フェニル基、又は５若しくは６員環ヘテロアリール基は、後記の＜置換基群Ｌ＞又は一般式：−Ｑ−Ａｒで表される基から選択される１乃至３個の置換基で置換されていてもよい）；
ここで、
Ｑは、単結合、低級アルキレン基、低級アルケニレン基又は低級アルキニレン基を表し（該低級アルキレン基を構成する１若しくは２以上のメチレン基は、それぞれ独立して、酸素原子、硫黄原子、スルフィニル基、スルホニル基、カルボニル基若しくは一般式：−Ｎ（Ｒ^N）−で表される基（Ｒ^Nは、水素原子又は低級アルキル基を表す）でメチレン基全体が置き換えられていてもよく、及び／又は、メチレン基を構成する水素がハロゲン原子、シアノ基、水酸基若しくは低級アルキル基で置換されていてもよい）；
Ａｒは、フェニル基又は、５若しくは６員環ヘテロアリール基を表し（該フェニル基、又は５若しくは６員環ヘテロアリール基は、後記の＜置換基群Ｍ＞から選択される１乃至３個の置換基で置換されていてもよい）；
Ｒ¹及びＲ²は、それぞれ独立して水素原子又は低級アルキル基を表し；
Ｘ¹は、単結合又は低級アルキレン基を表し、
Ｘ²は、単結合、酸素原子、硫黄原子、スルフィニル基、スルホニル基、一般式：−Ｎ（Ｒ^N）−で表される基、一般式：−Ｎ（Ｒ^N）ＣＯ−で表される基、一般式：−ＣＯＮ（Ｒ^N）−で表される基、一般式：−Ｎ（Ｒ^N）ＳＯ₂−又は一般式：−ＳＯ₂Ｎ（Ｒ^N）−で表される基を表し（各一般式中のＲ^Nは、水素原子又は低級アルキル基を表す）；
Ｂは、
一般式：

（式中、
Ｗ¹は、窒素原子、又はメチン基を表し：
Ｒ^b1は、後記の＜置換基群Ｎ＞から選択される置換基、又は、フェニル基又は５若しくは６員環ヘテロアリール基であり（該フェニル基、又は５若しくは６員環ヘテロアリール基は、低級アルキル基で置換されていてもよい）；
Ｒ^b2は、水素原子又はハロゲン原子を表す）で表される基、又は、
一般式：

（式中、
Ｗ²は、酸素原子、又は硫黄原子を表し；
Ｗ³は、窒素原子、又はメチン基を表し；
Ｒ^b1は、後記の＜置換基群Ｎ＞から選択される置換基、又は、フェニル基又は５若しくは６員環ヘテロアリール基である（該フェニル基、又は５若しくは６員環ヘテロアリール基は、低級アルキル基で置換されていてもよい））で表される基であり；
＜置換基群Ｌ＞、＜置換基群Ｍ＞及び＜置換基群Ｎ＞は、下記のように定義される。
＜置換基群Ｌ＞：
ハロゲン原子、水酸基、ニトロ基、シアノ基、アミノ基、低級アルキル基、シクロアルキル基、ハロ低級アルキル基、低級アルコキシ基、ハロ低級アルコキシ基、ヒドロキシ低級アルキル基、低級アルコキシ低級アルキル基、低級アルコキシカルボニル基、低級アルカノイル基、低級アルキルチオ基、低級アルキルスルホニル基、低級アルキルアミノ基、ジ低級アルキルアミノ基、環状アミノ基、カルバモイル基、モノ低級アルキルカルバモイル基、ジ低級アルキルカルバモイル基、低級アルカノイルアミノ基、低級アルキルスルホニルアミノ基及び低級アルコキシカルボニルアミノ基
＜置換基群Ｍ＞：
ハロゲン原子、水酸基、ニトロ基、シアノ基、アミノ基、低級アルキル基、シクロアルキル基、ハロ低級アルキル基、低級アルコキシ基、ハロ低級アルコキシ基、ヒドロキシ低級アルキル基、低級アルコキシ低級アルキル基、低級アルコキシカルボニル基、低級アルカノイル基、低級アルキルチオ基、低級アルキルスルホニル基、低級アルキルアミノ基、ジ低級アルキルアミノ基、環状アミノ基、カルバモイル基、モノ低級アルキルカルバモイル基、ジ低級アルキルカルバモイル基、低級アルカノイルアミノ基、低級アルキルスルホニルアミノ基及び低級アルコキシカルボニルアミノ基
＜置換基群Ｎ＞：
ハロゲン原子、水酸基、ニトロ基、シアノ基、アミノ基、低級アルキル基、シクロアルキル基、ハロ低級アルキル基、低級アルコキシ基、ハロ低級アルコキシ基、ヒドロキシ低級アルキル基、低級アルコキシ低級アルキル基、低級アルコキシカルボニル基、低級アルカノイル基、低級アルキルチオ基、低級アルキルスルホニル基、低級アルキルアミノ基、ジ低級アルキルアミノ基、カルバモイル基、モノ低級アルキルカルバモイル基、ジ低級アルキルカルバモイル基、アミノ低級アルキル基、低級アルキルアミノ低級アルキル基及びジ低級アルキルアミノ低級アルキル基］ As a result of widely synthesizing and examining an aryloxy compound in order to solve the above problems, the present inventors have found that the compound represented by the general formula (I) described later has excellent adrenaline β ₂ receptor antagonist activity and carbonic acid. The present invention has been completed by finding that it has a carbonic anhydrase inhibitory activity.
That is, the present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[During the ceremony,
A represents a phenyl group or a 5- or 6-membered ring heteroaryl group (the phenyl group or the 5- or 6-membered ring heteroaryl group is represented by the <substituent group L> described later or the general formula: -Q-Ar. It may be substituted with 1 to 3 substituents selected from the represented groups);
here,
Q represents a single bond, a lower alkylene group, a lower alkenylene group or a lower alkynylene group (one or two or more methylene groups constituting the lower alkylene group independently form an oxygen atom, a sulfur atom, a sulfinyl group, and the like. a sulfonyl group, a carbonyl group or the general formula: -N (R ^N) - group represented by (R ^N represents a hydrogen atom or a lower alkyl group) may be the entire methylene group is replaced by, and / or , The hydrogen constituting the methylene group may be substituted with a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
Ar represents a phenyl group or a 5- or 6-membered ring heteroaryl group (the phenyl group or the 5- or 6-membered ring heteroaryl group is 1 to 3 selected from the <substituent group M> described later. It may be substituted with a substituent);
R ¹ and R ² independently represent a hydrogen atom or a lower alkyl group;
X ¹ represents a single bond or lower alkylene group
X ² represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, the general formula: -N (R ^N) - group represented by the general formula: represented by -N (R ^N) CO- group, the general formula: -CON (R ^N) -, a group represented by the general _{^{formula: -N (R N) SO 2}} - or the ^{_{formula: -SO 2 N (R N)}} - represents a group represented by (R ^N in each formula represents a hydrogen atom or a lower alkyl group);
B is
General formula:

(During the ceremony,
W ¹ represents a nitrogen atom or a methine group:
R ^b1 is a substituent or a phenyl group or a 5- or 6-membered ring heteroaryl group selected from the <substituent group N> described later (the phenyl group or the 5- or 6-membered ring heteroaryl group is It may be substituted with a lower alkyl group);
R ^b2 represents a hydrogen atom or a halogen atom), or a group represented by
General formula:

(During the ceremony,
W ² represents an oxygen atom or a sulfur atom;
W ³ represents a nitrogen atom or a methine group;
R ^b1 is a substituent or a phenyl group or a 5- or 6-membered ring heteroaryl group selected from the <substituent group N> described later (the phenyl group or the 5- or 6-membered ring heteroaryl group is It is a group represented by)), which may be substituted with a lower alkyl group;
<Substitute group L>, <Substitute group M> and <Substitute group N> are defined as follows.
<Substituent group L>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, Lower alkylsulfonylamino group and lower alkoxycarbonylamino group <substituent group M>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, Lower alkylsulfonylamino group and lower alkoxycarbonylamino group <substituent group N>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, amino lower alkyl group, lower alkylamino lower Alkyl group and dilower alkylamino lower alkyl group]

The compound represented by the above formula (I) includes not only the racemate of the compound but also all possible enantiomers and diastereomers.

The present invention also relates to intraocular pressure selected from the group consisting of glaucoma, ocular hypertension, increased intraocular pressure due to trauma, increased intraocular pressure due to inflammation, increased intraocular pressure due to drugs, and increased intraocular pressure after surgery in mammals (particularly humans). A method for preventing or treating a disease associated with the above, characterized in that the mammal is administered with a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing the compound or an intraocular pressure lowering agent. Regarding how to do it.
Furthermore, the present invention relates to a pharmaceutical composition and an intraocular pressure lowering agent containing the compound of the formula (I) as an active ingredient. The pharmaceutical composition and the intraocular pressure lowering agent are selected from the group consisting of glaucoma, ocular hypertension, increased intraocular pressure due to trauma, increased intraocular pressure due to inflammation, increased intraocular pressure due to the drug, and increased intraocular pressure after surgery. It is used for the prevention or treatment of diseases associated with.

Since the compound of the present invention has adrenergic β ₂ receptor antagonist activity and carbonic anhydrase inhibitory activity, as shown in Examples described later, it is possible to reduce intraocular pressure. Therefore, the present invention is useful as a therapeutic or prophylactic agent for pathological conditions associated with intraocular pressure such as glaucoma and ocular hypertension.

The meanings of the terms used in the present invention will be described below, and the present invention will be described in more detail.

Examples of the "halogen atom" in the above formula (I) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The "lower alkyl group" in the above formula (I) means an alkyl group having a linear or branched carbon number of 1 to 6, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and the like. Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, isoamyl group, neopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group , Hexyl group, Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1 , 3-Dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group and 1-ethyl-3-methyl Examples include a propyl group.

The "cycloalkyl group" in the above formula (I) means a 3- to 8-membered aliphatic cyclic group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. And so on.

The "halo lower alkyl group" in the above formula (I) is the "lower alkyl group" in which any substitutable position is 1 or 2 or more, preferably 1 to 5 substituted with the same or different halogen atom. Means, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, chloromethyl Examples thereof include a group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a 2,2,2-trichloroethyl group, a bromomethyl group and an iodomethyl group.

The "lower alkoxy group" in the above formula (I) means a group in which the hydrogen atom of the hydroxyl group is substituted with the "lower alkyl group", for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or butoxy. Groups, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like can be mentioned.

The "halo lower alkoxy group" in the above formula (I) is the "lower alkoxy group" in which any substitutable position is 1 or 2 or more, preferably 1 to 3 substituted with the same or different halogen atom. Means, for example, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, chloromethoxy group, 2-chloro. Examples thereof include an ethoxy group, a 1,2-dichloroethoxy group, a bromomethoxy group and an iodomethoxy group.

The "hydroxy lower alkyl group" in the above formula (I) means the "lower alkyl group" in which any substitutable position is substituted with 1 or 2 or more, preferably 1 or 2 hydroxyl groups, for example. Hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 2-hydroxy-1-methylethyl group, 1-hydroxy-1-methylethyl group, 1, Examples thereof include 2-dihydroxyethyl group and 3-hydroxypropyl group.

The "lower alkoxy lower alkyl group" in the above formula (I) is the above-mentioned "lower alkoxy group" in which any substitutable position is 1 or 2 or more, preferably 1 or 2 of the same or different "lower alkoxy group". It means "lower alkyl group", for example, methoxymethyl group, ethoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 1-methoxy-1-methylethyl group, 1,2-dimethoxyethyl group and 3-methoxy. Examples include a propyl group.

The "lower alkoxycarbonyl group" in the above formula (I) means a group in which the "lower alkoxy group" and a carbonyl group are bonded, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, for example, a methoxycarbonyl group. , Ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group and the like.

The "lower alkanoyl group" in the above formula (I) means a group in which the lower alkyl group and the carbonyl group are bonded, that is, an alkanoyl group having 2 to 7 carbon atoms, for example, an acetyl group, a propionyl group, a butyryl group, and the like. Examples thereof include an isobutyryl group, a valeryl group, an isovaleryl group and a pivaloyl group.

The "lower alkylthio group" in the above formula (I) means a group in which the "lower alkyl group" and a sulfur atom are bonded, that is, an alkylthio group having 1 to 6 carbon atoms, for example, a methylthio group, an ethylthio group, and the like. Examples thereof include a propylthio group, an isopropylthio group, a butylthio group, a sec-butylthio group, an isobutylthio group, a tert-butylthio group, a pentylthio group, an isopentylthio group, a hexylthio group and an isohexylthio group.

The "lower alkylsulfonyl group" in the above formula (I) means a group in which the "lower alkyl group" and a sulfonyl group are bonded, for example, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, and an isopropanesulfonyl group. Examples thereof include a group, a butane sulfonyl group, a sec-butane sulfonyl group, an isobutan sulfonyl group, a tert-butane sulfonyl group, a pentane sulfonyl group, an isopentan sulfonyl group, a hexane sulfonyl group and an isohexane sulfonyl group.

The "lower alkylamino group" in the above formula (I) means an amino group N-mono-substituted by the "lower alkyl group", for example, N-methylamino group, N-ethylamino group, N-. Examples thereof include a propylamino group, an N-isopropylamino group, an N-butylamino group, an N-sec-butylamino group and an N-tert-butylamino group.

The "dilower alkylamino group" in the above formula (I) means an amino group N, N-di substituted with the same or different "lower alkyl group", for example, an N, N-dimethylamino group, N, N-diethylamino group, N, N-dipropylamino group, N, N-diisopropylamino group, N-methyl-N-ethylamino group, N-methyl-N-propylamino group and N-methyl-N- Examples thereof include an isopropylamino group.

The "cyclic amino group" in the above formula (I) may contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in the ring, and is saturated with 4 to 7 members. Cyclic amine means, for example, azetidine-1-yl group, pyrrolidine-1-yl group, piperidine-1-yl group, piperazin-1-yl group, morpholino group, thiomorpholino group, azepan-1-yl group, Examples thereof include 1,4-oxazepan-4-yl group and diazepan-1-yl group.

The "mono-lower alkylcarbamoyl group" in the above formula (I) means a group in which the "lower alkyl group" is N-mono-substituted with the nitrogen atom of the carbamoyl group, and is an N-methylcarbamoyl group or N-ethylcarbamoyl. Examples thereof include a group, an N-propylcarbamoyl group, an N-isopropylcarbamoyl group, an N-butylcarbamoyl group, an N-sec-butylcarbamoyl group and an N-tert-butylcarbamoyl group.

The "dilower alkylcarbamoyl group" in the above formula (I) means a group in which the same or different "lower alkyl group" is N, N-di substituted with the nitrogen atom of the carbamoyl group, and is N, N-dimethyl. Carbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N, N-dipropylcarbamoyl group, N-methyl-N-propylcarbamoyl group, N-methyl-N-tert-butylcarbamoyl group Examples include a group, an N-ethyl-N-tert-butylcarbamoyl group and an N, N-diisopropylcarbamoyl group.
Further, the "dilower alkylcarbamoyl group" is a 5- to 8-membered single formed by the nitrogen atom constituting the carbamoyl group and the same or different "lower alkyl group" bonded to the nitrogen atom. A ring (here, one or two or more methylene groups constituting the 5- to 8-membered monocycle may be independently replaced with the entire methylene group by an oxygen atom), or the monocycle. A twin ring formed by condensing a benzene ring or a pyridine ring is also included, and examples thereof include a group represented by the following formula.

The "lower alkanoylamino group" in the above formula (I) means a group in which the "lower alkanoyl group" and an amino group or the "lower alkylamino group" are bonded, for example, N-acetylamino group, N. -Propanoylamino group, N-butanoylamino group, N-pentanoylamino group, N-pivaloylamino group, N-methyl-N-acetylamino group, N-methyl-N-propanoylamino group, N-methyl- N-butanoylamino group, N-methyl-N-pentanoylamino group, N-ethyl-N-acetylamino group, N-ethyl-N-propanoylamino group, N-ethyl-N-butanoylamino group and Examples thereof include an N-ethyl-N-pentanoylamino group.

The "lower alkylsulfonylamino group" in the above formula (I) means a group in which the "lower alkylsulfonyl group" and an amino group or the "lower alkylamino group" are bonded, for example, a methanesulfonylamino group. Etansulfonylamino group, propanesulfonylamino group, isopropanesulfonylamino group, butanesulfonylamino group, sec-butanesulfonylamino group, tert-butanesulfonylamino group, N-methyl-methanesulfonylamino group, N-methyl-ethanesulfonyl group Amino group, N-methyl-propanesulfonylamino group, N-methyl-isopropanesulfonylamino group, N-methyl-butanesulfonylamino group, N-methyl-sec-butanesulfonylamino group, N-methyl-tert-butanesulfonyl Amino group, N-ethyl-methanesulfonylamino group, N-ethyl-ethanesulfonylamino group, N-ethyl-propanesulfonylamino group, N-ethyl-isopropanesulfonylamino group, N-ethyl-butanesulfonylamino group, N Examples thereof include -ethyl-sec-butanesulfonylamino group and N-ethyl-tert-butanesulfonylamino group.

The "lower alkoxycarbonylamino group" in the above formula (I) means a group in which the "lower alkoxycarbonyl group" is bonded to an amino group or the "lower alkylamino group", for example, a methoxycarbonylamino group, Ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, sec-butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, neopentyloxy Examples thereof include a carbonylamino group, a hexyloxycarbonylamino group, an isohexyloxycarbonylamino group, an N-methyl-methoxycarbonylamino group and an N-methyl-ethoxycarbonylamino group.

The "amino lower alkyl group" in the above formula (I) means the "lower alkyl group" in which any substitutable position is substituted with 1 or 2 or more, preferably 1 or 2 amino groups. For example, aminomethyl group, 1-aminoethyl group, 1-aminopropyl group, 2-aminoethyl group, 2-aminopropyl group, 2-amino-1-methylethyl group, 1-amino-1-methylethyl group, 1 , 2-Diaminoethyl group, 3-aminopropyl group and the like.

The "lower alkylamino lower alkyl group" in the above formula (I) is substituted with the same or different "lower alkylamino group" having an arbitrary substitutable position of 1 or 2 or more, preferably 1 or 2. It means the above-mentioned "lower alkyl group", for example, (methylamino) methyl group, 2- (methylamino) ethyl group, 3- (methylamino) propyl group, 4- (methylamino) butyl group, 5- (methylamino). ) Pentyl group, 6- (methylamino) hexyl group, (ethylamino) methyl group, 2- (ethylamino) ethyl group, (propylamino) methyl group, (isopropylamino) methyl group and 2- (ethylamino) ethyl Methyl group and the like can be mentioned.

The "dilower alkylamino lower alkyl group" in the above formula (I) is replaced with the same or different "dilower alkylamino group" having 1 or 2 or more substitutable arbitrary positions, preferably 1 or 2. Means the above-mentioned "lower alkyl group", for example, (dimethylamino) methyl group, 2- (dimethylamino) ethyl group, 3- (dimethylamino) propyl group, 4- (dimethylamino) butyl group, 5-( Examples thereof include a dimethylamino) pentyl group, a 6- (dimethylamino) hexyl group and a (diethylamino) methyl group.

The "5- or 6-membered ring heteroaryl group" in the above formula (I) is preferably 1 or 2 or more selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to the carbon atom. Means a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl. Group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,3- Thisiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, 1,2,4-triazinyl group And 1,3,5-triazinyl groups and the like.

The "lower alkylene group" in the above formula (I) means a linear or branched alkylene group having 1 to 6 carbon atoms, for example, a methylene group, a 1-methylmethylene group, or a 1,1-dimethylmethylene group. , Ethylene group, 1-methylethylene group, 1-ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, 1,1-diethylethylene group, 1,2-diethylethylene group, 1- Ethyl-2-methylethylene group, propylene group, 1-methylpropylene group, 2-methylpropylene group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethyl Ethylene group, 2-ethylpropylene group, 2-ethyl-2-methylpropylene group, butylene group, 1-methylbutylene group, 2-methylbutylene group, 1,1-dimethylbutylene group, 1,2-dimethylbutylene group, Examples thereof include 2,2-dimethylbutylene group, pentylene group and hexalene group.

The "lower alkenylene group" in the above formula (I) means a linear or branched alkenylene group having 2 to 6 carbon atoms, for example, a vinylene group, a 1-methylethenylene group, a 1-ethylethenylene group, 1 , 2-Dimethylethenylene group, 1,2-diethylethenylene group, 1-ethyl-2-methylethenylene group, propenylene group, 1-methyl-2-propenylene group, 2-methyl-2-propenylene group, 1 , 1-Dimethyl-2-propenylene group, 1,2-dimethyl-2-propenylene group, 1-ethyl-2-propenylene group, 2-ethyl-2-propenylene group, 1-butenylene group, 2-butenylene group, 1 -Methyl-2-butenylene group, 2-methyl-2-butenylene group, 1,1-dimethyl-2-butenylene group, 1,2-dimethyl-2-butenylene group and the like can be mentioned.

The "lower alkynylene group" in the above formula (I) means a linear or branched alkynylene group having 2 to 6 carbon atoms, and examples thereof include an ethynylene group and a propynylene group.

As used herein, the "arbitrary substitutable position" is a substitutable hydrogen atom on a carbon atom, a nitrogen atom, an oxygen atom and / or a sulfur atom, and the substitution of the hydrogen atom is chemically acceptable. And, as a result, means the site of what results in a stable compound.

In order to more specifically disclose the compound of the present invention, various symbols used in the formula (I) and the like will be described in more detail with reference to suitable specific examples thereof.

A represents a phenyl group or a 5- or 6-membered ring heteroaryl group. Here, the phenyl group or the 5- or 6-membered ring heteroaryl group is substituted with 1 to 3 substituents selected from the <substituent group L> or the group represented by the general formula: −Q—Ar. May be.

As the phenyl group or 5- or 6-membered ring heteroaryl group of A,
For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 , 4-Oxaziazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group , 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group and the like.
Of these, a phenyl group, a thienyl group, an isothiazolyl group, an isoxazolyl group, a 1,2,5-oxadiazolyl group, a 1,2,5-thiadiazolyl group, a pyridyl group, a pyrazinel group and the like are preferable.
Phenyl groups, 1,2,5-thiadiazolyl groups and pyrazinyl groups are particularly preferred.

The phenyl group or the 5- or 6-membered ring heteroaryl group, which may be substituted with 1 to 3 substituents of A, is preferably a group represented by the following formula, for example.

The phenyl group or the 5- or 6-membered ring heteroaryl group, which may be substituted with 1 to 3 substituents of A, is more preferably a group represented by the following formula, for example.

The phenyl group or the 5- or 6-membered ring heteroaryl group, which may be substituted with 1 to 3 substituents of A, is particularly preferably a group represented by the following formula, for example.

In each of the above groups, ^Ra1 is a substituent selected from the <substituent group L> or the group represented by the general formula: −Q—Ar;
R ^a2 and R ^a3 are hydrogen atoms independently or substituents selected from <substituent group L>, respectively.

Here, <substituent group L> is
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, It is a group consisting of a lower alkylsulfonylamino group and a lower alkoxycarbonylamino group.

The substituent selected from the <substituent group L> is preferably a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, or a lower alkanoyl group. , Dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group and dilower alkylcarbamoyl group.

The ^{substituent selected from the <substituent group L> of R a1} is preferably a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a monolower alkylcarbamoyl group and a dilower alkylcarbamoyl group. Can be mentioned.

Q represents a single bond, a lower alkylene group, a lower alkenylene group or a lower alkynylene group. Here, one or more methylene groups constituting the lower alkylene group are independently represented by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a general formula: -N ( ^RN )-. a group represented by (R ^N represents a hydrogen atom or a lower alkyl group) may be the entire methylene group is replaced by and / or hydrogen constituting a methylene group halogen atom, a cyano group, a hydroxyl group or a lower It may be substituted with an alkyl group.

As a lower alkylene group of Q,
For example, methylene group, 1-methylmethylene group, 1,1-dimethylmethylene group, ethylene group, 1-methylethylene group, 1-ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, 1,1-diethylethylene group, 1,2-diethylethylene group, 1-ethyl-2-methylethylene group, propylene group, 1-methylpropylene group, 2-methylpropylene group, 1,1-dimethylpropylene group, 1 , 2-Dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropylene group, 2-ethylpropylene group, 2-ethyl-2-methylpropylene group, butylene group, 1-methylbutylene group, 2-methylbutylene Groups, 1,1-dimethylbutylene group, 1,2-dimethylbutylene group, 2,2-dimethylbutylene group, pentylene group, hexalene group and the like can be mentioned.
Of these, a methylene group, an ethylene group and a propylene group are preferable.

As a lower alkenylene group of Q,
For example, vinylene group, 1-methylethenylene group, 1-ethylethenylene group, 1,2-dimethylethenylene group, 1,2-diethylethenylene group, 1-ethyl-2-methylethenylene group, propenylene group, 1 -Methyl-2-propenylene group, 2-methyl-2-propenylene group, 1,1-dimethyl-2-propenylene group, 1,2-dimethyl-2-propenylene group, 1-ethyl-2-propenylene group, 2- Ethyl-2-propenylene group, 1-butenylene group, 2-butenylene group, 1-methyl-2-butenylene group, 2-methyl-2-butenylene group, 1,1-dimethyl-2-butenylene group and 1,2- Examples include a dimethyl-2-butenylene group,
Of these, a vinylene group is preferable.

Examples of the lower alkynylene group of Q include an ethynylene group and a propynylene group, and among them, the ethynylene group is preferable.

One or two or more methylene groups constituting the lower alkylene group of Q are independently represented by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a general formula: -N ( ^RN )-. The entire methylene group may be replaced with a group ( ^RN represents a hydrogen atom or a lower alkyl group) and / or the hydrogen constituting the methylene group is a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group. It may be replaced with.

As such a substituted or substituted group, for example, a group selected from the following formula is preferable.

As Q, for example, a single bond, a methylene group and a group selected from the following formula are more preferable.

^RN is a hydrogen atom or a lower alkyl group.

R ^N is for example a hydrogen atom or a methyl group are preferred, more preferably a hydrogen atom.

Ar represents a phenyl group or a 5- or 6-membered ring heteroaryl group. Here, the phenyl group or the 5- or 6-membered ring heteroaryl group may be substituted with 1 to 3 substituents selected from the <substituent group M>.

As a phenyl group of Ar or a 5- or 6-membered ring heteroaryl group,
For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 , 4-Oxaziazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group , 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group and the like.
Among them, phenyl group, fryl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, triazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,3,4-thiadiazolyl group Pyridyl group, pyrimidinyl group and the like are preferable.

Here, <substituent group M> is
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, It is a group consisting of a lower alkylsulfonylamino group and a lower alkoxycarbonylamino group.

Preferred examples of the substituent selected from the <substituent group M> include a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group and a lower alkoxycarbonyl group.

Therefore, as Ar,
For example, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-Bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-propylphenyl group, 3-propylphenyl group, 4-propylphenyl group, 2-trifluoro Phenyl group, 3-trifluorophenyl group, 4-trifluorophenyl group, 2-hydroxymethylphenyl group, 3-hydroxymethylphenyl group, 4-hydroxymethylphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl Group, 4-methoxycarbonylphenyl group, 2-methylsulfonylphenyl group, 3-methylsulfonylphenyl group, 4-methylsulfonylphenyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 5- (Hydroxymethyl) thiophen-2-yl group, 1H-imidazol-1-yl group, 1H-imidazol-2-yl group, 1H-imidazol-4-yl group, 1H-pyrazole-1-yl group, 1H -Pyrazole-3-yl group, 1H-pyrazole-4-yl group, 1-methyl-1H-pyrazol-4-yl group, 1H-pyrazole-5-yl group, thiazole-2-yl group, thiazole-4-yl group Il group, thiazole-5-yl group, 1H-1,2,3-triazole-1-yl group, 1H-1,2,3-triazol-2-yl group, 1H-1,2,3-triazole- 4-yl group, 1H-1,2,4-triazole-1-yl group, 1,2,4-oxadiazol-5-yl group, 1,3,4-oxadiazol-2-yl group, 1,3,4-Thiasiazol-2-yl group, pyridine-2-yl group, pyridine-3-yl group, pyridine-4-yl group, 2-fluoropyridine-3-yl group, 2-fluoropyridine-4 -Il group, 6-fluoropyridine-3-yl group, 6-methylpyridine-3-yl group, 2- (trifluoromethyl) pyridine-4-yl group, pyrimidin-2-yl group, pyrimidin-4-yl group Group, pyrimidin-5-yl group, etc. Get rid of
Among them, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-hydroxy Methylphenyl group, 3-hydroxymethylphenyl group, 4-hydroxymethylphenyl group, 4-methoxycarbonylphenyl group, 4-methylsulfonylphenyl group, 2-furyl group, 2-thienyl group, 5- (hydroxymethyl) thiophene- 2-yl group, 1H-imidazol-1-yl group, 1H-pyrazole-1-yl group, 1-methyl-1H-pyrazol-4-yl group, thiazole-2-yl group, thiazole-4-yl group, Thiazol-5-yl group, 1H-1,2,4-triazole-1-yl group, 1,2,4-oxadiazol-5-yl group, 1,3,4-oxadiazol-2-yl group Group, 1,3,4-thiadiazolyl-2-yl group, pyridine-3-yl group, pyridine-4-yl group, 2-fluoropyridine-3-yl group, 2-fluoropyridine-4-yl group, 6 -Fluoropyridine-3-yl group, 6-methylpyridine-3-yl group, 2- (trifluoromethyl) pyridine-4-yl group, pyrimidin-5-yl group and the like are preferable.

R ^a2 is a hydrogen atom or a substituent selected from the <substituent group L>.

As R ^a2 , for example, a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group and the like are preferable, and a lower alkyl group is more preferable.

R ^a2 is preferably a methyl group, an ethyl group, a propyl group or an isopropyl group.

R ^a3 is a hydrogen atom or a substituent selected from the <substituent group L>.

As R ^a3 , for example, a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group and the like are preferable, and a hydrogen atom and a hydroxyl group are more preferable.

R ¹ and R ² independently represent a hydrogen atom or a lower alkyl group, respectively.

As lower alkyl groups of ^{R 1} and R ^2,
For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, isoamyl group, neopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, Examples thereof include 1,2,2-trimethylpropyl group and 1-ethyl-3-methylpropyl group.
Among them, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like are preferable, and a methyl group is more preferable.

As R ¹ and R ² , for example, a hydrogen atom or a methyl group is preferable.

X ¹ represents a single bond or lower alkylene group.

As a lower alkylene group of ^{X 1,}
For example, methylene group, 1-methylmethylene group, 1,1-dimethylmethylene group, ethylene group, 1-methylethylene group, 1-ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, 1,1-diethylethylene group, 1,2-diethylethylene group, 1-ethyl-2-methylethylene group, propylene group, 1-methylpropylene group, 2-methylpropylene group, 1,1-dimethylpropylene group, 1 , 2-Dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropylene group, 2-ethylpropylene group, 2-ethyl-2-methylpropylene group, butylene group, 1-methylbutylene group, 2-methylbutylene Groups, 1,1-dimethylbutylene group, 1,2-dimethylbutylene group, 2,2-dimethylbutylene group, pentylene group, hexalene group and the like can be mentioned.
Of these, a methylene group, an ethylene group, a propylene group and the like are preferable.

X ² represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, the general formula: -N (R ^N) - group represented by the general formula: represented by -N (R ^N) CO- group, the general formula: -CON (R ^N) - group represented by the general _{^{formula: -N (R N) SO 2}} - or the ^{_{formula: -SO 2 N (R N)}} - represents a group represented by ..
Incidentally, R ^N in the general formula represents a hydrogen atom or a lower alkyl group.

Therefore, to exemplify the combination ^{of R 1} , R ² , X ¹ and X ² of the formula (I),
(1) When R ¹ and R ² are lower alkyl groups and X ¹ and X ² are single bonds, the general formula (I) is expressed as the following formula (I-1).

(2) When R ¹ and R ² are lower alkyl groups, X ¹ is a methylene group, and X ² is a single bond, the general formula (I) is expressed as the following formula (I-2).

(3) When R ¹ and R ² are hydrogen atoms, X ¹ is a methylene group, and X ² is a single bond, the general formula (I) is expressed as the following formula (I-3).

(4) When R ¹ and R ² are lower alkyl groups, X ¹ is an ethylene group, and X ² is a single bond, the general formula (I) is expressed as the following formula (I-4).

(5) When R ¹ and R ² are hydrogen atoms, X ¹ is an ethylene group, and X ² is a single bond, the general formula (I) is expressed as the following formula (I-5).

(6) When R ¹ and R ² are hydrogen atoms, X ¹ is a methylene group, and X ² is a general formula: −N ( ^RN ) SO ₂ −, the general formula (I) is the following formula (I-6). It is expressed as.

(7) When R ¹ and R ² are hydrogen atoms, X ¹ is an ethylene group, and X ² is a sulfur atom, the general formula (I) is expressed as the following formula (I-7).

(8) When R ¹ and R ² are hydrogen atoms, X ¹ is an ethylene group, and X ² sulfonyl group, the general formula (I) is expressed as the following formula (I-8).

又は、一般式：

で表される基である。 B is
General formula:

Or, general formula:

It is a group represented by.

In the above general formula,
W ¹ represents a nitrogen atom or a methine group:
W ² represents an oxygen atom or a sulfur atom;
W ³ represents a nitrogen atom or a methine group.

An example of W ¹ , W ² and W ³ of B is as follows.

B is preferably selected from any of the following formulas.

More preferably, the following formula can be mentioned as B.

R ^b1 is a substituent selected from <substituent group N>, a phenyl group, or a 5- or 6-membered ring heteroaryl group. Here, the phenyl group or the 5- or 6-membered ring heteroaryl group may be substituted with a lower alkyl group.

As ^{the phenyl group of R b1} or the 5- or 6-membered ring heteroaryl group,
For example, phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, 1,2,3-oxadiazolyl group, 1,2 , 4-Oxaziazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group , 1,2,5-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group and the like.
Of these, a pyrazolyl group, a triazolyl group, a tetrazolyl group and the like are preferable.
Pyrazolyl groups are more preferred.

<Substituent group N> is
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, amino lower alkyl group, lower alkylamino lower It is a group consisting of an alkyl group and a dilower alkylamino lower alkyl group.

The substituent selected from the <substituent group N> is preferably a halogen atom, a lower alkoxy lower alkyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a lower alkylamino lower alkyl group or a dilower. Alkylamino lower alkyl groups and the like can be mentioned.
Of these, halogen atoms, carbamoyl groups, monolower alkylcarbamoyl groups, dilower alkylcarbamoyl groups and the like are more preferable.

The "phenyl group or 5- or 6-membered ring heteroaryl group optionally substituted with a lower alkyl group" of R ^{b1 is an unsubstituted phenyl group, an unsubstituted 5- or 6-membered ring heteroaryl group, or a lower alkyl.} Means a 5- or 6-membered ring heteroaryl group substituted with a phenyl group substituted with a group or a lower alkyl group.
For example, phenyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1H-pyrazole-1-yl group, 1H-pyrazole-3-yl group, 1H-pyrazole-4-yl group, 1-methyl-1H-pyrazole-5-yl group, 3-methyl-1H -Pyrazole-5-yl group, 4-methyl-1H-pyrazole-5-yl group, 4-methyl-1H-pyrazole-3-yl group, 1-methyl-1H-pyrazole-4-yl group, 5-methyl -1H-pyrazole-4-yl group, 1-ethyl-1H-pyrazole-5-yl group, 1-propyl-1H-pyrazole-5-yl group, 1-isopropyl-1H-pyrazole-5-yl group, 1 -Ethyl-1H-pyrazole-4-yl group, 1-propyl-1H-pyrazole-4-yl group, 1-isopropyl-1H-pyrazole-4-yl group, thiazole-2-yl group, thiazole-4-yl group Group, thiazole-5-yl group, isothiazole-3-yl group, isothiazole-4-yl group, isothiazole-5-yl group, oxazole-2-yl group, oxazole-4-yl group, oxazole-5 -Il group, isoxazole-3-yl group, isoxazole-4-yl group, isoxazole-5-yl group, 1H-1,2,3-triazole-5-yl group, 1-methyl-1H-1,2, 3-Pyrazole-5-yl group, 1-ethyl-1H-1,2,3-triazole-5-yl group, 1-propyl-1H-1,2,3-triazole-5-yl group, 1-isopropyl -1H-1,2,3-triazole-5-yl group, 1H-1,2,4-triazole-5-yl group, 1-methyl-1H-1,2,4-triazole-5-yl group, 1-Ethyl-1H-1,2,4-Pyrazole-5-yl group, 1-propyl-1H-1,2,4-Pyrazole-5-yl group, 1-isopropyl-1H-1,2,4- Pyrazole-5-yl group, 4-methyl-4H-1,2,4-triazole-3-yl group, 4-ethyl-4H-1,2,4-triazole-3-yl group, 4-propyl-4H -1,2,4-triazole-3-yl group, 4-isopropyl-4H-1,2,4-triazole-3-yl group, 2-methyl-2H-1,2,3-triazole-4-yl group Group, 2-ethyl-2H-1,2,3-triazole- 4-yl group, 2-propyl-2H-1,2,3-triazole-4-yl group, 2-isopropyl-2H-1,2,3-triazole-4-yl group, 1-methyl-1H-1 , 2,4-Triazole-3-yl group, 1-ethyl-1H-1,2,4-triazole-3-yl group, 1-propyl-1H-1,2,4-triazole-3-yl group, 1-Isopropyl-1H-1,2,4-triazole-3-yl group, 1H-tetrazol-5-yl group, 1-methyl-1H-tetrazol-5-yl group, 1-ethyl-1H-tetrazole-5 -Il group, 1-propyl-1H-tetrazol-5-yl group, 1-isopropyl-1H-tetrazol-5-yl group, 2-methyl-2H-tetrazol-5-yl group, 2-ethyl-2H-tetrazole -5-yl group, 2-propyl-2H-tetrazole-5-yl group, 2-isopropyl-2H-tetrazol-5-yl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5 -Thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group and the like.
Among them, 1H-pyrazole-1-yl group, 1H-pyrazole-3-yl group, 1H-pyrazole-4-yl group, 1-methyl-1H-pyrazole-5-yl group, 3-methyl-1H-pyrazol- 5-yl group, 4-methyl-1H-pyrazole-5-yl group, 4-methyl-1H-pyrazole-3-yl group, 1-methyl-1H-pyrazole-4-yl group, 5-methyl-1H- Pyrazole-4-yl group, 1-ethyl-1H-pyrazol-5-yl group, 1-propyl-1H-pyrazol-5-yl group, 1-isopropyl-1H-pyrazole-5-yl group, 1-ethyl- 1H-pyrazole-4-yl group, 1-propyl-1H-pyrazole-4-yl group, 1-isopropyl-1H-pyrazole-4-yl group and the like are preferable.
Particularly preferred are 1-ethyl-1H-pyrazole-5-yl group, 1-ethyl-1H-pyrazole-4-yl group and the like.

Therefore, a preferred example of ^{R b1 is}
For example, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxymethyl group, ethoxymethyl group, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, amino. Methyl group, (methylamino) methyl group, (ethylamino) methyl group, (propylamino) methyl group, (isopropylamino) methyl group, (dimethylamino) methyl group, 1H-pyrazol-1-yl group, 1H-pyrazole -3-yl group, 1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-5-yl group, 3-methyl-1H-pyrazole-5-yl group, 4-methyl-1H-pyrazol-5 -Il group, 4-methyl-1H-pyrazole-3-yl group, 1-methyl-1H-pyrazol-4-yl group, 5-methyl-1H-pyrazole-4-yl group, 1-ethyl-1H-pyrazole -5-yl group, 1-propyl-1H-pyrazole-5-yl group, 1-isopropyl-1H-pyrazole-5-yl group, 1-ethyl-1H-pyrazole-4-yl group, 1-propyl-1H -Pyrazole-4-yl group, 1-isopropyl-1H-pyrazol-4-yl group and the like can be mentioned.
Of these, a fluorine atom, a chlorine atom, a bromine atom, an N-methylcarbamoyl group, an N-ethylcarbamoyl group and a 1-ethyl-1H-pyrazole-5-yl group are preferable.

R ^b2 is a hydrogen atom or a halogen atom.

Examples of the halogen atom of R ^b2 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are preferable.

The compounds of the present invention may have an asymmetric center, a chiral axis, and a chiral plane.

Some chemical structural formulas herein are represented using thick and dashed lines to represent chemical bonds. These thick and dashed lines represent absolute stereochemistry. The thick line indicates that the substituent is above the plane of the bonded carbon atom, and the broken line indicates that the substituent is below the plane of the bonded carbon atom.

The compounds of the invention can occur as racemates, as racemic mixtures, and as individual diastereomers.
In addition, all optical isomers and mixtures thereof are included in the present invention.
Furthermore, the compounds disclosed herein may exist as tautomers, and both tautomer types are within the scope of the invention, even if only one tautomer structure is depicted. Intended to be conjugated by.

In the present invention, the replacement of the methylene group constituting the lower alkylene group with, for example, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a group represented by the ^{general formula: -N (RN)-is} The replacement is acceptable if it is chemically acceptable, resulting in a stable compound.

The present invention also includes the N-oxide of the compound represented by the above formula (I) within the scope thereof. In general, such N-oxides can form on any available nitrogen atom. The N-oxide can be formed by conventional means, for example, by reacting the compound of formula (I) with oxone in the presence of wet alumina.

The compounds of the present invention also include so-called labeled compounds in which some or all of the atoms constituting the compound represented by the formula (I) are replaced by their isotopes. Isotopes used for labeling are not limited to, for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁵ I and the like can be preferably used. These labeled compounds can be prepared by the methods disclosed herein by substituting the non-isotope labeling reagents with the corresponding isotope labeling reagents, or by any suitable method.

Next, the above-mentioned "pharmaceutically acceptable salt" will be described.

The "pharmaceutically acceptable salt" of the compound of the present invention means a pharmaceutically acceptable idiomatic salt. For example, the base addition salt in the carboxyl group, the hydroxyl group or the acidic heteroaryl group when it has an acidic heteroaryl group such as a carboxyl group, a hydroxyl group or a tetrazolyl group, or the amino when it has an amino group or a basic heteroaryl group. Examples thereof include salts of acid addition salts in groups or basic heteroaryl groups.

Examples of the base addition salt include inorganic salts such as aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt; for example, arginine salt, benzatin salt, chloroprocine salt, choline salt and diethanolamine salt. Examples thereof include organic amine salts such as ethanolamine salt, ethylenediamine salt, histidine salt, lysine salt, meglumin salt and prokine salt.

Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, borate, nitrate, phosphate, hydrogen phosphate, and dihydrogen phosphate. , Hexafluorophosphate, perchlorate, hydrogen carbonate, carbonate, formate and other inorganic acid salts; for example, maleate, fumarate, malonate, succinate, lactate, malate. , Tartrate, citrate, acetate, oxalate, asparagate, trifluoroacetate, ascorbate, benzoate, gluceptate, gluconate, glucronate, hibenzate, nicotinic acid Organic acid salts such as salts, otroates, palmitates, pamoates, glycosates, stearate; for example, methanesulfonate (mesylate), ethanesulfonate (esylate), ISEthione. Sulfates such as acid salt, benzene sulfonate (vesylate), p-toluene sulfonate (tosilate), cansilate, edicylate, methylsulfate, napcilic acid (2-naphthalene sulfonate) Examples include acid salts.

The method for producing a pharmaceutically acceptable salt of the compound according to the present invention can be carried out by appropriately combining methods usually used in the field of synthetic organic chemistry. Specifically, a free solution of the compound according to the present invention may be neutralized and titrated with an alkaline solution or an acidic solution.

The "pharmaceutically acceptable salt" of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol.

[General manufacturing method]
Next, a method for producing the compound of the present invention will be specifically described. However, the present invention is not limited to these production methods. In producing the compound of the present invention, the order of reactions can be appropriately changed. The reaction may be carried out from a process or site that seems reasonable.
Further, a substituent conversion (substituent conversion or further modification) step may be inserted between the steps as appropriate.
If there is a reactive functional group, protection / deprotection may be performed as appropriate. The protecting group and the method of protection / deprotection that can be used in each reaction are not limited as long as they are the protecting group and the method of protection / deprotection used in ordinary organic synthesis. Protecting groups that can be used in each reaction and methods of protection and deprotection include, for example, the methods described in the literature [Protective Groups in Organic Synthesis, 3rd Edition, T.K. W. See Green (TW Greene), John Wiley & Sons (1999)] or a method similar thereto, which may be appropriately selected and used. If necessary, the protection / deprotection may be carried out any number of times at any stage during the series of manufacturing steps of the compound represented by the formula (I).

In the following description of the method for producing the compound of the present invention, for convenience, unless otherwise specified, a free compound is used, but in some cases, a salt of the free compound may be used for production. ..
In addition, reagents other than the exemplified reagents can be appropriately used in order to promote the progress of the reaction. If necessary, microwave irradiation may be used to heat each reaction. Further, the raw material compound whose production method is not described is a compound that is commercially available or can be easily prepared by combining known synthetic reactions.
The compound obtained in each step can be isolated and purified by conventional conventional methods such as crystallization, recrystallization, column chromatography, preparative HPLC, etc., but in some cases, it is not isolated and purified. You can proceed to the process of.
In the following manufacturing method, "room temperature" means 1 ° C. to 40 ° C.

[Method for producing the compound of formula (I)]
Scheme 1: Method for producing the compound of formula (I)

The above formula (I) [in the formula, A, R ¹ , R ² , X ¹ , X ² and B are synonymous with the above. ] (Compound (I)) is synonymous with the above formula (a) [in the formula, A is the above. ] And the above formula (b) [in the formula, R ¹ , R ² , X ¹ , X ² and B are synonymous with the above. ], It can be obtained by reacting the compound (compound (b)).

Compound (b) may be used as a free amine or as an acid addition salt. Examples of the acid addition salt include hydrochloride, sulfate, phosphate, perchlorate, p-toluene sulfonate, benzene sulfonate, methane sulfonate, trifluoroacetate and the like.

The amount of compound (b) used is usually 1 to 3 mol, preferably 1 to 2 mol, relative to 1 mol of compound (a).

In the reaction of Scheme 1 above, a base may be added if necessary.
Examples of the base used include N, N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, cesium fluoride, sodium hydride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide and the like. Examples thereof include potassium hydroxide, for example, N, N-diisopropylethylamine, triethylamine and the like are preferable, and for example, N, N-diisopropylethylamine is more preferable.

The amount of the base is usually 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound (b).

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 10 ° C. to 150 ° C., and more preferably 20 ° C. to 130 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, toluene, methanol, ethanol, 1-propanol, 2-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl. -2-Pyrrolidone, dimethylsulfoxide, chloroform, dichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate, acetonitrile and the like. It is preferably toluene, methanol, ethanol, 1-propanol, 2-propanol and the like, and more preferably toluene, methanol and ethanol.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Examples of the combination of two or more of the above reaction solvents include a combination of methanol and toluene, a combination of ethanol and toluene, a combination of 1-propanol and toluene, a combination of 2-propanol and toluene, and a combination of methanol and ethanol and toluene. Etc., preferably a combination of methanol and toluene, a combination of ethanol and toluene, and a combination of methanol, ethanol and toluene.

[Method for producing the compound of formula (a)]
Scheme 2: Method for producing the compound of formula (a)

The above formula (a) [In the formula, A is synonymous with the above. ] (Compound (a)) is synonymous with the above formula (1) [in the formula, A is synonymous with the above. ] (Compound (1)) and the above formula (2) [in the formula, LG represents a leaving group. ], It can be obtained by reacting the compound (compound (2)).

A commercially available product can be used as the compound (1), and the compound (1) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

The desorbing group LG of the compound (2) is not particularly limited as long as it is desorbed by the reaction with the compound (1) to produce the compound (a), but the desorbing group is, for example, 2-methyl. Benzenesulfonyloxy group, 3-methylbenzenesulfonyloxy group, 4-methylbenzenesulfonyloxy group, 2-nitrobenzenesulfonyloxy group, 3-nitrobenzenesulfonyloxy group, 4-nitrobenzenesulfonyloxy group, 2-chlorobenzenesulfonyloxy group, 3 -Chlorobenzenesulfonyloxy group, 4-chlorobenzenesulfonyloxy group, 2-bromobenzenesulfonyloxy group, 3-bromobenzenesulfonyloxy group, 4-bromobenzenesulfonyloxy group, 4-ethylbenzenesulfonyloxy group, 2,5-dichlorobenzene Sulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group, ethanesulfonyloxy group, propanesulfonyloxy group, isopropanesulfonyloxy group, butanesulfonyloxy group, trifluoromethanesulfonyloxy group and halogen atom (chlorine atom, bromine atom and (Ido atom, etc.), for example, 3-nitrobenzenesulfonyloxy group is preferable.

A commercially available product can be used as the compound (2), and the compound (2) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of the compound (2) include 2-methylbenzenesulfonic acid (S) -glycidyl, 3-methylbenzenesulfonic acid (S) -glycidyl, 4-methylbenzenesulfonic acid (S) -glycidyl, and 2-nitrobenzene. Sulphonic acid (S) -glycidyl, 3-nitrobenzenesulfonic acid (S) -glycidyl, 4-nitrobenzenesulfonic acid (S) -glycidyl, 2-chlorobenzenesulfonic acid (S) -glycidyl, 3-chlorobenzenesulfonic acid (S)- Glycidyl, 4-chlorobenzenesulfonic acid (S) -glycidyl, 2-bromobenzenesulfonic acid (S) -glycidyl, 3-bromobenzenesulfonic acid (S) -glycidyl, 4-bromobenzenesulfonic acid (S) -glycidyl, 4 -Ethylbenzenesulfonic acid (S) -glycidyl, 2,5-dichlorobenzenesulfonic acid (S) -glycidyl, benzenesulfonic acid (S) -glycidyl, methanesulfonic acid (S) -glycidyl, ethanesulfonic acid (S) -glycidyl , Benzenesulfonic acid (S) -glycidyl, isopropanesulfonic acid (S) -glycidyl, butanesulfonic acid (S) -glycidyl, trifluoromethanesulfonic acid (S) -glycidyl, (R) -2- (chloromethyl) oxylane , (R) -2- (bromomethyl) oxylane, (R) -2- (iodomethyl) oxylane, 2-methylbenzenesulfonic acid (R) -glycidyl, 3-methylbenzenesulfonic acid (R) -glycidyl, 4-methyl Benzenesulfonic acid (R) -glycidyl, 2-nitrobenzenesulfonic acid (R) -glycidyl, 3-nitrobenzenesulfonic acid (R) -glycidyl, 4-nitrobenzenesulfonic acid (R) -glycidyl, 2-chlorobenzenesulfonic acid (R) -Glysidyl, 3-chlorobenzenesulfonic acid (R) -glycidyl, 4-chlorobenzenesulfonic acid (R) -glycidyl, 2-bromobenzenesulfonic acid (R) -glycidyl, 3-bromobenzenesulfonic acid (R) -glycidyl, 4 -Bromobenzenesulfonic acid (R) -glycidyl, 4-ethylbenzenesulfonic acid (R) -glycidyl, 2,5-dichlorobenzenesulfonic acid (R) -glycidyl, benzenesulfonic acid (R) -glycidyl, methanesulfonic acid (R) ) -Glysidyl, ethanesulfonic acid (R) -glycidyl, propanesulfonic acid (R) -glycidyl, isopropanesulfonic acid (R) -glycidyl, butanesulfonic acid (R)- Examples thereof include glycidyl, trifluoromethanesulfonic acid (R) -glycidyl, (S) -2- (chloromethyl) oxylan, (S) -2- (bromomethyl) oxylan and (S) -2- (iodomethyl) oxylan.

The amount of compound (2) used is usually 1 to 3 mol, preferably 1 to 2 mol, relative to 1 mol of compound (1).
Alternatively, compound (1) may be used in excess of compound (2). In that case, the amount of compound (1) used is usually 1.5 to 5 mol, preferably 2 to 3 mol, relative to 1 mol of compound (2).

The reaction of the above scheme 2 is preferably carried out in the presence of a base.
Examples of the base used include cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, and the like. Examples thereof include sodium hydroxide, potassium hydroxide, N, N-diisopropylethylamine and triethylamine, and for example, cesium fluoride and sodium hydride are preferable.

The amount of the base is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (1).

The reaction temperature is usually 0 ° C. to 120 ° C., preferably 5 ° C. to 100 ° C., and more preferably 10 ° C. to 40 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 20 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, chloroform, dichloromethane, etc. Examples thereof include tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate, acetone, acetonitrile and the like, preferably N, N-dimethylformamide. And dimethyl sulfoxide.

[Method for producing the compound of formula (b): Part 1]
The following schemes 3 to 8 are methods for producing a compound (formula (b-1)) in which the group represented by ^{X 1} and X ^{2 is a single bond in the compound represented by the formula (b).}

Scheme 3: Method for producing the compound of formula (5)

In the above formula (5) [in the formula, B is synonymous with the above, X is a bromine atom, a chlorine atom or an iodine atom, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] (Compound (5)) is the above formula (3) [in the formula, B is synonymous with the above, and X is a bromine atom, a chlorine atom or an iodine atom. ] And the above formula (4) [in the formula, P ¹ is a protecting group and P ² is a protecting group or a hydrogen atom. ] Can be obtained by an amidation reaction with the compound represented by (Compound (4)).

The ^{“protecting group” of P 1} and P ² represents the protecting group of the nitrogen atom of the sulfonamide group. The protective groups P ¹ and P ² are not particularly limited as long as they have the function, but are, for example, a tert-butyl group; for example, a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, 3,4-. Aralkyl groups such as dimethoxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, benzhydryl group and trityl group; for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group and pivaloyl group. Lower alkanoyl groups such as; arylacyl groups such as benzoyl groups and 4-acetoxybenzoyl groups; arylalkanoyl groups such as phenylacetyl groups; aryloxyalkanoyl groups such as phenoxyacetyl groups; eg methoxycarbonyl groups, ethoxycarbonyl groups , Lower alkoxycarbonyl groups such as propyloxycarbonyl group and tert-butoxycarbonyl group; for example, benzyloxycarbonyl group, aralkyloxycarbonyl group such as 4-nitrobenzyloxycarbonyl group and phenethyloxycarbonyl group, etc., in particular tert- A butyl group or a 4-methoxybenzyl group is preferable.

A commercially available product can be used as the compound (3), and the compound (3) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of the compound (3) include, for example, 4-bromo-3-fluorobenzenesulfonyl chloride, 4-bromo-3-methylbenzenesulfonyl chloride, 4-bromo-3-chlorobenzenesulfonyl chloride, 4-bromo-3, 5 Examples thereof include -dimethylbenzenesulfonyl chloride and 5-bromo-4-chlorothiophene-2-sulfonyl chloride.

A commercially available product can be used as the compound (4), and the compound (4) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of the compound (4) include tert-butylamine, dibenzylamine, bis (4-methoxybenzyl) amine, bis (2,4-dimethoxybenzyl) amine and the like.

The amount of compound (4) used is usually 1 to 3 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound (3).

The reaction of Scheme 3 above is preferably carried out in the presence of a base.
Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide, and the like. Examples thereof include potassium hydroxide, N, N-diisopropylethylamine, triethylamine, N-methylmorpholin and pyridine, and N, N-diisopropylethylamine and triethylamine are preferable.

The amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound (3).

The reaction temperature is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, chloroform, dichloromethane, etc. Solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, ethyl acetate, methyl acetate, propyl acetate and acetonitrile can be mentioned, with preference given to tetrahydrofuran.

Scheme 4: Method for producing the compound of formula (7)

In the above formula (7) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] Compound (Compound (7)) is the above formula (5) [In the formula, B is synonymous with the above, X is a bromine atom, a chlorine atom or an iodine atom, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] And the above formula (6) [in the formula, R ¹ and R ² are synonymous with the above, and M ⁺ is an element that can constitute a base addition salt of a carboxylic acid. Represent. ] Can be obtained by a coupling reaction with the compound (compound (6)). More specifically, in the presence of a palladium catalyst (and, if necessary, a phosphine ligand), the carboxylate of compound (6), which is a cyanoacetate, has a halogen atom while decarboxylating. ), The compound (7) can be obtained.

A commercially available product can be used as the compound (6), and the compound (6) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of compound (6) include, for example, sodium 2-cyanoacetate, potassium 2-cyanoacetate, sodium 2-cyanopropionate, potassium 2-cyanopropionate, potassium 2-cyano-2-methylpropionate, 2-. Examples thereof include sodium cyano-2-methylpropionate, potassium 2-cyanobutate and sodium 2-cyanobutate.

The amount of compound (6) used is usually 1 to 3 mol, preferably 1 to 2 mol, relative to 1 mol of compound (5).

Examples of the palladium catalyst used include allylpalladium (II) chloride dimer, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) and bis (triphenylphosphine) palladium (II) dichloride ( (PPh ₃ ) ₂ PdCl ₂ ) and the like.

The amount of the palladium catalyst used is usually 0.01 to 0.5 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (5).

Examples of the phosphine ligand used include 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (XantPhos) and 2- (dicyclohexylphosphino) -2', 4', 6'-triisopropyl. -1,1'-biphenyl (XPhos), dicyclohexyl (2', 6'-dimethoxy- [1,1'-biphenyl] -2-yl) phosphine (SPhos) and 9,9-dimethyl-4,5-bis (Di-tert-butylphosphino) xanthene and the like can be mentioned.

The amount of phosphine ligand used is generally 0.01 to 1.5 mol, preferably 0.05 to 0.5 mol, per 1 mol of compound (5).

The reaction temperature is usually 0 ° C. to 160 ° C., preferably 25 ° C. to 150 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include toluene, xylene, mesitylene, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methyl tert-butyl ether and the like. Preferred are xylene, mesitylene and diethylene glycol dimethyl ether.

Scheme 5: Method for producing the compound of formula (8)

The above formula (8) [In the formula, R ¹ , R ² and B have the same meanings as described above. ] Compound (Compound (8)) is the above formula (7) [In the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. Is. ], It can be obtained by removing the protecting groups ^{of P 1} and P ² of the compound (compound (7)). More specifically, compound (8) can be obtained by removing the protecting groups for ^{P 1} and P ² of compound (7) in the presence of an acid (and optionally anisole or thioanisole). ..

Examples of the acid used include trifluoroacetic acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid and the like, and trifluoroacetic acid and sulfuric acid are preferable.

The amount of acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (7).

The amount of anisole or thioanisole used is usually 0.01 mol to a large excess per 1 mol of compound (7).

The reaction temperature is usually 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 1 to 6 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, 1,2-dichloroethane, chloroform and the like, preferably dichloromethane and chloroform.
This reaction may be carried out without a solvent.

Scheme 6: Method for producing the compound of formula (9)

The above formula (9) [In the formula, R ¹ , R ² and B have the same meanings as described above. ] (Compound (9)) has the above formula (8) [in the formula, R ¹ , R ² and B have the same meanings as described above. ], It can be obtained by hydrolyzing the cyano group of the compound (compound (8)). More specifically, it can be obtained by hydrolyzing the cyano group of compound (8) in the presence of an acid or base.

Examples of the acid used include acetic acid, formic acid, phthalic acid, sulfuric acid, hydrochloric acid and the like, and sulfuric acid and hydrochloric acid are preferable.

The amount of acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (8).

Examples of the base used include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and sodium hydroxide and potassium hydroxide are preferable.

The amount of base used is usually 0.01 mol to a large excess with respect to 1 mol of compound (8).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 160 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 16 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, tetrahydrofuran, etc. Examples thereof include 2-methyl tetrahydrofuran, 1,4-dioxane, cyclohexane, 1,3-dimethylbenzene and toluene, and methanol, ethanol, ethylene glycol and water are preferable.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Examples of the combination of two or more of the reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethanol and water.

Scheme 7: Method for producing the compound of formula (10)

The above formula (10) [In the formula, R ¹ , R ² and B are synonymous with the above. ] (Compound (10)) has the above formula (9) [in the formula, R ¹ , R ² and B have the same meanings as described above. ] Can be obtained by acid azide conversion of the compound (compound (9)). More specifically, the compound (10) is obtained by allowing an azide agent such as diarylphosphate azide (for example, diphenylphosphoryl azide) to act on the compound (9) having a carboxylic acid group in the presence of a base. be able to.

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (9).

Examples of the base used include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.

The amount of base used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (9).

The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 -Propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform and the like, preferably acetonitrile and It is 1,4-dioxane.

The compound (10) is a compound (9) and a halide for halide (eg, methyl chlorostate) in the presence of the corresponding acid halide (eg, acid chloride, acid bromide, acid iodide, etc.) or base of the compound (9). Alkalimetal azides (eg, sodium azide, etc.) to mixed acid anhydrides obtained from ethyl chloroate, ethyl bromogeate, propyl chlorogeate, butyl chloroate, isobutyl chlorogeate, isobutyl bromogeate, hexyl chlorogeate, etc. It can also be obtained by reacting an azidizing agent such as potassium azide) or trialkylsilyl azide (for example, trimethylsilyl azide, triethylsilyl azide, tritert-butylsilyl azide, etc.).

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (9).

The reaction temperature is usually −30 ° C. to 100 ° C., preferably −20 ° C. to 30 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl. Examples thereof include acetoamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform and water, and acetonitrile, tetrahydrofuran, acetone, methylene chloride, chloroform and water are preferable.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Scheme 8: Method for producing the compound of formula (b-1)

The above formula (b-1) [In the formula, R ¹ , R ² and B have the same meanings as described above. ] (Compound (b-1)) has the above formula (10) [in the formula, R ¹ , R ² and B have the same meanings as described above. ] Can be obtained from the compound (compound (10)) through two steps (step (8-1) and step (8-2)).
In addition, the steps (8-1) and (8-2) of Scheme 8 may be performed continuously without isolating the intermediates of each step and / or the intermediates of each step. You may.

[Step (8-1)]
In the step (8-1), the above formula (10) [in the formula, R ¹ , R ² and B are synonymous with the above. ] By the Curtius rearrangement reaction of the acid azide group of the compound (compound (10)), the above formula (11) [in the formula, R ¹ , R ² and B are synonymous with the above. ] Is a step of obtaining the compound (compound (11)).

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran and 1,4-dioxane. And water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (8-2)]
In the step (8-2), the above formula (11) [in the formula, R ¹ , R ² and B are synonymous with the above. ], By allowing a base to act on the compound (compound (11)), the formula (b-1) [in the formula, R ¹ , R ² and B are synonymous with the above. ] Is a step of obtaining a compound (compound (b-1)).

Examples of the base used include sodium hydroxide, potassium hydroxide and the like.

The amount of base used is usually 1 mol to 20 mol, preferably 1 mol to 10 mol, per 1 mol of the starting compound (10).

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran and 1,4-dioxane. And water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Method for producing the compound of formula (b): Part 2]
In the following schemes 9 to 14, among the compounds represented by the formula (b), the ^{group represented by X 1} is a methylene group and the ^{group represented by X 2} is a single bond (formula (b-). 2)) is the manufacturing method.

Scheme 9: Method for producing the compound of formula (13)

In the above formula (13) [in the formula, B is synonymous with the above, P ¹ is a protecting group, P ² is a protecting group or a hydrogen atom, and Me is a methyl group. ] (Compound (13)) has the above formula (12) [in the formula, B is synonymous with the above, and Me is a methyl group. ] And formula (4) [in the formula, P ¹ is a protecting group and P ² is a protecting group or a hydrogen atom. ] Can be obtained by an amidation reaction with the compound represented by (Compound (4)).

A commercially available product can be used as the compound (12), and the compound (12) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of the compound (12) include, for example, 3-fluoro-4-methylbenzenesulfonyl chloride, 3-chloro-4-methylbenzenesulfonyl chloride, 3-bromo-4-methylbenzenesulfonyl chloride, 3-iodo-4-. Methylbenzenesulfonyl chloride, 4-methyl-3-nitrobenzenesulfonyl chloride, 4-methyl-3- (trifluoromethyl) benzenesulfonyl chloride, 3-cyano-4-methylbenzenesulfonyl chloride, 3-acetyl-4-methylbenzenesulfonyl Chloride, 3-acetamido-4-methylbenzenesulfonyl chloride, 3-carbamoyl-4-methylbenzenesulfonyl chloride, methyl 5- (chlorosulfonyl) -2-methylbenzoate and 5- (chlorosulfonyl) -2-methylbenzoic acid Benzene and the like can be mentioned.

A commercially available product can be used as the compound (4), and the compound (4) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of the compound (4) include tert-butylamine, dibenzylamine, bis (4-methoxybenzyl) amine, bis (2,4-dimethoxybenzyl) amine and the like.

The amount of compound (4) used is generally 1 to 3 mol, preferably 1 to 2.5 mol, per 1 mol of compound (12).

The reaction of Scheme 9 above may be carried out in the presence of a base.
Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide, and the like. Examples thereof include potassium hydroxide, pyridine, N, N-diisopropylethylamine and triethylamine, and for example, N, N-diisopropylethylamine and triethylamine are preferable.

The amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, more preferably 1 to 1.3 mol, relative to 1 mol of compound (12).

The reaction temperature is usually −10 ° C. to 40 ° C., preferably −10 ° C. to 30 ° C.

The reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 2 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, chloroform, dichloromethane, etc. Diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, pyridine, acetone, ethyl acetate, methyl acetate, propyl acetate, acetonitrile and the like can be mentioned, preferably tetrahydrofuran. Is.

Scheme 10: Method for producing the compound of formula (14)

In the above formula (14) [in the formula, B is synonymous with the above, X is a halogen atom, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] Compound (Compound (14)) is the above formula (13) [In the formula, B is synonymous with the above, P ¹ is a protecting group, P ² is a protecting group or a hydrogen atom, and Me is methyl. It is a base. ] Can be obtained by the halogenation reaction of the methyl group of the compound (compound (13)). More specifically, compound (14) can be obtained by reacting compound (13) with a halogenating agent (radical initiator, if necessary) such as N-bromosuccinimide or N-chlorosuccinimide.

Specific examples of the halogenating agent used include N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, chlorine and the like.

The amount of the halogenating agent used is usually 1 to 3 mol, preferably 1 to 2 mol, more preferably 1 to 1.5 mol, relative to 1 mol of compound (13).

Specific examples of the radical initiator used include 2,2'-azobis (isobutyronitrile) (AIBN), 1,1'-azobis (cyclohexanecarbonitrile) (ABCN), benzoyl peroxide and the like. ..

The amount of radical initiator used is usually 0.01 to 1 mol, preferably 0.05 to 0.5 mol, more preferably 0.1 to 0.3 mol, relative to 1 mol of compound (13). ..

The reaction temperature is usually −10 ° C. to 100 ° C., preferably 0 ° C. to 90 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 1 hour to 6 hours.

The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include acetonitrile, chloroform, carbon tetrachloride, ethyl acetate, propyl acetate, isopropyl acetate, cyclohexane, benzene, chlorobenzene, trifluoromethylbenzene and the like.

Scheme 11: Method for producing the compound of formula (16)

In the above formula (16) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] Compound (Compound (16)) is the above formula (14) [In the formula, B is synonymous with the above, X is a halogen atom, P ¹ is a protecting group, and P ² is a protecting group or hydrogen. It is an atom. ] (Compound (14)) and the above formula (15) [in the formula, R ¹ and R ² are synonymous with the above. ] Can be obtained from the compound represented by (Compound (15)). More specifically, compound (16) can be obtained by reacting compound (14) with an anion generated by reacting compound (15) with a base.

A commercially available product can be used as the compound (15), and the compound (15) may be produced by appropriately combining a known method, the method described in Examples, or a method similar thereto as necessary.

Specific examples of compound (15) include acetonitrile, propionitrile, butyronitrile, isobutyronitrile, isovaleronitrile, 2-methylbutyronitrile, and the like.

The amount of compound (15) used is usually 1-10 mol, preferably 1-5 mol, more preferably 1-3 mol, relative to 1 mol of compound (14).

Examples of the base used include lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, lithium dicyclohexylamide, sodium dicyclohexylamide, lithium cyclohexylisopropylamide and the like, which are preferable. Is lithium bis (trimethylsilyl) amide or lithium diisopropylamide.

The amount of the base is usually 1 to 3 mol, preferably 1 to 1.5 mol, more preferably 1 to 1.2 mol, relative to 1 mol of compound (15).

The reaction temperature is usually −78 ° C. to 40 ° C., preferably −10 ° C. to 10 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, hexane, cyclohexane and the like. , Which is preferably tetrahydrofuran.

Scheme 12: A method for producing a compound of the formula (17).

In the above formula (17) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] Compound (Compound (17)) has the above formula (16) [in the formula, R ¹ , R ² and B have the same meanings as described above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. Is. ] Can be obtained by hydrolyzing the cyano group of the compound (compound (16)). More specifically, compound (17) can be obtained by hydrolyzing the cyano group of compound (16) in the presence of an acid or base.

Examples of the acid used include acetic acid, formic acid, sulfuric acid, phthalic acid and hydrochloric acid.

The amount of acid used is usually 0.01 mol to a large excess with respect to 1 mol of compound (16).

Examples of the base used include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The amount of base used is usually 0.01 mol to a large excess, preferably 0.1 to 10 mol, per 1 mol of compound (16).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 160 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 1 to 15 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, water, tetrahydrofuran, etc. Examples thereof include 1,4-dioxane, cyclohexane, 1,3-dimethylbenzene and toluene, and ethylene glycol and water are preferable.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Examples of the combination of two or more of the reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethylene glycol and water.

Scheme 13: Method for producing the compound of formula (21)

In the above formula (21) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ and P ³ are protecting groups, and P ² is a protecting group or a hydrogen atom. ] Compound (Compound (21)) has the above formula (17) [in the formula, R ¹ , R ² and B have the same meanings as described above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. Is. ] Can be obtained from the compound (compound (17)) through four steps (step (13-1), step (13-2), step (13-3) and step (13-4)). ..
In the steps (13-1), (13-2), steps (13-3) and (13-4) of Scheme 13, intermediates of each step may be isolated and / or. The intermediate of each step may be carried out continuously without isolation.

[Step (13-1)]
In the step (13-1), the above formula (17) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] By the acid azide reaction of the compound represented by (Compound (17)), the above formula (18) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group and P. ² is a protecting group or a hydrogen atom. ] Is a step of obtaining the compound (compound (18)) represented by.

Examples of the azide agent used include diarylphosphoryl azide such as diphenylphosphoryl azide.

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (17).

The reaction in the above step (13-1) is preferably carried out in the presence of a base.
Examples of the base used include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.

The amount of base used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (17).

The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 -Propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform and the like, preferably acetonitrile and It is 1,4-dioxane.

The compound (18) is a compound (17) and a halide for halide (eg, methyl chlorostate) in the presence of a corresponding acid halide (eg, acid chloride, acid bromide, acid iodide, etc.) or base of the compound (17). Alkalimetal azides (eg, sodium azide, etc.) to mixed acid anhydrides obtained from ethyl chloroate, ethyl bromogeate, propyl chlorogeate, butyl chloroate, isobutyl chlorogeate, isobutyl bromogeate, hexyl chlorogeate, etc. It can also be obtained by reacting an azidizing agent such as potassium azide) or trialkylsilyl azide (for example, trimethylsilyl azide, triethylsilyl azide, tritert-butylsilyl azide, etc.).

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (17).

The reaction temperature is usually −30 ° C. to 100 ° C., preferably −20 ° C. to 30 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl. Examples thereof include acetoamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform and water, and acetonitrile, tetrahydrofuran, acetone, methylene chloride, chloroform and water are preferable.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (13-2)]
In the step (13-2), the above formula (18) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] By the Curtius rearrangement reaction of the acid azide group of the compound (compound (18)), the above formula (19) [in the formula, R ¹ , R ² and B are synonymous with the above, and P ¹ is a protecting group. Yes, P ² is a protecting group or a hydrogen atom. ] Is a step of obtaining the compound (compound (19)).

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 5 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, and tetrahydrofuran and 1,4-dioxane are preferable. Is.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (13-3)]
In the step (13-3), the above formula (19) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ], By allowing a base to act on the compound (compound (19)), the above formula (20) [in the formula, R ¹ , R ² and B are synonymous with the above, and P ¹ is a protecting group. , P ² are protecting groups or hydrogen atoms. ] Is a step of obtaining the compound (compound (20)) represented by.

Examples of the base used include sodium hydroxide, potassium hydroxide and the like.

The amount of base used is usually from 1 mol to a large excess, preferably 1 to 20 mol, per 1 mol of starting compound (17).

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran and 1,4-dioxane. And water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (13-4)]
In the step (13-4), the above formula (20) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ is a protecting group, and P ² is a protecting group or a hydrogen atom. ] By protecting the amino group of the compound (compound (20)) with the protecting group P ³ , the above formula (21) [in the formula, R ¹ , R ² and B are synonymous with the above, and P ¹ and P ³ are protecting groups, and P ² is a protecting group or a hydrogen atom. ] Is a step of obtaining the compound (compound (21)).

Here, the protective group P ³ of the compound (21) is not particularly limited as long as it has that function, and is, for example, a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, or a 3,4-dimethoxy. Aralkyl groups such as benzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, benzhydryl group and trityl group; for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group and the like. Lower alkanoyl groups; eg, arylacyl groups such as benzoyl groups and 4-acetoxybenzoyl groups; eg, arylalkanoyl groups such as phenylacetyl groups; eg, aryloxyalkanoyl groups such as phenoxyacetyl groups; eg, methoxycarbonyl groups, ethoxycarbonyl groups, Lower alkoxycarbonyl groups such as propyloxycarbonyl group and tert-butoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group and phenethyloxycarbonyl group; eg trimethylsilyl group and tert-butyldimethyl group Lower alkylsilyl groups such as silyl groups; eg tetrahydropyranyl groups; eg 2- (trimethylsilyl) ethoxymethyl groups; eg lower alkylsulfonyl groups such as methanesulfonyl groups and ethanesulfonyl groups; eg benzenesulfonyl groups and p-toluenesulfonyl groups And the like, such as an arylsulfonyl group, and a tert-butoxycarbonyl group is particularly preferable.
The method for introducing a protecting group differs depending on the type of the protecting group, the stability of the compound, etc., but for example, the method described in the literature [Protective Groups in Organic Synthesis, 3rd Edition, T. W. See John Wiley & Sons (1999) by TW Greene] or a similar method.

Scheme 14: Method for producing the compound of formula (b-2)

The above formula (b-2) [In the formula, R ¹ , R ² and B have the same meanings as described above. ] Compound (Compound (b-2)) has the above formula (21) [in the formula, R ¹ , R ² and B are synonymous with the above, P ¹ and P ³ are protecting groups, and P ² is It is a protecting group or a hydrogen atom. ] Can be obtained by deprotecting ^{the protecting groups P 1} , P ² and P ³ of the compound (compound (21)).

The method for removing the protecting group differs depending on the type of the protecting group, the stability of the target compound (b-2), etc., but for example, the method described in the literature [Protective Groups in Organic Synthesis ), 3rd edition, T.I. W. See John Willey & Sons (1999) by TW Greene] or similar methods, for example hydrogenated with an acid (eg 0.01 mol to a large excess of acid, preferably trifluoro). A method of acting on acetic acid, formic acid, hydrochloric acid, etc.; for example, a method of acting on a catalytic decomposition using a base (for example, equimolar to large excess base, preferably potassium hydroxide, sodium hydroxide, etc.); for example, a metal hydrogenated complex. It is carried out by chemical reduction using the above, or catalytic reduction using a palladium-carbon catalyst, a lane nickel catalyst, or the like.

[Method for producing the compound of formula (b): Part 3]
In the following schemes 15 to 19, in the compound represented by the formula (b), the ^{group represented by R 1} and R ² is a hydrogen atom, the ^{group represented by X 1} is a methylene group, and X ² is used. This is a method for producing a compound (formula (b-3)) in which the group represented is a single bond.

Scheme 15: Method for producing the compound of formula (22)

In the above formula (22) [in the formula, B is synonymous with the above, and X is a bromine atom, a chlorine atom or an iodine atom. ] (Compound (22)) is the above formula (3) [in the formula, B is synonymous with the above, and X is a bromine atom, a chlorine atom or an iodine atom. ], It can be obtained by an amidation reaction between the compound (compound (3)) and ammonia.

Examples of the ammonia used include 28% aqueous ammonia, 4% ammonia solution, 4% ammonia ethanol solution, ammonia gas and the like.

The amount of ammonia used is usually from 2 mol to a large excess, preferably 2 to 20 mol, per 1 mol of compound (3).

The reaction temperature is usually −10 ° C. to 40 ° C., preferably −10 ° C. to 30 ° C.

The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 1 hour.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and for example, toluene, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether, etc. Examples thereof include ethyl acetate, methyl acetate, propyl acetate and acetonitrile, and tetrahydrofuran is preferable.

Scheme 16: Method for producing the compound of formula (24)

In the above formula (24) [in the formula, B is synonymous with the above, and P ⁴ is a lower alkyl group. ] (Compound (24)) is the above formula (22) [in the formula, B is synonymous with the above, and X is a bromine atom, a chlorine atom or an iodine atom. ] And the above formula (23) [in the formula, P ⁴ is a lower alkyl group. ] Can be obtained by a coupling reaction of the compound (compound (23)). More specifically, compound (24) can be obtained by reacting compound (22) with compound (23) in the presence of a base and a palladium catalyst (and, if necessary, a phosphine ligand).

Specific examples of compound (23) include methyl acrylate, ethyl acrylate, propyl acrylate, tert-butyl acrylate and the like.

The amount of compound (23) used is generally 1-10 mol, preferably 1-2 mol, relative to 1 mol of compound (22).

Examples of the base used include triethylamine, sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, cesium fluoride, potassium fluoride, potassium carbonate, potassium phosphate and the like.

The amount of base used is usually 1-10 mol, preferably 1-3 mol, per 1 mol of compound (22).

Examples of the palladium catalyst used include tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), palladium (II) acetate (Pd (OAc) ₂ ), and tris (dibenzylideneacetone) dipalladium (0). ) (Pd ₂ (dba) ₃ ), bis (triphenylphosphine) palladium (II) dichloride ((PPh ₃ ) ₂ PdCl ₂ ) and the like.

The amount of the palladium catalyst used is generally 0.01 to 0.5 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (22).

Examples of the phosphine ligand used include triphenylphosphine (PPh ₃ ), tris (2-methylphenyl) phosphine (P (o-trol) ₃ ), tri (2-furyl) phosphine, and tri-tert-butylphosphine. (P (tert-Bu) ₃ ), 2- [di (tert-butyl) phosphine] -1,1'-biphenyl (JohnPhos), 2- [di (tert-butyl) phosphine] -2'-N, N -Dimethylamino-1,1'-biphenyl (tBuDavePhos), 2- (dicyclohexylphosphine) -1,1'-biphenyl (CyJohnPhos) and 2- (dicyclohexylphosphine) -2'-N, N-dimethylamino- Examples thereof include 1,1'-biphenyl (DavePhos).

The amount of phosphine ligand used is generally 0.01 to 1 mol, preferably 0.05 to 0.5 mol, per 1 mol of compound (22).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 25 ° C. to 160 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and for example, N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc. Examples thereof include acetonitrile and toluene, and N, N-dimethylformamide is preferable.

Scheme 17: Method for producing the compound of formula (25)

In the above formula (25) [in the formula, B is synonymous with the above, and P ⁴ is a lower alkyl group. ] (Compound (25)) is the above formula (24) [in the formula, B is synonymous with the above, and P ⁴ is a lower alkyl group. ] Can be obtained by a reduction reaction of the compound (compound (24)). More specifically, the compound (25) can be obtained by reacting the compound (24) having an olefin in the presence of a reduction catalyst such as palladium carbon in a hydrogen atmosphere.

Examples of the catalyst used include 5% palladium-activated carbon, 10% palladium-activated carbon, 20% palladium hydroxide-activated carbon, Raney nickel, platinum, platinum oxide and the like.

The amount of catalyst used is generally 0.01 to 1 mol, preferably 0.05 to 0.2 mol, per 1 mol of compound (24).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 18 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, etc. Examples thereof include 1,4-dioxane and toluene, preferably methanol and ethanol.

Scheme 18: Method for producing the compound represented by the formula (26)

Formula (26) [In the formula, B has the same meaning as described above. ] (Compound (26)) is the above formula (25) [in the formula, B is synonymous with the above, and P ⁴ is a lower alkyl group. ] Can be obtained by the hydrolysis reaction of the compound (compound (25)). More specifically, the compound (26) can be obtained by hydrolyzing ^{the substituent P 4} of the compound (25) in the presence of a base.

Examples of the base used include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The amount of base used is usually 0.01 mol to a large excess with respect to 1 mol of compound (25).

The reaction temperature is usually 0 ° C. to 160 ° C., preferably 0 ° C. to 130 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 5 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, and water, which are preferable. Is ethanol or water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Examples of the combination of two or more of the reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethanol and water.

Scheme 19: Preparation of the compound of formula (b-3)

The above formula (b-3) [In the formula, B is synonymous with the above. ] (Compound (b-3)) is synonymous with the above formula (26) [in the formula, B is the above. ] Can be obtained from the compound (compound (26)) through three steps (step (19-1), step (19-2) and step (19-3)).
In the steps (19-1), (19-2) and (19-3) of Scheme 19, the intermediates of each step may be isolated, and / or the intermediates of each step may be simply isolated. It may be carried out continuously without separating.

[Step (19-1)]
Step (19-1) has the same meaning as described above in the above formula (26) [in the formula, B is synonymous with the above. ] By the acid azide reaction of the compound (compound (26)) represented by the above formula (27) [in the formula, B is synonymous with the above. ] Is a step of obtaining the compound (compound (27)) represented by.

Examples of the azide agent used include diarylphosphoryl azide such as diphenylphosphoryl azide.

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (26).

The reaction in the above step (19-1) is preferably carried out in the presence of a base.
Examples of the base used include triethylamine, N, N-diisopropylethylamine, N-methylpyrrolidine and the like.

The amount of base used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (26).

The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2 -Propanol, tert-butanol, toluene, benzene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform and the like, preferably acetonitrile and It is 1,4-dioxane.

The compound (27) is a compound (26) and a halide for halide (eg, methyl chlorostate) in the presence of a corresponding acid halide (eg, acid chloride, acid bromide, acid iodide, etc.) or base of the compound (26). Alkalimetal azides (eg, sodium azide, etc.) to mixed acid anhydrides obtained from ethyl chloroate, ethyl bromogeate, propyl chlorogeate, butyl chloroate, isobutyl chlorogeate, isobutyl bromogeate, hexyl chlorogeate, etc. It can also be obtained by reacting an azidizing agent such as potassium azide) or trialkylsilyl azide (for example, trimethylsilyl azide, triethylsilyl azide, tritert-butylsilyl azide, etc.).

The amount of the azidizing agent used is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (26).

The reaction temperature is usually −30 ° C. to 100 ° C., preferably −20 ° C. to 30 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide, N, N-dimethyl. Examples thereof include acetamide, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methylene chloride, chloroform, water and the like, preferably tetrahydrofuran and water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (19-2)]
In the step (19-2), the above formula (27) [in the formula, B is synonymous with the above. ] By the Curtius rearrangement reaction of the acid azide group of the compound represented by the above formula (28) [in the formula, B is synonymous with the above. ] Is a step of obtaining the compound (compound (28)) represented by.

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran. 1,4-dioxane and water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Step (19-3)]
Step (19-3) has the same meaning as described above in the above formula (28) [in the formula, B is synonymous with the above. ] By allowing a base to act on the compound (compound (28)) represented by the above formula (b-3) [in the formula, B is synonymous with the above. ] Is a step of obtaining the compound (compound (b-3)).

Examples of the base used include sodium hydroxide, potassium hydroxide, ethylenediamine and the like.

The amount of base used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of starting compound (26).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 160 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, xylene, water and the like, preferably tetrahydrofuran. 1,4-dioxane and water.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

[Method for producing the compound of formula (b): Part 4]
In the following schemes 20 to 21, the compounds represented by the formula (b) in which R ¹ and R ² are lower alkyl groups and the ^{group represented by X 2} is a single bond (formula (b-4)). ) Is the manufacturing method.

Scheme 20: Method for producing the compound of formula (30)

In the above formula (30) [in the formula, R ¹ and R ² are lower alkyl groups, and X ¹ and B are synonymous with the above. ] (Compound (30)) is the above formula (29) [in the formula, X ¹ and B are synonymous with the above, and P ⁴ is a lower alkyl group. ] Can be obtained by acting a Grignard reagent on the compound represented by (Compound (29)).

Specific examples of the Grinard reagent include, for example, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, ethylmagnesium chloride, propylmagnesium bromide, butylmagnesium chloride and the like.

The amount of Grignard reagent used is generally 2-10 mol, preferably 3-7 mol, per 1 mol of compound (29).

The reaction temperature is usually −10 ° C. to 80 ° C., preferably 0 ° C. to 60 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 4 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether and the like. , Preferably tetrahydrofuran.

Scheme 21: Method for producing the compound of formula (b-4)

In the above formula (b-4) [in the formula, R ¹ and R ² are lower alkyl groups, and X ¹ and B are synonymous with the above. ] (Compound (b-4)) has the above formula (30) [in the formula, R ¹ and R ² are lower alkyl groups, and X ¹ and B are synonymous with the above. ] Can be obtained from the compound (compound (30)) through two steps (step (21-1) and step (21-2)).
The steps (21-1) and (21-2) of Scheme 21 may be performed continuously without isolating the intermediates of each step and / or the intermediates of each step. You may.

[Step (21-1)]
In the step (21-1), the above formula (30) [in the formula, R ¹ and R ² are lower alkyl groups, and X ¹ and B are synonymous with the above. ] (Compound (30)) is reacted with acetonitrile under acidic conditions by a Ritter reaction to the above formula (31) [in the formula, R ¹ and R ² are lower alkyl groups, and Me is It is a methyl group, and X ¹ and B are synonymous with the above. ] Is a step of obtaining the compound (compound (31)).

The amount of acetonitrile used is usually from 1 mol to a large excess with respect to 1 mol of compound (30) and can be used as a reaction solvent.

Examples of the acid used include concentrated sulfuric acid (and acetic acid if necessary).

The amount of acid used is usually from 1 mol to a large excess, preferably 1 to 20 mol, per 1 mol of compound (30).

The reaction temperature is usually −10 ° C. to 80 ° C., preferably 0 ° C. to 40 ° C.

The reaction time is usually 0.5 to 48 hours, preferably 0.5 to 3 hours.

[Step (21-2)]
In the step (21-2), the above formula (31) [in the formula, R ¹ and R ² are lower alkyl groups, Me is a methyl group, and X ¹ and B are synonymous with the above. ], By hydrolyzing the acetamide group of the compound (compound (31)) in the presence of a base, the above formula (b-4) [in the formula, R ¹ and R ² are lower alkyl groups. , X ¹ and B are synonymous with the above. ] Is a step of obtaining the compound (compound (b-4)) represented by.

Examples of the base used include lithium hydroxide, potassium hydroxide, sodium hydroxide and the like, and potassium hydroxide is preferable.

The amount of base used is usually from 1 mol to a large excess with respect to 1 mol of starting compound (30).

The reaction temperature is usually 0 ° C. to 170 ° C., preferably 80 ° C. to 170 ° C.

The reaction time is usually 1 hour to 100 hours, preferably 3 hours to 95 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, ethylene glycol and water, and ethylene glycol and water are preferable. Is.

The reaction solvent may be a single solvent, or a mixed solvent in which two or more are combined.

Examples of the combination of two or more of the reaction solvents include a combination of methanol and water, a combination of ethanol and water, a combination of ethylene glycol and water, and the like, preferably a combination of ethylene glycol and water.

[Method for producing the compound of formula (b): Part 5]
In the following schemes 22 to 23, among the compounds represented by the formula (b), R ¹ and R ² are hydrogen atoms, and the ^{group represented by X 1} and X ² is a single bond compound (formula (b-)). 5)) is the manufacturing method.

Scheme 22: Method for producing the compound represented by the formula (32)

The above formula (32) [In the formula, B has the same meaning as described above. ] (Compound (32)) is the above formula (22) [in the formula, B is synonymous with the above, and X is a bromine atom, a chlorine atom or an iodine atom. ] (Compound (22)) and a cyanide such as zinc cyanide can be obtained by a coupling reaction. More specifically, compound (32) can be obtained by reacting compound (22) with cyanide in the presence of a palladium catalyst (and, if necessary, a phosphine ligand).

Examples of the cyanide used include zinc cyanide, sodium cyanide, potassium cyanide and the like.

The amount of cyanide used is generally 1-10 mol, preferably 1-2 mol, per 1 mol of compound (22).

Examples of the palladium catalyst used include tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), palladium (II) acetate (Pd (OAc) ₂ ), and bis (dibenzylideneacetone) palladium (0). ) (Pd ₂ (dba) ₃ ), bis (triphenylphosphine) palladium (II) dichloride ((PPh ₃ ) ₂ PdCl ₂ ) and the like.

The amount of the palladium catalyst used is generally 0.01 to 0.5 mol, preferably 0.025 to 0.2 mol, per 1 mol of compound (22).

Examples of the phosphine ligand used include triphenylphosphine (PPh ₃ ), tris (2-methylphenyl) phosphine (P (o-trol) ₃ ), tri (2-furyl) phosphine, and tri-tert-butylphosphine. (P (tert-Bu) ₃ ), 2- [di (tert-butyl) phosphine] -1,1'-biphenyl (JohnPhos), 2- [di (tert-butyl) phosphine] -2'-N, N -Dimethylamino-1,1'-biphenyl (tBuDavePhos), 2- (dicyclohexylphosphine) -1,1'-biphenyl (CyJohnPhos), 2- (dicyclohexylphosphine) -2'-N, N-dimethylamino- Examples thereof include 1,1'-biphenyl (DavePhos) and 2- (dicyclohexylphosphine) -2', 4', 6'-triisopropyl-1,1'-biphenyl (XPhos).

The amount of phosphine ligand used is generally 0.01 to 1 mol, preferably 0.25 to 0.4 mol, relative to 1 mol of compound (22).

A reducing agent such as zinc can be added to this reaction if necessary.

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 25 ° C. to 130 ° C.

The reaction time is usually 1 hour to 100 hours, preferably 1 hour to 50 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and is, for example, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4. -Dioxane, acetonitrile, toluene and the like can be mentioned, with preference given to N, N-dimethylformamide.

Scheme 23: Method for producing a compound represented by the formula (b-5)

The above formula (b-5) [In the formula, B is synonymous with the above. ] (Compound (b-5)) is synonymous with the above formula (32) [in the formula, B is the above. ], It can be obtained by reducing the cyano group of the compound (compound (32)). More specifically, the compound (b-5) can be obtained by reacting the compound (32) having a cyano group in the presence of a reduction catalyst such as palladium carbon in a hydrogen atmosphere.

Examples of the catalyst used include 5% palladium-activated carbon, 10% palladium-activated carbon, 20% palladium hydroxide-activated carbon, Raney nickel, platinum, platinum oxide and the like.

The amount of catalyst used is generally 0.01 to 1 mol, preferably 0.05 to 0.2 mol, relative to 1 mol of compound (32).

The reaction temperature is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, Solvents such as 2-methyltetrahydrofuran, 1,4-dioxane and toluene can be mentioned, with preference given to methanol.

Next, a pharmaceutical composition containing the compound of the formula (I) (hereinafter, also referred to as “compound of the present invention”), a preventive agent, a therapeutic agent, and an intraocular pressure lowering agent (hereinafter, collectively referred to as “the pharmaceutical of the present invention”) will be described. To do.

The medicament of the present invention _{utilizes the adrenaline β 2} receptor antagonist activity and carbonic anhydrase inhibitory activity of the compound of the present invention to prevent or treat eye diseases.

As used herein, the term "adrenaline β ₂ receptor antagonist activity" refers _{to an action of the compound of the present invention acting on an adrenergic β 2} receptor to suppress the function expression of the receptor, or the function of the receptor. (Hereinafter, collectively referred to as "function suppression, etc.").
_{Since the adrenergic β 2} receptor expressed in the ciliary body of the eye is involved in the production of aqueous humor, the production of aqueous humor is suppressed when its function is suppressed, and as a result, the intraocular pressure decreases.

The above-mentioned "adrenaline β ₂ receptor antagonist activity" includes so-called "β blocking action", "β receptor blocking action", "adrenaline β 2 receptor inverse agonist activity", "adrenaline β ₂ receptor partial agonist activity" and the like. Is also included.

As used herein, "β-blocking action" and "β-receptor blocking action" _{mean that the compound of the present invention inhibits the binding of an adrenaline β 2} receptor to an agonist (adrenaline, etc.), and thus the function of the receptor. It means to suppress.

As used herein, the term "adrenaline β ₂ receptor inverse agonist activity" means that the compound of the present invention _{has a preferential affinity for the "adrenaline β 2} receptor in an inactivated state" and that the receptor is inactive. By stabilizing the active state, it means suppressing its function.

As used herein, "adrenaline β ₂ receptor partial agonist activity" refers to an agonist activity that is weaker than a full agonist (adrenaline, etc.).
A weakly active partial agonist is known to act as an antagonist against a receptor that is in an activated state in the presence of a full agonist.
Therefore, the "adrenaline β _{2 receptor partial agonist" acts in a direction of inhibiting the activation of the adrenaline β 2} receptor by a full agonist (adrenaline or the like), and as a result, suppresses the function of the receptor.

_{In addition to the adrenergic β 2} receptor antagonist activity, the compound of the present invention may have antagonistic activity against other adrenergic receptor subtypes (for example, adrenergic β ₁ receptor).

As used herein, "carbonic anhydrase inhibitory activity" means that the compound of the present invention inhibits the function of carbonic anhydrase and eliminates or attenuates the activity.
Since carbonic anhydrase is involved in aqueous humor production, when its activity disappears or diminishes, it suppresses aqueous production, resulting in a decrease in intraocular pressure.

The "carbonic anhydrase" exists as many different isoforms in nature. Examples of such carbonic anhydrase isozymes include carbonic anhydrase I (CA-I), carbonic anhydrase II (CA-II), carbonic anhydrase III (CA-III), and carbonic anhydrase IV (CA-IV). ), Carbonic anhydrase VA (CA-VA), carbonic anhydrase VB (CA-VB), carbonic anhydrase VI (CA-VI), carbonic anhydrase VII (CA-VII), carbonic anhydrase VIII (CA-VIII) ), Carbonic anhydrase IX (CA-IX), carbonic anhydrase X (CA-X), carbonic anhydrase XI (CA-XI), carbonic anhydrase XII (CA-XII), carbonic anhydrase XIII (CA-XIII) ), Carbonic anhydrase XIV (CA-XIV) and the like are known. Among them, carbonic anhydrase II (CA-II) expressed in the ciliary body of the eye is known to be involved in the production of aqueous humor.

Therefore, carbonic anhydrase II (CA-II) is a suitable target carbonic anhydrase isozyme for the compounds of the present invention. The compound of the present invention can eliminate or attenuate its activity by inhibiting carbonic anhydrase II (CA-II).

The compound of the present invention may have an inhibitory activity against other isozymes of carbonic anhydrase in addition to the inhibitory activity against carbonic anhydrase II (CA-II).

Based on the fact that the compound of the present invention (pharmaceutical of the present invention) has both adrenergic β ₂ receptor antagonist activity and carbonic anhydrase inhibitory activity _{, either or both of the adrenergic β 2} receptor and carbonic anhydrase are present. It can be used to treat or prevent related diseases.

Diseases involving the adrenergic β ₂ receptor include, for example, (1) eye diseases (glaucoma, ocular hypertension, etc.), (2) chronic obstructive pulmonary disease (COPD), and (3) infantile hemangioma.

Diseases associated with carbonate dehydration include, for example, (1) eye diseases (glaucoma, hypertension, etc.), (2) epilepsy, (3) respiratory acidosis, (4) cardiac edema, (5) hepatic edema, etc. Examples thereof include (6) premenstrual tension, (7) Meniere's disease and Meniere's syndrome, and (8) sleep apnea syndrome.

As mentioned above, eye diseases are _{diseases in which both adrenergic β 2} receptors and carbonic anhydrase are involved. Therefore, the compound of the present invention (the medicament of the present invention) is particularly useful for the treatment or prevention of eye diseases.

Examples of the above-mentioned "eye diseases" include glaucoma (primary open-angle glaucoma, normal tension glaucoma, primary closed-angle glaucoma, plateau iris glaucoma, secondary open-angle glaucoma, secondary closed-angle glaucoma, developmental glaucoma, etc.) and high-grade glaucoma. Intraocular pressure, luteal edema, luteal degeneration, increased retinal and optic nerve tension, myopia, far vision, glaucoma, dry eye, retinal detachment, glaucoma, increased intraocular pressure due to trauma or inflammation, increased intraocular pressure due to drugs such as steroids or hormones Postoperative increase in intraocular pressure and the like can be mentioned, but the present invention is not limited to these.

The compound of the present invention _{can reduce intraocular pressure based on having both adrenergic β 2} receptor antagonist activity and carbonic anhydrase inhibitory activity.
Therefore, the compound of the present invention (the pharmaceutical of the present invention) is a disease that is greatly affected by intraocular pressure, specifically, glaucoma, ocular hypertension, increased intraocular pressure due to trauma, increased intraocular pressure due to inflammation, increased intraocular pressure due to a drug, and surgery. It is particularly useful for the prevention and treatment of subsequent increases in intraocular pressure.

The compound of the present invention can be used in combination with another drug (hereinafter, also referred to as “combination drug”).

"Combination" means using a combination of a plurality of drugs as an active ingredient. For example, use as a combination drug, use as a kit, use in a combination characterized by being administered separately by the same or different administration routes, and the like can be mentioned.

The administration time of the concomitant drug is not limited, and the concomitant drug may be administered to the administration subject at the same time as the compound of the present invention, or may be administered at a time lag.
The dose of the concomitant drug may be based on the clinically used dose, and may be appropriately selected depending on the administration target, the age and weight of the administration target, the symptoms, the administration time, the dosage form, the administration method, the combination, and the like. it can.
The administration form of the concomitant drug is not particularly limited, and the compound of the present invention (pharmaceutical of the present invention) and the concomitant drug may be combined at the time of administration.

In the case of treatment of eye diseases (especially glaucoma), concomitant drugs include, for example, "sympathetic nerve stimulant", "sympathetic nerve blocker", "parasympathetic nerve stimulant", "prostaglandin-related drug", and "carbonic anhydrase". Examples thereof include "inhibitors", "Rho-kinase (ROCK) inhibitors" and "hypertonic osmotic agents". One or more of these, preferably 1 to 4 concomitant agents, and the compound of the present invention (pharmaceutical of the present invention) can be used in combination.

Examples of the above-mentioned "sympathetic nerve stimulant" include adrenergic α ₂ receptor stimulants such as apraclonidine hydrochloride and brimonidine tartrate; for example, adrenergic β ₂ receptor stimulants such as dipivefrine hydrochloride.

Examples of the above-mentioned "sympathetic nerve blocker" include adrenaline α _{1 receptor blockers such as bunazosin hydrochloride; adrenaline β 2} receptor antagonists such as timorol maleate and carteolol hydrochloride; and adrenaline such as betaxolol hydrochloride. β ₁ receptor antagonists; αβ receptor blockers such as levobnorol and nipradilol can be mentioned.

Examples of the above-mentioned "parasympathetic nerve stimulant" include pilocarpine hydrochloride, carbachol, demepotassium bromide, ecothiopate, distigmine bromide and the like.

Examples of the above-mentioned "prostaglandin-related drug" include prost drugs such as latanoprost, tafluprost and travoprost; prostamide drugs such as bimatoprost; proston drugs such as isopropylunoprostone; for example, Omi. EP2 agonists such as denepagisopropyl; for example, EP3 agonists; for example, FP / EP3 dual agonists such as sepetaprost; for example, EP4 agonists and the like.

Examples of the above-mentioned "carbonic anhydrase inhibitor" include dorzolamide hydrochloride, brinzolamide, acetazolamide, diclofenamide, metazolamide and the like.

Examples of the above-mentioned "Rho kinase (ROCK) inhibitor" include lipasudil hydrochloride, fasdyl hydrochloride, and Y-27632 ([(R)-(+)-trans-N- (4-pyridyl) -4- (1). -Aminoethyl) -Cyclohexanecarboxamide dihydrochloride monohydrate]), Y-39983 (SNJ-1656) (4-[(1R) -1-aminoethyl] -N- (1H-pyrrolo [2,3-) b] Pyridine-4-yl) benzamide dihydrochloride), AR-13324, AMA0076, H-1129 and the like.

Examples of the above-mentioned "hypertonic osmotic drug" include a combination preparation of glycerin, glycerin and fructose, isosorbide, D-mannitol and the like.

Both the compound of the present invention and the medicament of the present invention can be provided as a preparation.

"Preparations" include oral and parenteral preparations.
Examples of the oral preparation include tablets, capsules, powders and granules.
Examples of parenteral preparations include sterilized liquid preparations such as solutions and suspensions, and specific examples thereof include eye drops, eye ointments, injections and infusions.

The formulations according to the invention may usually contain a therapeutically effective amount of the compounds of the invention, along with a pharmaceutically acceptable carrier or diluent. This formulation technology is considered to be common technical knowledge for those skilled in the art and is well known. Preferably, it is formulated for oral or parenteral preparations (eg, eye drops, eye ointments, etc.) by many methods well known to those skilled in the art, along with pharmaceutically acceptable carriers or diluents. can do.

"Pharmaceutically acceptable carriers or diluents" include excipients (eg, fats, mannitol, semi-solid and liquid polyols, natural or cured oils, etc.); water (eg, distilled water, especially distilled water for injection). Water, etc.), physiological saline, alcohol (eg, ethanol), glycerol, polyol, aqueous glucose solution, mannitol, vegetable oil, etc .; additives (eg, bulking agents, disintegrants, binders, lubricants, wetting agents, stables) Agents, emulsifiers, dispersants, preservatives, sweeteners, colorants, seasonings or fragrances, thickeners, diluents, buffers, solvents or solubilizers, agents to achieve storage effects, osmotic pressure Salts, coatings, or antioxidants to change) and the like.

Various forms of the preparation according to the present invention can be selected. Examples thereof include oral preparations such as tablets, capsules, powders, granules or liquids, sterilized liquid parenteral preparations such as solutions or suspensions, suppositories, ointments and the like.

The preparation according to the present invention may be a solid preparation or a liquid preparation.

The solid preparation can be produced as it is in the form of tablets, capsules, granules or powders, but it can also be produced using an appropriate carrier (additive). Such carriers (additives) include, for example, sugars such as lactose or glucose; starches such as corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium aluminometasilicate or anhydrous calcium phosphate. Synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; for example methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose Synthetic cellulose derivatives and other commonly used additives such as gelatin, talc, vegetable oil, and gum arabic can be mentioned.

The solid preparations such as these tablets, capsules, granules and powders are generally based on the total mass of the preparation, for example, 0.1 to 100% by mass of the compound represented by the above formula (I), preferably 0.1 to 100% by mass. May contain 5 to 98% by mass as an active ingredient.

The liquid preparation uses water, alcohols, and appropriate additives usually used in the liquid preparation, and is used in the form of suspension, syrup, injection, drip (intravenous infusion), eye drop, eye ointment, etc. Manufactured.

Suitable solvents or diluents for parenteral administration in the form of intramuscular, intravenous or subcutaneous injection include, for example, distilled water for injection, lidocaine hydrochloride aqueous solution (for intramuscular injection), physiological saline, etc. Examples thereof include an aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, a liquid for intravenous injection (for example, an aqueous solution of citric acid and sodium citrate), an electrolyte solution (for intravenous drip infusion and intravenous injection), and the like. These solvents or diluents can be used as a mixed solution thereof.

These injections may be prepared by dissolving the active ingredient in advance, or by dissolving the active ingredient in powder form or by adding an appropriate carrier (additive) at the time of use. These injections can contain, for example, 0.1 to 10% by weight of the active ingredient based on the total mass of the formulation.

In addition, suspensions for oral administration and liquid preparations such as syrups can each contain, for example, 0.1 to 10% by mass of an active ingredient based on the total mass of the preparation.

The preparation of the present invention can be preferably administered as an eye drop.

Additives commonly used in eye drops include, for example, polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, solubilizers such as polyvinylpyrrolidone and polysorbate 80; and stabilizers such as sodium citrate, polyvinylpyrrolidone and polysorbate 80. Isotonic agents such as potassium chloride, sodium chloride, concentrated glycerin, glucose and D-mannitol; for example, sodium citrate, sodium acetate, sodium hydrogen carbonate, tromethamole, boric acid, boric acid, sodium hydrogen phosphate and phosphate. Buffering agents such as sodium dihydrogen; pH adjusters such as hydrochloric acid and sodium hydroxide; preservatives (preservatives) such as benzalkonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and sorbic acid; For example, additives usually used as ophthalmic preparations such as carboxyvinyl polymer, polyvinylpyrrolidone, polovinyl alcohol, hydroxyethyl cellulose, hypromerose, and thickeners such as methyl cellulose and glycerin can be mentioned.

The pH of the eye drops may be within the range acceptable for ophthalmic preparations.
The pH range of the eye drops is preferably in the range of pH 4 to 8.

The osmotic pressure ratio of the eye drops to the physiological saline may be within the range acceptable for ophthalmic preparations.
The osmotic pressure ratio of the eye drops to the physiological saline is preferably in the range of 0 to 4, more preferably in the range of 0 to 2, and most preferably in the vicinity of 1.

The preparation of the present invention can also be administered as an eye ointment.
As the eye ointment, for example, a base usually used as an ophthalmic preparation such as white petrolatum and liquid paraffin can be used.

The concentration of the compound of the present invention in the eye drops and the eye ointment is not particularly limited, but is, for example, 0.00001 to 5 w / v%, preferably 0.0001 to 2 w / v%, based on the total volume of the eye drops. More preferably, it can contain 0.001 to 1 w / v% of the active ingredient. The concentration of the compound of the present invention in the eye drops may be calculated based on the weight of either the free form of the compound or a salt thereof.

The number of administrations of the eye drops and the eye ointment can be appropriately set, and may be, for example, once to several times a day.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the scope of the present invention is not limited thereto. As the various reagents used in Examples and Reference Examples, commercially available products were used unless otherwise specified.
In the examples and reference examples, in silica gel column chromatography, unless otherwise specified, as a column, Biotage (registered trademark) SNAP Ultra Silka Cartridge or SNAP KP-Sil Cartride manufactured by Fuji Silysia Chemical Ltd., CHROMATORE manufactured by Fuji Silysia Chemical Ltd. Ethyl acetate-hexane as mobile phase using Q-PACK SI, CHROMATOREX (registered trademark) Q-PACK NH manufactured by Fuji Silysia Chemical Ltd. or CHROMATOREX (registered trademark) Q-PACK CO _{2 H manufactured by Fuji Silysia Chemical Ltd.} , Methanol-chloroform or methanol-ethyl acetate was used.
In reverse phase silica gel column chromatography, Biotage (registered trademark) SNAP Ultra C18 Cartridge manufactured by Biotage is used as a column, and a 0.1% trifluoroacetic acid aqueous solution and a 0.1% trifluoroacetic acid acetonitrile solution are used as mobile phases. Was used.
In the reverse phase preparative liquid chromatography, CombiPrep Pro C18 manufactured by YMC was used as a column, and a 0.1% trifluoroacetic acid aqueous solution and a 0.1% trifluoroacetic acid acetonitrile solution were used as the mobile phase.

^{1 1} H-NMR was measured using AL400 or ECZ400S (400 MHz) manufactured by JEOL Ltd. Tetramethylsilane is used as an internal standard when measuring with a deuterated chloroform solution, methanol is used as an internal standard when measuring with a deuterated methanol solution, and water is used as an internal standard when measuring with a deuterated aqueous solution. There was.
When the product was used in the next step without purification, a part of the product was taken or the product separately prepared by the same method was appropriately purified, and then ^{1 1} H-NMR was measured.
The mass spectrum was measured by electrospray ionization (ESI) using ACQUITY® SQD manufactured by Waters.
The microwave reaction was carried out using an Initiator® manufactured by Biotage.

The meaning of the abbreviations is shown below.
s: Singlet d: Doublet t: Triplet q: Quartet dd: Double Doublet dt: Triple Doublet m: Multiplet br: Broad CDCl ₃ : Deuterated chloroform CD ₃ OD: Heavy methanol D ₂ O: Heavy water TFA: Trifluoroacetic acid HCl: HCO ₂ H hydrochloride: CH _{3 for} formate CN: Acetonitrile PMB: 4-methoxybenzyl group Boc: tert-butoxycarbonyl group DMSO: Dimethyl sulfoxide DMF: N, N-dimethylformamide THF: tetrahydrofuranDIPEA: N, N-diisopropylethylamine NCS: N-chlorosuccinimide NBS: N-bromosuccinimide AIBN: 2,2'-azobis (isobutyronitrile)
Pd (PPh ₃ ) ₄ : Tetrakis (triphenylphosphine) palladium (0)
PdCl ₂ (dppf) · CH ₂ Cl ₂ : [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium (0)
XPhos: 2-Dicyclohexylphosphino-2'-4'-6'-triisopropylbiphenyl XantPhos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene quant. :quantitative

In the following Reference Examples A-1 to A-33, the compound corresponding to the compound (a) of Scheme 1 was synthesized.

[Reference Example A-1]
Synthesis of (S) -2-[(2-chloro-5-methylphenoxy) methyl] oxylan [A-1] (hereinafter referred to as compound [A-1])

3-Nitrobenzenesulfonic acid (S) -glycidyl (653 mg, 2.5 mmol) and cesium fluoride (957 mg) in a DMSO (3.0 mL) solution of commercially available 2-chloro-5-methylphenol (300 mg, 2.1 mmol). , 6.3 mmol) was added at room temperature, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (404 mg, 2.0 mmol, 97% yield) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.23 (1H, d, J = 7.8 Hz), 6.77-6.72 (2H, m), 4.27 (1H, dd, J = 11.0, 3.2Hz), 4.05 (1H, dd, J = 11.2, 5.3Hz), 3.41-3.38 (1H, m), 2.92 (1H, t, J) = 4.6Hz), 2.83 (1H, dd, J = 5.0, 2.7Hz), 2.32 (3H, s).
ESI-MSfound: 240 [M + H + CH ₃ CN] ⁺

[Reference Example A-2]
Synthesis of (S) -4-methyl-2- (oxylan-2-ylmethoxy) benzonitrile [A-2] (hereinafter referred to as compound [A-2])

市販の２−ヒドロキシ−４−メチルベンズアルデヒド（３０５ｍｇ，２．２ｍｍｏｌ）のエタノール（７．５ｍＬ）溶液に、塩酸ヒドロキシルアミン（２３３ｍｇ，３．４ｍｍｏｌ）及びピリジン（１．１ｍＬ，１３ｍｍｏｌ）を室温で加え、室温で２時間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（３３７ｍｇ，２．２ｍｍｏｌ，収率９９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１５２［Ｍ＋Ｈ］⁺ (A) Synthesis of 2-hydroxy-4-methylbenzaldehyde oxime [A-2-a] (hereinafter referred to as compound [A-2-a])

Hydroxylamine hydrochloride (233 mg, 3.4 mmol) and pyridine (1.1 mL, 13 mmol) are added to a commercially available solution of 2-hydroxy-4-methylbenzaldehyde (305 mg, 2.2 mmol) in ethanol (7.5 mL) at room temperature. , Stirred for 2 hours at room temperature. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (337 mg, 2.2 mmol, yield 99%) as a white solid.
ESI-MSfound: 152 [M + H] ⁺

化合物［Ａ−２−ａ］（６１ｍｇ，０．４１ｍｍｏｌ）のアセトニトリル（４．１ｍＬ）溶液に、トリフェニルホスフィン（１．１ｇ，４．１ｍｍｏｌ）及び１，１’−（アゾジカルボニル）ジピペリジン（１．０ｇ，４．１ｍｍｏｌ）を室温で加え、室温で１９時間撹拌した。反応混合物に１Ｎ−水酸化ナトリウム水溶液を加え、酢酸エチルで洗浄した。次いで、水層に１Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（９５ｍｇ）を黄色固体として得た。得られた化合物は精製することなく次の反応に用いた。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．８１（１Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），６．７０（１Ｈ，ｓ），２．３５（３Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１３２［Ｍ−Ｈ］^- (B) Synthesis of 2-hydroxy-4-methylbenzonitrile [A-2-b] (hereinafter referred to as compound [A-2-b])

Triphenylphosphine (1.1 g, 4.1 mmol) and 1,1'-(azodicarbonyl) dipiperidine (Azodicarbonyl) dipiperidine in a solution of compound [A-2-a] (61 mg, 0.41 mmol) in acetonitrile (4.1 mL). 1.0 g, 4.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 19 hours. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was washed with ethyl acetate. Then, 1N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (95 mg) as a yellow solid. The obtained compound was used in the next reaction without purification.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.37 (1H, d, J = 7.8 Hz), 6.81 (1H, s), 6.78 (1H, d, J = 8.2 Hz) , 6.70 (1H, s), 2.35 (3H, s).
ESI-MSfound: 132 [MH] ^-

(C) Synthesis of (S) -4-methyl-2- (oxylan-2-ylmethoxy) benzonitrile [A-2] 3-Nitrobenzene in a DMSO (2.0 mL) solution of compound [A-2-b] Sulfonic acid (S) -glycidyl (157 mg, 0.61 mmol) and cesium fluoride (246 mg, 1.6 mmol) were added at room temperature, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (65 mg, 0.35 mmol, total yield of 2 steps from compound [A-2-a] 85%) as a colorless oil. ..
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.44 (1H, d, J = 7.8 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.81 (1H, s) , 4.33 (1H, dd, J = 11.4, 3.2Hz), 4.11 (1H, dd, J = 11.2, 5.3Hz), 3.42-3.38 (1H, m) ), 2.94 (1H, t, J = 4.6Hz), 2.84 (1H, dd, J = 4.8, 2.5Hz), 2.40 (3H, s).
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-3]
Synthesis of (R) -2-[(2-chloro-5-methylphenoxy) methyl] oxylan [A-3] (hereinafter referred to as compound [A-3])

From commercially available 2-chloro-5-methylphenol (210 mg, 1.5 mmol) and 3-nitrobenzenesulfonic acid (R) -glycidyl (572 mg, 2.2 mmol) according to the method of Reference Example A-1, the title compound (284 mg). , 1.4 mmol, yield 97%) was obtained as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.22 (1H, d, J = 7.8 Hz), 6.77 (1H, s), 6.73 (1H, d, J = 8.2 Hz) , 4.27 (1H, dd, J = 11.2, 3.0Hz), 4.05 (1H, dd, J = 11.2, 5.3Hz), 3.41-3.37 (1H, m) ), 2.92 (1H, t, J = 4.3Hz), 2.83 (1H, dd, J = 5.0, 2.7Hz), 2.32 (3H, s).
ESI-MSfound: 240 [M + H + CH ₃ CN] ⁺

[Reference Example A-4]
Synthesis of (S) -5-methyl-2- (oxylan-2-ylmethoxy) benzonitrile [A-4] (hereinafter referred to as compound [A-4])

市販の２−ヒドロキシ−５−メチルベンズアルデヒド（４９ｍｇ，０．３６ｍｍｏｌ）から参考例Ａ−２の工程（ａ）の方法に準じて表題化合物（５４ｍｇ，収率ｑｕａｎｔ．）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１５２［Ｍ＋Ｈ］⁺ (A) Synthesis of 2-hydroxy-5-methylbenzaldehyde oxime [A-4-a] (hereinafter referred to as compound [A-4-a])

The title compound (54 mg, yield quant.) Was obtained as a yellow solid from commercially available 2-hydroxy-5-methylbenzaldehyde (49 mg, 0.36 mmol) according to the method of step (a) of Reference Example A-2.
ESI-MSfound: 152 [M + H] ⁺

(B) Synthesis of (S) -5-methyl-2- (oxylan-2-ylmethoxy) benzonitrile [A-4] Reference example A-2 from compound [A-4-a] (54 mg, 0.36 mmol) The title compound (56 mg, 0.30 mmol, yield 83%) was obtained as a white solid according to the method of step (b) and Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.36 (1H, d, J = 1.8 Hz), 7.31 (1H, dd, J = 8.7, 1.8 Hz), 6.90 ( 1H, d, J = 8.7Hz), 4.33 (1H, dd, J = 11.2, 3.0Hz), 4.09 (1H, dd, J = 11.2, 5.3Hz), 3 .40-3.36 (1H, m), 2.92 (1H, t, J = 4.6Hz), 2.83 (1H, dd, J = 4.8, 2.5Hz), 2.30 ( 3H, s).
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-5]
Synthesis of (S) -2-methyl-6- (oxylan-2-ylmethoxy) benzonitrile [A-5] (hereinafter referred to as compound [A-5])

市販の２−アミノ−３−メチルフェノール（５．１ｇ，４１ｍｍｏｌ）のＤＭＳＯ（４１ｍＬ）溶液に、シアン化銅（Ｉ）（４．４ｇ，４９ｍｍｏｌ）及び亜硝酸ｔｅｒｔ−ブチル（６．５ｍＬ，４９ｍｍｏｌ）を室温で加え、１００℃で３０分間撹拌した。反応混合物を酢酸エチルで希釈した後、１０％リン酸二水素カリウム水溶液を加え、室温で２時間撹拌した。反応混合物を濾過した後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣を逆相シリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５９０ｍｇ，４．４ｍｍｏｌ，収率１１％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．３３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），２．８７（１Ｈ，ｂｒ），２．５０（３Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１３２［Ｍ−Ｈ］^- (A) Synthesis of 2-hydroxy-6-methylbenzonitrile [A-5a] (hereinafter referred to as compound [A-5a])

Copper (I) cyanide (4.4 g, 49 mmol) and tert-butyl nitrite (6.5 mL, 49 mmol) in a DMSO (41 mL) solution of commercially available 2-amino-3-methylphenol (5.1 g, 41 mmol). ) Was added at room temperature, and the mixture was stirred at 100 ° C. for 30 minutes. After diluting the reaction mixture with ethyl acetate, a 10% aqueous potassium dihydrogen phosphate solution was added, and the mixture was stirred at room temperature for 2 hours. After filtering the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (590 mg, 4.4 mmol, yield 11%) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.33 (1H, t, J = 7.8 Hz), 6.84 (1H, d, J = 7.3 Hz), 6.79 (1H, d, J = 8.2Hz), 2.87 (1H, br), 2.50 (3H, s).
ESI-MSfound: 132 [MH] ^-

(B) Synthesis of (S) -2-methyl-6- (oxylan-2-ylmethoxy) benzonitrile [A-5] DMSO (8.3 mL) of compound [A-5a] (513 mg, 3.9 mmol) ), 3-Nitrobenzenesulfonic acid (S) -glycidyl (1.6 g, 6.2 mmol) and cesium fluoride (2.5 g, 17 mmol) were added at room temperature, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (706 mg, 3.7 mmol, 97% yield) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.38 (1H, t, J = 8.0 Hz), 6.90 (1H, d, J = 7.8 Hz), 6.81 (1H, d, J = 8.2Hz), 4.33 (1H, dd, J = 11.4, 3.2Hz), 4.11 (1H, dd, J = 11.4, 5.0Hz), 3.41-3 .38 (1H, m), 2.93 (1H, t, J = 4.6Hz), 2.85 (1H, dd, J = 5.0, 2.7Hz), 2.51 (3H, s) ..
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-6]
Synthesis of (S) -3-methyl-5- (oxylan-2-ylmethoxy) benzonitrile [A-6] (hereinafter referred to as compound [A-6])

市販の３−ブロモ−５−ヒドロキシ安息香酸（２９７ｍｇ，１．４ｍｍｏｌ）の１，２−ジメトキシエタン（２．５ｍＬ）溶液に、トリメチルボロキシン（０．３８ｍＬ，２．７ｍｍｏｌ）、Ｐｄ（ＰＰｈ₃）₄（１５８ｍｇ，０．１４ｍｍｏｌ）及び２Ｎ−炭酸ナトリウム水溶液（２．１ｍＬ，４．１ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて９０℃で２時間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６８ｍｇ，０．４５ｍｍｏｌ，収率３３％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１５１［Ｍ−Ｈ］^- (A) Synthesis of 3-hydroxy-5-methylbenzoic acid [A-6-a] (hereinafter referred to as compound [A-6-a])

In a solution of commercially available 3-bromo-5-hydroxybenzoic acid (297 mg, 1.4 mmol) in 1,2-dimethoxyethane (2.5 mL), trimethylboroxin (0.38 mL, 2.7 mmol), Pd (PPh _3). ) ₄ (158 mg, 0.14 mmol) and a 2N-sodium carbonate aqueous solution (2.1 mL, 4.1 mmol) were added at room temperature, and the mixture was stirred at 90 ° C. for 2 hours under an argon atmosphere using a microwave reactor. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (68 mg, 0.45 mmol, yield 33%) as a yellow solid.
ESI-MSfound: 151 [MH] ^-

化合物［Ａ−６−ａ］（６８ｍｇ，０．４５ｍｍｏｌ）のＴＨＦ（２．３ｍＬ）溶液に、ＤＭＦ（０．００５０ｍＬ，０．０６５ｍｍｏｌ）及び塩化チオニル（０．０４９ｍＬ，０．６８ｍｍｏｌ）を室温で加え、室温で２時間撹拌した。塩化チオニル（０．０８２ｍＬ，１．１ｍｍｏｌ）を室温で加え、室温で２時間撹拌した。反応混合物を減圧濃縮することにより、黄色油状物を得た。得られた黄色油状物のＴＨＦ（２．３ｍＬ）溶液を０℃に冷却し、２８％アンモニア水（０．０７６ｍＬ，１．１ｍｍｏｌ）を０℃で加え、室温で１時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４７ｍｇ，０．３１ｍｍｏｌ，収率６９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１５０［Ｍ−Ｈ］^- (B) Synthesis of 3-hydroxy-5-methylbenzamide [A-6-b] (hereinafter referred to as compound [A-6-b])

DMF (0.0050 mL, 0.065 mmol) and thionyl chloride (0.049 mL, 0.68 mmol) in a solution of compound [A-6-a] (68 mg, 0.45 mmol) in THF (2.3 mL) at room temperature. In addition, the mixture was stirred at room temperature for 2 hours. Thionyl chloride (0.082 mL, 1.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oil. A solution of the obtained yellow oil in THF (2.3 mL) was cooled to 0 ° C., 28% aqueous ammonia (0.076 mL, 1.1 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (47 mg, 0.31 mmol, yield 69%) as a white solid.
ESI-MSfound: 150 [MH] ^-

化合物［Ａ−６−ｂ］（４７ｍｇ，０．３１ｍｍｏｌ）を０℃に冷却し、ＤＭＦ（０．００５０ｍＬ，０．０６５ｍｍｏｌ）及び塩化チオニル（２．０ｍＬ，２７ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３５ｍｇ，０．２６ｍｍｏｌ，収率８５％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１３２［Ｍ−Ｈ］^- (C) Synthesis of 3-hydroxy-5-methylbenzonitrile [A-6-c] (hereinafter referred to as compound [A-6-c])

Compound [A-6-b] (47 mg, 0.31 mmol) was cooled to 0 ° C., DMF (0.0050 mL, 0.065 mmol) and thionyl chloride (2.0 mL, 27 mmol) were added at 0 ° C. and at room temperature. The mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (35 mg, 0.26 mmol, yield 85%) as a yellow solid.
ESI-MSfound: 132 [MH] ^-

(D) Synthesis of -3-methyl-5- (oxylan-2-ylmethoxy) benzonitrile [A-6] From compound [A-6-c] (35 mg, 0.26 mmol), Reference Example A-1 The title compound (47 mg, 0.25 mmol, yield 95%) was obtained as a colorless oil according to the above method.
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-7]
Synthesis of (S) -4-methoxy-2- (oxylan-2-ylmethoxy) benzonitrile [A-7] (hereinafter referred to as compound [A-7])

市販の２−ヒドロキシ−４−メトキシベンズアルデヒド（５０ｍｇ，０．３３ｍｍｏｌ）から参考例Ａ−２の工程（ａ）の方法に準じて表題化合物（５５ｍｇ，収率ｑｕａｎｔ．）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１６８［Ｍ＋Ｈ］⁺ (A) Synthesis of 2-hydroxy-4-methoxybenzaldehyde oxime [A-7-a] (hereinafter referred to as compound [A-7-a])

The title compound (55 mg, yield quant.) Was obtained as a white solid from a commercially available 2-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol) according to the method of step (a) of Reference Example A-2.
ESI-MSfound: 168 [M + H] ⁺

(B) Synthesis of (S) -4-methoxy-2- (oxylan-2-ylmethoxy) benzonitrile [A-7] Reference example A-2 from compound [A-7-a] (55 mg, 0.33 mmol) The title compound (67 mg, 0.33 mmol, yield 99%) was obtained as a yellow oil according to the method of step (b) and Reference Example A-1.
ESI-MSfound: 206 [M + H] ⁺

[Reference Example A-8]
Synthesis of (S) -4-fluoro-2- (oxylan-2-ylmethoxy) benzonitrile [A-8] (hereinafter referred to as compound [A-8])

市販の２−ブロモ−５−フルオロフェノール（１７４ｍｇ，０．９１ｍｍｏｌ）のＤＭＦ（２．３ｍＬ）溶液に、シアン化亜鉛（１６１ｍｇ，１．４ｍｍｏｌ）及びＰｄ（ＰＰｈ₃）₄（１０５ｍｇ，０．０９１ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１００℃で１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６５ｍｇ，０．４８ｍｍｏｌ，収率５２％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１３６［Ｍ−Ｈ］^- (A) Synthesis of 4-fluoro-2-hydroxybenzonitrile [A-8-a] (hereinafter referred to as compound [A-8-a])

_{Zinc cyanide (161 mg, 1.4 mmol) and Pd (PPh 3} ) ₄ (105 mg, 0.091 mmol) in a commercially available solution of 2-bromo-5-fluorophenol (174 mg, 0.91 mmol) in DMF (2.3 mL). ) Was added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour using a microwave reactor under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (65 mg, 0.48 mmol, yield 52%) as a yellow solid.
ESI-MSfound: 136 [MH] ^-

(B) Synthesis of (S) -4-fluoro-2- (oxylan-2-ylmethoxy) benzonitrile [A-8] Reference Example A-1 from compound [A-8-a] (65 mg, 0.47 mmol) The title compound (84 mg, 0.43 mmol, yield 92%) was obtained as a white solid according to the above method.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.58-7.55 (1H, m), 6.78-6.73 (2H, m), 4.39 (1H, dd, J = 11. 4,2.7Hz), 4.07 (1H, dd, J = 11.4, 5.5Hz), 3.42-3.38 (1H, m), 2.95 (1H, t, J = 4) .3Hz), 2.84 (1H, dd, J = 4.8, 2.5Hz).
ESI-MSfound: 235 [M + H + CH ₃ CN] ⁺

[Reference Example A-9]
Synthesis of (S) -2- (oxylan-2-ylmethoxy) -4- (trifluoromethyl) benzonitrile [A-9] (hereinafter referred to as compound [A-9])

市販の２−クロロ−４−（トリフルオロメチル）ベンゾニトリル（１４１ｍｇ，０．６９ｍｍｏｌ）の１，４−ジオキサン（２．３ｍＬ）溶液に、ビス（ピナコラート）ジボロン（３４８ｍｇ，１．４ｍｍｏｌ）、ＰｄＣｌ₂（ｄｐｐｆ）・ＣＨ₂Ｃｌ₂（５６ｍｇ，０．０６９ｍｍｏｌ）及び酢酸カリウム（２０２ｍｇ，２．１ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１１０℃で４時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、白色固体（１４０ｍｇ）を得た。得られた白色固体のメタノール（２．３ｍＬ）溶液に、３０％過酸化水素水（０．１４ｍＬ，１．４ｍｍｏｌ）を室温で加え、室温で３時間撹拌した。次いで、３０％過酸化水素水（０．１４ｍＬ，１．４ｍｍｏｌ）を室温で追加し、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２９ｍｇ，０．１６ｍｍｏｌ，収率２３％）を白色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１８６［Ｍ−Ｈ］^- (A) Synthesis of 2-hydroxy-4- (trifluoromethyl) benzonitrile [A-9-a] (hereinafter referred to as compound [A-9-a])

Bis (pinacholate) diboron (348 mg, 1.4 mmol), PdCl in a 1,4-dioxane (2.3 mL) solution of commercially available 2-chloro-4- (trifluoromethyl) benzonitrile (141 mg, 0.69 mmol). ₂ (dppf) · CH ₂ Cl ₂ (56 mg, 0.069 mmol) and potassium acetate (202 mg, 2.1 mmol) were added at room temperature, and the mixture was stirred at 110 ° C. for 4 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a white solid (140 mg). A 30% hydrogen peroxide solution (0.14 mL, 1.4 mmol) was added to the obtained white solid methanol (2.3 mL) solution at room temperature, and the mixture was stirred at room temperature for 3 hours. Then, 30% hydrogen peroxide solution (0.14 mL, 1.4 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (29 mg, 0.16 mmol, yield 23%) as a white amorphous substance.
ESI-MSfound: 186 [MH] ^-

(B) Synthesis of (S) -2- (oxylan-2-ylmethoxy) -4- (trifluoromethyl) benzonitrile [A-9] Reference from compound [A-9-a] (29 mg, 0.16 mmol) The title compound (34 mg, 0.14 mmol, yield 88%) was obtained as a white solid according to the method of Example A-1.
ESI-MSfound: 285 [M + H + CH ₃ CN] ⁺

[Reference Example A-10]
Synthesis of (S) -2-fluoro-6- (oxylan-2-ylmethoxy) benzonitrile [A-10] (hereinafter referred to as compound [A-10])

The title compound (42 mg, 0.22 mmol, yield 99%) was obtained as a white solid from a commercially available 2-fluoro-6-hydroxybenzonitrile (30 mg, 0.22 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.49 (1H, td, J = 8.6, 6.6 Hz), 6.83-6.79 (2H, m), 4.40 (1H, 1H, dd, J = 11.4, 2.7Hz), 4.12 (1H, dd, J = 11.2, 5.3Hz), 3.42-3.38 (1H, m), 2.95 (1H) , T, J = 4.6Hz), 2.84 (1H, dd, J = 4.8, 2.5Hz).
ESI-MSfound: 235 [M + H + CH ₃ CN] ⁺

[Reference Example A-11]
Synthesis of (S) -3- (oxylan-2-ylmethoxy) phthalonitrile [A-11] (hereinafter referred to as compound [A-11])

市販の２，３−ジクロロフェノール（６１ｍｇ，０．３８ｍｍｏｌ）のＤＭＦ（２．３ｍＬ）溶液に、シアン化亜鉛（１８２ｍｇ，１．６ｍｍｏｌ）、ＸＰｈｏｓ（７２ｍｇ，０．１５ｍｍｏｌ）及びＰｄ₂（ｄｂａ）₃（６９ｍｇ，０．０７５ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１００℃で１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２７ｍｇ，０．１９ｍｍｏｌ，収率５０％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１４３［Ｍ−Ｈ］^- (A) Synthesis of 3-hydroxyphthalonitrile [A-11-a] (hereinafter referred to as compound [A-11-a])

_{Zinc cyanide (182 mg, 1.6 mmol), XPhos (72 mg, 0.15 mmol) and Pd 2} (dba) in a commercially available solution of 2,3-dichlorophenol (61 mg, 0.38 mmol) in DMF (2.3 mL). ₃ (69 mg, 0.075 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour using a microwave reactor under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (27 mg, 0.19 mmol, yield 50%) as a white solid.
ESI-MSfound: 143 [MH] ^-

(B) Synthesis of (S) -3- (oxylan-2-ylmethoxy) phthalonitrile [A-11] From compound [A-11-a] (26 mg, 0.18 mmol) according to the method of Reference Example A-1. The title compound (30 mg, 0.15 mmol, yield 84%) was obtained as a white solid.
ESI-MSfound: 242 [M + H + CH ₃ CN] ⁺

[Reference Example A-12]
Synthesis of (S) -2- (oxylan-2-ylmethoxy) -6- (trifluoromethyl) benzonitrile [A-12] (hereinafter referred to as compound [A-12])

市販の２−クロロ−３−（トリフルオロメチル）フェノール（５３ｍｇ，０．２７ｍｍｏｌ）のＤＭＦ（０．８９ｍＬ）溶液に、シアン化亜鉛（６３ｍｇ，０．５４ｍｍｏｌ）、ＸＰｈｏｓ（２６ｍｇ，０．０５３ｍｍｏｌ）及びＰｄ₂（ｄｂａ）₃（２４ｍｇ，０．０２７ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１００℃で４時間撹拌した。反応混合物にシアン化亜鉛（６３ｍｇ，０．５３ｍｍｏｌ）、ＸＰｈｏｓ（２６ｍｇ，０．０５３ｍｍｏｌ）及びＰｄ₂（ｄｂａ）₃（２４ｍｇ，０．０２７ｍｍｏｌ）を室温で追加し、アルゴン雰囲気下、マイクロ波反応装置を用いて１００℃で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２４ｍｇ，０．１３ｍｍｏｌ，収率４８％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１８６［Ｍ−Ｈ］^- (A) Synthesis of 2-hydroxy-6- (trifluoromethyl) benzonitrile [A-12-a] (hereinafter referred to as compound [A-12-a])

Zinc cyanide (63 mg, 0.54 mmol), XPhos (26 mg, 0.053 mmol) in a solution of commercially available 2-chloro-3- (trifluoromethyl) phenol (53 mg, 0.27 mmol) in DMF (0.89 mL). And Pd ₂ (dba) ₃ (24 mg, 0.027 mmol) were added at room temperature, and the mixture was stirred at 100 ° C. for 4 hours under an argon atmosphere. Zinc cyanide (63 mg, 0.53 mmol), XPhos (26 mg, 0.053 mmol) and Pd ₂ (dba) ₃ (24 mg, 0.027 mmol) were added to the reaction mixture at room temperature, and a microwave reactor was added under an argon atmosphere. Was stirred at 100 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (24 mg, 0.13 mmol, yield 48%) as a yellow solid.
ESI-MSfound: 186 [MH] ^-

(B) Synthesis of (S) -2- (oxylan-2-ylmethoxy) -6- (trifluoromethyl) benzonitrile [A-12] Reference from compound [A-12-a] (24 mg, 0.13 mmol) The title compound (31 mg, 0.13 mmol, yield 99%) was obtained as a yellow solid according to the method of Example A-1.
ESI-MSfound: 285 [M + H + CH ₃ CN] ⁺

[Reference Example A-13]
(S) Synthesis of -2-methyl-3- (oxylan-2-ylmethoxy) benzonitrile [A-13] (hereinafter referred to as compound [A-13])

市販の２−メチル−３−ニトロフェノール（３８１ｍｇ，２．５ｍｍｏｌ）のメタノール（５．０ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（１００ｍｇ）を室温で加え、水素雰囲気下、室温で１６時間撹拌した。反応混合物を濾過した後、濾液を減圧濃縮することにより、表題化合物（３０６ｍｇ，収率ｑｕａｎｔ．）を褐色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１２４［Ｍ＋Ｈ］⁺ (A) Synthesis of 3-amino-2-methylphenol [A-13-a] (hereinafter referred to as compound [A-13-a])

Add 10% palladium-activated carbon (about 55% water) (100 mg) to a commercially available solution of 2-methyl-3-nitrophenol (381 mg, 2.5 mmol) in methanol (5.0 mL) at room temperature under a hydrogen atmosphere. , Stirred at room temperature for 16 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to give the title compound (306 mg, yield quant.) As a brown solid.
ESI-MSfound: 124 [M + H] ⁺

(B) Synthesis of (S) -2-methyl-3- (oxylan-2-ylmethoxy) benzonitrile [A-13] DMSO (5.0 mL) of compound [A-13-a] (306 mg, 2.5 mmol) ) Copper (I) cyanide (268 mg, 3.0 mmol) and tert-butyl nitrite (0.40 mL, 3.0 mmol) were added to the solution at room temperature, and the mixture was stirred at 100 ° C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown oil. From the obtained brown oil, the title compound (41 mg, 0.21 mmol, yield 9%) was obtained as a brown solid according to the method of Reference Example A-1.
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-14]
Synthesis of (S) -2-methoxy-6- (oxylan-2-ylmethoxy) benzonitrile [A-14] (hereinafter referred to as compound [A-14])

市販の２−ヒドロキシ−６−メトキシ安息香酸（２４９ｍｇ，１．５ｍｍｏｌ）から参考例Ａ−６の工程（ｂ）の方法に準じて表題化合物（１１９ｍｇ，０．７１ｍｍｏｌ，収率４８％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．３１（１Ｈ，ｔ，Ｊ＝８．２Ｈｚ），６．５６−６．５０（２Ｈ，ｍ），３．９４（３Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１６８［Ｍ＋Ｈ］⁺ (A) Synthesis of 2-hydroxy-6-methoxybenzamide [A-14-a] (hereinafter referred to as compound [A-14-a])

Whitening the title compound (119 mg, 0.71 mmol, yield 48%) from commercially available 2-hydroxy-6-methoxybenzoic acid (249 mg, 1.5 mmol) according to the method of step (b) of Reference Example A-6. Obtained as a solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.31 (1 H, t, J = 8.2 Hz), 6.56-6.50 (2 H, m), 3.94 (3 H, s).
ESI-MSfound: 168 [M + H] ⁺

化合物［Ａ−１４−ａ］（３２ｍｇ，０．１９ｍｍｏｌ）のアセトニトリル（１．０ｍＬ）−水（１．０ｍＬ）混合溶液に、塩化パラジウム（ＩＩ）（３．４ｍｇ，０．０１９ｍｍｏｌ）を室温で加え、室温で９６時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１３ｍｇ，０．０８９ｍｍｏｌ，収率４６％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１４８［Ｍ−Ｈ］^- (B) Synthesis of 2-hydroxy-6-methoxybenzonitrile [A-14-b] (hereinafter referred to as compound [A-14-b])

Palladium (II) chloride (3.4 mg, 0.019 mmol) in a mixed solution of compound [A-14-a] (32 mg, 0.19 mmol) in acetonitrile (1.0 mL) -water (1.0 mL) at room temperature. In addition, the mixture was stirred at room temperature for 96 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (13 mg, 0.089 mmol, yield 46%) as a white solid.
ESI-MSfound: 148 [MH] ^-

(C) Synthesis of (S) -2-methoxy-6- (oxylan-2-ylmethoxy) benzonitrile [A-14] Reference example A-1 from compound [A-14-b] (13 mg, 0.089 mmol) The title compound (18 mg, 0.088 mmol, yield 99%) was obtained as a colorless oil according to the above method.
ESI-MSfound: 206 [M + H] ⁺ , 247 [M + H + CH ₃ CN] ⁺

[Reference Example A-15]
(S) Synthesis of -2-chloro-6- (oxylan-2-ylmethoxy) benzonitrile [A-15] (hereinafter referred to as compound [A-15])

市販の２−クロロ−６−ヒドロキシベンズアルデヒド（１９１ｍｇ，１．２ｍｍｏｌ）から参考例Ａ−２の工程（ａ）の方法に準じて表題化合物（１９８ｍｇ，１．２ｍｍｏｌ，収率９５％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１７２［Ｍ＋Ｈ］⁺ (A) Synthesis of 2-chloro-6-hydroxybenzaldehyde oxime [A-15-a] (hereinafter referred to as compound [A-15-a])

A white solid of the title compound (198 mg, 1.2 mmol, yield 95%) from commercially available 2-chloro-6-hydroxybenzaldehyde (191 mg, 1.2 mmol) according to the method of step (a) of Reference Example A-2. Obtained as.
ESI-MSfound: 172 [M + H] ⁺

化合物［Ａ−１５−ａ］（１９８ｍｇ，１．２ｍｍｏｌ）のアセトニトリル（２３ｍＬ）溶液に、トリフェニルホスフィン（７６１ｍｇ，２．９ｍｍｏｌ）及び１，１’−（アゾジカルボニル）ジピペリジン（７３２ｍｇ，２．９ｍｍｏｌ）を室温で加え、室温で１８時間撹拌した。反応混合物に１Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１６９ｍｇ，０．０８９ｍｍｏｌ，収率９５％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１５２［Ｍ−Ｈ］^- (B) Synthesis of 2-chloro-6-hydroxybenzonitrile [A-15-b] (hereinafter referred to as compound [A-15-b])

Triphenylphosphine (761 mg, 2.9 mmol) and 1,1'-(azodicarbonyl) dipiperidine (732 mg, 2.) in a solution of compound [A-15-a] (198 mg, 1.2 mmol) in acetonitrile (23 mL). 9 mmol) was added at room temperature, and the mixture was stirred at room temperature for 18 hours. 1N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (169 mg, 0.089 mmol, yield 95%) as a yellow solid.
ESI-MSfound: 152 [MH] ^-

(C) Synthesis of (S) -2-chloro-6- (oxylan-2-ylmethoxy) benzonitrile [A-15] Reference example A-1 from compound [A-15-b] (31 mg, 0.20 mmol) The title compound (41 mg, 0.20 mmol, yield 99%) was obtained as a white solid according to the above method.
ESI-MSfound: 251 [M + H + CH ₃ CN] ⁺

[Reference Example A-16]
Synthesis of (S) -2-ethyl-6- (oxylan-2-ylmethoxy) benzonitrile [A-16] (hereinafter referred to as compound [A-16])

市販の２−ブロモ−６−ヒドロキシベンズアルデヒド（２５０ｍｇ，１．２ｍｍｏｌ）から参考例Ａ−２の工程（ａ）の方法に準じて表題化合物（２６４ｍｇ，１．２ｍｍｏｌ，収率９８％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：１０．４１（１Ｈ，ｓ），８．７９（１Ｈ，ｓ），７．３８（１Ｈ，ｓ），７．１８−７．０９（２Ｈ，ｍ），６．９３（１Ｈ，ｄｄ，Ｊ＝７．５，１．６Ｈｚ）． (A) Synthesis of 2-bromo-6-hydroxybenzaldehyde oxime [A-16-a] (hereinafter referred to as compound [A-16-a])

A white solid of the title compound (264 mg, 1.2 mmol, yield 98%) from commercially available 2-bromo-6-hydroxybenzaldehyde (250 mg, 1.2 mmol) according to the method of step (a) of Reference Example A-2. Obtained as.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 10.41 (1H, s), 8.79 (1H, s), 7.38 (1H, s), 7.18-7.09 (2H, m) ), 6.93 (1H, dd, J = 7.5, 1.6Hz).

化合物［Ａ−１６−ａ］（２６０ｍｇ，１．２ｍｍｏｌ）から参考例Ａ−１５の工程（ｂ）の方法に準じて表題化合物（１８８ｍｇ，０．９５ｍｍｏｌ，収率７９％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．３２（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．２３−７．２１（１Ｈ，ｍ），６．９７−６．９４（１Ｈ，ｍ）． (B) Synthesis of 2-bromo-6-hydroxybenzonitrile [A-16-b] (hereinafter referred to as compound [A-16-b])

The title compound (188 mg, 0.95 mmol, yield 79%) was obtained as a white solid from the compound [A-16-a] (260 mg, 1.2 mmol) according to the method of step (b) of Reference Example A-15. It was.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.32 (1H, t, J = 8.0 Hz), 7.23-7.21 (1H, m), 6.97-6.94 (1H, 1H,) m).

化合物［Ａ−１６−ｂ］（１７４ｍｇ，０．８８ｍｍｏｌ）の１，２−ジメトキシエタン（２．９ｍＬ）溶液に、カリウムビニルトリフルオロボラート（２３５ｍｇ，１．８ｍｍｏｌ）、Ｐｄ（ＰＰｈ₃）₄（１０２ｍｇ，０．０８８ｍｍｏｌ）及び２Ｎ−炭酸ナトリウム水溶液（１．３ｍＬ，２．６ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１３０℃で３０分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１２８ｍｇ，収率ｑｕａｎｔ．）を黄色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．４０（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．９８（１Ｈ，ｄｄ，Ｊ＝１７．４，１１．０Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），６．３９（１Ｈ，ｂｒ），５．９４（１Ｈ，ｄ，Ｊ＝１７．４Ｈｚ），５．５３（１Ｈ，ｄ，Ｊ＝１１．０Ｈｚ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１４４［Ｍ−Ｈ］^- (C) Synthesis of 2-hydroxy-6-vinylbenzonitrile [A-16-c] (hereinafter referred to as compound [A-16-c])

_{Potassium vinyl trifluoroborate (235 mg, 1.8 mmol), Pd (PPh 3} ) ₄ (in a solution of compound [A-16-b] (174 mg, 0.88 mmol) in 1,2-dimethoxyethane (2.9 mL). 102 mg, 0.088 mmol) and a 2N-sodium carbonate aqueous solution (1.3 mL, 2.6 mmol) were added at room temperature, and the mixture was stirred at 130 ° C. for 30 minutes under an argon atmosphere using a microwave reactor. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (128 mg, yield quant.) As a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.40 (1H, t, J = 8.0 Hz), 7.19 (1H, d, J = 7.8 Hz), 6.98 (1H, dd, J = 17.4,11.0Hz), 6.89 (1H, d, J = 8.2Hz), 6.39 (1H, br), 5.94 (1H, d, J = 17.4Hz), 5.53 (1H, d, J = 11.0Hz).
ESI-MSfound: 144 [MH] ^-

化合物［Ａ−１６−ｃ］（１２６ｍｇ，０．８７ｍｍｏｌ）のメタノール（２．９ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（１００ｍｇ）を室温で加え、水素雰囲気下、室温で３時間撹拌した。反応混合物を濾過した後、濾液を減圧濃縮することにより、表題化合物（１２４ｍｇ，０．８４ｍｍｏｌ，収率９７％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．３５（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），６．８６−６．８１（２Ｈ，ｍ），２．８２（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ），１．２８（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１４６［Ｍ−Ｈ］^- (D) Synthesis of 2-ethyl-6-hydroxybenzonitrile [A-16-d] (hereinafter referred to as compound [A-16-d])

Add 10% palladium-activated carbon (about 55% water) (100 mg) to a solution of compound [A-16-c] (126 mg, 0.87 mmol) in methanol (2.9 mL) at room temperature, and add 10% palladium-activated carbon (about 55% water) (100 mg) to room temperature under a hydrogen atmosphere. Was stirred for 3 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to give the title compound (124 mg, 0.84 mmol, yield 97%) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.35 (1H, t, J = 8.0 Hz), 6.86-6.81 (2H, m), 2.82 (2H, q, J =) 7.6Hz), 1.28 (3H, t, J = 7.5Hz).
ESI-MSfound: 146 [MH] ^-

(E) Synthesis of (S) -2-ethyl-6- (oxylan-2-ylmethoxy) benzonitrile [A-16] Reference Example A-1 from compound [A-16-d] (119 mg, 0.81 mmol) The title compound (130 mg, 0.64 mmol, yield 79%) was obtained as a colorless oil according to the above method.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.42 (1H, t, J = 8.0 Hz), 6.92 (1H, d, J = 7.8 Hz), 6.82 (1H, d, J = 8.7Hz), 4.33 (1H, dd, J = 11.2, 3.0Hz), 4.11 (1H, dd, J = 11.2, 5.3Hz), 3.42-3 .38 (1H, m), 2.93 (1H, t, J = 4.6Hz), 2.87-2.81 (3H, m), 1.28 (3H, t, J = 7.5Hz) ..
ESI-MSfound: 245 [M + H + CH ₃ CN] ⁺

[Reference Example A-17]
Synthesis of (R) -2-methyl-6- (oxylan-2-ylmethoxy) benzonitrile [A-17] (hereinafter referred to as compound [A-17])

市販の２−アミノ−３−メチルフェノール（２０２ｍｇ，１．６ｍｍｏｌ）のＤＭＳＯ（３．３ｍＬ）溶液に、シアン化銅（Ｉ）（１７３ｍｇ，１．９ｍｍｏｌ）及び亜硝酸ｔｅｒｔ−ブチル（０．２６ｍＬ，２．０ｍｍｏｌ）を室温で加え、１００℃で３０分間撹拌した。反応混合物を濾過し、濾液を減圧濃縮することにより、褐色油状物を得た。得られた褐色油状物及び３−ニトロベンゼンスルホン酸（Ｒ）−グリシジル（２１３ｍｇ，０．８２ｍｍｏｌ）から参考例Ａ−１の方法に準じて表題化合物（４０ｍｇ，０．２１ｍｍｏｌ，収率１３％）を褐色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２３１［Ｍ＋Ｈ＋ＣＨ₃ＣＮ］⁺

Copper (I) cyanide (173 mg, 1.9 mmol) and tert-butyl nitrite (0.26 mL) in a DMSO (3.3 mL) solution of commercially available 2-amino-3-methylphenol (202 mg, 1.6 mmol). , 2.0 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown oil. From the obtained brown oil and 3-nitrobenzenesulfonic acid (R) -glycidyl (213 mg, 0.82 mmol), the title compound (40 mg, 0.21 mmol, yield 13%) was added according to the method of Reference Example A-1. Obtained as a brown solid.
ESI-MSfound: 231 [M + H + CH ₃ CN] ⁺

[Reference Example A-18]
(S) Synthesis of -1-methyl-4- [2-methyl-6- (oxylan-2-ylmethoxy) phenyl] -1H-pyrazole [A-18] (hereinafter referred to as compound [A-18])

市販の２−ブロモ−３−ニトロトルエン（５６６ｍｇ，２．６ｍｍｏｌ）の２−プロパノール（１０ｍＬ）溶液に、ビス（ピナコラート）ジボロン（２．１ｇ，８．１ｍｍｏｌ）及びカリウムｔｅｒｔ−ブトキシド（３５３ｍｇ，３．１ｍｍｏｌ）を室温で加え、１１０℃で２時間撹拌した。反応混合物に５Ｎ−水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、褐色油状物（３４４ｍｇ）を得た。得られた褐色油状物のＤＭＳＯ（３．７ｍＬ）溶液に、５Ｍ−硫酸（３．７ｍＬ）を室温で加え、０℃に冷却した。反応混合物に亜硝酸ナトリウム（１５２ｍｇ，２．２ｍｍｏｌ）を０℃で加え、１００℃で３０分間撹拌した後、１５０℃で３０分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、褐色油状物（８３ｍｇ）を得た。得られた褐色油状物の１，２−ジメトキシエタン（０．６６ｍＬ）溶液に、１−メチルピラゾール−４−ボロン酸ピナコールエステル（８２ｍｇ，０．４０ｍｍｏｌ）、Ｐｄ（ＰＰｈ₃）₄（２３ｍｇ，０．０２０ｍｍｏｌ）及び２Ｎ−炭酸ナトリウム水溶液（０．３０ｍＬ，０．５９ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１３０℃で３０分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１７ｍｇ，０．０８９ｍｍｏｌ，収率８％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１８９［Ｍ＋Ｈ］⁺ (A) Synthesis of 3-methyl-2- (1-methyl-1H-pyrazole-4-yl) phenol [A-18-a] (hereinafter referred to as compound [A-18-a])

Bis (pinacolat) diboron (2.1 g, 8.1 mmol) and potassium tert-butoxide (353 mg, 3.) in a solution of commercially available 2-bromo-3-nitrotoluene (566 mg, 2.6 mmol) in 2-propanol (10 mL). 1 mmol) was added at room temperature, and the mixture was stirred at 110 ° C. for 2 hours. A 5N-sodium hydroxide aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a brown oil (344 mg). To a solution of the obtained brown oil in DMSO (3.7 mL) was added 5M-sulfuric acid (3.7 mL) at room temperature and cooled to 0 ° C. Sodium nitrite (152 mg, 2.2 mmol) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 100 ° C. for 30 minutes and then at 150 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a brown oil (83 mg). In a solution of the obtained brown oil in 1,2-dimethoxyethane (0.66 mL), 1-methylpyrazole-4-boronic acid pinacol ester (82 mg, 0.40 mmol), Pd (PPh ₃ ) ₄ (23 mg, 0) .020 mmol) and a 2N-sodium carbonate aqueous solution (0.30 mL, 0.59 mmol) were added at room temperature, and the mixture was stirred at 130 ° C. for 30 minutes using a microwave reactor under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (17 mg, 0.089 mmol, yield 8%) as a yellow solid.
ESI-MSfound: 189 [M + H] ⁺

(B) Synthesis of (S) -1-methyl-4- [2-methyl-6- (oxylan-2-ylmethoxy) phenyl] -1H-pyrazole [A-18] Compound [A-18-a] (17 mg) , 0.089 mmol) to give the title compound (18 mg, 0.074 mmol, yield 83%) as a yellow oil according to the method of Reference Example A-1.
ESI-MSfound: 245 [M + H] ⁺

[Reference Example A-19]
Synthesis of (S) -2-[(2-fluoro-5-methylphenoxy) methyl] oxylan [A-19] (hereinafter referred to as compound [A-19])

市販の２−フルオロ−５−メチルフェノール（１００ｍｇ，０．７９ｍｍｏｌ）から参考例Ａ−１の方法に準じて表題化合物（１２０ｍｇ，０．６６ｍｍｏｌ，収率８３％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：６．９８−６．９３（１Ｈ，ｍ），６．８０（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），６．７３−６．６９（１Ｈ，ｍ），４．２５（１Ｈ，ｄｄ，Ｊ＝１１．２，３．４Ｈｚ），４．０３（１Ｈ，ｄｄ，Ｊ＝１１．２，５．７Ｈｚ），３．３９−３．３５（１Ｈ，ｍ），２．９１（１Ｈ，ｔ，Ｊ＝４．３Ｈｚ），２．７６（１Ｈ，ｄｄ，Ｊ＝４．８，２．５Ｈｚ），２．３０（３Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２２４［Ｍ＋Ｈ＋ＣＨ₃ＣＮ］⁺

The title compound (120 mg, 0.66 mmol, yield 83%) was obtained as a white solid from a commercially available 2-fluoro-5-methylphenol (100 mg, 0.79 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 6.98-6.93 (1H, m), 6.80 (1H, dd, J = 8.2, 1.8 Hz), 6.73-6. 69 (1H, m), 4.25 (1H, dd, J = 11.2, 3.4Hz), 4.03 (1H, dd, J = 11.2, 5.7Hz), 3.39-3 .35 (1H, m), 2.91 (1H, t, J = 4.3Hz), 2.76 (1H, dd, J = 4.8, 2.5Hz), 2.30 (3H, s) ..
ESI-MSfound: 224 [M + H + CH ₃ CN] ⁺

[Reference Example A-20]
Synthesis of (S) -2-[(3-methylphenoxy) methyl] oxylan [A-20] (hereinafter referred to as compound [A-20])

The title compound (83 mg, 0.51 mmol, yield 55%) was obtained as a colorless oil from commercially available 3-methylphenol (100 mg, 0.93 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.17 (1H, t, J = 8.0 Hz), 6.80-6.71 (3H, m), 4.19 (1H, dd, J = 11.0, 3.2Hz), 3.96 (1H, dd, J = 11.0, 5.5Hz), 3.37-3-33 (1H, m), 2.91 (1H, dd, J) = 5.0, 4.1 Hz), 2.76 (1H, dd, J = 5.0, 2.7 Hz), 2.33 (3H, s).
ESI-MSfound: 206 [M + H + CH ₃ CN] ⁺

[Reference Example A-21]
Synthesis of (S) -2-[(3-methoxyphenoxy) methyl] oxylan [A-21] (hereinafter referred to as compound [A-21])

The title compound (154 mg, yield quant.) Was obtained as a colorless oil from commercially available 3-methoxyphenol (100 mg, 0.81 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.18 (1H, t, J = 8.2 Hz), 6.55-6.49 (3H, m), 4.20 (1H, dd, J = 11.0, 3.2Hz), 3.95 (1H, dd, J = 11.0, 5.5Hz), 3.79 (3H, s), 3.37-3.34 (1H, m), 2.91 (1H, t, J = 4.6Hz), 2.76 (1H, dd, J = 5.0, 2.7Hz).

[Reference Example A-22]
(S) -2-[(2-Methylphenoxy) methyl] oxylan [A-22] (hereinafter referred to as compound [A-22]) synthesis)

The title compound (51 mg, 0.31 mmol, yield 83%) was obtained as a colorless oil from commercially available 2-methylphenol (40 mg, 0.37 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.16-7.13 (2H, m), 6.90-6.86 (1H, m), 6.82-6.80 (1H, m) , 4.23 (1H, dd, J = 11.0, 3.2Hz), 3.99 (1H, dd, J = 11.0, 5.5Hz), 3.40-3.36 (1H, m) ), 2.91 (1H, dd, J = 5.0, 4.1Hz), 2.79 (1H, dd, J = 5.0, 2.7Hz), 2.25 (3H, s).
ESI-MSfound: 206 [M + H + CH ₃ CN] ⁺

[Reference Example A-23]
Synthesis of (S) -2-[(4-methylphenoxy) methyl] oxylan [A-23] (hereinafter referred to as compound [A-23])

The title compound (57 mg, 0.35 mmol, yield 94%) was obtained as a colorless oil from commercially available 4-methylphenol (40 mg, 0.37 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.09-7.07 (2H, m), 6.84-6.80 (2H, m), 4.18 (1H, dd, J = 11. 0, 3.2Hz), 3.95 (1H, dd, J = 11.0, 5.5Hz), 3.37-3.33 (1H, m), 2.90 (1H, t, J = 4) .6Hz), 2.75 (1H, dd, J = 4.8, 2.5Hz), 2.29 (3H, s).
ESI-MSfound: 206 [M + H + CH ₃ CN] ⁺

[Reference Example A-24]
Synthesis of (S) -2-[(2-fluoro-3-methylphenoxy) methyl] oxylan [A-24] (hereinafter referred to as compound [A-24])

The title compound (131 mg, 0.72 mmol, yield 91%) was obtained as a colorless oil from a commercially available 2-fluoro-3-methylphenol (100 mg, 0.79 mmol) according to the method of Reference Example A-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 6.95-6.91 (1H, m), 6.85-6.77 (2H, m), 4.25 (1H, dd, J = 11. 2,3.4Hz), 4.04 (1H, dd, J = 11.2, 5.7Hz), 3.40-3.36 (1H, m), 2.91-2.90 (1H, m) ), 2.76 (1H, dd, J = 5.0, 2.7Hz), 2.28 (3H, d, J = 2.3Hz).
ESI-MSfound: 224 [M + H + CH ₃ CN] ⁺

[Reference Example A-25]
Synthesis of (S) -1- [2-methyl-6- (oxylan-2-ylmethoxy) phenyl] -1H-pyrazole [A-25] (hereinafter referred to as compound [A-25])

市販の３−メチル−２−ニトロフェノール（１．０ｇ，６．５ｍｍｏｌ）のクロロホルム（１３ｍＬ）溶液に、トリエチルアミン（３．２ｍＬ，２３ｍｍｏｌ）及びメタンスルホニルクロリド（１．３ｍＬ，１６ｍｍｏｌ）を０℃で加え、室温で１時間撹拌した。反応混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、黄色油状物を得た。得られた黄色油状物のエタノール（１５ｍＬ）−水（７．３ｍＬ）混合溶液に、塩化アンモニウム（１．８ｇ，３３ｍｍｏｌ）及び鉄粉末（１．８ｇ，３３ｍｍｏｌ）を室温で加え、１００℃で４時間撹拌した。不溶物を濾過した後、濾液に水を加え、酢酸エチルで抽出することにより、表題化合物（１．１ｇ，５．３ｍｍｏｌ，収率８１％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２０２［Ｍ＋Ｈ］⁺ (A) Synthesis of methanesulfonic acid 2-amino-3-methylphenyl ester [A-25-a] (hereinafter referred to as compound [A-25-a])

Triethylamine (3.2 mL, 23 mmol) and methanesulfonyl chloride (1.3 mL, 16 mmol) in a commercially available 3-methyl-2-nitrophenol (1.0 g, 6.5 mmol) chloroform (13 mL) solution at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. Ammonium chloride (1.8 g, 33 mmol) and iron powder (1.8 g, 33 mmol) were added to the obtained mixed solution of ethanol (15 mL) and water (7.3 mL) of the yellow oil at room temperature, and 4 at 100 ° C. Stirred for hours. After filtering the insoluble material, water was added to the filtrate and the mixture was extracted with ethyl acetate to give the title compound (1.1 g, 5.3 mmol, yield 81%) as a yellow oil.
ESI-MSfound: 202 [M + H] ⁺

化合物［Ａ−２５−ａ］（１．１ｇ，５．３ｍｍｏｌ）を５Ｍ−硫酸（１１ｍＬ）に溶解した。当該溶液に亜硝酸ナトリウム（４４０ｍｇ，６．４ｍｍｏｌ）の水（６．４ｍＬ）溶液を０℃で加え、０℃で４０分間撹拌した。反応混合物にヨウ化カリウム（１．３ｇ，８．０ｍｍｏｌ）の水（４．０ｍＬ）溶液を０℃で加え、０℃で４時間撹拌した。反応混合物に５Ｎ−水酸化ナトリウム水溶液を加え、ｐＨ＝３に調整した。反応混合物に飽和亜硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（９６０ｍｇ，３．１ｍｍｏｌ，収率５８％）を黒色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３１１［Ｍ−Ｈ］^- (B) Synthesis of methanesulfonic acid 2-iodo-3-methylphenyl ester [A-25-b] (hereinafter referred to as compound [A-25-b])

Compound [A-25-a] (1.1 g, 5.3 mmol) was dissolved in 5M-sulfuric acid (11 mL). A solution of sodium nitrite (440 mg, 6.4 mmol) in water (6.4 mL) was added to the solution at 0 ° C., and the mixture was stirred at 0 ° C. for 40 minutes. A solution of potassium iodide (1.3 g, 8.0 mmol) in water (4.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 4 hours. A 5N-sodium hydroxide aqueous solution was added to the reaction mixture to adjust the pH to 3. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (960 mg, 3.1 mmol, yield 58%) as a black oil.
ESI-MSfound: 311 [MH] ^-

化合物［Ａ−２５−ｂ］（９６０ｍｇ，３．１ｍｍｏｌ）のメタノール（７．７ｍＬ）−エタノール（１．５ｍＬ）混合溶液に、１Ｎ−水酸化ナトリウム水溶液（７．７ｍＬ）を室温で加え、室温で１４時間撹拌した。次いで、４５℃で４時間撹拌した。反応混合物に１Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５１８ｍｇ，２．２ｍｍｏｌ，収率７２％）を褐色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．１２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），６．８３−６．８１（２Ｈ，ｍ），５．４１（１Ｈ，ｓ），２．４５（３Ｈ，ｓ）． (C) Synthesis of 2-iodo-3-methylphenol [A-25-c] (hereinafter referred to as compound [A-25-c])

A 1N-sodium hydroxide aqueous solution (7.7 mL) was added to a mixed solution of compound [A-25-b] (960 mg, 3.1 mmol) in methanol (7.7 mL) -ethanol (1.5 mL) at room temperature. Was stirred for 14 hours. Then, the mixture was stirred at 45 ° C. for 4 hours. 1N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (518 mg, 2.2 mmol, yield 72%) as a brown oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.12 (1H, t, J = 7.8 Hz), 6.83-6.81 (2H, m), 5.41 (1H, s), 2 .45 (3H, s).

化合物［Ａ−２５−ｃ］（７３ｍｇ，０．３１ｍｍｏｌ）のＤＭＦ（１．６ｍＬ）溶液に、ピラゾール（２１２ｍｇ，３．１ｍｍｏｌ）、ヨウ化銅（Ｉ）（５９ｍｇ，０．３１ｍｍｏｌ）、（１Ｒ，２Ｒ）−（−）−Ｎ，Ｎ’−ジメチルシクロヘキサン−１，２−ジアミン（４９μＬ，０．３１ｍｍｏｌ）及び炭酸セシウム（５０８ｍｇ，１．６ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１３０℃で１９時間撹拌した。不溶物を濾別した後、濾液に２Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１８ｍｇ，０．１０ｍｍｏｌ，収率３２％）を褐色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１７５［Ｍ＋Ｈ］⁺ (D) Synthesis of 3-methyl-2- (1H-pyrazole-1-yl) phenol [A-25-d] (hereinafter referred to as compound [A-25-d])

Pyrazole (212 mg, 3.1 mmol), copper (I) iodide (59 mg, 0.31 mmol), (1R) in a solution of compound [A-25-c] (73 mg, 0.31 mmol) in DMF (1.6 mL). , 2R)-(-)-N, N'-dimethylcyclohexane-1,2-diamine (49 μL, 0.31 mmol) and cesium carbonate (508 mg, 1.6 mmol) were added at room temperature and at 130 ° C. under an argon atmosphere. The mixture was stirred for 19 hours. After filtering the insoluble material, 2N-hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (18 mg, 0.10 mmol, yield 32%) as a brown oil.
ESI-MSfound: 175 [M + H] ⁺

(E) Synthesis of (S) -1- [2-methyl-6- (oxylan-2-ylmethoxy) phenyl] -1H-pyrazole [A-25] Compound [A-25-d] (18 mg, 0.10 mmol) ), The title compound (23 mg, 0.099 mmol, yield 99%) was obtained as a colorless oil according to the method of Reference Example A-1.
ESI-MSfound: 231 [M + H] ⁺

[Reference Example A-26]
Synthesis of (S) -4- [4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole-3-yl] morpholine [A-26] (hereinafter referred to as compound [A-26])

市販の３−クロロ−４−モルホリノ−１，２，５−チアジアゾール（５．０ｇ，２４ｍｍｏｌ）のＤＭＳＯ（４．４ｍＬ）溶液に、２Ｎ−水酸化カリウム水溶液（４９ｍＬ）を室温で加え、１２０℃で１３時間撹拌した。反応混合物に５Ｎ−塩酸を加え、析出した固体を濾取することにより、表題化合物（３．８ｇ，２０ｍｍｏｌ，収率８２％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１８８［Ｍ＋Ｈ］⁺ (A) Synthesis of 4-morpholino-1,2,5-thiadiazole-3-ol [A-26-a] (hereinafter referred to as compound [A-26-a])

To a commercially available solution of 3-chloro-4-morpholino-1,2,5-thiadiazole (5.0 g, 24 mmol) in DMSO (4.4 mL), a 2N-potassium hydroxide aqueous solution (49 mL) was added at room temperature to 120 ° C. Was stirred for 13 hours. 5N-Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound (3.8 g, 20 mmol, yield 82%) as a white solid.
ESI-MSfound: 188 [M + H] ⁺

(B) Synthesis of (S) -4- [4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole-3-yl] morpholine [A-26] Compound [A-26-a] (1) To a solution of .1 g, 5.8 mmol) of DMF (19 mL) was added 60% sodium hydride (232 mg, 5.8 mmol) at 0 ° C. and stirred at 0 ° C. for 5 minutes. Then, 3-nitrobenzenesulfonic acid (S) -glycidyl (500 mg, 1.9 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (289 mg, 1.2 mmol, yield 21%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 4.77 (1H, dd, J = 11.9, 2.7 Hz), 4.23 (1H, dd, J = 12.1, 6.6 Hz) , 3.78 (4H, t, J = 4.8Hz), 3.50 (4H, t, J = 4.8Hz), 3.41-3.37 (1H, m), 2.88 (1H, 1H, dd, J = 5.0, 4.1Hz), 2.72 (1H, dd, J = 4.8, 2.5Hz).
ESI-MSfound: 244 [M + H] ⁺

[Reference Example A-27]
Synthesis of (R) -4- [4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole-3-yl] morpholine [A-27] (hereinafter referred to as compound [A-27])

From compound [A-26-a] (1.0 g, 5.3 mmol) and 3-nitrobenzene sulfonic acid (R) -glycidyl (602 mg, 2.3 mmol) according to the method of step (b) of Reference Example A-26. The title compound (428 mg, 1.7 mmol, yield 33%) was obtained as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.76 (1H, dd, J = 11.9, 2.7 Hz), 4.25 (1 H, dd, J = 12.1, 6.6 Hz), 3.82 (4H, t, J = 4.8Hz), 3.53 (4H, t, J = 4.8Hz), 3.42-3.38 (1H, m), 2.92 (1H, t) , J = 4.3Hz), 2.72 (1H, dd, J = 4.8, 2.5Hz).
ESI-MSfound: 244 [M + H] ⁺

[Reference Example A-28]
Synthesis of (S) -3-ethyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-28] (hereinafter referred to as compound [A-28])

市販の（Ｓ）−２−アミノブチルアミド塩酸塩（１０２ｍｇ，０．７４ｍｍｏｌ）のＤＭＦ（０．７４ｍＬ）溶液に、二塩化二硫黄（０．１８ｍＬ，２．２ｍｍｏｌ）を室温で加え、室温で１８時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（７６ｍｇ，０．５８ｍｍｏｌ，収率７９％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１３１［Ｍ＋Ｈ］⁺ (A) Synthesis of 4-ethyl-1,2,5-thiadiazole-3-ol [A-28-a] (hereinafter referred to as compound [A-28-a])

Disulfur dichloride (0.18 mL, 2.2 mmol) was added to a commercially available solution of (S) -2-aminobutylamide hydrochloride (102 mg, 0.74 mmol) in DMF (0.74 mL) at room temperature, and at room temperature. The mixture was stirred for 18 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (76 mg, 0.58 mmol, 79% yield) as a yellow solid.
ESI-MSfound: 131 [M + H] ⁺

(B) Synthesis of (S) -3-ethyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-28] Compound [A-28-a] (76 mg, 0.58 mmol) The title compound (51 mg, 0.27 mmol, yield 47%) was obtained as a colorless oil according to the method of step (b) of Reference Example A-26.
ESI-MSfound: 187 [M + H] ⁺

[Reference Example A-29]
Synthesis of (S) -3-isopropyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-29] (hereinafter referred to as compound [A-29])

市販のＬ−バリンアミド塩酸塩（１０５ｍｇ，０．６９ｍｍｏｌ）から参考例Ａ−２８の工程（ａ）の方法に準じて表題化合物（８９ｍｇ，０．６１ｍｍｏｌ，収率８９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１４５［Ｍ＋Ｈ］⁺ (A) Synthesis of 4-isopropyl-1,2,5-thiadiazole-3-ol [A-29-a] (hereinafter referred to as compound [A-29-a])

The title compound (89 mg, 0.61 mmol, yield 89%) was obtained as a white solid from commercially available L-valinamide hydrochloride (105 mg, 0.69 mmol) according to the method of step (a) of Reference Example A-28. ..
ESI-MSfound: 145 [M + H] ⁺

(B) Synthesis of (S) -3-isopropyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-29] Compound [A-29-a] (89 mg, 0.61 mmol) The title compound (57 mg, 0.28 mmol, yield 46%) was obtained as a colorless oil according to the method of step (b) of Reference Example A-26.
ESI-MSfound: 201 [M + H] ⁺

[Reference Example A-30]
Synthesis of (S) -3- (oxylan-2-ylmethoxy) -4- (piperidine-1-yl) -1,2,5-thiadiazole [A-30] (hereinafter referred to as compound [A-30])

市販の３，４−ジクロロ−１，２，５−チアジアゾール（２００ｍｇ，１．３ｍｍｏｌ）に、ピペリジン（０．５１ｍＬ，５．２ｍｍｏｌ）を室温で加え、マイクロ波反応装置を用いて１００℃で３０分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２２８ｍｇ，１．１ｍｍｏｌ，収率８７％）を黄色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：３．４１（４Ｈ，ｔ，Ｊ＝５．５Ｈｚ），１．７５−１．６９（４Ｈ，ｍ），１．６６−１．６０（２Ｈ，ｍ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２０４［Ｍ＋Ｈ］⁺ (A) Synthesis of 3-chloro-4- (piperidine-1-yl) -1,2,5-thiadiazole [A-30-a] (hereinafter referred to as compound [A-30-a])

Piperidine (0.51 mL, 5.2 mmol) was added to commercially available 3,4-dichloro-1,2,5-thiadiazole (200 mg, 1.3 mmol) at room temperature, and 30 at 100 ° C. using a microwave reactor. Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (228 mg, 1.1 mmol, 87% yield) as a yellow oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.41 (4H, t, J = 5.5 Hz), 1.75-1.69 (4H, m), 1.66-1.60 (2H, m).
ESI-MSfound: 204 [M + H] ⁺

化合物［Ａ−３０−ａ］（１３６ｍｇ，０．６７ｍｍｏｌ）のＤＭＳＯ（１．１ｍＬ）溶液に、５Ｎ−水酸化ナトリウム水溶液（１．１ｍＬ）を室温で加え、マイクロ波反応装置を用いて１５０℃で３０分間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１０２ｍｇ，０．５５ｍｍｏｌ，収率８２％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：３．４７−３．４６（４Ｈ，ｍ），１．６８−１．６１（６Ｈ，ｍ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１８６［Ｍ＋Ｈ］⁺ (B) Synthesis of 4- (piperidine-1-yl) -1,2,5-thiadiazole-3-ol [A-30-b] (hereinafter referred to as compound [A-30-b])

A 5N-sodium hydroxide aqueous solution (1.1 mL) was added to a DMSO (1.1 mL) solution of compound [A-30-a] (136 mg, 0.67 mmol) at room temperature, and the temperature was 150 ° C. using a microwave reactor. Was stirred for 30 minutes. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (102 mg, 0.55 mmol, yield 82%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 3.47-3.46 (4H, m), 1.68-1.61 (6H, m).
ESI-MSfound: 186 [M + H] ⁺

(C) Synthesis of (S) -3- (oxylan-2-ylmethoxy) -4- (piperidine-1-yl) -1,2,5-thiadiazole [A-30] Compound [A-30-b] ( From 83 mg (0.45 mmol), the title compound (46 mg, 0.19 mmol, yield 42%) was obtained as a colorless oil according to the method of step (b) of Reference Example A-26.
ESI-MSfound: 242 [M + H] ⁺

[Reference Example A-31]
Synthesis of (S) -N, N-dimethyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole-3-amine [A-31] (hereinafter referred to as compound [A-31])

市販の３，４−ジクロロ−１，２，５−チアジアゾール（３０１ｍｇ，１．９ｍｍｏｌ）及びジメチルアミンのＴＨＦ溶液（２．０Ｍ，３．９ｍＬ，７．８ｍｍｏｌ）から参考例Ａ−３０の工程（ａ）の方法に準じて表題化合物（１３８ｍｇ，０．８４ｍｍｏｌ，収率４４％）を黄色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：３．１２（６Ｈ，ｓ）． (A) Synthesis of 4-chloro-N, N-dimethyl-1,2,5-thiadiazole-3-amine [A-31-a] (hereinafter referred to as compound [A-31-a])

Steps of Reference Example A-30 from a commercially available solution of 3,4-dichloro-1,2,5-thiadiazole (301 mg, 1.9 mmol) and dimethylamine in THF (2.0 M, 3.9 mL, 7.8 mmol). The title compound (138 mg, 0.84 mmol, yield 44%) was obtained as a yellow oil according to the method of a).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.12 (6 H, s).

化合物［Ａ−３１−ａ］（１３８ｍｇ，０．８４ｍｍｏｌ）から参考例Ａ−３０の工程（ｂ）の方法に準じて表題化合物（８３ｍｇ，０．５７ｍｍｏｌ，収率６８％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：３．０６（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１４６［Ｍ＋Ｈ］⁺ (B) Synthesis of 4- (dimethylamino) -1,2,5-thiadiazole-3-ol [A-31-b] (hereinafter referred to as compound [A-31-b])

The title compound (83 mg, 0.57 mmol, yield 68%) was obtained as a white solid from the compound [A-31-a] (138 mg, 0.84 mmol) according to the method of step (b) of Reference Example A-30. It was.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 3.06 (6 H, s).
ESI-MSfound: 146 [M + H] ⁺

(C) Synthesis of (S) -N, N-dimethyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole-3-amine [A-31] Compound [A-31-b] ( From 62 mg, 0.43 mmol), the title compound (47 mg, 0.23 mmol, yield 54%) was obtained as a white solid according to the method of step (b) of Reference Example A-26.
ESI-MSfound: 202 [M + H] ⁺

[Reference Example A-32]
Synthesis of (S) -3- (oxylan-2-ylmethoxy) -4-phenyl-1,2,5-thiadiazole [A-32] (hereinafter referred to as compound [A-32])

市販の３，４−ジクロロ−１，２，５−チアジアゾール（１．０ｇ，６．５ｍｍｏｌ）のトルエン（６．５ｍＬ）−水（６．５ｍＬ）混合溶液に、フェニルボロン酸（９４４ｍｇ，７．７ｍｍｏｌ）、Ｐｄ（ＰＰｈ₃）₄（７４５ｍｇ，０．６５ｍｍｏｌ）及びフッ化カリウム（１．１ｇ，１９ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１１０℃で６時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより黄色油状物（２２４ｍｇ）を得た。得られた黄色油状物から参考例Ａ−２６の工程（ａ）の方法に準じて表題化合物（１０１ｍｇ，０．５７ｍｍｏｌ，収率９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１７７［Ｍ−Ｈ］^- (A) Synthesis of 4-Phenyl-1,2,5-thiadiazole-3-ol [A-32-a] (hereinafter referred to as compound [A-32-a])

Phenylboronic acid (944 mg, 7.) in a commercially available mixed solution of 3,4-dichloro-1,2,5-thiadiazole (1.0 g, 6.5 mmol) in toluene (6.5 mL) -water (6.5 mL). 7 mmol), Pd (PPh ₃ ) ₄ (745 mg, 0.65 mmol) and potassium fluoride (1.1 g, 19 mmol) were added at room temperature, and the mixture was stirred at 110 ° C. for 6 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a yellow oil (224 mg). From the obtained yellow oil, the title compound (101 mg, 0.57 mmol, yield 9%) was obtained as a white solid according to the method of step (a) of Reference Example A-26.
ESI-MSfound: 177 [MH] ^-

(B) Synthesis of (S) -3- (oxylan-2-ylmethoxy) -4-phenyl-1,2,5-thiadiazole [A-32] Compound [A-32-a] (101 mg, 0.57 mmol) The title compound (27 mg, 0.12 mmol, yield 20%) was obtained as a colorless oil according to the method of step (b) of Reference Example A-26.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.16-8.14 (2H, m), 7.52-7.42 (3H, m), 4.84 (1H, dd, J = 11. 9,2.7Hz), 4.42 (1H, dd, J = 11.9, 5.9Hz), 3.50-3.46 (1H, m), 2.95 (1H, t, J = 4) .6Hz), 2.80 (1H, dd, J = 4.6, 2.7Hz).
ESI-MSfound: 235 [M + H] ⁺

[Reference Example A-33]
Synthesis of (S) -3-cyclopropyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-33] (hereinafter referred to as compound [A-33])

ＴＨＦ（１４ｍＬ）−水（４３ｍＬ）混合溶液に、塩化アンモニウム（８４１ｍｇ，１６ｍｍｏｌ）、シアン化ナトリウム（７０４ｍｇ，１４ｍｍｏｌ）及び２８％アンモニア水（１４ｍＬ）を室温で加え、０℃に冷却した。反応混合物に市販のシクロプロパンカルボキシアルデヒド（１．０ｇ，１４ｍｍｏｌ）を０℃で加え、室温で２４時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１．１ｇ，１１ｍｍｏｌ，収率７９％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：３．５４−３．３９（１Ｈ，ｍ），１．３１−１．１５（１Ｈ，ｍ），０．７１−０．６２（２Ｈ，ｍ），０．５５−０．４２（２Ｈ，ｍ）． (A) Synthesis of 2-amino-2-cyclopropylacetonitrile [A-33-a] (hereinafter referred to as compound [A-33-a])

Ammonium chloride (841 mg, 16 mmol), sodium cyanide (704 mg, 14 mmol) and 28% aqueous ammonia (14 mL) were added to a mixed solution of THF (14 mL) -water (43 mL) at room temperature and cooled to 0 ° C. Commercially available cyclopropanecarboxyaldehyde (1.0 g, 14 mmol) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.1 g, 11 mmol, yield 79%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 3.54-3.39 (1H, m), 1.31-1.15 (1H, m), 0.71-0.62 (2H, m) ), 0.55-0.42 (2H, m).

化合物［Ａ−３３−ａ］（１８０ｍｇ，１．９ｍｍｏｌ）のＤＭＦ（１．９ｍＬ）溶液を０℃に冷却し、二塩化二硫黄（０．４５ｍＬ，５．６ｍｍｏｌ）を０℃で加え、室温で１７時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィーにて精製することにより、褐色油状物（１４１ｍｇ）を得た。得られた褐色油状物から参考例Ａ−３０の工程（ｂ）の方法に準じて表題化合物（５９ｍｇ，０．４２ｍｍｏｌ，収率２３％）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：１４３［Ｍ＋Ｈ］⁺ (B) Synthesis of 4-cyclopropyl-1,2,5-thiadiazole-3-ol [A-33-b] (hereinafter referred to as compound [A-33-b])

A solution of compound [A-33-a] (180 mg, 1.9 mmol) in DMF (1.9 mL) was cooled to 0 ° C., disulfur dichloride (0.45 mL, 5.6 mmol) was added at 0 ° C. to room temperature. Was stirred for 17 hours. The reaction mixture was purified by silica gel column chromatography to give a brown oil (141 mg). From the obtained brown oil, the title compound (59 mg, 0.42 mmol, yield 23%) was obtained as a yellow solid according to the method of step (b) of Reference Example A-30.
ESI-MSfound: 143 [M + H] ⁺

(C) Synthesis of (S) -3-cyclopropyl-4- (oxylan-2-ylmethoxy) -1,2,5-thiadiazole [A-33] Compound [A-33-b] (59 mg, 0.42 mmol) ), The title compound (35 mg, 0.17 mmol, yield 42%) was obtained as a colorless oil according to the method of step (b) of Reference Example A-26.
ESI-MSfound: 199 [M + H] ⁺

In the following Reference Examples B-1 to B-5, the compound corresponding to the compound (b) of Scheme 1 was synthesized.

[Reference Example B-1]
Synthesis of 4- (2-aminopropan-2-yl) -3-fluorobenzenesulfonamide [B-1] (hereinafter referred to as compound [B-1])

ビス（４−メトキシベンジル）アミン（２３ｇ，８８ｍｍｏｌ）のＴＨＦ（２９０ｍＬ）溶液に、トリエチルアミン（１２ｍＬ，８８ｍｍｏｌ）を室温で加え、０℃に冷却した。反応混合物に市販の４−ブロモ−３−フルオロベンゼンスルホニルクロリド（２０ｇ，７３ｍｍｏｌ）を０℃で加え、室温で１９時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣にジエチルエーテルを加えた。得られた懸濁液を濾取することにより、表題化合物（３１ｇ，６２ｍｍｏｌ，収率８５％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．６８−７．６４（１Ｈ，ｍ），７．４６−７．４１（２Ｈ，ｍ），７．０３−６．９９（４Ｈ，ｍ），６．８０−６．７７（４Ｈ，ｍ），４．２６（４Ｈ，ｓ），３．７９（６Ｈ，ｓ）． (A) Synthesis of 4-bromo-3-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide [B-1-a] (hereinafter referred to as compound [B-1-a])

Triethylamine (12 mL, 88 mmol) was added to a solution of bis (4-methoxybenzyl) amine (23 g, 88 mmol) in THF (290 mL) at room temperature, and the mixture was cooled to 0 ° C. Commercially available 4-bromo-3-fluorobenzenesulfonyl chloride (20 g, 73 mmol) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the obtained residue. The obtained suspension was collected by filtration to give the title compound (31 g, 62 mmol, yield 85%) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.68-7.64 (1 H, m), 7.46-7.41 (2 H, m), 7.03-6.99 (4 H, m) , 6.80-6.77 (4H, m), 4.26 (4H, s), 3.79 (6H, s).

市販の２−シアノ−２−メチルプロピオン酸エチル（２５ｇ，１７７ｍｍｏｌ）のエタノール（３００ｍＬ）−水（３．４ｍＬ）混合溶液にカリウムｔｅｒｔ−ブトキシド（２０ｇ，１７７ｍｍｏｌ）のエタノール（１５０ｍＬ）溶液を６０℃で加え、６０℃で４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣にジエチルエーテル及びエタノールを加えた。得られた懸濁液を濾取することにより、表題化合物（２５ｇ，１６３ｍｍｏｌ，収率９２％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ₂Ｏ）δ：１．３６（６Ｈ，ｓ）． (B) Synthesis of potassium 2-cyano-2-methylpropionate [B-1-b] (hereinafter referred to as compound [B-1-b])

A commercially available mixed solution of ethyl 2-cyano-2-methylpropionate (25 g, 177 mmol) in ethanol (300 mL) -water (3.4 mL) was mixed with a solution of potassium tert-butoxide (20 g, 177 mmol) in ethanol (150 mL) at 60 ° C. And stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and diethyl ether and ethanol were added to the obtained residue. The obtained suspension was collected by filtration to give the title compound (25 g, 163 mmol, yield 92%) as a white solid.
^{1 1} H-NMR (400 MHz, D ₂ O) δ: 1.36 (6 H, s).

化合物［Ｂ−１−ａ］（２０ｇ，４１ｍｍｏｌ）のメシチレン（８１ｍＬ）溶液に、化合物［Ｂ−１−ｂ］（９．２ｇ，６１ｍｍｏｌ）、アリルパラジウム（ＩＩ）クロリド二量体（１．５ｇ，４．１ｍｍｏｌ）及びＸａｎｔＰｈｏｓ（７．０ｇ，１２ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１４０℃で１時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６．８ｇ，１４ｍｍｏｌ，収率３５％）を褐色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．６３−７．５５（２Ｈ，ｍ），７．４３（１Ｈ，ｄｄ，Ｊ＝１１．２，１．７Ｈｚ），７．０３−６．９９（４Ｈ，ｍ），６．７９−６．７７（４Ｈ，ｍ），４．２９（４Ｈ，ｓ），３．７９（６Ｈ，ｓ），１．８３（６Ｈ，ｓ）． (C) 4- (2-Cyanopropan-2-yl) -3-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide [B-1-c] (hereinafter, compound [B-1-] c])

Compound [B-1-b] (9.2 g, 61 mmol), allylpalladium (II) chloride dimer (1.5 g) in a solution of compound [B-1-a] (20 g, 41 mmol) in mesitylene (81 mL). , 4.1 mmol) and XantPhos (7.0 g, 12 mmol) were added at room temperature, and the mixture was stirred at 140 ° C. for 1 hour under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography to give the title compound (6.8 g, 14 mmol, 35% yield) as a brown solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.63-7.55 (2H, m), 7.43 (1H, dd, J = 11.2, 1.7 Hz), 7.03-6. 99 (4H, m), 6.79-6.77 (4H, m), 4.29 (4H, s), 3.79 (6H, s), 1.83 (6H, s).

化合物［Ｂ−１−ｃ］（１４ｇ，３１ｍｍｏｌ）のジクロロメタン（３１ｍＬ）溶液に、アニソール（２６ｍＬ）及びＴＦＡ（６２ｍＬ）を室温で加え、室温で２時間撹拌した。次いで、６０℃で２時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６．０ｇ，２５ｍｍｏｌ，収率８２％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．７７−７．６６（３Ｈ，ｍ），４．９２（２Ｈ，ｓ），１．８４（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２４１［Ｍ−Ｈ］^- (D) Synthesis of 4- (2-cyanopropan-2-yl) -3-fluorobenzenesulfonamide [B-1-d] (hereinafter referred to as compound [B-1-d])

Anisole (26 mL) and TFA (62 mL) were added to a solution of compound [B-1-c] (14 g, 31 mmol) in dichloromethane (31 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (6.0 g, 25 mmol, yield 82%) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.66 (3H, m), 4.92 (2H, s), 1.84 (6H, s).
ESI-MSfound: 241 [MH] ^-

化合物［Ｂ−１−ｄ］（６．８ｇ，２８ｍｍｏｌ）のエタノール（５０ｍＬ）溶液に、５Ｎ−水酸化ナトリウム水溶液（５０ｍＬ）を室温で加え、１２０℃で２時間撹拌した。反応混合物に６Ｎ−塩酸を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、白色固体（７．２ｇ）を得た。得られた白色固体のエタノール（５６ｍＬ）溶液に、６Ｎ−塩酸（５６ｍＬ）を室温で加え、１２０℃で１６時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（８．５ｇ）を褐色アモルファスとして得た。得られた化合物は精製することなく次の反応に用いた。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．７０（１Ｈ，ｄｄ，Ｊ＝８．３，１．７Ｈｚ），７．６２−７．５５（２Ｈ，ｍ），１．５７（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３０３［Ｍ＋Ｈ＋ＣＨ₃ＣＮ］⁺ (E) Synthesis of 2- (2-fluoro-4-sulfamoylphenyl) -2-methylpropionic acid [B-1-e] (hereinafter referred to as compound [B-1-e])

A 5N-sodium hydroxide aqueous solution (50 mL) was added to a solution of compound [B-1-d] (6.8 g, 28 mmol) in ethanol (50 mL) at room temperature, and the mixture was stirred at 120 ° C. for 2 hours. 6N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid (7.2 g). To the obtained white solid ethanol (56 mL) solution, 6N-hydrochloric acid (56 mL) was added at room temperature, and the mixture was stirred at 120 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.5 g) as a brown amorphous substance. The obtained compound was used in the next reaction without purification.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.70 (1 H, dd, J = 8.3, 1.7 Hz), 7.62-7.55 (2 H, m), 1.57 (6 H) , S).
ESI-MSfound: 303 [M + H + CH ₃ CN] ⁺

化合物［Ｂ−１−ｅ］のアセトニトリル（５５ｍＬ）溶液に、トリエチルアミン（１２ｍＬ，８３ｍｍｏｌ）及びジフェニルリン酸アジド（１２ｍＬ，５５ｍｍｏｌ）を室温で加え、室温で３０分間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６．０ｇ，２１ｍｍｏｌ，化合物［Ｂ−１−ｄ］から２工程の通算収率７４％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．７５−７．７３（１Ｈ，ｍ），７．６２（１Ｈ，ｄｄ，Ｊ＝１０．４，１．８Ｈｚ），７．５０−７．４６（１Ｈ，ｍ），５．００（２Ｈ，ｓ），１．６０（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２８５［Ｍ−Ｈ］^- (F) Synthesis of 2- (2-fluoro-4-sulfamoylphenyl) -2-methylpropionic acid azide [B-1-f] (hereinafter referred to as compound [B-1-f])

Triethylamine (12 mL, 83 mmol) and diphenylphosphoryl azide (12 mL, 55 mmol) were added to a solution of compound [B-1-e] in acetonitrile (55 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (6.0 g, 21 mmol, total yield of 2 steps from compound [B-1-d], 74%). Was obtained as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.75-7.73 (1H, m), 7.62 (1H, dd, J = 10.4, 1.8 Hz), 7.50-7. 46 (1H, m), 5.00 (2H, s), 1.60 (6H, s).
ESI-MSfound: 285 [MH] ^-

(G) Synthesis of 4- (2-aminopropan-2-yl) -3-fluorobenzenesulfonamide [B-1] THF (21 mL) of compound [B-1-f] (5.9 g, 21 mmol)- The mixed solution of water (21 mL) was stirred at 100 ° C. for 1 hour. THF (20 mL) and water (20 mL) were added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 2 hours. A 5N-sodium hydroxide aqueous solution (41 mL) was added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.9 g, 8.1 mmol, yield 39%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.69-7.64 (2H, m), 7.59-7.56 (1H, m), 1.55 (6H, s).
ESI-MSfound: 231 [MH] ^-

[Reference Example B-2]
Synthesis of 4- (2-amino-2-methylpropyl) -3-fluorobenzenesulfonamide trifluoroacetate [B-2] (hereinafter referred to as compound [B-2])

市販の３−フルオロ−４−メチルベンゼンスルホニルクロリド（１０ｇ，４９ｍｍｏｌ）のＴＨＦ（４９ｍＬ）溶液を０℃に冷却し、ｔｅｒｔ−ブチルアミン（１３ｍＬ，１２３ｍｍｏｌ）を０℃で加え、室温で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１２ｇ，収率ｑｕａｎｔ．）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．５８−７．５１（２Ｈ，ｍ），７．３０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），４．５２（１Ｈ，ｓ），２．３４（３Ｈ，ｄ，Ｊ＝１．４Ｈｚ），１．２４（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２４４［Ｍ−Ｈ］^- (A) Synthesis of N- (tert-butyl) -3-fluoro-4-methylbenzenesulfonamide [B-2-a] (hereinafter referred to as compound [B-2-a])

A solution of commercially available 3-fluoro-4-methylbenzenesulfonyl chloride (10 g, 49 mmol) in THF (49 mL) was cooled to 0 ° C., tert-butylamine (13 mL, 123 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. .. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (12 g, yield quant.) As a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.58-7.51 (2H, m), 7.30 (1H, t, J = 7.8 Hz), 4.52 (1H, s), 2 .34 (3H, d, J = 1.4Hz), 1.24 (9H, s).
ESI-MSfound: 244 [MH] ^-

化合物［Ｂ−２−ａ］（１２ｇ，４８ｍｍｏｌ）のアセトニトリル（９７ｍＬ）溶液に、ＮＢＳ（１０ｇ，５８ｍｍｏｌ）及びＡＩＢＮ（１．６ｇ，９．７ｍｍｏｌ）を室温で加え、８０℃で３時間撹拌した。反応混合物に１Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣に水を加えた。得られた懸濁液を濾取することにより、表題化合物（１６ｇ，収率ｑｕａｎｔ．）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．６６（１Ｈ，ｄｄ，Ｊ＝８．０，１．６Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝９．４，１．６Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．５９（１Ｈ，ｓ），４．５１（２Ｈ，ｓ），１．２６（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３２２［Ｍ−Ｈ］^- (B) Synthesis of 4- (bromomethyl) -N- (tert-butyl) -3-fluorobenzenesulfonamide [B-2-b] (hereinafter referred to as compound [B-2-b])

NBS (10 g, 58 mmol) and AIBN (1.6 g, 9.7 mmol) were added to a solution of compound [B-2-a] (12 g, 48 mmol) in acetonitrile (97 mL) at room temperature, and the mixture was stirred at 80 ° C. for 3 hours. .. 1N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue. The obtained suspension was collected by filtration to give the title compound (16 g, yield quant.) As a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (1H, dd, J = 8.0, 1.6 Hz), 7.59 (1H, dd, J = 9.4, 1.6 Hz), 7.53 (1H, t, J = 7.5Hz), 4.59 (1H, s), 4.51 (2H, s), 1.26 (9H, s).
ESI-MSfound: 322 [MH] ^-

アルゴン雰囲気下、リチウムビス（トリメチルシリル）アミドのＴＨＦ溶液（１．０Ｍ，１４５ｍＬ，１４５ｍｍｏｌ）を０℃に冷却し、イソブチロニトリル（１３ｍＬ，１４５ｍｍｏｌ）を０℃で加え、０℃で１０分間撹拌した。反応混合物に化合物［Ｂ−２−ｂ］（１６ｇ，４８ｍｍｏｌ）のＴＨＦ（４８ｍＬ）溶液を０℃で加え、０℃で１時間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１７ｇ）を褐色油状物として得た。得られた化合物は精製することなく次の反応に用いた。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．６８（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），７．６１（１Ｈ，ｄｄ，Ｊ＝９．１，１．８Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．５２（１Ｈ，ｓ），２．９４（２Ｈ，ｄ，Ｊ＝０．９Ｈｚ），１．４０（６Ｈ，ｓ），１．２６（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３１１［Ｍ−Ｈ］^- (C) N- (tert-butyl) -4- (2-cyano-2-methylpropyl) -3-fluorobenzenesulfonamide [B-2-c] (hereinafter referred to as compound [B-2-c]) Synthesis of

Under an argon atmosphere, a THF solution of lithium bis (trimethylsilyl) amide (1.0 M, 145 mL, 145 mmol) was cooled to 0 ° C., isobutyronitrile (13 mL, 145 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. did. A solution of compound [B-2-b] (16 g, 48 mmol) in THF (48 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (17 g) as a brown oil. The obtained compound was used in the next reaction without purification.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (1H, dd, J = 8.2, 1.8 Hz), 7.61 (1 H, dd, J = 9.1, 1.8 Hz), 7.53 (1H, t, J = 7.5Hz), 4.52 (1H, s), 2.94 (2H, d, J = 0.9Hz), 1.40 (6H, s), 1. 26 (9H, s).
ESI-MSfound: 311 [MH] ^-

化合物［Ｂ−２−ｃ］のエチレングリコール（６４ｍＬ）溶液に、１２Ｎ−水酸化カリウム水溶液（３２ｍＬ）を室温で加え、１５０℃で１２時間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣に酢酸エチルを加え、１Ｎ−水酸化ナトリウム水溶液で抽出した。水層に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１２ｇ，３７ｍｍｏｌ，化合物［Ｂ−２−ｂ］から２工程の通算収率７６％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５９（１Ｈ，ｄｄ，Ｊ＝８．０，１．６Ｈｚ），７．５４（１Ｈ，ｄｄ，Ｊ＝９．６，１．８Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），２．９９（２Ｈ，ｓ），１．１７（１５Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３３０［Ｍ−Ｈ］^- (D) 3- {4- [N- (tert-butyl) sulfamoyl] -2-fluorophenyl} -2,2-dimethylpropionic acid [B-2-d] (hereinafter, compound [B-2-d]] ) Synthesis

A 12N-potassium hydroxide aqueous solution (32 mL) was added to a solution of compound [B-2-c] in ethylene glycol (64 mL) at room temperature, and the mixture was stirred at 150 ° C. for 12 hours. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was extracted with a 1N aqueous sodium hydroxide solution. 5N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (12 g, 37 mmol, total yield of 2 steps from compound [B-2-b] 76%) as a white solid. Obtained.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.59 (1H, dd, J = 8.0, 1.6 Hz), 7.54 (1 H, dd, J = 9.6, 1.8 Hz) , 7.42 (1H, t, J = 7.8Hz), 2.99 (2H, s), 1.17 (15H, s).
ESI-MSfound: 330 [MH] ^-

化合物［Ｂ−２−ｄ］（７．２ｇ，２２ｍｍｏｌ）の１，４−ジオキサン（７２ｍＬ）溶液に、トリエチルアミン（９．１ｍＬ，６５ｍｍｏｌ）及びジフェニルリン酸アジド（７．０ｍＬ，３３ｍｍｏｌ）を室温で加え、室温で１時間撹拌した。反応混合物は、８０℃で１時間撹拌した。反応混合物に２Ｎ−水酸化ナトリウム水溶液（７２ｍＬ）を８０℃で加え、１００℃で１時間撹拌した。反応混合物に５Ｎ−塩酸を加えて中性にし、減圧濃縮した。得られた残渣にＴＨＦ（７２ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（５１ｍＬ，６２ｍｍｏｌ）及び二炭酸ジ−ｔｅｒｔ−ブチル（１４ｇ，６５ｍｍｏｌ）を０℃で加えた。得られた反応混合物は、室温で１７時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（７．５ｇ，１９ｍｍｏｌ，収率８６％）を白色アモルファスとして得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．６０−７．５４（２Ｈ，ｍ），７．３０−７．２６（１Ｈ，ｍ），４．４９（１Ｈ，ｓ），４．３０（１Ｈ，ｓ），３．１４（２Ｈ，ｓ），１．４７（９Ｈ，ｓ），１．２７（６Ｈ，ｓ），１．２５（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：４０１［Ｍ−Ｈ］^- (E) (1- {4- [N- (tert-butyl) sulfamoyl] -2-fluorophenyl} -2-methylpropan-2-yl) tert-butyl carbamic acid [B-2-e] (hereinafter, Synthesis of compound [B-2-e])

Triethylamine (9.1 mL, 65 mmol) and diphenylphosphoryl azide (7.0 mL, 33 mmol) in a solution of compound [B-2-d] (7.2 g, 22 mmol) in 1,4-dioxane (72 mL) at room temperature. In addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was stirred at 80 ° C. for 1 hour. A 2N-sodium hydroxide aqueous solution (72 mL) was added to the reaction mixture at 80 ° C., and the mixture was stirred at 100 ° C. for 1 hour. 5N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. THF (72 mL) was added to the obtained residue, and saturated aqueous sodium hydrogen carbonate solution (51 mL, 62 mmol) and di-tert-butyl dicarbonate (14 g, 65 mmol) were added at 0 ° C. The resulting reaction mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (7.5 g, 19 mmol, yield 86%) as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.60-7.54 (2H, m), 7.30-7.26 (1H, m), 4.49 (1H, s), 4.30 (1H, s), 3.14 (2H, s), 1.47 (9H, s), 1.27 (6H, s), 1.25 (9H, s).
ESI-MSfound: 401 [MH] ^-

(F) Synthesis of 4- (2-amino-2-methylpropyl) -3-fluorobenzenesulfonamide trifluoroacetic acid salt [B-2] In the compound [B-2-e] (7.5 g, 19 mmol), Anisole (6.2 mL, 57 mmol) and TFA (62 mL) were added at room temperature and stirred at 80 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethanol and chloroform to give the title compound (5.5 g, 15 mmol, yield 83%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.72 (1H, dd, J = 7.8, 1.8 Hz), 7.68 (1 H, dd, J = 9.6, 1.8 Hz) , 7.49 (1H, t, J = 7.8Hz), 3.04 (2H, s), 1.34 (6H, s).
ESI-MSfound: 247 [M-TFA + H] ⁺

[Reference Example B-3]
Synthesis of 4- (2-aminoethyl) -3-fluorobenzenesulfonamide [B-3] (hereinafter referred to as compound [B-3])

市販の４−ブロモ−３−フルオロベンゼンスルホニルクロリド（２．０ｇ，７．３ｍｍｏｌ）のＴＨＦ（１５ｍＬ）溶液に、２８％アンモニア水（１．５ｍＬ，２２ｍｍｏｌ）を０℃で加え、室温で１５分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を０．５Ｎ−塩酸、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１．８ｇ，７．２ｍｍｏｌ，収率９９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２５２［Ｍ−Ｈ］^- (A) Synthesis of 4-bromo-3-fluorobenzenesulfonamide [B-3-a] (hereinafter referred to as compound [B-3-a])

28% aqueous ammonia (1.5 mL, 22 mmol) was added to a solution of commercially available 4-bromo-3-fluorobenzenesulfonyl chloride (2.0 g, 7.3 mmol) in THF (15 mL) at 0 ° C. and at room temperature for 15 minutes. Stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.5N-hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g, 7.2 mmol, yield). 99%) was obtained as a white solid.
ESI-MSfound: 252 [MH] ^-

化合物［Ｂ−３−ａ］（５００ｍｇ，２．０ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に、アクリル酸エチル（４２９μＬ，３．９ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（４４ｍｇ，０．２０ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン（１２０ｍｇ，０．３９ｍｍｏｌ）及びトリエチルアミン（５４６μＬ，３．９ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１４０℃で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５５６ｍｇ，収率ｑｕａｎｔ．）を黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２７２［Ｍ−Ｈ］^- (B) Synthesis of 3- (2-fluoro-4-sulfamoylphenyl) ethyl acrylate [B-3-b] (hereinafter referred to as compound [B-3-b])

Ethyl acrylate (429 μL, 3.9 mmol), palladium (II) acetate (44 mg, 0.20 mmol), tris (2) in a solution of compound [B-3-a] (500 mg, 2.0 mmol) in DMF (10 mL). -Methylphenyl) phosphine (120 mg, 0.39 mmol) and triethylamine (546 μL, 3.9 mmol) were added at room temperature, and the mixture was stirred at 140 ° C. for 2 hours under an argon atmosphere using a microwave reactor. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (556 mg, yield quant.) As a yellow solid.
ESI-MSfound: 272 [MH] ^-

化合物［Ｂ−３−ｂ］（５５６ｍｇ，２．０ｍｍｏｌ）のエタノール（１３ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（４８０ｍｇ）を室温で加え、水素雰囲気下、室温で１６時間撹拌した。パラジウム炭素を濾別した後、濾液を減圧濃縮することにより、表題化合物（５０３ｍｇ，１．８ｍｍｏｌ，収率９０％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２７４［Ｍ−Ｈ］^- (C) Synthesis of ethyl 3- (2-fluoro-4-sulfamoylphenyl) propionate [B-3-c] (hereinafter referred to as compound [B-3-c])

10% Palladium-activated carbon (about 55% hydrous) (480 mg) was added to a solution of compound [B-3-b] (556 mg, 2.0 mmol) in ethanol (13 mL) at room temperature, and 16 at room temperature under a hydrogen atmosphere. Stirred for hours. Palladium carbon was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (503 mg, 1.8 mmol, 90% yield) as a white solid.
ESI-MSfound: 274 [MH] ^-

化合物［Ｂ−３−ｃ］（２．２ｇ，７．９ｍｍｏｌ）のエタノール（２６ｍＬ）溶液に５Ｎ−水酸化ナトリウム水溶液（１３ｍＬ）を室温で加え、１２０℃で４時間撹拌した。反応混合物に水を加え、酢酸エチルで洗浄した。水層に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１．８ｇ，７．１ｍｍｏｌ，収率９１％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２４８［Ｍ＋Ｈ］⁺ (D) Synthesis of 3- (2-fluoro-4-sulfamoylphenyl) propionic acid [B-3-d] (hereinafter referred to as compound [B-3-d])

A 5N-sodium hydroxide aqueous solution (13 mL) was added to a solution of compound [B-3-c] (2.2 g, 7.9 mmol) in ethanol (26 mL) at room temperature, and the mixture was stirred at 120 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. 5N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g, 7.1 mmol, yield 91%) as a white solid.
ESI-MSfound: 248 [M + H] ⁺

(E) Synthesis of 4- (2-aminoethyl) -3-fluorobenzenesulfonamide [B-3] In a solution of compound [B-3-d] (835 mg, 3.1 mmol) in THF (15 mL), triethylamine ( 850 μL, 6.1 mmol) and ethyl chloroformate (321 μL, 3.4 mmol) were added at −20 ° C. and stirred at −20 ° C. for 1 hour. A solution of sodium azide (220 mg, 3.4 mmol) in water (1.7 mL) was added to the reaction mixture at −20 ° C., and the mixture was stirred at −5 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid (627 mg). The resulting white solid was dissolved in a mixed solution of THF (5.8 mL) -water (5.8 mL) and stirred at 120 ° C. for 1 hour using a microwave reactor. Ethylenediamine (1.54 mL, 23 mmol) was added at room temperature, and the mixture was stirred at 160 ° C. for 3 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (314 mg, 1.4 mmol, yield 49%) as a yellowish white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.65 (1 H, dd, J = 8.0, 1.6 Hz), 7.58 (1 H, dd, J = 9.6, 1.4 Hz) , 7.46 (1H, t, J = 7.5Hz), 2.93-2.85 (4H, m).
ESI-MSfound: 219 [M + H] ⁺

[Reference Example B-4]
Synthesis of 4- (3-amino-3-methylbutyl) -3-fluorobenzenesulfonamide trifluoroacetate [B-4] (hereinafter referred to as compound [B-4])

化合物［Ｂ−３−ｃ］（５０３ｍｇ，１．８ｍｍｏｌ）のＴＨＦ（１２ｍＬ）溶液に、アルゴン雰囲気下、メチルマグネシウムブロミドのＴＨＦ溶液（１．０Ｍ，８．３ｍＬ，８．３ｍｍｏｌ）を０℃で加え、０℃で３時間撹拌した。次いで、メチルマグネシウムブロミドのＴＨＦ溶液（１．０Ｍ，４．０ｍＬ，４．０ｍｍｏｌ）を０℃で追加し、５０℃で３０分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３５８ｍｇ，１．４ｍｍｏｌ，収率７５％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２６０［Ｍ−Ｈ］^- (A) Synthesis of 3-fluoro-4- (3-hydroxy-3-methylbutyl) benzenesulfonamide [B-4-a] (hereinafter referred to as compound [B-4-a]))

A solution of compound [B-3-c] (503 mg, 1.8 mmol) in THF (12 mL) was mixed with a solution of methyl magnesium bromide in THF (1.0 M, 8.3 mL, 8.3 mmol) at 0 ° C. under an argon atmosphere. In addition, the mixture was stirred at 0 ° C. for 3 hours. Then, a THF solution of methylmagnesium bromide (1.0 M, 4.0 mL, 4.0 mmol) was added at 0 ° C., and the mixture was stirred at 50 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (358 mg, 1.4 mmol, yield 75%) as a white solid.
ESI-MSfound: 260 [MH] ^-

(B) Synthesis of 4- (3-amino-3-methylbutyl) -3-fluorobenzenesulfonamide trifluoroacetate [B-4] Acetonitrile (108 mg, 0.41 mmol) of the compound [B-4-a] (108 mg, 0.41 mmol). Concentrated sulfuric acid (188 μL) was added to a mixed solution of 938 μL) -acetic acid (938 μL) at room temperature, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction mixture to 0 ° C., a 4N-sodium carbonate aqueous solution and a 5N-sodium hydroxide aqueous solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil (165 mg). A 40% aqueous potassium hydroxide solution (3.0 mL) was added to the obtained colorless oily ethylene glycol (3.0 mL) solution at room temperature, and the mixture was stirred at 160 ° C. for 90 hours. After adding methanol and water to the reaction mixture, 5N-hydrochloric acid was added to neutralize the reaction mixture, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (101 mg, 0.27 mmol, yield 65%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.66 (1H, dd, J = 8.2, 1.8 Hz), 7.60 (1 H, dd, J = 9.6, 1.8 Hz) , 7.48 (1H, t, J = 7.5Hz), 2.83-2.78 (2H, m), 1.92-1.87 (2H, m), 1.42 (6H, s) ..
ESI-MSfound: 261 [M-TFA + H] ⁺

[Reference Example B-5]
Synthesis of 4- (aminomethyl) -3-fluorobenzenesulfonamide [B-5] (hereinafter referred to as compound [B-5])

化合物［Ｂ−３−ａ］（１５ｇ，５８ｍｍｏｌ）のＤＭＦ（５７ｍＬ）溶液に、シアン化亜鉛（１０ｇ，８６ｍｍｏｌ）及びＰｄ（ＰＰｈ₃）₄（３．３ｇ，２．９ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、１００℃で４８時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製した後、クロロホルムに懸濁し、濾取することにより、表題化合物（５．２ｇ，２６ｍｍｏｌ，収率４５％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．８５−７．７９（３Ｈ，ｍ），５．０２（２Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：１９９［Ｍ−Ｈ］^- (A) Synthesis of 4-cyano-3-fluorobenzenesulfonamide [B-5-a] (hereinafter referred to as compound [B-5-a])

_{Zinc cyanide (10 g, 86 mmol) and Pd (PPh 3} ) ₄ (3.3 g, 2.9 mmol) were added to a solution of compound [B-3-a] (15 g, 58 mmol) in DMF (57 mL) at room temperature. The mixture was stirred at 100 ° C. for 48 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, suspended in chloroform, and collected by filtration to give the title compound (5.2 g, 26 mmol, yield 45%) as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.85-7.79 (3H, m), 5.02 (2H, s).
ESI-MSfound: 199 [MH] ^-

(B) Synthesis of 4- (aminomethyl) -3-fluorobenzenesulfonamide [B-5] 10% palladium- in a solution of compound [B-5-a] (4.5 g, 23 mmol) in methanol (110 mL). Activated carbon (about 55% hydrous) (2.4 g) was added at room temperature, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (2.0 g, 9.8 mmol, yield 44%) as a brown solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.70 (1H, dd, J = 8.0, 1.6 Hz), 7.62-7.59 (2H, m), 3.93 (2H) , S).
ESI-MSfound: 205 [M + H] ⁺ , 246 [M + H + CH ₃ CN] ⁺

In Examples 1 to 39, various target compounds were synthesized according to the following reaction formulas.

以下に、代表的な合成方法の詳細（反応条件：Ａ、Ｂ、Ｃの代表例）を記載する。

Details of typical synthesis methods (reaction conditions: representative examples of A, B, and C) are described below.

[Reaction condition: A]
[Example 1]
(S) -4- (2-{[3- (2-Chloro-5-methylphenoxy) -2-hydroxypropyl] amino} propan-2-yl) -3-fluorobenzenesulfonamide [1] (hereinafter, Synthesis of compound [1])

Compound [B-1] (53 mg, 0.23 mmol) was added to a mixed solution of compound [A-1] (30 mg, 0.15 mmol) in ethanol (570 μL) -toluene (570 μL) at room temperature. The resulting mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (38 mg, 0.089 mmol, yield 59%) as a colorless oil.

[Reaction condition: B]
[Example 2]
(S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide [2] (hereinafter, Synthesis of compound [2])

Compound [B-2] (161 mg, 0.45 mmol) and DIPEA (0.20 mL) in a mixed solution of compound [A-2] (56 mg, 0.30 mmol) in methanol (1.0 mL) -toluene (1.0 mL). , 1.2 mmol) was added at room temperature. The resulting mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (118 mg, 0.27 mmol, yield 91%) as a white amorphous substance.

[Reaction condition: C]
[Example 12]
(S) -4- (2-{[3- (2-Cyano-3-fluorophenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide [12] (hereinafter, Synthesis of compound [12])

Compound [B-2] (119 mg, 0.33 mmol) and DIPEA (0.15 mL) in a mixed solution of compound [A-10] (43 mg, 0.22 mmol) in methanol (1.1 mL) -toluene (1.1 mL). , 0.88 mmol) was added at room temperature, and the mixture was stirred at 120 ° C. for 3 hours. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (66 mg, 0.15 mmol, yield 68%) as a white amorphous substance.

Table 1 below shows the reaction conditions and results of Examples Compounds 1 to 39.

Table 1

^{Table 2 shows 1 1} H-NMR and ESI-MSfound data of the compounds synthesized in Examples 1 to 39.
Table 2

[Example 40]
(R) -4- (2-{[3- (2-Chloro-5-methylphenoxy) -2-hydroxypropyl] amino} propan-2-yl) -3-fluorobenzenesulfonamide [40] (hereinafter, Synthesis of compound [40])

A mixed solution of compound [B-1-f] (5.9 g, 21 mmol) in THF (21 mL) -water (21 mL) was stirred at 100 ° C. for 1 hour. THF (20 mL) and water (20 mL) were added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 2 hours. A 5N-sodium hydroxide aqueous solution (41 mL) was added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a white amorphous substance (3.2 g). From the obtained white amorphous (145 mg) and compound [A-3] (72 mg, 0.36 mmol), the title compound (81 mg, 0.19 mmol, yield 52%) was obtained as a white amorphous according to the method of Example 2. It was.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.66-7.54 (3H, m), 7.18 (1H, d, J = 8.2 Hz), 6.85-6.71 (2H) , M), 4.04-3.88 (3H, m), 2.70 (1H, dd, J = 11.4, 4.1Hz), 2.40 (1H, dd, J = 11.9, 7.3Hz), 2.29 (3H, s), 1.57 (3H, s), 1.55 (3H, s).
ESI-MSfound: 431 [M + H] ⁺

[Example 41]
(S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propan-2-yl) -3-fluorobenzenesulfonamide [41] (hereinafter, Synthesis of compound [41])

化合物［Ｂ−１−ｆ］（５．９ｇ，２１ｍｍｏｌ）のＴＨＦ（２１ｍＬ）−水（２１ｍＬ）混合溶液を、１００℃で１時間撹拌した。反応混合物にＴＨＦ（２０ｍＬ）及び水（２０ｍＬ）を１００℃で追加し、１００℃で２時間撹拌した。反応混合物に５Ｎ−水酸化ナトリウム水溶液（４１ｍＬ）を１００℃で加え、１００℃で１２時間撹拌した。反応混合物を、マイクロ波反応装置を用いて１２０℃で１時間撹拌した。反応混合物に５Ｎ−塩酸を加え、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、白色アモルファス（３．２ｇ）を得た。得られた白色アモルファス（１３６ｍｇ）及び化合物［Ａ−２］（６４ｍｇ，０．３４ｍｍｏｌ）から実施例２の方法に準じて表題化合物（６３ｍｇ，０．１５ｍｍｏｌ，収率４４％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．６７−７．５４（３Ｈ，ｍ），７．４６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．９８（１Ｈ，ｓ），６．８９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．１１−４．００（３Ｈ，ｍ），２．７０（１Ｈ，ｄｄ，Ｊ＝１１．４，３．７Ｈｚ），２．４４−２．４０（４Ｈ，ｍ），１．５８（３Ｈ，ｓ），１．５７（３Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：４２２［Ｍ＋Ｈ］⁺

A mixed solution of compound [B-1-f] (5.9 g, 21 mmol) in THF (21 mL) -water (21 mL) was stirred at 100 ° C. for 1 hour. THF (20 mL) and water (20 mL) were added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 2 hours. A 5N-sodium hydroxide aqueous solution (41 mL) was added to the reaction mixture at 100 ° C., and the mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a white amorphous substance (3.2 g). From the obtained white amorphous (136 mg) and compound [A-2] (64 mg, 0.34 mmol), the title compound (63 mg, 0.15 mmol, yield 44%) was obtained as a white solid according to the method of Example 2. It was.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.67-7.54 (3H, m), 7.46 (1H, d, J = 7.8 Hz), 6.98 (1H, s), 6.89 (1H, d, J = 7.8Hz), 4.11-4.00 (3H, m), 2.70 (1H, dd, J = 11.4, 3.7Hz), 2.44 -2.40 (4H, m), 1.58 (3H, s), 1.57 (3H, s).
ESI-MSfound: 422 [M + H] ⁺

[Example 42]
(S) -4- (3-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) -3-fluorobenzenesulfonamide [42] (hereinafter, compound [42] ) Synthesis

化合物［Ｂ−３−ａ］（５０８ｍｇ，２．０ｍｍｏｌ）のＤＭＦ（５．０ｍＬ）溶液に、アクリロニトリル（２６２μＬ，４．０ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（４５ｍｇ，０．２０ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン（１２２ｍｇ，０．４０ｍｍｏｌ）及びトリエチルアミン（５５４μＬ，４．０ｍｍｏｌ）を室温で加え、マイクロ波反応装置を用いて１４０℃で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製した。得られた固体にクロロホルムを加えた。得られた懸濁液を濾取することにより、表題化合物（２４０ｍｇ，１．１ｍｍｏｌ，収率５３％）を淡黄色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２２５［Ｍ−Ｈ］^- (1) Synthesis of 4- (2-cyanovinyl) -3-fluorobenzenesulfonamide [42-1] (hereinafter referred to as compound [42-1])

Acrylonitrile (262 μL, 4.0 mmol), palladium (II) acetate (45 mg, 0.20 mmol), tris (2) in a solution of compound [B-3-a] (508 mg, 2.0 mmol) in DMF (5.0 mL). -Methylphenyl) phosphine (122 mg, 0.40 mmol) and triethylamine (554 μL, 4.0 mmol) were added at room temperature, and the mixture was stirred at 140 ° C. for 2 hours using a microwave reactor. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. Chloroform was added to the obtained solid. The obtained suspension was collected by filtration to give the title compound (240 mg, 1.1 mmol, 53% yield) as a pale yellow solid.
ESI-MSfound: 225 [MH] ^-

化合物［４２−１］（２４０ｍｇ，１．１ｍｍｏｌ）のメタノール（１１ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（４１０ｍｇ）を室温で加え、水素雰囲気下、室温で４時間撹拌した。反応混合物を濾過した後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（８０ｍｇ，０．３５ｍｍｏｌ，収率３３％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２２７［Ｍ−Ｈ］^- (2) Synthesis of 4- (2-cyanoethyl) -3-fluorobenzenesulfonamide [42-2] (hereinafter referred to as compound [42-2])

To a solution of compound [42-1] (240 mg, 1.1 mmol) in methanol (11 mL), add 10% palladium-activated carbon (about 55% water) (410 mg) at room temperature, and stir at room temperature for 4 hours under a hydrogen atmosphere. did. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (80 mg, 0.35 mmol, yield 33%) as a white solid.
ESI-MSfound: 227 [MH] ^-

化合物［４２−２］（８０ｍｇ，０．３５ｍｍｏｌ）のアセトニトリル（１．７ｍＬ）溶液に、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール（５６μＬ，０．４２ｍｍｏｌ）を室温で加え、室温で１時間撹拌した。反応混合物を減圧濃縮することにより、表題化合物（１００ｍｇ）を白色固体として得た。得られた化合物は精製することなく次の反応に用いた。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８４［Ｍ＋Ｈ］⁺ (3) Synthesis of N'-{[4- (2-cyanoethyl) -3-fluorophenyl] sulfonyl} -N, N-dimethylformamidine [42-3] (hereinafter referred to as compound [42-3])

N, N-Dimethylformamide dimethylacetal (56 μL, 0.42 mmol) was added to a solution of compound [42-2] (80 mg, 0.35 mmol) in acetonitrile (1.7 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg) as a white solid. The obtained compound was used in the next reaction without purification.
ESI-MSfound: 284 [M + H] ⁺

化合物［４２−３］（２４ｍｇ）のメタノール（２．１ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（５０ｍｇ）及び塩化水素の１，４−ジオキサン溶液（４．０Ｍ，２７μＬ，０．１１ｍｍｏｌ）を室温で加え、水素雰囲気下、室温で１６時間撹拌した。パラジウム炭素を濾別した後、濾液を減圧濃縮することにより、表題化合物（２５ｍｇ，０．０７８ｍｍｏｌ，化合物［４２−２］から２工程の通算収率９１％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：８．１８（１Ｈ，ｓ），７．６１（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），７．５４（１Ｈ，ｄｄ，Ｊ＝９．８，１．６Ｈｚ），７．４５（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．１７（３Ｈ，ｓ），３．００（３Ｈ，ｓ），２．９６（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），２．８１（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），２．００−１．９２（２Ｈ，ｍ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２８８［Ｍ−ＨＣｌ＋Ｈ］⁺ (4) N'-{[4- (3-aminopropyl) -3-fluorophenyl] sulfonyl} -N, N-dimethylformamidine hydrochloride [42-4] (hereinafter referred to as compound [42-4]) Synthesis of

A solution of compound [42-3] (24 mg) in methanol (2.1 mL) with 10% palladium-activated carbon (about 55% water) (50 mg) and hydrogen chloride in a 1,4-dioxane solution (4.0 M, 27 μL). , 0.11 mmol) was added at room temperature, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. Palladium carbon was separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (25 mg, 0.078 mmol, total yield of 2 steps from compound [42-2]: 91%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.18 (1H, s), 7.61 (1H, dd, J = 8.2, 1.8 Hz), 7.54 (1H, dd, J) = 9.8, 1.6Hz), 7.45 (1H, t, J = 7.5Hz), 3.17 (3H, s), 3.00 (3H, s), 2.96 (2H, t) , J = 8.0Hz), 2.81 (2H, t, J = 7.8Hz), 2.00-1.92 (2H, m).
ESI-MSfound: 288 [M-HCl + H] ⁺

(5) Synthesis of (S) -4- (3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) -3-fluorobenzenesulfonamide [42] Compound [ 42-4] (25 mg, 0.078 mmol) in ethanol (400 μL) was added with 2N-sodium hydroxide aqueous solution (400 μL) at room temperature, and the mixture was stirred at 95 ° C. for 1 hour. 2N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethanol, the solid was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid (32 mg). Compound [A-2] (15 mg, 0.078 mmol) and DIPEA (55 μL, 0.32 mmol) were added to the obtained white solid ethanol (781 μL) solution at room temperature, and the temperature was 80 ° C. using a microwave reactor. The mixture was stirred for 1 hour. The reaction mixture was stirred at 100 ° C. for 1 hour using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography. The obtained fraction was concentrated under reduced pressure, a 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.8 mg, 0.0044 mmol, yield 6%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.63 (1 H, dd, J = 8.0, 1.6 Hz), 7.55 (1 H, dd, J = 9.6, 1.4 Hz) , 7.47-7.44 (2H, m), 7.01 (1H, s), 6.90 (1H, d, J = 7.8Hz), 4.12-4.05 (3H, m) , 2.94-2.89 (1H, m), 2.83-2.70 (5H, m), 2.40 (3H, s), 1.91-1.84 (2H, m).
ESI-MSfound: 422 [M + H] ⁺

[Example 43]
(S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -3-fluorobenzenesulfonamide trifluoroacetic acid salt [43] (hereinafter, Synthesis of compound [43])

市販の４−ブロモ−３−フルオロベンゼンスルホニルクロリド（６．３ｇ，２３ｍｍｏｌ）及びｔｅｒｔ−ブチルアミン（６．１ｍＬ，５７ｍｍｏｌ）から参考例Ｂ−３の工程（ａ）の方法に準じて表題化合物（７．１ｇ，収率ｑｕａｎｔ．）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３０８［Ｍ−Ｈ］^- (1) Synthesis of 4-bromo-N- (tert-butyl) -3-fluorobenzenesulfonamide [43-1] (hereinafter referred to as compound [43-1])

From commercially available 4-bromo-3-fluorobenzenesulfonyl chloride (6.3 g, 23 mmol) and tert-butylamine (6.1 mL, 57 mmol) according to the method of step (a) of Reference Example B-3, the title compound (7). .1 g, yield tert.) Was obtained as a white solid.
ESI-MSfound: 308 [MH] ^-

アルゴン雰囲気下、化合物［４３−１］（５００ｍｇ，１．６ｍｍｏｌ）のＴＨＦ（８．０ｍＬ）溶液に、イソプロピルマグネシウムクロリド−リチウムクロリド錯体のＴＨＦ溶液（１．３Ｍ，３．７ｍＬ，４．８ｍｍｏｌ）を０℃で加え、０℃で１時間撹拌した。反応混合物にＤＭＦ（１．３ｍＬ，１６ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３６４ｍｇ，１．４ｍｍｏｌ，収率８７％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２５８［Ｍ−Ｈ］^- (2) Synthesis of N- (tert-butyl) -3-fluoro-4-formylbenzenesulfonamide [43-2] (hereinafter referred to as compound [43-2])

Under an argon atmosphere, a solution of compound [43-1] (500 mg, 1.6 mmol) in THF (8.0 mL) and a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.3 M, 3.7 mL, 4.8 mmol) Was added at 0 ° C. and stirred at 0 ° C. for 1 hour. DMF (1.3 mL, 16 mmol) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (364 mg, 1.4 mmol, yield 87%) as a white solid.
ESI-MSfound: 258 [MH] ^-

アルゴン雰囲気下、（メトキシメチル）トリフェニルホスホニウムクロリド（１．２ｇ，３．６ｍｍｏｌ）のＴＨＦ（３．５ｍＬ）溶液に、ナトリウムビス（トリメチルシリル）アミドのＴＨＦ溶液（１．０Ｍ，３．６ｍＬ，３．６ｍｍｏｌ）を０℃で加え、０℃で３０分間撹拌した。反応混合物に化合物［４３−２］（３７３ｍｇ，１．４ｍｍｏｌ）のＴＨＦ（１．３ｍＬ）溶液を−７８℃で加え、室温で１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３６１ｍｇ，１．３ｍｍｏｌ，収率８７％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８６［Ｍ−Ｈ］^- (3) Synthesis of N- (tert-butyl) -3-fluoro-4- (2-methoxyvinyl) benzenesulfonamide [43-3] (hereinafter referred to as compound [43-3])

Under an argon atmosphere, a solution of (methoxymethyl) triphenylphosphonium chloride (1.2 g, 3.6 mmol) in THF (3.5 mL) and a solution of sodium bis (trimethylsilyl) amide in THF (1.0 M, 3.6 mL, 3) .6 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 30 minutes. A solution of compound [43-2] (373 mg, 1.4 mmol) in THF (1.3 mL) was added to the reaction mixture at −78 ° C., and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (361 mg, 1.3 mmol, yield 87%) as a yellow oil.
ESI-MSfound: 286 [MH] ^-

化合物［４３−３］（３６１ｍｇ，１．３ｍｍｏｌ）の水（１．２ｍＬ）−ギ酸（１２ｍＬ）混合溶液を５０℃で２時間撹拌した。反応混合物を減圧濃縮し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（３４４ｍｇ，収率ｑｕａｎｔ．）を黄色油状物として得た。得られた化合物は精製することなく次の反応に用いた。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：９．８０−９．７９（１Ｈ，ｍ），７．６８（１Ｈ，ｄｄ，Ｊ＝７．８，１．８Ｈｚ），７．６３（１Ｈ，ｄｄ，Ｊ＝９．１，１．８Ｈｚ），７．３４（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．８４（２Ｈ，ｓ），１．２７（９Ｈ，ｓ）． (4) Synthesis of N- (tert-butyl) -3-fluoro-4- (2-oxoethyl) benzenesulfonamide [43-4] (hereinafter referred to as compound [43-4])

A mixed solution of compound [43-3] (361 mg, 1.3 mmol) in water (1.2 mL) -formic acid (12 mL) was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (344 mg, yield quant.) As a yellow oil. The obtained compound was used in the next reaction without purification.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 9.80-9.79 (1H, m), 7.68 (1H, dd, J = 7.8, 1.8 Hz), 7.63 (1H, 1H, dd, J = 9.1, 1.8 Hz), 7.34 (1H, t, J = 7.5 Hz), 3.84 (2H, s), 1.27 (9H, s).

化合物［４３−４］（１１５ｍｇ，０．４２ｍｍｏｌ）の１，２−ジクロロエタン（１．４ｍＬ）溶液に、２，４−ジメトキシベンジルアミン（７６μＬ，０．５０ｍｍｏｌ）を室温で加えた。次いで、ナトリウムトリアセトキシボロヒドリド（２６７ｍｇ，１．３ｍｍｏｌ）を０℃で加え、室温で１６時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４７ｍｇ，０．１１ｍｍｏｌ，化合物［４３−３］から２工程の通算収率２６％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４２５［Ｍ＋Ｈ］⁺ (5) N- (tert-butyl) -4- {2-[(2,4-dimethoxybenzyl) amino] ethyl} -3-fluorobenzenesulfonamide [43-5] (hereinafter, compound [43-5]). ) Synthesis

2,4-Dimethoxybenzylamine (76 μL, 0.50 mmol) was added to a solution of compound [43-4] (115 mg, 0.42 mmol) in 1,2-dichloroethane (1.4 mL) at room temperature. Then, sodium triacetoxyborohydride (267 mg, 1.3 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (47 mg, 0.11 mmol, total yield of 2 steps from compound [43-3], 26%) as a yellow oil.
ESI-MSfound: 425 [M + H] ⁺

(6) (S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -3-fluorobenzenesulfonamide trifluoroacetate [43] Synthesis of compound [43-5] (23 mg, 0.055 mmol) Add compound [A-2] (11 mg, 0.055 mmol) to a mixed solution of ethanol (550 μL) -toluene (550 μL) at room temperature, and microwave reaction. The device was used to stir at 120 ° C. for 1 hour. After concentrating the reaction mixture under reduced pressure, TFA (824 μL) and anisole (275 μL) were added at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. Then, the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (5.0 mg, 0.0096 mmol, yield 17%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.70 (1 H, dd, J = 7.8, 1.8 Hz), 7.64 (1 H, dd, J = 9.6, 1.4 Hz) , 7.56-7.49 (2H, m), 7.03 (1H, s), 6.95 (1H, d, J = 8.7Hz), 4.33-4.27 (1H, m) , 4.21 (1H, dd, J = 9.6, 4.6Hz), 4.13 (1H, dd, J = 10.1, 5.5Hz), 3.40-3.24 (4H, m) ), 3.18-3.12 (2H, m), 2.42 (3H, s).
ESI-MSfound: 408 [M-TFA + H] ⁺

[Example 44]
(S) -4- (2-{[3- (2-Cyano-3-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -3-fluorobenzenesulfonamide trifluoroacetic acid salt [44] (hereinafter, Synthesis of compound [44])

From compound [A-5] (11 mg, 0.055 mmol) and compound [43-5] (23 mg, 0.055 mmol) according to the method of step (6) of Example 43, the title compound (4.6 mg, 0. 0088 mmol, yield 16%) was obtained as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.71-7.70 (1 H, m), 7.66-7.64 (1 H, m), 7.56-7.48 (2 H, m) ), 7.02-6.98 (2H, m), 4.37-4.28 (1H, m), 4.23-4.19 (1H, m), 4.15-4.11 (1H) , M), 3.44-3.30 (4H, m), 3.20-3.16 (2H, m), 2.48 (3H, s).
ESI-MSfound: 408 [M-TFA + H] ⁺

[Example 45]
(S) -3-chloro -N ² - [2 - ({2-hydroxy-3 - [(4-morpholino-1,2,5-thiadiazol-3-yl) oxy] propyl} amino) ethyl] thiophene - Synthesis of 2,5-disulfonamide [45] (hereinafter referred to as compound [45])

市販の３−クロロチオフェン（５．０ｇ，４２ｍｍｏｌ）のクロロホルム（３５ｍＬ）−酢酸（７．０ｍＬ）混合溶液に、ＮＢＳ（９．０ｇ，５１ｍｍｏｌ）を室温で加え、７０℃で３時間撹拌した。反応混合物を減圧濃縮した後、水を加え、ｎ−ヘキサンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５．３ｇ，２７ｍｍｏｌ，収率６４％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．２７（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），６．８８（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）． (1) Synthesis of 2-bromo-3-chlorothiophene [45-1] (hereinafter referred to as compound [45-1])

NBS (9.0 g, 51 mmol) was added to a commercially available mixed solution of 3-chlorothiophene (5.0 g, 42 mmol) in chloroform (35 mL) -acetic acid (7.0 mL) at room temperature, and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with n-hexane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (5.3 g, 27 mmol, 64% yield) as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.27 (1H, d, J = 6.4 Hz), 6.88 (1H, d, J = 5.5 Hz).

化合物［４５−１］（１．０ｇ，５．１ｍｍｏｌ）のクロロホルム（１０ｍＬ）溶液に、塩化スルホン酸（６７４μＬ，１０ｍｍｏｌ）のクロロホルム（１０ｍＬ）溶液を−１５℃で加え、−１５℃で１時間撹拌した。反応混合物に塩化スルホン酸（６７４μＬ，１０ｍｍｏｌ）を室温で加え、５０℃で１９時間撹拌した。反応混合物に塩化スルホン酸（７００μＬ，１１ｍｍｏｌ）を５０℃で追加し、５０℃で３時間撹拌した。反応混合物を０℃に冷却したクロロホルム−水混合溶液に滴下し、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物を黄白色固体として得た。得られた化合物は精製することなく次の反応に用いた。 (2) Synthesis of 5-bromo-4-chlorothiophene-2-sulfonyl chloride [45-2] (hereinafter referred to as compound [45-2])

To a solution of compound [45-1] (1.0 g, 5.1 mmol) in chloroform (10 mL) was added a solution of chlorosulfuric acid (674 μL, 10 mmol) in chloroform (10 mL) at -15 ° C and at -15 ° C for 1 hour. Stirred. Chlorosulfuric acid (674 μL, 10 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at 50 ° C. for 19 hours. Chlorosulfuric acid (700 μL, 11 mmol) was added to the reaction mixture at 50 ° C., and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was added dropwise to a mixed solution of chloroform-water cooled to 0 ° C., and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellowish white solid. The obtained compound was used in the next reaction without purification.

化合物［４５−２］のＴＨＦ（１０ｍＬ）溶液に、ｔｅｒｔ−ブチルアミン（２．１ｍＬ，２０ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物を減圧濃縮した後、水を加え、酢酸エチルで抽出した。有機層を０．５Ｎ−塩酸、水及び飽和食塩水で順次洗浄した。得られた有機層を、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１．４ｇ，４．３ｍｍｏｌ，化合物［４５−１］から２工程の通算収率８４％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３３０［Ｍ−Ｈ］^- (3) Synthesis of 5-bromo-N- (tert-butyl) -4-chlorothiophene-2-sulfonamide [45-3] (hereinafter referred to as compound [45-3])

To a solution of compound [45-2] in THF (10 mL) was added tert-butylamine (2.1 mL, 20 mmol) at 0 ° C. and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.5N-hydrochloric acid, water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.4 g, 4.3 mmol, total yield of 2 steps 84% from compound [45-1]) as a white solid.
ESI-MSfound: 330 [MH] ^-

化合物［４５−３］（５００ｍｇ，１．５ｍｍｏｌ）の１，４−ジオキサン（３．８ｍＬ）溶液に、フェニルメタンチオール（２１１μＬ，１．８ｍｍｏｌ）、Ｐｄ₂（ｄｂａ）₃（１３７ｍｇ，０．１５ｍｍｏｌ）、ＸａｎｔＰｈｏｓ（１７４ｍｇ，０．３０ｍｍｏｌ）及びＤＩＰＥＡ（８６４μＬ，５．０ｍｍｏｌ）を室温で加え、マイクロ波反応装置を用いて１００℃で１時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５３９ｍｇ，１．４ｍｍｏｌ，収率９６％）を橙色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３７４［Ｍ−Ｈ］^- (4) Synthesis of 5- (benzylthio) -N- (tert-butyl) -4-chlorothiophene-2-sulfonamide [45-4] (hereinafter referred to as compound [45-4])

In a solution of compound [45-3] (500 mg, 1.5 mmol) in 1,4-dioxane (3.8 mL), phenylmethanethiol (211 μL, 1.8 mmol), Pd ₂ (dba) ₃ (137 mg, 0.15 mmol). ), XantPhos (174 mg, 0.30 mmol) and DIPEA (864 μL, 5.0 mmol) were added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (539 mg, 1.4 mmol, yield 96%) as an orange solid.
ESI-MSfound: 374 [MH] ^-

化合物［４５−４］（３７１ｍｇ，０．９９ｍｍｏｌ）のＴＨＦ（１．４ｍＬ）−水（４７０μＬ）−酢酸（１．４ｍＬ）混合溶液に、ＮＣＳ（５２７ｍｇ，４．０ｍｍｏｌ）を室温で加え、室温で２時間撹拌した。反応混合物を減圧濃縮することにより、白色固体を得た。Ｎ−（２−アミノエチル）カルバミン酸ｔｅｒｔ−ブチル（３１６ｍｇ，２．０ｍｍｏｌ）のＴＨＦ（５００μＬ）溶液に、上記で得られた白色固体のＴＨＦ（１．０ｍＬ）溶液を０℃で加え、室温で２０分間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を０．５Ｎ−塩酸、水及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３６７ｍｇ，０．７７ｍｍｏｌ，収率７８％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５４（１Ｈ，ｓ），３．１５−３．０６（４Ｈ，ｍ），１．４２（９Ｈ，ｓ），１．２７（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：４７４［Ｍ−Ｈ］^- (5) 2-({5- [N- (tert-butyl) sulfamoyl] -3-chlorothiophene} -2-sulfonamide) tert-butyl ethylcarbamate [45-5] (hereinafter, compound [45-5] ]) Synthesis

NCS (527 mg, 4.0 mmol) was added to a mixed solution of compound [45-4] (371 mg, 0.99 mmol) in THF (1.4 mL) -water (470 μL) -acetic acid (1.4 mL) at room temperature. Was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give a white solid. To a solution of tert-butyl N- (2-aminoethyl) carbamate (316 mg, 2.0 mmol) in THF (500 μL) was added a solution of the white solid THF (1.0 mL) obtained above at 0 ° C. to room temperature. Was stirred for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.5N-hydrochloric acid, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (367 mg, 0.77 mmol, yield 78%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.54 (1H, s), 3.15-3.06 (4H, m), 1.42 (9H, s), 1.27 (9H, s).
ESI-MSfound: 474 [MH] ^-

化合物［４５−５］（３３８ｍｇ，０．７１ｍｍｏｌ）の酢酸エチル（１．８ｍＬ）溶液に、塩化水素の１，４−ジオキサン溶液（４．０Ｍ，１．８ｍＬ）を０℃で加え、室温で５時間撹拌した。反応混合物を減圧濃縮することにより、白色固体を得た。得られた白色固体のメタノール（１．０ｍＬ）−エタノール（１．０ｍＬ）−トルエン（１．０ｍＬ）混合溶液に、化合物［Ａ−２６］（１５７ｍｇ，０．６５ｍｍｏｌ）及びＤＩＰＥＡ（４５１μＬ，２．６ｍｍｏｌ）を室温で加え、８０℃で１５時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１８９ｍｇ，０．３１ｍｍｏｌ，収率４７％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５５（１Ｈ，ｓ），４．４２（１Ｈ，ｄｄ，Ｊ＝１１．２，４．３Ｈｚ），４．３５（１Ｈ，ｄｄ，Ｊ＝１１．０，５．９Ｈｚ），４．０７−４．０２（１Ｈ，ｍ），３．７７（４Ｈ，ｔ，Ｊ＝４．８Ｈｚ），３．５０（４Ｈ，ｔ，Ｊ＝４．８Ｈｚ），３．１５（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），２．７５−２．７１（３Ｈ，ｍ），２．６５（１Ｈ，ｄｄ，Ｊ＝１２．３，７．８Ｈｚ）１．２７（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：６１９［Ｍ＋Ｈ］⁺ (6) (S) -N ⁵ - (tert-butyl) -3-chloro -N ² - [2 - ({2-hydroxy-3 - [(4-morpholino-1,2,5-thiadiazol-3 Synthesis of yl) oxy] propyl} amino) ethyl] thiophene-2,5-disulfoneamide [45-6] (hereinafter referred to as compound [45-6])

To a solution of compound [45-5] (338 mg, 0.71 mmol) in ethyl acetate (1.8 mL) was added a solution of hydrogen chloride 1,4-dioxane (4.0 M, 1.8 mL) at 0 ° C. and at room temperature. The mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to give a white solid. Compound [A-26] (157 mg, 0.65 mmol) and DIPEA (451 μL, 2.) were added to the obtained mixed solution of methanol (1.0 mL) -ethanol (1.0 mL) -toluene (1.0 mL) as a white solid. 6 mmol) was added at room temperature and stirred at 80 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (189 mg, 0.31 mmol, yield 47%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.55 (1H, s), 4.42 (1H, dd, J = 11.2, 4.3 Hz), 4.35 (1H, dd, J) = 11.0, 5.9Hz), 4.07-4.02 (1H, m), 3.77 (4H, t, J = 4.8Hz), 3.50 (4H, t, J = 4. 8Hz), 3.15 (2H, t, J = 6.2Hz), 2.75-2.71 (3H, m), 2.65 (1H, dd, J = 12.3,7.8Hz) 1 .27 (9H, s).
ESI-MSfound: 619 [M + H] ⁺

(7) (S) -3-chloro -N ² - [2 - ({2-hydroxy-3 - [(4-morpholino-1,2,5-thiadiazol-3-yl) oxy] propyl} amino) ethyl ] Synthesis of thiophene-2,5-disulfonamide [45] Anisole (158 μL) and TFA (788 μL) were added to compound [45-6] (117 mg, 0.19 mmol) at room temperature, and the mixture was stirred at 45 ° C. for 16 hours. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (83 mg, 0.15 mmol, yield 78%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.55 (1H, s), 4.43 (1H, dd, J = 11.0, 4.1 Hz), 4.36 (1H, dd, J) = 11.0, 5.9Hz), 4.08-4.02 (1H, m), 3.77 (4H, t, J = 4.8Hz), 3.50 (4H, t, J = 4. 8Hz), 3.17-3.14 (2H, m), 2.76-2.72 (3H, m), 2.66 (1H, dd, J = 12.1, 8.0Hz).
ESI-MSfound: 563 [M + H] ⁺

[Example 46]
(S)-3-chloro ^{-N 2 - (2 - {[} 3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) thiophene-2,5-trifluoroacetate salt Synthesis of [46] (hereinafter referred to as compound [46])

化合物［Ａ−２］（１９４ｍｇ，１．０ｍｍｏｌ）のエタノール（３．４ｍＬ）溶液に、Ｎ−（２−アミノエチル）カルバミン酸ｔｅｒｔ−ブチル（０．４１ｍＬ，２．６ｍｍｏｌ）を室温で加え、８０℃で２時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３０２ｍｇ，０．８６ｍｍｏｌ，収率８４％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３５０［Ｍ＋Ｈ］⁺，３９４［Ｍ＋ＨＣＯ₂Ｈ−Ｈ］^- (1) (S)-(2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) tert-butyl carbamate [46-1] (hereinafter, compound [46-1]) -1])

To a solution of compound [A-2] (194 mg, 1.0 mmol) in ethanol (3.4 mL) was added tert-butyl N- (2-aminoethyl) carbamate (0.41 mL, 2.6 mmol) at room temperature. The mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (302 mg, 0.86 mmol, yield 84%) as a white solid.
^{ESI-MSfound: 350 [M +} H] +, 394 [M + HCO 2 H-H] -

化合物［４６−１］（３０１ｍｇ，０．８６ｍｍｏｌ）のメタノール（２．９ｍＬ）溶液に、塩化水素の１，４−ジオキサン溶液（４．０Ｍ，２．２ｍＬ，８．６ｍｍｏｌ）を室温で加え、室温で３時間撹拌した。析出した固体を濾取することにより、表題化合物（１９６ｍｇ，０．６１ｍｍｏｌ，収率７１％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２５０［Ｍ−２ＨＣｌ＋Ｈ］⁺ (2) (S) -2- {3-[(2-Aminoethyl) amino] -2-hydroxypropoxy} -4-methylbenzonitrile dihydrochloride [46-2] (hereinafter, compound [46-2]) ) Synthesis

A solution of hydrogen chloride in 1,4-dioxane (4.0 M, 2.2 mL, 8.6 mmol) was added to a solution of compound [46-1] (301 mg, 0.86 mmol) in methanol (2.9 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration to give the title compound (196 mg, 0.61 mmol, yield 71%) as a white solid.
ESI-MSfound: 250 [M-2HCl + H] ⁺

化合物［４５−４］（２３２ｍｇ，０．６２ｍｍｏｌ）のＴＨＦ（２．６ｍＬ）溶液に、酢酸（２．６ｍＬ）、水（０．８８ｍＬ）及びＮＣＳ（１６５ｍｇ，１．２ｍｍｏｌ）を室温で加え、室温で１時間撹拌した。反応混合物にＮＣＳ（１６５ｍｇ，１．２ｍｍｏｌ）を室温で追加し、室温で２時間撹拌した。反応混合物を減圧濃縮することにより、褐色固体を得た。化合物［４６−２］（１９５ｍｇ，０．６１ｍｍｏｌ）のＤＭＦ（３．０ｍＬ）懸濁液に、ＤＩＰＥＡ（０．４１ｍＬ，２．４ｍｍｏｌ）を室温で加え、０℃に冷却した。反応混合物に上記で得られた褐色固体のＴＨＦ（３．０ｍＬ）溶液を０℃で加え、０℃で１時間撹拌した。反応混合物に１Ｎ−水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１７７ｍｇ，０．３１ｍｍｏｌ，収率５２％）を白色アモルファスとして得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５５（１Ｈ，ｓ），７．４７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０１（１Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），４．１２−４．０４（３Ｈ，ｍ），３．１８（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），２．８８−２．７２（４Ｈ，ｍ），２．４０（３Ｈ，ｓ），１．２７（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：５６５［Ｍ＋Ｈ］^{+ (3) (S) -N 5} - (tert- butyl) -3-chloro ^{-N 2 - (2 - {[} 3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) Synthesis of thiophene-2,5-disulfone amide [46-3] (hereinafter referred to as compound [46-3])

Acetic acid (2.6 mL), water (0.88 mL) and NCS (165 mg, 1.2 mmol) were added to a solution of compound [45-4] (232 mg, 0.62 mmol) in THF (2.6 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. NCS (165 mg, 1.2 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a brown solid. DIPEA (0.41 mL, 2.4 mmol) was added to a suspension of compound [46-2] (195 mg, 0.61 mmol) in DMF (3.0 mL) at room temperature and cooled to 0 ° C. The brown solid THF (3.0 mL) solution obtained above was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (177 mg, 0.31 mmol, yield 52%) as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.55 (1H, s), 7.47 (1H, d, J = 7.8 Hz), 7.01 (1H, s), 6.90 ( 1H, d, J = 8.2Hz), 4.12-4.04 (3H, m), 3.18 (2H, t, J = 6.4Hz), 2.88-2.72 (4H, m) ), 2.40 (3H, s), 1.27 (9H, s).
ESI-MSfound: 565 [M + H] ⁺

(4) (S) -3- chloro ^{-N 2 - (2 - {[} 3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) thiophene-2,5-sulfonamide tri Synthesis of Fluoroacetate [46] Anisole (0.073 mL, 0.67 mmol) and TFA (2.0 mL) were added to compound [46-3] (38 mg, 0.067 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. did. The reaction mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (39 mg, 0.062 mmol, yield 92%) as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.60 (1 H, s), 7.50 (1 H, d, J = 7.8 Hz), 7.03 (1 H, s), 6.95 ( 1H, d, J = 7.8Hz), 4.36-4.30 (1H, m), 4.20 (1H, dd, J = 10.1, 4.6Hz), 4.14 (1H, dd) , J = 10.1, 5.5Hz), 3.41-3.37 (3H, m), 3.34-3.25 (3H, m), 2.42 (3H, s).
ESI-MSfound: 509 [M-TFA + H] ⁺

[Example 47]
(S)-3-chloro ^{-N 2 - [2 - ({} 3- (2- chloro-5-methylphenoxy) -2-hydroxypropyl} amino) ethyl] thiophene-2,5-sulfonamide [47] ( Hereinafter, synthesis of compound [47])

化合物［Ａ−１］（４６７ｍｇ，２．４ｍｍｏｌ）から実施例４６の工程（１）の方法に準じて表題化合物（６６７ｍｇ，１．９ｍｍｏｌ，収率７９％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３５９［Ｍ＋Ｈ］⁺ (1) (S)-(2-{[3- (2-Chloro-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) tert-butyl carbamic acid [47-1] (hereinafter, compound [47]) -1])

From compound [A-1] (467 mg, 2.4 mmol), the title compound (667 mg, 1.9 mmol, yield 79%) was obtained as a white solid according to the method of step (1) of Example 46.
ESI-MSfound: 359 [M + H] ⁺

化合物［４７−１］（６６７ｍｇ，１．９ｍｍｏｌ）のＴＨＦ（１９ｍＬ）溶液に、１，１’−カルボニルジイミダゾール（３９２ｍｇ，２．４ｍｍｏｌ）及び４−ジメチルアミノピリジン（４５ｍｇ，０．３７ｍｍｏｌ）を室温で加え、室温で１７時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６１７ｍｇ，１．６ｍｍｏｌ，収率８６％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ：７．５５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），６．７７−６．７５（２Ｈ，ｍ），４．８９−４．８３（１Ｈ，ｍ），４．８０（１Ｈ，ｂｒ）， ４．２１−４．１５（２Ｈ，ｍ），３．８６（１Ｈ，ｔ，Ｊ＝８．７Ｈｚ），３．７３（１Ｈ，ｄｄ，Ｊ＝８．５，５．７Ｈｚ），３．４６−３．３０（４Ｈ，ｍ），２．３２（３Ｈ，ｓ），１．４２（９Ｈ，ｓ）． (2) (S)-(2- {5-[(2-chloro-5-methylphenoxy) methyl] -2-oxooxazolidine-3-yl} ethyl) tert-butyl carbamate [47-2] (hereinafter , Compound [47-2])

1,1'-carbonyldiimidazole (392 mg, 2.4 mmol) and 4-dimethylaminopyridine (45 mg, 0.37 mmol) in a solution of compound [47-1] (667 mg, 1.9 mmol) in THF (19 mL). The mixture was added at room temperature and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (617 mg, 1.6 mmol, yield 86%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.55 (1H, d, J = 8.2 Hz), 6.77-6.75 (2H, m), 4.89-4.83 (1H, 1H, m), 4.80 (1H, br), 4.21-4.15 (2H, m), 3.86 (1H, t, J = 8.7Hz), 3.73 (1H, dd, J = 8.5,5.7 Hz), 3.46-3.30 (4H, m), 2.32 (3H, s), 1.42 (9H, s).

化合物［４７−２］（６１７ｍｇ，１．６ｍｍｏｌ）に、アニソール（５２０μＬ）及びＴＦＡ（３．２ｍＬ）を室温で加え、室温で２４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆相シリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６７５ｍｇ，収率ｑｕａｎｔ．）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８５［Ｍ−ＴＦＡ＋Ｈ］⁺ (3) (S) -3- (2-aminoethyl) -5-[(2-chloro-5-methylphenoxy) methyl] oxazolidine-2-onetrifluoroacetate [47-3] (hereinafter, compound [ 47-3])

Anisole (520 μL) and TFA (3.2 mL) were added to compound [47-2] (617 mg, 1.6 mmol) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (675 mg, yield quant.) As a colorless oil.
ESI-MSfound: 285 [M-TFA + H] ⁺

(4) (S) -3- chloro ^{-N 2 - [2 - ({} 3- (2- chloro-5-methylphenoxy) -2-hydroxypropyl} amino) ethyl] thiophene-2,5-sulfonamide [ 47] Synthesis Compound [45-4] (263 mg, 0.70 mmol) in a mixed solution of THF (1.0 mL) -water (333 μL) -acetic acid (1.0 mL) with NCS (374 mg, 2.8 mmol) at room temperature. And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a white solid. A solution of the white solid THF (2.0 mL) obtained above was added to a solution of compound [47-3] (279 mg, 0.70 mmol) in THF (2.0 mL) at 0 ° C. DIPEA (183 μL, 1.1 mmol) was then added at room temperature and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.5N-hydrochloric acid, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless oil (245 mg). Anisole (340 μL) and TFA (1.7 mL) were added to the obtained colorless oil at room temperature, and the mixture was stirred at 45 ° C. for 16 hours. After concentrating the reaction mixture under reduced pressure, ethanol (2.0 mL) and 5N-sodium hydroxide aqueous solution (2.0 mL) were added at room temperature, and the mixture was stirred at 95 ° C. for 1 hour. To the reaction mixture was added 2N-hydrochloric acid until pH = 9, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (80 mg, 0.15 mmol, yield 22%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.55 (1H, s), 7.19 (1H, d, J = 7.8 Hz), 6.89 (1H, d, J = 1.4 Hz) ), 6.74-6.73 (1H, m), 4.08-3.95 (3H, m), 3.17 (2H, t, J = 6.2Hz), 2.86 (1H, dd) , J = 12.1, 3.9Hz), 2.80-2.71 (3H, m), 2.31 (3H, s).
ESI-MSfound: 516 [MH] ^-

[Example 48]
^{(S) -N 2 - (2} - {[3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -3- (1-ethyl -1H- pyrazol-5-yl) Synthesis of thiophene-2,5-disulfonamide trifluoroacetate [48] (hereinafter referred to as compound [48])

化合物［４６−３］（３０ｍｇ，０．０５３ｍｍｏｌ）から実施例４７の工程（２）の方法に準じて表題化合物（３１ｍｇ，０．０５２ｍｍｏｌ，収率９８％）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：５８９［Ｍ−Ｈ］^{- (1) (S) -N 5} - (tert- butyl) -3-chloro ^{-N 2 - (2- {5 -} [(2- cyano-5-methylphenoxy) methyl] -2-oxo-oxazolidine-3 Il} Ethyl) Synthesis of thiophene-2,5-disulfoneamide [48-1] (hereinafter referred to as compound [48-1])

From compound [46-3] (30 mg, 0.053 mmol), the title compound (31 mg, 0.052 mmol, yield 98%) was obtained as a colorless oil according to the method of step (2) of Example 47.
ESI-MSfound: 589 [MH] ^-

化合物［４８−１］（３１ｍｇ，０．０５２ｍｍｏｌ）の１，４−ジオキサン（５３１μＬ）溶液に、１−エチルピラゾール−５−ボロン酸ピナコールエステル（２９ｍｇ，０．１３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２．０ｍｇ，０．０１０ｍｍｏｌ）、ＸＰｈｏｓ（１０ｍｇ，０．０２１ｍｍｏｌ）及び２Ｍ−炭酸ナトリウム水溶液（７８μＬ，０．１６ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１２０℃で１時間撹拌した。反応混合物に１−エチルピラゾール−５−ボロン酸ピナコールエステル（５０ｍｇ，０．２３ｍｍｏｌ）を室温で追加し、マイクロ波反応装置を用いて１２０℃で１時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１６ｍｇ，０．０２５ｍｍｏｌ，収率４８％）を褐色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５６−７．５５（２Ｈ，ｍ），７．４７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０３（１Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．５０（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），４．９７−４．９３（１Ｈ，ｍ），４．３６（１Ｈ，ｄｄ，Ｊ＝１１．０，３．２Ｈｚ），４．２４（１Ｈ，ｄｄ，Ｊ＝１１．０，４．１Ｈｚ），４．０３（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），３．８３（１Ｈ，ｔ，Ｊ＝９．１Ｈｚ），３．６２（１Ｈ，ｄｄ，Ｊ＝８．７，５．９Ｈｚ），３．４１−３．２５（２Ｈ，ｍ），３．０８（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），２．４１（３Ｈ，ｓ），１．３３−１．２８（１２Ｈ，ｍ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：６５１［Ｍ＋Ｈ］^{+ (2) (S) -N 5} - (tert- ^{butyl) -N 2 - (2- {5} - [(2- cyano-5-methylphenoxy) methyl] -2-oxo-oxazolidine-3-yl} ethyl) Synthesis of -3- (1-ethyl-1H-pyrazol-5-yl) thiophene-2,5-disulfoneamide [48-2] (hereinafter referred to as compound [48-2])

In a solution of compound [48-1] (31 mg, 0.052 mmol) in 1,4-dioxane (531 μL), 1-ethylpyrazole-5-boronic acid pinacol ester (29 mg, 0.13 mmol), palladium (II) acetate 2.0 mg, 0.010 mmol), XPhos (10 mg, 0.021 mmol) and 2M-sodium carbonate aqueous solution (78 μL, 0.16 mmol) were added at room temperature, and 1 at 120 ° C. using a microwave reactor under an argon atmosphere. Stirred for hours. 1-Ethylpyrazole-5-boronic acid pinacol ester (50 mg, 0.23 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (16 mg, 0.025 mmol, yield 48%) as a brown oil.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.56-7.55 (2H, m), 7.47 (1H, d, J = 7.8 Hz), 7.03 (1H, s), 6.93 (1H, d, J = 7.8Hz), 6.50 (1H, d, J = 1.8Hz), 4.97-4.93 (1H, m), 4.36 (1H, dd) , J = 11.0, 3.2Hz), 4.24 (1H, dd, J = 11.0, 4.1Hz), 4.03 (2H, q, J = 7.3Hz), 3.83 ( 1H, t, J = 9.1Hz), 3.62 (1H, dd, J = 8.7, 5.9Hz), 3.41-3.25 (2H, m), 3.08 (2H, t) , J = 5.9Hz), 2.41 (3H, s), 1.33-1.28 (12H, m).
ESI-MSfound: 651 [M + H] ⁺

^{(3) (S) -N 2} - (2 - {[3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -3- (1-ethyl--1H- pyrazole -5 -Il) Synthesis of thiophene-2,5-disulfonamide trifluoroacetic acid [48] Anisol (41 μL) and TFA (208 μL) were added to compound [48-2] (16 mg, 0.025 mmol) at room temperature, and at room temperature The mixture was stirred for 20 hours. After concentrating the reaction mixture under reduced pressure, ethanol (495 μL) and an aqueous 2N-sodium hydroxide solution (83 μL) were added at room temperature, and the mixture was stirred at room temperature for 15 hours. A 2N-sodium hydroxide aqueous solution (100 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 24 hours. 2N-hydrochloric acid was added to the reaction mixture until pH = 8, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (4.0 mg, 0.0059 mmol, yield 47%) as a colorless oil.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.60-7.58 (2H, m), 7.50 (1H, d, J = 8.2Hz), 7.03 (1H, s), 6.95 (1H, d, J = 7.8Hz), 6.50 (1H, d, J = 2.3Hz), 4.32-4.26 (1H, m), 4.19 (1H, dd) , J = 9.8, 4.3Hz), 4.12 (1H, dd, J = 10.1, 5.5Hz), 4.05 (2H, q, J = 7.3Hz), 3.34- 3.18 (6H, m), 2.42 (3H, s), 1.34 (3H, t, J = 7.2Hz).
ESI-MSfound: 569 [M-TFA + H] ⁺

[Example 49]
(S) -4-Chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) thio] thiophene-2-sulfonamide trifluoroacetate Synthesis of [49] (hereinafter referred to as compound [49])

化合物［４５−４］（５３５ｍｇ，１．４ｍｍｏｌ）のＴＨＦ（２．０ｍＬ）−水（６８１μＬ）−酢酸（２．０ｍＬ）混合溶液に、ＮＣＳ（５７３ｍｇ，４．３ｍｍｏｌ）を室温で加え、室温で４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、白色固体（５２０ｍｇ）を得た。得られた白色固体のＴＨＦ（７．２ｍＬ）溶液に、アルゴン雰囲気下、トリフェニルホスフィン（１．１ｇ，４．３ｍｍｏｌ）を室温で加え、室温で１５分間撹拌した。反応混合物に水を加え、減圧濃縮した。得られた残渣に１Ｎ−水酸化ナトリウム水溶液を加え、酢酸エチルで洗浄した。水層に２Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（４０３ｍｇ，１．４ｍｍｏｌ，収率９９％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８４［Ｍ−Ｈ］^- (1) Synthesis of N- (tert-butyl) -4-chloro-5-mercaptothiophene-2-sulfonamide [49-1] (hereinafter referred to as compound [49-1])

NCS (573 mg, 4.3 mmol) was added to a mixed solution of compound [45-4] (535 mg, 1.4 mmol) in THF (2.0 mL) -water (681 μL) -acetic acid (2.0 mL) at room temperature, and the mixture was added to room temperature. Was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain a white solid (520 mg). Triphenylphosphine (1.1 g, 4.3 mmol) was added to the obtained white solid THF (7.2 mL) solution under an argon atmosphere at room temperature, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution was added to the obtained residue, and the mixture was washed with ethyl acetate. 2N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (403 mg, 1.4 mmol, yield 99%) as a yellow oil.
ESI-MSfound: 284 [MH] ^-

化合物［４９−１］（２００ｍｇ，０．７０ｍｍｏｌ）のエタノール（３．５ｍＬ）溶液に、３−（ｔｅｒｔ−ブトキシカルボニルアミノ）プロピルブロミド（２５０ｍｇ，１．１ｍｍｏｌ）及びナトリウムエトキシドのエタノール溶液（２０％，８１１μＬ，２．１ｍｍｏｌ）を室温で加え、室温で６時間撹拌した。反応混合物に強酸性陽イオン交換樹脂（ダウエックス^TM（Ｈ）形）を加え、室温で１０分間撹拌した。樹脂を濾別した後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２０３ｍｇ，０．４６ｍｍｏｌ，収率６６％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４４１［Ｍ−Ｈ］^- (2) 3-({5- [N- (tert-butyl) sulfamoyl] -3-chlorothiophene-2-yl} thio) tert-butyl propylcarbamate [49-2] (hereinafter, compound [49-2] ]) Synthesis

An ethanol solution of 3- (tert-butoxycarbonylamino) propyl bromide (250 mg, 1.1 mmol) and sodium ethoxide (20) in an ethanol (3.5 mL) solution of compound [49-1] (200 mg, 0.70 mmol). %, 811 μL, 2.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. A strongly acidic cation exchange resin (Dowex ^TM (H) type) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. After the resin was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (203 mg, 0.46 mmol, yield 66%) as a yellow oil.
ESI-MSfound: 441 [MH] ^-

化合物［４９−２］（２０３ｍｇ，０．４６ｍｍｏｌ）の酢酸エチル（１．２ｍＬ）溶液に、塩化水素の１，４−ジオキサン溶液（４．０Ｍ，１．２ｍＬ）を０℃で加え、室温で５時間撹拌した。反応混合物を減圧濃縮した後、得られた残渣にエタノール及びジイソプロピルエーテルを加えた。析出した固体を濾取することにより、表題化合物（１６８ｍｇ，０．４４ｍｍｏｌ，収率９６％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．４９（１Ｈ，ｓ），３．０７−２．９９（４Ｈ，ｍ），１．９９−１．９０（２Ｈ，ｍ），１．２５（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３４３［Ｍ−ＨＣｌ＋Ｈ］⁺ (3) 5-[(3-Aminopropyl) thio] -N- (tert-butyl) -4-chlorothiophene-2-sulfonamide hydrochloride [49-3] (hereinafter referred to as compound [49-3]) Synthesis of

To a solution of compound [49-2] (203 mg, 0.46 mmol) in ethyl acetate (1.2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 1.2 mL) at 0 ° C. and at room temperature. The mixture was stirred for 5 hours. After concentrating the reaction mixture under reduced pressure, ethanol and diisopropyl ether were added to the obtained residue. The precipitated solid was collected by filtration to give the title compound (168 mg, 0.44 mmol, yield 96%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.49 (1 H, s), 3.07-2.99 (4 H, m), 1.99-1.90 (2 H, m), 1. 25 (9H, s).
ESI-MSfound: 343 [M-HCl + H] ⁺

化合物［Ａ−２］（３０ｍｇ，０．１６ｍｍｏｌ）のエタノール（４００μＬ）−トルエン（４００μＬ）混合溶液に、化合物［４９−３］（７２ｍｇ，０．１９ｍｍｏｌ）及びＤＩＰＥＡ（１０７μＬ，０．６４ｍｍｏｌ）を室温で加え、マイクロ波反応装置を用いて１００℃で２時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４４ｍｇ，０．０８２ｍｍｏｌ，収率５１％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．４７−７．４４（２Ｈ，ｍ），７．０１（１Ｈ，ｓ），６．８９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），４．１３−４．０５（３Ｈ，ｍ），３．０１（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．８９−２．８５（１Ｈ，ｍ），２．８２−２．７３（３Ｈ，ｍ），２．４０（３Ｈ，ｓ），１．８９−１．８２（２Ｈ，ｍ），１．２５（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：５３２［Ｍ＋Ｈ］⁺ (4) (S) -N- (tert-butyl) -4-chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) thio ] Synthesis of thiophene-2-sulfonamide [49-4] (hereinafter referred to as compound [49-4])

Compound [49-3] (72 mg, 0.19 mmol) and DIPEA (107 μL, 0.64 mmol) are added to a mixed solution of compound [A-2] (30 mg, 0.16 mmol) in ethanol (400 μL) -toluene (400 μL). It was added at room temperature and stirred at 100 ° C. for 2 hours using a microwave reactor. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (44 mg, 0.082 mmol, yield 51%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.47-7.44 (2H, m), 7.01 (1H, s), 6.89 (1H, d, J = 8.2Hz), 4.13-4.05 (3H, m), 3.01 (2H, t, J = 7.3Hz), 2.89-2.85 (1H, m), 2.82-2.73 (3H) , M), 2.40 (3H, s), 1.89-1.82 (2H, m), 1.25 (9H, s).
ESI-MSfound: 532 [M + H] ⁺

(5) (S) -4-chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) thio] thiophene-2-sulfonamide tri Synthesis of Fluoroacetate [49] Anisole (62 μL) and TFA (313 μL) were added to compound [49-4] (10 mg, 0.019 mmol) at room temperature, and the mixture was stirred at 45 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (3.6 mg, 0.0061 mmol, yield 32%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.50-7.47 (2H, m), 7.02 (1H, s), 6.94-6.91 (1H, m), 4. 28-4.22 (1H, m), 4.18 (1H, dd, J = 9.7, 4.5Hz), 4.10 (1H, dd, J = 10.1, 5.5Hz), 3 .33-3.00 (6H, m), 2.41 (3H, s), 2.07-1.92 (2H, m).
ESI-MSfound: 476 [M-TFA + H] ⁺

[Example 50]
(S) -4-Chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) sulfonyl] thiophene-2-sulfonamide trifluoroacetate Synthesis of [50] (hereinafter referred to as compound [50])

化合物［４９−４］（１１８ｍｇ，０．２２ｍｍｏｌ）から実施例４７の工程（２）の方法に準じて表題化合物（８７ｍｇ，０．１６ｍｍｏｌ，収率７０％）を白色アモルファスとして得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．４８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（１Ｈ，ｓ），７．０５（１Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．９９−４．９３（１Ｈ，ｍ），４．３９（１Ｈ，ｄｄ，Ｊ＝１１．０，２．７Ｈｚ），４．２４（１Ｈ，ｄｄ，Ｊ＝１１．０，３．７Ｈｚ），３．８０（１Ｈ，ｔ，Ｊ＝９．１Ｈｚ），３．６５（１Ｈ，ｄｄ，Ｊ＝８．７，５．９Ｈｚ），３．４８−３．４１（２Ｈ，ｍ），３．０５−２．９４（２Ｈ，ｍ），２．４１（３Ｈ，ｓ），１．９８−１．８６（２Ｈ，ｍ），１．２４（９Ｈ，ｓ）． (1) (S) -N- (tert-butyl) -4-chloro-5-[(3- {5-[(2-cyano-5-methylphenoxy) methyl] -2-oxooxazolidine-3-yl } Propyl) Thio] Thiophene-2-sulfonamide [50-1] (hereinafter referred to as compound [50-1])

From compound [49-4] (118 mg, 0.22 mmol), the title compound (87 mg, 0.16 mmol, yield 70%) was obtained as a white amorphous substance according to the method of step (2) of Example 47.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.48 (1H, d, J = 8.2 Hz), 7.44 (1H, s), 7.05 (1H, s), 6.93 ( 1H, d, J = 7.8Hz), 4.99-4.93 (1H, m), 4.39 (1H, dd, J = 11.0, 2.7Hz), 4.24 (1H, dd) , J = 11.0, 3.7Hz), 3.80 (1H, t, J = 9.1Hz), 3.65 (1H, dd, J = 8.7, 5.9Hz), 3.48- 3.41 (2H, m), 3.05-2.94 (2H, m), 2.41 (3H, s), 1.98-1.86 (2H, m), 1.24 (9H, 9H, s).

化合物［５０−１］（３８ｍｇ，０．０６９ｍｍｏｌ）のクロロホルム（１．４ｍＬ）溶液に、３−クロロ過安息香酸（３０％含水）（５１ｍｇ，０．２１ｍｍｏｌ）を０℃で加え、室温で４時間撹拌した。反応混合物に飽和亜硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（３７ｍｇ，０．０６２ｍｍｏｌ，収率９１％）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：５８８［Ｍ−Ｈ］^- (2) (S) -N- (tert-butyl) -4-chloro-5-[(3- {5-[(2-cyano-5-methylphenoxy) methyl] -2-oxooxazolidine-3-yl } Propyl) Sulfonyl] Thiophene-2-sulfonamide [50-2] (hereinafter referred to as compound [50-2])

To a solution of compound [50-1] (38 mg, 0.069 mmol) in chloroform (1.4 mL) was added 3-chloroperbenzoic acid (30% water content) (51 mg, 0.21 mmol) at 0 ° C. and 4 at room temperature. Stirred for hours. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (37 mg, 0.062 mmol, yield 91%) as a colorless oil.
ESI-MSfound: 588 [MH] ^-

(3) (S) -4-chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) sulfonyl] thiophene-2-sulfonamide tri Synthesis of Fluoroacetate [50] Anisole (149 μL) and TFA (742 μL) were added to compound [50-2] (37 mg, 0.062 mmol) at room temperature, and the mixture was stirred at 45 ° C. for 15 hours. After concentrating the reaction mixture under reduced pressure, ethanol (445 μL) and 5N-sodium hydroxide aqueous solution (445 μL) were added at room temperature, and the mixture was stirred at room temperature for 24 hours. 5N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (25 mg, 0.040 mmol, yield 64%) as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.66 (1H, s), 7.50 (1H, d, J = 7.8 Hz), 7.02 (1H, s), 6.94 ( 1H, d, J = 7.8Hz), 4.31-4.25 (1H, m), 4.20 (1H, dd, J = 9.8, 4.3Hz), 4.12 (1H, dd) , J = 10.1, 5.5Hz), 3.64 (2H, t, J = 7.5Hz), 3.36-3.22 (4H, m), 2.41 (3H, s), 2 .27-2.20 (2H, m).
ESI-MSfound: 508 [M-TFA + H] ⁺

[Example 51]
(S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3- (1-ethyl-1H-pyrazole-5) -Il) Synthesis of benzenesulfonamide trifluoroacetate [51] (hereinafter referred to as compound [51])

市販の３−ブロモ−４−メチルベンゼンスルホニルクロリド（７００ｍｇ，２．６ｍｍｏｌ）から参考例Ｂ−２の工程（ａ）の方法に準じて表題化合物（６６１ｍｇ，２．２ｍｍｏｌ，収率８３％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３０４［Ｍ−Ｈ］^- (1) Synthesis of 3-bromo-N- (tert-butyl) -4-methylbenzenesulfonamide [51-1] (hereinafter referred to as compound [51-1])

From commercially available 3-bromo-4-methylbenzenesulfonyl chloride (700 mg, 2.6 mmol), the title compound (661 mg, 2.2 mmol, yield 83%) was added according to the method of step (a) of Reference Example B-2. Obtained as a white solid.
ESI-MSfound: 304 [MH] ^-

化合物［５１−１］（６６１ｍｇ，２．２ｍｍｏｌ）の四塩化炭素（１１ｍＬ）溶液に、ＮＢＳ（４６１ｍｇ，２．６ｍｍｏｌ）及びＡＩＢＮ（７１ｍｇ，０．４３ｍｍｏｌ）を室温で加え、８０℃で３時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４６９ｍｇ，１．２ｍｍｏｌ，収率５６％）を白色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３８２［Ｍ−Ｈ］^- (2) Synthesis of 3-bromo-4- (bromomethyl) -N- (tert-butyl) benzenesulfonamide [51-2] (hereinafter referred to as compound [51-2])

NBS (461 mg, 2.6 mmol) and AIBN (71 mg, 0.43 mmol) were added to a solution of compound [51-1] (661 mg, 2.2 mmol) in carbon tetrachloride (11 mL) at room temperature, and the mixture was added at room temperature for 3 hours at 80 ° C. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (469 mg, 1.2 mmol, yield 56%) as a white amorphous substance.
ESI-MSfound: 382 [MH] ^-

アルゴン雰囲気下、ＴＨＦ（２．０ｍＬ）にリチウムビス（トリメチルシリル）アミドのＴＨＦ溶液（１．０Ｍ，２．５ｍＬ，１．０ｍｍｏｌ）及びイソブチロニトリル（２２７μＬ，２．５ｍｍｏｌ）を０℃で加え、０℃で２０分間撹拌した。反応混合物に化合物［５１−２］（３８９ｍｇ，１．０ｍｍｏｌ）のＴＨＦ（２．０ｍＬ）溶液を０℃で加え、０℃で１時間撹拌した。反応混合物に０．５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（２９９ｍｇ，０．８０ｍｍｏｌ，収率７９％）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３７１［Ｍ−Ｈ］^- (3) Synthesis of 3-bromo-N- (tert-butyl) -4- (2-cyano-2-methylpropyl) benzenesulfonamide [51-3] (hereinafter referred to as compound [51-3])

Under an argon atmosphere, a THF solution of lithium bis (trimethylsilyl) amide (1.0 M, 2.5 mL, 1.0 mmol) and isobutyronitrile (227 μL, 2.5 mmol) were added to THF (2.0 mL) at 0 ° C. , Stirred at 0 ° C. for 20 minutes. A solution of compound [51-2] (389 mg, 1.0 mmol) in THF (2.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. 0.5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (299 mg, 0.80 mmol, yield 79%) as a colorless oil.
ESI-MSfound: 371 [MH] ^-

化合物［５１−３］（１５０ｍｇ，０．４０ｍｍｏｌ）の１，４−ジオキサン（１．２ｍＬ）−水（１３４μＬ）混合溶液に、１−エチルピラゾール−５−ボロン酸ピナコールエステル（１７８ｍｇ，０．８０ｍｍｏｌ）、Ｐｄ（ＰＰｈ₃）₄（９３ｍｇ，０．０８０ｍｍｏｌ）及び炭酸カリウム（１６７ｍｇ，１．２ｍｍｏｌ）を室温で加え、アルゴン雰囲気下、マイクロ波反応装置を用いて１２０℃で１時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１１２ｍｇ，０．２９ｍｍｏｌ，収率７２％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３８９［Ｍ＋Ｈ］⁺ (4) N- (tert-butyl) -4- (2-cyano-2-methylpropyl) -3- (1-ethyl-1H-pyrazole-5-yl) benzenesulfonamide [51-4] (hereinafter, Synthesis of compound [51-4])

1-Ethylpyrazole-5-boronic acid pinacol ester (178 mg, 0.80 mmol) in a mixed solution of compound [51-3] (150 mg, 0.40 mmol) in a 1,4-dioxane (1.2 mL) -water (134 μL) mixture. ), Pd (PPh ₃ ) ₄ (93 mg, 0.080 mmol) and potassium carbonate (167 mg, 1.2 mmol) were added at room temperature, and the mixture was stirred at 120 ° C. for 1 hour under an argon atmosphere using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (112 mg, 0.29 mmol, yield 72%) as a yellow oil.
ESI-MSfound: 389 [M + H] ⁺

化合物［５１−４］（１１２ｍｇ，０．２９ｍｍｏｌ）のエチレングリコール（１．９ｍＬ）懸濁液に、４０％水酸化カリウム水溶液（９６０μＬ）を室温で加え、１５０℃で７時間撹拌した。反応混合物に、ｐＨ＝９になるまで２Ｎ−塩酸を加え、酢酸エチルで洗浄した。水層に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をＣＯ₂Ｈシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（８０ｍｇ，０．２０ｍｍｏｌ，収率６８％）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４０６［Ｍ−Ｈ］^- (5) 3- {4- [N- (tert-butyl) sulfamoyl] -2- (1-ethyl-1H-pyrazole-5-yl) phenyl} -2,2-dimethylpropionic acid [51-5] ( Synthesis of compound [51-5])

A 40% aqueous potassium hydroxide solution (960 μL) was added to a suspension of compound [51-4] (112 mg, 0.29 mmol) in ethylene glycol (1.9 mL) at room temperature, and the mixture was stirred at 150 ° C. for 7 hours. 2N-hydrochloric acid was added to the reaction mixture until pH = 9, and the mixture was washed with ethyl acetate. 5N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a CO ₂ H silica gel column chromatography to give the title compound (80 mg, 0.20 mmol, 68% yield) as a colorless oil.
ESI-MSfound: 406 [MH] ^-

化合物［５１−５］（８０ｍｇ，０．２０ｍｍｏｌ）のアセトニトリル（２．０ｍＬ）溶液に、トリエチルアミン（９５μＬ，０．６９ｍｍｏｌ）及びジフェニルリン酸アジド（８５μＬ，０．３９ｍｍｏｌ）を室温で加え、室温で６時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより（６８ｍｇ，０．１６ｍｍｏｌ，収率８０％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４３１［Ｍ−Ｈ］^- (6) 3- {4- [N- (tert-butyl) sulfamoyl] -2- (1-ethyl-1H-pyrazole-5-yl) phenyl} -2,2-dimethylpropionic acid azide [51-6] Synthesis of compound (hereinafter referred to as compound [51-6])

Triethylamine (95 μL, 0.69 mmol) and diphenylphosphoryl azide (85 μL, 0.39 mmol) were added to a solution of compound [51-5] (80 mg, 0.20 mmol) in acetonitrile (2.0 mL) at room temperature, and at room temperature. The mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (68 mg, 0.16 mmol, yield 80%) to obtain a white solid.
ESI-MSfound: 431 [MH] ^-

化合物［５１−６］（６８ｍｇ，０．１６ｍｍｏｌ）の１，４−ジオキサン（８００μＬ）−ＴＨＦ（８００μＬ）混合溶液を、８０℃で５時間撹拌した。反応混合物に２Ｎ−水酸化ナトリウム水溶液（１．６ｍＬ）を室温で加え、１００℃で１時間撹拌した。反応混合物に２Ｎ−塩酸を加えて中性にし、減圧濃縮した。得られた残渣をエタノールに懸濁させた後、固体を濾別し、濾液を減圧濃縮した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（５９ｍｇ，０．１６ｍｍｏｌ，収率９９％）を黄色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．９２（１Ｈ，ｄｄ，Ｊ＝８．２，２．３Ｈｚ），７．７３（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）７．６１（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），６．３５（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），３．８８（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），２．７７（２Ｈ，ｂｒ），１．３１（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．１９（９Ｈ，ｓ），０．９１（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３７７［Ｍ−Ｈ］^- (7) 4- (2-Amino-2-methylpropyl) -N- (tert-butyl) -3- (1-ethyl-1H-pyrazole-5-yl) benzenesulfonamide [51-7] (hereinafter, Synthesis of compound [51-7])

A mixed solution of compound [51-6] (68 mg, 0.16 mmol) in 1,4-dioxane (800 μL) -THF (800 μL) was stirred at 80 ° C. for 5 hours. A 2N-sodium hydroxide aqueous solution (1.6 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. 2N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethanol, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography to give the title compound (59 mg, 0.16 mmol, yield 99%) as a yellow oil.
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.92 (1H, dd, J = 8.2, 2.3 Hz), 7.73 (1 H, d, J = 2.3 Hz), 7.64 (1H, d, J = 8.2Hz) 7.61 (1H, d, J = 1.8Hz), 6.35 (1H, d, J = 1.8Hz), 3.88 (2H, q, J) = 7.2Hz), 2.77 (2H, br), 1.31 (3H, t, J = 7.3Hz), 1.19 (9H, s), 0.91 (6H, s).
ESI-MSfound: 377 [MH] ^-

(8) (S) -4- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3- (1-ethyl-1H-) Synthesis of pyrazole-5-yl) benzenesulfonamide trifluoroacetate [51] Compound [A-2] was added to a mixed solution of compound [51-7] (41 mg, 0.11 mmol) in ethanol (450 μL) -toluene (450 μL). ] (17 mg, 0.090 mmol) and DIPEA (47 μL, 0.27 mmol) were added at room temperature, and the mixture was stirred at 100 ° C. for 2 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain a colorless oil (21 mg). From the obtained colorless oil, the title compound (19 mg, 0.031 mmol, yield 34%) was obtained as a white amorphous substance according to step (5) of Example 49.
¹ H-NMR (400MHz, CD ₃ OD) δ: 7.99 (1H, dd, J = 8.0, 2.1Hz), 7.82 (1H, d, J = 1.8Hz), 7.68 (1H, d, J = 8.2Hz), 7.61 (1H, d, J = 1.8Hz), 7.51 (1H, d, J = 7.8Hz), 7.03 (1H, s) , 6.95 (1H, d, J = 7.8Hz), 6.42 (1H, d, J = 1.8Hz), 4.24-4.18 (2H, m), 4.12-4. 07 (1H, m), 3.97-3.87 (2H, m), 3.35-3.03 (4H, m) 2.42 (3H, s), 1.34 (3H, t, J) = 7.3Hz), 1.17 (6H, s).
ESI-MSfound: 512 [M-TFA + H] ⁺

[Example 52]
(S) -3-Bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) benzenesulfonamide [52] (hereinafter, Synthesis of compound [52])

化合物［５１−３］（１０５ｍｇ，０．２８ｍｍｏｌ）のエチレングリコール（１．９ｍＬ）溶液に、１２Ｎ−水酸化カリウム水溶液（０．９４ｍＬ）を室温で加え、１５０℃で６時間撹拌した。反応混合物に５Ｎ−塩酸を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物（１１２ｍｇ）を褐色固体として得た。得られた化合物は精製することなく次の反応に用いた。
ＥＳＩ−ＭＳｆｏｕｎｄ：３９０［Ｍ−Ｈ］^- (1) Synthesis of 3- {2-bromo-4- [N- (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylpropionic acid [52-1] (hereinafter referred to as compound [52-1])

A 12N-potassium hydroxide aqueous solution (0.94 mL) was added to a solution of compound [51-3] (105 mg, 0.28 mmol) in ethylene glycol (1.9 mL) at room temperature, and the mixture was stirred at 150 ° C. for 6 hours. 5N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (112 mg) as a brown solid. The obtained compound was used in the next reaction without purification.
ESI-MSfound: 390 [MH] ^-

化合物［５２−１］から参考例Ｂ−１の工程（ｆ）の方法に準じて白色固体（１０７ｍｇ）を得た。得られた白色固体の１，４−ジオキサン（２．６ｍＬ）溶液を、８０℃で１時間撹拌した。次いで、２Ｎ−水酸化ナトリウム水溶液（２．６ｍＬ）を８０℃で加え、１００℃で１時間撹拌した。反応混合物に５Ｎ−塩酸を加えて中性にし、減圧濃縮した。得られた残渣をＴＨＦ（２．６ｍＬ）に溶解し、飽和炭酸水素ナトリウム水溶液（０．３１ｍＬ，０．３８ｍｍｏｌ）及び二炭酸ジ−ｔｅｒｔ−ブチル（８４ｍｇ，０．３８ｍｍｏｌ）を０℃で加えた。反応混合物を、室温で１４時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（１１８ｍｇ，０．２５ｍｍｏｌ，化合物［５１−３］から２工程の通算収率９１％）を白色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４６１［Ｍ−Ｈ］^- (2) (1- {2-Bromo-4- [N- (tert-butyl) sulfamoyl] phenyl} -2-methylpropan-2-yl) tert-butyl carbamic acid [52-2] (hereinafter, compound [52-2] 52-2])

A white solid (107 mg) was obtained from compound [52-1] according to the method of step (f) of Reference Example B-1. The obtained white solid solution of 1,4-dioxane (2.6 mL) was stirred at 80 ° C. for 1 hour. Then, a 2N-sodium hydroxide aqueous solution (2.6 mL) was added at 80 ° C., and the mixture was stirred at 100 ° C. for 1 hour. 5N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in THF (2.6 mL), and saturated aqueous sodium hydrogen carbonate solution (0.31 mL, 0.38 mmol) and di-tert-butyl dicarbonate (84 mg, 0.38 mmol) were added at 0 ° C. .. The reaction mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (118 mg, 0.25 mmol, total yield of 2 steps from compound [51-3]: 91%) as a white amorphous substance.
ESI-MSfound: 461 [MH] ^-

化合物［５２−２］（１１７ｍｇ，０．２５ｍｍｏｌ）に、ＴＦＡ（２．５ｍＬ）を室温で加え、室温で２４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆相シリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（９１ｍｇ，０．２２ｍｍｏｌ，収率８６％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：８．１６（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．８７（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），７．５３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．２４（２Ｈ，ｓ），１．３９（６Ｈ，ｓ）． (3) Synthesis of 4- (2-amino-2-methylpropyl) -3-bromobenzenesulfonamide trifluoroacetate [52-3] (hereinafter referred to as compound [52-3])

To compound [52-2] (117 mg, 0.25 mmol), TFA (2.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to give the title compound (91 mg, 0.22 mmol, yield 86%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.16 (1H, d, J = 1.8 Hz), 7.87 (1H, dd, J = 8.2, 1.8 Hz), 7.53 (1H, d, J = 8.2Hz), 3.24 (2H, s), 1.39 (6H, s).

(4) (S) -3-bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) benzenesulfonamide [52] Synthesis of compound [A-2] (34 mg, 0.18 mmol) and compound [52-3] (91 mg, 0.22 mmol) according to the method of Example 2 and the title compound (59 mg, 0.12 mmol, yield 65). %) Was obtained as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.07 (1 H, d, J = 1.1 Hz), 7.72 (1 H, dd, J = 8.0, 1.6 Hz), 7.54 (1H, d, J = 8.2Hz), 7.47 (1H, d, J = 7.8Hz), 7.03 (1H, s), 6.91 (1H, d, J = 7.8Hz) , 4.19-4.06 (3H, m), 3.07 (2H, s), 2.99 (1H, dd, J = 11.7, 3.9Hz), 2.91 (1H, dd, J = 11.4, 7.3 Hz) 2.41 (3H, s), 1.15 (3H, s), 1.13 (3H, s).
ESI-MSfound: 494 [MH] ^-

[Example 53]
(S) -2- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -N-ethyl-5-sulfamoylbenzamide trifluoro Synthesis of acetate [53] (hereinafter referred to as compound [53])

Compound [52] (30 mg, 0.059 mmol) was mixed with 70% aqueous ethylamine solution (2.0 mL), Pd (PPh ₃ ) ₄ (6.9 mg, 0.0059 mmol) and triethylamine (0.025 mL, 0.18 mmol). The mixture was added at room temperature, and the mixture was stirred at 70 ° C. for 1 hour using a microwave reactor under a carbon monoxide atmosphere. 70% aqueous ethylamine solution (2.0 mL), Pd (PPh ₃ ) ₄ (6.9 mg, 0.0059 mmol) and triethylamine (0.025 mL, 0.18 mmol) were added to the reaction mixture at room temperature under a carbon monoxide atmosphere. , Stirred at 110 ° C. for 1 hour using a microwave reactor. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the title compound (13 mg, 0.021 mmol, yield 35%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.02-8.00 (2H, m), 7.62 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J) = 7.8Hz), 7.02 (1H, s), 6.94 (1H, d, J = 7.8Hz), 4.24-4.08 (3H, m), 3.38-3.12 (6H, m), 2.41 (3H, s), 1.47 (3H, s), 1.45 (3H, s), 1.20 (3H, t, J = 7.3Hz).
ESI-MSfound: 489 [M-TFA + H] ⁺

[Example 54]
(S) -2- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -N-methyl-5-sulfamoylbenzamide [54] ] (Hereinafter referred to as compound [54])

Compound [52] (21 mg, 0.043 mmol) in methanol solution of 40% methylamine (2.0 mL), Pd (PPh ₃ ) ₄ (4.9 mg, 0.0043 mmol) and triethylamine (0.018 mL, 0. 13 mmol) was added at room temperature, and the mixture was stirred at 110 ° C. for 1 hour using a microwave reactor under a carbon monoxide atmosphere. To the reaction mixture was added 40% methylamine in methanol (2.0 mL), Pd (PPh ₃ ) ₄ (4.9 mg, 0.0043 mmol) and triethylamine (0.018 mL, 0.13 mmol) at room temperature to monoxide. The mixture was stirred at 110 ° C. for 1 hour using a microwave reactor under a carbon atmosphere. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12 mg, 0.024 mmol, yield 57%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.91 (1H, d, J = 2.3 Hz), 7.84 (1H, dd, J = 8.0, 2.1 Hz), 7.53 (1H, d, J = 8.2Hz), 7.47 (1H, d, J = 7.8Hz), 7.01 (1H, s), 6.90 (1H, d, J = 7.3Hz) , 4.13-3.98 (3H, m), 3.08 (2H, s), 2.92-2.89 (4H, m), 2.80 (1H, dd, J = 11.7, 7.5Hz), 2.41 (3H, s), 1.12 (3H, s), 1.11 (3H, s).
ESI-MSfound: 475 [M + H] ⁺

[Example 55]
(S) -3-Bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzenesulfonamide [55] ] (Hereinafter referred to as compound [55])

市販の２−フルオロ−６−ニトロトルエン（１．０ｇ，６．５ｍｍｏｌ）を０℃に冷却し、塩化スルホン酸（６．５ｍＬ）を０℃で加え、１３０℃で１時間撹拌した。次いで、１５０℃で１時間撹拌した。反応混合物をクロロホルムで希釈した後、水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮することにより、表題化合物を褐色油状物として得た。得られた化合物は精製することなく次の反応に用いた。 (1) Synthesis of 3-fluoro-4-methyl-5-nitrobenzenesulfonyl chloride [55-1] (hereinafter referred to as compound [55-1])

Commercially available 2-fluoro-6-nitrotoluene (1.0 g, 6.5 mmol) was cooled to 0 ° C., sulfonic acid chloride (6.5 mL) was added at 0 ° C., and the mixture was stirred at 130 ° C. for 1 hour. Then, the mixture was stirred at 150 ° C. for 1 hour. The reaction mixture was diluted with chloroform, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil. The obtained compound was used in the next reaction without purification.

化合物［５５−１］のＴＨＦ（１３ｍＬ）溶液を０℃に冷却し、ｔｅｒｔ−ブチルアミン（２．７ｍＬ，２６ｍｍｏｌ）を０℃で加え、室温で１３時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６８８ｍｇ，２．４ｍｍｏｌ，２−フルオロ−６−ニトロトルエンから２工程の通算収率３７％）を褐色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：８．２３（１Ｈ，ｓ），７．８７（１Ｈ，ｄｄ，Ｊ＝８．７，１．４Ｈｚ），２．５０（３Ｈ，ｄ，Ｊ＝２．３Ｈｚ），１．２１（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：２８９［Ｍ−Ｈ］^- (2) Synthesis of N- (tert-butyl) -3-fluoro-4-methyl-5-nitrobenzenesulfonamide [55-2] (hereinafter referred to as compound [55-2])

A solution of compound [55-1] in THF (13 mL) was cooled to 0 ° C., tert-butylamine (2.7 mL, 26 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (688 mg, 2.4 mmol, 2-fluoro-6-nitrotoluene, total yield of 2 steps 37%) as a brown solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.23 (1H, s), 7.87 (1H, dd, J = 8.7, 1.4 Hz), 2.50 (3H, d, J) = 2.3Hz), 1.21 (9H, s).
ESI-MSfound: 289 [MH] ^-

化合物［５５−２］（６８５ｍｇ，２．４ｍｍｏｌ）のメタノール（７．９ｍＬ）溶液に、１０％パラジウム−活性炭素（約５５％含水）（１５０ｍｇ）を室温で加え、水素雰囲気下、室温で３時間撹拌した。反応混合物を濾過した後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６１４ｍｇ，収率ｑｕａｎｔ．）を褐色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２６１［Ｍ＋Ｈ］⁺，３０２［Ｍ＋Ｈ＋ＣＨ₃ＣＮ］⁺ (3) Synthesis of 3-amino-N- (tert-butyl) -5-fluoro-4-methylbenzenesulfonamide [55-3] (hereinafter referred to as compound [55-3])

To a solution of compound [55-2] (685 mg, 2.4 mmol) in methanol (7.9 mL) was added 10% palladium-activated carbon (approximately 55% hydrous) (150 mg) at room temperature and 3 at room temperature under a hydrogen atmosphere. Stirred for hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (614 mg, yield quant.) As a brown amorphous substance.
ESI-MSfound: 261 [M + H] ⁺ , 302 [M + H + CH ₃ CN] ⁺

化合物［５５−３］（６１４ｍｇ，２．４ｍｍｏｌ）のＤＭＳＯ（４．７ｍＬ）溶液に、４７％臭化水素酸（４．７ｍＬ）を室温で加え、０℃に冷却した。次いで臭化銅（Ｉ）（４０６ｍｇ，２．８ｍｍｏｌ）及び亜硝酸ナトリウム（１９５ｍｇ，２．８ｍｍｏｌ）を０℃で加え、室温で３０分間撹拌した。反応混合物に５Ｎ−水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４８８ｍｇ，１．５ｍｍｏｌ，収率６４％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３２２［Ｍ−Ｈ］^- (4) Synthesis of 3-bromo-N- (tert-butyl) -5-fluoro-4-methylbenzenesulfonamide [55-4] (hereinafter referred to as compound [55-4])

47% hydrobromic acid (4.7 mL) was added to a solution of compound [55-3] (614 mg, 2.4 mmol) in DMSO (4.7 mL) at room temperature and cooled to 0 ° C. Copper (I) bromide (406 mg, 2.8 mmol) and sodium nitrite (195 mg, 2.8 mmol) were then added at 0 ° C. and stirred at room temperature for 30 minutes. A 5N-sodium hydroxide aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (488 mg, 1.5 mmol, yield 64%) as a white solid.
ESI-MSfound: 322 [MH] ^-

化合物［５５−４］（４８８ｍｇ，１．５ｍｍｏｌ）の四塩化炭素（７．６ｍＬ）溶液に、ＮＢＳ（３２２ｍｇ，１．８ｍｍｏｌ）及びＡＩＢＮ（５０ｍｇ，０．３０ｍｍｏｌ）を室温で加え、８０℃で６時間撹拌した。反応混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、白色固体（６１３ｍｇ）を得た。得られた白色固体から参考例Ｂ−２の工程（ｃ）、実施例５２の工程（１）及び参考例Ｂ−１の工程（ｆ）の方法に準じて表題化合物（４６７ｍｇ，１．１ｍｍｏｌ，収率７２％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４３３［Ｍ−Ｈ］^- (5) 3- {2-Bromo-4- [N- (tert-butyl) sulfamoyl] -6-fluorophenyl} -2,2-dimethylpropionic acid azide [55-5] (hereinafter, compound [55-5] ]) Synthesis

NBS (322 mg, 1.8 mmol) and AIBN (50 mg, 0.30 mmol) were added to a solution of compound [55-4] (488 mg, 1.5 mmol) in carbon tetrachloride (7.6 mL) at room temperature at 80 ° C. The mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a white solid (613 mg). From the obtained white solid, the title compound (467 mg, 1.1 mmol, according to the method of the step (c) of Reference Example B-2, the step (1) of Example 52 and the step (f) of Reference Example B-1. Yield 72%) was obtained as a white solid.
ESI-MSfound: 433 [MH] ^-

化合物［５５−５］（４６７ｍｇ，１．１ｍｍｏｌ）の１，４−ジオキサン（５．４ｍＬ）溶液を８０℃で２時間撹拌した。反応混合物に２Ｎ−水酸化ナトリウム水溶液（５．４ｍＬ）を８０℃で加え、１００℃で１時間撹拌した。反応混合物に５Ｎ−塩酸を加えて中性にし、減圧濃縮した。得られた残渣のＴＨＦ（２１ｍＬ）溶液を０℃に冷却し、飽和炭酸水素ナトリウム水溶液（１．３ｍＬ，１．６ｍｍｏｌ）及び二炭酸ジ−ｔｅｒｔ−ブチル（３５０ｍｇ，１．６ｍｍｏｌ）を０℃で加え、室温で２４時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（４０８ｍｇ，０．８５ｍｍｏｌ，収率７９％）を白色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４７９［Ｍ−Ｈ］^- (6) (1- {2-Bromo-4- [N- (tert-butyl) sulfamoyl] -6-fluorophenyl} -2-methylpropan-2-yl) tert-butyl carbamate [55-6] ( Synthesis of compound [55-6])

A solution of compound [55-5] (467 mg, 1.1 mmol) in 1,4-dioxane (5.4 mL) was stirred at 80 ° C. for 2 hours. A 2N-sodium hydroxide aqueous solution (5.4 mL) was added to the reaction mixture at 80 ° C., and the mixture was stirred at 100 ° C. for 1 hour. 5N-Hydrochloric acid was added to the reaction mixture to make it neutral, and the mixture was concentrated under reduced pressure. A solution of the obtained residue in THF (21 mL) was cooled to 0 ° C., and saturated aqueous sodium hydrogen carbonate solution (1.3 mL, 1.6 mmol) and di-tert-butyl dicarbonate (350 mg, 1.6 mmol) were added at 0 ° C. In addition, it was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (408 mg, 0.85 mmol, yield 79%) as a white amorphous substance.
ESI-MSfound: 479 [MH] ^-

化合物［５５−６］（４０８ｍｇ，０．８５ｍｍｏｌ）に、ＴＦＡ（８．５ｍＬ）を室温で加え、室温で１９時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をＴＨＦ、クロロホルム及びｎ−ヘキサンの混合溶媒から再結晶することにより、表題化合物（３５０ｍｇ，０．８０ｍｍｏｌ，収率９４％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：８．０２（１Ｈ，ｔ，Ｊ＝１．４Ｈｚ），７．６９（１Ｈ，ｄｄ，Ｊ＝９．１，１．８Ｈｚ），３．２８（２Ｈ，ｄ，Ｊ＝２．７Ｈｚ），１．４２（６Ｈ，ｓ）． (7) Synthesis of 4- (2-amino-2-methylpropyl) -3-bromo-5-fluorobenzenesulfonamide trifluoroacetic acid salt [55-7] (hereinafter referred to as compound [55-7])

To compound [55-6] (408 mg, 0.85 mmol), TFA (8.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of THF, chloroform and n-hexane to give the title compound (350 mg, 0.80 mmol, yield 94%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.02 (1 H, t, J = 1.4 Hz), 7.69 (1 H, dd, J = 9.1, 1.8 Hz), 3.28 (2H, d, J = 2.7Hz), 1.42 (6H, s).

(8) (S) -3-bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzene sulfone Synthesis of Amid [55] From compound [A-2] (34 mg, 0.18 mmol) and compound [55-7] (70 mg, 0.16 mmol) according to the method of Example 2, the title compound (36 mg, 0.070 mmol). , Yield 52%) was obtained as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.93 (1H, s), 7.57 (1H, d, J = 8.7 Hz), 7.47 (1H, d, J = 7.8 Hz) ), 7.02 (1H, s), 6.90 (1H, d, J = 7.8Hz), 4.15-4.04 (3H, m), 3.15-3.07 (2H, m) ), 2.98 (1H, dd, J = 11.7, 4.3Hz), 2.88 (1H, dd, J = 11.4, 7.3Hz), 2.41 (3H, s), 1 .17 (6H, s).
ESI-MSfound: 514 [M + H] ⁺

[Example 56]
(S) -2- (2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -N-ethyl-3-fluoro-5-sulfa Synthesis of moylbenzamide trifluoroacetic acid salt [56] (hereinafter referred to as compound [56])

From compound [55] (36 mg, 0.070 mmol), the title compound (17 mg, 0.027 mmol, yield 39%) was obtained as a white amorphous substance according to the method of Example 53.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.84-7.81 (2H, m), 7.49 (1H, d, J = 7.8 Hz), 7.03 (1H, s), 6.94 (1H, d, J = 7.8Hz), 4.28-4.11 (3H, m), 3.39-3.21 (6H, m), 2.42 (3H, s), 1.45 (3H, s), 1.44 (3H, s), 1.20 (3H, t, J = 7.3Hz).
ESI-MSfound: 507 [M-TFA + H] ⁺

[Example 57]
(S) -4-Chloro-5-(2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) thiophene-2-sulfonamide trifluoroacetic acid Synthesis of salt [57] (hereinafter referred to as compound [57])

化合物［４５−３］（２００ｍｇ，０．６０ｍｍｏｌ）から実施例４３の工程（２）の方法に準じて表題化合物（１２０ｍｇ，０．４３ｍｍｏｌ，収率７１％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８０［Ｍ−Ｈ］^- (1) Synthesis of N- (tert-butyl) -4-chloro-5-formylthiophen-2-sulfonamide [57-1] (hereinafter referred to as compound [57-1])

From compound [45-3] (200 mg, 0.60 mmol), the title compound (120 mg, 0.43 mmol, yield 71%) was obtained as a yellow oil according to the method of step (2) of Example 43.
ESI-MSfound: 280 [MH] ^-

化合物［５７−１］（１２０ｍｇ，０．４３ｍｍｏｌ）のエタノール（２．１ｍＬ）溶液に、水素化ホウ素ナトリウム（２１ｍｇ，０．５６ｍｍｏｌ）を０℃で加え、０℃で３０分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（９１ｍｇ，０．３２ｍｍｏｌ，収率７５％）を黄色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：２８２［Ｍ−Ｈ］^- (2) Synthesis of N- (tert-butyl) -4-chloro-5- (hydroxymethyl) thiophen-2-sulfonamide [57-2] (hereinafter referred to as compound [57-2])

Sodium borohydride (21 mg, 0.56 mmol) was added to a solution of compound [57-1] (120 mg, 0.43 mmol) in ethanol (2.1 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (91 mg, 0.32 mmol, yield 75%) as a yellow oil.
ESI-MSfound: 282 [MH] ^-

化合物［５７−２］（９１ｍｇ，０．３２ｍｍｏｌ）のジクロロメタン（１．６ｍＬ）溶液に、四臭化炭素（２１２ｍｇ，０．６４ｍｍｏｌ）及びトリフェニルホスフィン（１６８ｍｇ，０．６４ｍｍｏｌ）を０℃で加え、室温で１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することにより、表題化合物（６５ｍｇ，０．１９ｍｍｏｌ，収率５８％）を無色油状物として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３４４［Ｍ−Ｈ］^- (3) Synthesis of 5- (bromomethyl) -N- (tert-butyl) -4-chlorothiophene-2-sulfonamide [57-3] (hereinafter referred to as compound [57-3])

Carbon tetrabromide (212 mg, 0.64 mmol) and triphenylphosphine (168 mg, 0.64 mmol) were added to a solution of compound [57-2] (91 mg, 0.32 mmol) in dichloromethane (1.6 mL) at 0 ° C. , Stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (65 mg, 0.19 mmol, yield 58%) as a colorless oil.
ESI-MSfound: 344 [MH] ^-

化合物［５７−３］（６５ｍｇ，０．１９ｍｍｏｌ）から実施例５１の工程（３）及び実施例５１の工程（５）〜（７）の方法に準じて表題化合物（１９ｍｇ，０．０５９ｍｍｏｌ，収率３１％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．４２（１Ｈ，ｓ），２．９５（２Ｈ，ｓ），１．２５（９Ｈ，ｓ），１．１６（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３２５［Ｍ＋Ｈ］⁺ (4) Of 5- (2-amino-2-methylpropyl) -N- (tert-butyl) -4-chlorothiophene-2-sulfonamide [57-4] (hereinafter referred to as compound [57-4]) Synthetic

The title compound (19 mg, 0.059 mmol, yield) from compound [57-3] (65 mg, 0.19 mmol) according to the method of step (3) of Example 51 and steps (5) to (7) of Example 51. A rate of 31%) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.42 (1H, s), 2.95 (2H, s), 1.25 (9H, s), 1.16 (6H, s).
ESI-MSfound: 325 [M + H] ⁺

(5) (S) -4-chloro-5- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) thiophene-2-sulfonamide Synthesis of trifluoroacetic acid salt [57] From compound [A-2] (11 mg, 0.059 mmol) and compound [57-4] (19 mg, 0.059 mmol) in step (5) of Examples 2 and 49. The title compound (15 mg, 0.026 mmol, yield 44%) was obtained as a colorless oil according to the method.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.52-7.50 (2 H, m), 7.05 (1 H, s), 6.95 (1 H, d, J = 7.8 Hz), 4.30-4.24 (2H, m), 4.18-4.14 (1H, m), 3.51-3.45 (1H, m), 3.36-3.29 (3H, m) ) 2.42 (3H, s), 1.45 (6H, s).
ESI-MSfound: 458 [M-TFA + H] ⁺

[Example 58]
(S) -3-Bromo-4- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzenesulfonamide [58] ] (Hereinafter referred to as compound [58])

From compound [A-5] (26 mg, 0.14 mmol) and compound [55-7] (74 mg, 0.17 mmol) according to the method of Example 2, the title compound (33 mg, 0.063 mmol, yield 45%). Was obtained as a brown amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.93 (1 H, s), 7.59-7.56 (1 H, m), 7.47 (1 H, t, J = 8.2 Hz), 6.98-6.95 (2H, m), 4.14-4.05 (3H, m), 3.16-3.07 (2H, m), 3.00 (1H, dd, J = 11) .2,3.9Hz), 2.90 (1H, dd, J = 11.2, 7.5Hz), 2.47 (3H, s), 1.17 (6H, s).
ESI-MSfound: 514 [M + H] ⁺

[Example 59]
(S) -2- (2-{[3- (2-Cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -N-ethyl-3-fluoro-5-sulfa Synthesis of MethylBenzamide [59] (hereinafter referred to as Compound [59])

Compound [58] (33 mg, 0.063 mmol) was mixed with 70% aqueous ethylamine solution (2.0 mL), Pd (PPh ₃ ) ₄ (7.3 mg, 0.0063 mmol) and triethylamine (0.026 mL, 0.19 mmol). The mixture was added at room temperature, and the mixture was stirred at 110 ° C. for 1 hour using a microwave reactor under a carbon monoxide atmosphere. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography. A 1N aqueous sodium hydroxide solution was added to the obtained compound, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.5 mg, 0.017 mmol, yield 27%) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.78 (1H, d, J = 1.8 Hz), 7.70 (1H, dd, J = 9.4, 1.6 Hz), 7.47 (1H, t, J = 8.0Hz), 6.98-6.96 (2H, m), 4.15-4.04 (3H, m), 3.37 (2H, q, J = 7. 2Hz), 3.26-3.16 (2H, m), 3.03 (1H, d, J = 10.5Hz), 2.93-2.88 (1H, m), 2.47 (3H, 3H, s), 1.28-1.19 (9H, m).
ESI-MSfound: 507 [M + H] ⁺

[Example 60]
(S) -4- (2-{[3- (2-Cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3- (1-ethyl-1H-pyrazole-5) -Il) Synthesis of benzenesulfonamide trifluoroacetic acid salt [60] (hereinafter referred to as compound [60])

From compound [A-5] (14 mg, 0.071 mmol) and compound [51-7] (40 mg, 0.078 mmol) according to the method of step (8) of Example 51, the title compound (22 mg, 0.035 mmol, Yield 49%) was obtained as a white amorphous substance.
^{1 H-NMR (400MHz, CD} 3 OD) δ: 7.98 (1H, dd, J = 8.2,2.3Hz), 7.81 (1H, d, J = 2.3Hz), 7.67 (1H, d, J = 8.2Hz) 7.60 (1H, d, J = 2.3Hz), 7.49 (1H, t, J = 8.2Hz), 7.01-6.97 (2H) , M), 6.41 (1H, d, J = 1.8Hz), 4.22-4.18 (2H, m), 4.10-4.06 (1H, m), 3.91-3 .90 (2H, m), 3.35-3.06 (4H, m), 2.47 (3H, s), 1.33 (3H, t, J = 7.1Hz), 1.16 (6H) , S).
ESI-MSfound: 512 [M-TFA + H] ⁺

[Example 61]
(S) -3-Bromo-4- (2-{[3- (2-chloro-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzenesulfonamide [61] ] (Hereinafter referred to as compound [61])

From compound [A-1] (41 mg, 0.21 mmol) and compound [55-7] (109 mg, 0.25 mmol) according to the method of Example 2, the title compound (65 mg, 0.13 mmol, yield 60%). Was obtained as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.93 (1H, s), 7.57 (1H, dd, J = 9.1, 1.8 Hz), 7.20 (1H, d, J) = 8.2Hz), 6.91 (1H, d, J = 0.9Hz), 6.74 (1H, dd, J = 8.0, 1.1Hz), 4.11-4.00 (3H, 3H, m), 3.15-3.06 (2H, m), 3.00 (1H, dd, J = 11.2, 3.9Hz), 2.91-2.84 (1H, m), 2. 32 (3H, s), 1.16 (6H, s).
ESI-MSfound: 523 [M + H] ⁺

[Example 62]
(S) -2- (2-{[3- (2-Chloro-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -N-ethyl-3-fluoro-5-sulfa Synthesis of MethylBenzamide [62] (hereinafter referred to as Compound [62])

From compound [61] (31 mg, 0.059 mmol), the title compound (11 mg, 0.022 mmol, yield 37%) was obtained as a white solid according to the method of Example 59.
¹ H-NMR (400MHz, CD ₃ OD) δ: 7.78 (1H, d, J = 1.8Hz), 7.69 (1H, dd, J = 9.4, 1.6Hz), 7.20 (1H, d, J = 8.2Hz), 6.90 (1H, d, J = 1.1Hz), 6.75 (1H, dd, J = 8.0, 1.1Hz), 4.10- 3.96 (3H, m), 3.37 (2H, q, J = 7.3Hz), 3.24-3.16 (2H, m), 3.00 (1H, d, J = 10.1Hz ), 2.89-2.84 (1H, m), 2.31 (3H, s), 1.21 (3H, t, J = 7.3Hz), 1.17 (6H, s).
ESI-MSfound: 516 [M + H] ⁺

[Example 63]
(S) -5-(2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -4- (1-ethyl-1H-pyrazol-5) -Il) Synthesis of thiophene-2-sulfonamide trifluoroacetic acid salt [63] (hereinafter referred to as compound [63])

化合物［５７−１］（１００ｍｇ，０．３６ｍｍｏｌ）から実施例４８の工程（２）及び実施例５７の工程（２）の方法に準じて表題化合物（４１ｍｇ，０．１２ｍｍｏｌ，収率３４％）を白色固体として得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：３４４［Ｍ＋Ｈ］⁺ (1) N- (tert-butyl) -4- (1-ethyl-1H-pyrazole-5-yl) -5- (hydroxymethyl) thiophen-2-sulfonamide [63-1] (hereinafter, compound [63] -1])

The title compound (41 mg, 0.12 mmol, yield 34%) from compound [57-1] (100 mg, 0.36 mmol) according to the method of step (2) of Example 48 and step (2) of Example 57. Was obtained as a white solid.
ESI-MSfound: 344 [M + H] ⁺

化合物［６３−１］（１１０ｍｇ，０．３２ｍｍｏｌ）から実施例５７の工程（３）、実施例５１の工程（３）及び実施例５１の工程（５）〜（７）の方法に準じて表題化合物（２０ｍｇ，０．０４９ｍｍｏｌ，収率１５％）を無色油状物として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：７．５６（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４４（１Ｈ，ｓ），６．３１（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），３．９７（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），２．８７（２Ｈ，ｓ），１．３３（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．２６（９Ｈ，ｓ），１．０１（６Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３８３［Ｍ−Ｈ］^- (2) 5- (2-Amino-2-methylpropyl) -N- (tert-butyl) -4- (1-ethyl-1H-pyrazole-5-yl) thiophene-2-sulfonamide [63-2] Synthesis of compound (hereinafter referred to as compound [63-2])

From compound [63-1] (110 mg, 0.32 mmol) according to the method of Step 57 of Example 57, Step (3) of Example 51 and Steps (5) to (7) of Example 51. Compound (20 mg, 0.049 mmol, yield 15%) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.56 (1H, d, J = 1.8 Hz), 7.44 (1H, s), 6.31 (1H, d, J = 1.8 Hz) ), 3.97 (2H, q, J = 7.2Hz), 2.87 (2H, s), 1.33 (3H, t, J = 7.3Hz), 1.26 (9H, s), 1.01 (6H, s).
ESI-MSfound: 383 [MH] ^-

(3) (S) -5-(2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -4- (1-ethyl-1H-) Synthesis of pyrazole-5-yl) thiophen-2-sulfonamide trifluoroacetate [63] In a mixed solution of compound [63-2] (9.8 mg, 0.025 mmol) in ethanol (310 μL) -toluene (310 μL). Compound [A-5] (4.6 mg, 0.025 mmol) and DIPEA (16 μL, 0.098 mmol) were added at room temperature, and the mixture was stirred at 110 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography to obtain a colorless oil (9.8 mg). From the obtained colorless oil, the title compound (7.7 mg, 0.012 mmol, yield 50%) was obtained as a colorless oil according to the method of step (5) of Example 49.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.57 (1H, d, J = 1.8 Hz), 7.52-7.46 (2H, m), 7.00-6.96 (2H) , M), 6.38 (1H, d, J = 1.8Hz), 4.22-4.17 (2H, m), 4.09-4.05 (1H, m), 4.00 (2H) , Q, J = 7.2Hz), 3.37-3.24 (3H, m), 3.19 (1H, dd, J = 12.6, 8.9Hz), 2.47 (3H, s) , 1.36 (3H, t, J = 7.1Hz), 1.29 (3H, s), 1.28 (3H, s).
ESI-MSfound: 518 [M-TFA + H] ⁺

[Example 64]
(S) -5-(2-{[3- (2-Cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -4- (1-ethyl-1H-pyrazole-5) -Il) Synthesis of thiophene-2-sulfonamide trifluoroacetic acid salt [64] (hereinafter referred to as compound [64])

From compound [A-2] (5.1 mg, 0.027 mmol) and compound [63-2] (10 mg, 0.027 mmol) according to the method of step (3) of Example 63, the title compound (6.7 mg, 0.011 mmol, yield 40%) was obtained as a white amorphous substance.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.58 (1 H, d, J = 1.8 Hz), 7.53-7.49 (2 H, m), 7.02 (1 H, s), 6.95 (1H, d, J = 7.8Hz), 6.40 (1H, d, J = 1.8Hz), 4.23-4.18 (2H, m), 4.11-4.07 (1H, m), 4.01 (2H, q, J = 7.3Hz), 3.37-3.16 (4H, m), 2.42 (3H, s), 1.37 (3H, t) , J = 7.3Hz), 1.30 (3H, s), 1.29 (3H, s).
ESI-MSfound: 518 [M-TFA + H] ⁺

[Example 65]
(S) -N ^1- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -2-fluorobenzene-1,4-disulfonamide trifluoroacetate Synthesis of [65] (hereinafter referred to as compound [65])

化合物［４３−１］（５００ｍｇ，１．６ｍｍｏｌ）から実施例４５の工程（４）〜（５）の方法に準じて表題化合物（６１０ｍｇ，１．４ｍｍｏｌ，収率８４％）を白色アモルファスとして得た。
ＥＳＩ−ＭＳｆｏｕｎｄ：４５２［Ｍ−Ｈ］^- (1) 2-({4- [N- (tert-butyl) sulfamoyl] -2-fluorophenyl} sulfonamide) tert-butyl ethylcarbamate [65-1] (hereinafter referred to as compound [65-1]) Synthesis of

From compound [43-1] (500 mg, 1.6 mmol), the title compound (610 mg, 1.4 mmol, yield 84%) was obtained as a white amorphous substance according to the methods of steps (4) to (5) of Example 45. It was.
ESI-MSfound: 452 [MH] ^-

化合物［６５−１］（６１０ｍｇ，１．４ｍｍｏｌ）の酢酸エチル（４．５ｍＬ）溶液に、塩化水素の１，４−ジオキサン溶液（４．０Ｍ，４．５ｍＬ）を０℃で加え、室温で７時間撹拌した。反応混合物を減圧濃縮した後、０℃に冷却したｎ−ヘキサンを加えた。得られた懸濁液を濾取することにより、表題化合物（４７４ｍｇ，１．２ｍｍｏｌ，収率９０％）を白色固体として得た。
¹Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ：８．０７−８．０３（１Ｈ，ｍ），７．８５（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝９．６，１．４Ｈｚ），３．２５−３．２２（２Ｈ，ｍ），３．０８−３．０３（２Ｈ，ｍ），１．２１（９Ｈ，ｓ）．
ＥＳＩ−ＭＳｆｏｕｎｄ：３５４［Ｍ−ＨＣｌ＋Ｈ］⁺ (2) N ¹ - (2-aminoethyl) -N ⁴ - (tert-butyl) -2-fluoro-1,4-di-nitrobenzene [65-2] (hereinafter, referred to as the compound [65-2] ) Synthesis

To a solution of compound [65-1] (610 mg, 1.4 mmol) in ethyl acetate (4.5 mL) was added a solution of hydrogen chloride 1,4-dioxane (4.0 M, 4.5 mL) at 0 ° C. and at room temperature. The mixture was stirred for 7 hours. The reaction mixture was concentrated under reduced pressure, and then n-hexane cooled to 0 ° C. was added. The obtained suspension was collected by filtration to give the title compound (474 mg, 1.2 mmol, 90% yield) as a white solid.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.07-8.03 (1H, m), 7.85 (1H, dd, J = 8.2, 1.8 Hz), 7.82 (1H) , Dd, J = 9.6, 1.4Hz), 3.25-3.22 (2H, m), 3.08-3.03 (2H, m), 1.21 (9H, s).
ESI-MSfound: 354 [M-HCl + H] ⁺

(3) (S) -N ^1- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -2-fluorobenzene-1,4-disulfoneamide tri Synthesis of Fluoroacetate [65] Compound [65-2] (74 mg, 0.19 mmol) and DIPEA in a mixed solution of ethanol (530 μL) -toluene (530 μL) of compound [A-5] (30 mg, 0.16 mmol). (107 μL, 0.64 mmol) was added at room temperature, and the mixture was stirred at 85 ° C. for 7 hours. Then, the mixture was stirred at 80 ° C. for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography to obtain a colorless oil. From the obtained colorless oil, the title compound (29 mg, 0.048 mmol, yield 31%) was obtained as a white amorphous substance according to the method of step (5) of Example 49.
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 8.07 (1H, dd, J = 8.0, 7.1 Hz), 7.88-7.82 (2H, m), 7.50 (1H) , T, J = 8.2Hz), 7.02-6.98 (2H, m), 4.36-4.31 (1H, m), 4.20 (1H, dd, J = 9.8, 4.3Hz), 4.13 (1H, dd, J = 10.1, 5.5Hz), 3.41 (1H, dd, J = 12.8, 3.2Hz), 3.36-3.26 (5H, m), 2.48 (3H, s).
ESI-MSfound: 487 [M-TFA + H] ⁺

[Test Example 1]
Receptor binding test using human adrenergic β ₂ (hβ ₂ ) receptor-expressing cell membrane In this test example, _{based on the inhibition of competitive binding of the radiolabeled adrenergic β 2} receptor ligand and the example compound to the receptor. The binding activity of the example compound to the adrenergic β _{2 receptor was evaluated.}
The full-length cDNA of the human adrenaline β ₂ receptor was introduced into the expression vector cDNA5 / FRT / V5-His-TOPO® (Thermo Fisher Scientific). The obtained expression vector was introduced into Chinese hamster ovary cells (hereinafter referred to as CHO cells) by the liposome method using Lipofectamine LTX (Thermofisher Scientific), and 10% bovine fetal serum (hereinafter referred to as FBS). , Hyglomycin B-containing Dulvecco's Modified Eagle Medium: Nutrient Mixture F-12 medium (hereinafter referred to as DMEM / F-12 medium) was used _{to prepare human adrenaline β 2} receptor stable expression cells.

Human adrenaline β ₂ receptor-expressing CHO cells were cultured in DMEM / F-12 medium containing 10% FBS and hygromycin B at 37 ° C. in the presence of _{5% CO 2.} After collecting the cells and disrupting the cells with a polytron homogenizer, the cell homogenate was centrifuged at 100,000 × g, and the obtained microsome fraction was used as a _{cell membrane fraction derived from human adrenaline β 2} receptor-expressing cells (hereinafter, β). _{2 It} was used as a receptor cell membrane) and the following binding test was performed.

_1-2 μg of β 2 receptor cell membrane is contained in 100 μL of assay buffer containing 50 mM Tris, 0.5 mM ethylenediaminetetraacetic acid (hereinafter referred to as EDTA), 5 mM magnesium chloride, and 120 mM sodium chloride. Prepared. Various concentrations assay buffer 50μL containing test compound, and (CGP-12177 labeled with ³ H (adrenergic beta ₂ receptor ligand); final concentration 0.2 nM) the radioligand assay buffer 50μL containing the 1.2mL It was added to the cluster tube (Corning) and mixed well. To this, _{100 μL of the assay buffer containing the β 2} receptor cell membrane prepared above was added, mixed well, and then reacted at 25 ° C. for 1 hour with shaking. A polyethyleneimine-coated Unifilter-96 GF / B plate (PerkinElmer) (hereinafter abbreviated as GF / B plate) was attached to a FilterMate cell harvester (PerkinElmer), and the reaction solution after the reaction was aspirated, and further. It was washed twice with a wash buffer containing 50 mM Tris. After drying the GF / B plate until it was dry, 40 μL of MicroScint-20 (PerkinElmer) was added to each well, and the radioactivity was measured with a microplate scintillation counter TopCount NXT (PerkinElmer).

Each of the test compounds, with the difference in radioactivity between the non-added test compound (DMSO added) and the positive control compound ICI-118,551 (known adrenaline β _{2 receptor selective inhibitor) 10 μM as 100%.} (binding activity of CGP-12177 labeled with ³ H,%) radioactivity at concentrations added calculates, ³ H-labeled inhibitory test compound concentration binding activity to 50% of the CGP-12177 (IC ₅₀ ) was asked.
The results are _{shown in the "hβ 2} inhibitory activity" column of Table 3.

[Test Example 2]
Evaluation of agonist activity using human adrenaline β ₂ (hβ ₂ ) receptor-expressing cells When an agonist (adrenaline, etc.) binds to the _{adrenaline β 2} receptor expressed on the hair-like non-pigmented epithelium, it is conjugated to the receptor. Adenylate cyclase is activated via the G protein, and the production of the second messenger, cAMP, occurs. Since cAMP is involved in the production of aqueous humor, increased production of cAMP increases intraocular pressure. Therefore, in order to lower the intraocular pressure using a certain compound, it is required that the agonist activity of the compound with respect to the _{adrenergic β 2 receptor is weak.} Therefore, in this test example, _{in order to determine the agonist activity of the example compound on the adrenergic β 2} receptor, evaluation using cAMP as an index was carried out.
_{Agonist activity was evaluated by expressing human Adrenaline β 2} Cell Line (hereinafter referred to as VariScreen β ₂ receptor), which is a cell expressing _{human adrenaline β 2} receptor among VariScreen® GPCR Cell Line (PerkinElmer). (Called a cell) was used.

EX-CELL Advanced CHO Fed-bach Medium containing 10% FBS, sodium pyruvate, L-glutamine or GlutaMAX-I (Thermofisher Scientific), VariScreen β _{2 receptor-expressing cells.} Alternatively, EX-CELL CHO DHFR ^- Medium (Nichirei Bioscience) was used, and the cells were cultured at _{37 ° C. in the presence of 5% CO 2.}

The evaluation using cAMP as an index was carried out according to the experimental procedure manual attached to the LANCE Ultra cAMP kit (PerkinElmer). HBSS (1x) containing a final concentration of 5 mM HEPES, 0.5 mM IBMX, and 0.1% bovine serum albumin was prepared and used as Stimulation Buffer. 5 μL of Stimulation Buffer containing various concentrations of test compound was added to a white 384-well plate, and the recovered cells were subsequently suspended in the Stimulation Buffer and added to 1000 cells / 5 μL / well. After reacting at 25 ° C. for 30 minutes, 5 μL of Eu-cAMP tracer working solution and 5 μL of ULlight-anti-cAMP working solution attached to the kit were added, and the mixture was further reacted at 25 ° C. for 1 hour. After the reaction, the time-resolved fluorescence energy transfer (TR-FRET) signal was read in a multi-label plate reader EnVision (PerkinElmer).

From the TR-FRET signal at each concentration of the positive control compound salbutamol (a known adrenergic β ₂ receptor selective stimulant), a dose-response curve was prepared using GraphpadPrism5, and Emax was calculated. The Emax of salbutamol was set to 100%, and the Emax was calculated from the dose-response curve of the test compound. Based on the Emax of carteolol, which is a known β-blocker, + when Emax is higher than carteolol, ± when Emax is lower than carteolol and 0 or more, and-when Emax is less than 0. Was judged.
The results are _{shown in the "hβ 2} agonist activity" column of Table 3.
Here, the reference carteolol is a typical β-blocker used in the treatment of glaucoma, and is known to be a partial agonist having a weak agonist activity. Therefore, it was shown that each Example compound determined to be "±" or "-" in Test Example 2 had a weaker agonist or antagonist activity than carteolol.
Furthermore, since the compound _{was shown to have hβ 2} inhibitory activity in Test Example 1, it was shown that each Example compound had a β blocking action.

[Test Example 3]
Test for Inhibiting Esterase Activity of Human Carbonic Anhydrase II (hCA-II) Carbonic anhydrase is an enzyme that reversibly converts carbon dioxide and water into bicarbonate ions and hydrogen ions, and in particular, human carbonic anhydrase II (CA-II). II) is known to be involved in aqueous production in the hairy non-pigmented epithelium. Zinc ions are coordinated to the histidine residue existing near the active center of this enzyme, and it is considered that it plays an important role in the enzyme activity. While over time method of measuring is known pH changes as an active measuring method of carbonic anhydrase, molecular activity is extremely high as 10 ⁶ s ^-1, measured is not easy.
Carbonic anhydrase is known to have esterase activity that hydrolyzes esters. As for the esterase activity of carbonic anhydrase, it is said that histidine residues and coordinated zinc ions existing near the active center are involved in the enzyme activity, and esterase is due to the sulfonamide structure common to carbonic anhydrase inhibitors. It is known that activity is also inhibited. That is, since the basic enzymatic properties of carbonic anhydrase's original enzyme activity and esterase activity are the same, the esterase activity of carbonic anhydrase is widely recognized as an alternative index of carbonic anhydrase's original enzyme activity. Has been done.
For the measurement of esterase activity, 4-nitrophenylacetic acid (hereinafter abbreviated as 4-NPA) is reacted with carbonic anhydrase using 4-nitrophenylacetic acid (hereinafter abbreviated as 4-NPA) as a substrate, and 4-nitrophenol (hereinafter, 4-NP) which is a hydrolyzate of 4-NPA is used. A method of measuring the absorbance of (abbreviated as) at a wavelength of 400 nm is widely used. Therefore, in this test example, whether or not the compound used inhibits the enzymatic activity of human carbonic anhydrase II (CA-II) was evaluated using the esterase activity as an index.
Recombinant human carbonic anhydrase II (Sigma) expressed in E. coli was mixed in an assay buffer containing 50 mM MOPS, 33 mM sodium sulfate, and 1 mM EDTA to a concentration of 0.1 to 0.2 μg / 100 μL, and a clear 96-well was used. 100 μL was added to the plate. 1 μL of test compounds of various concentrations dissolved in DMSO was added, and 10 μL of substrate dissolved in assay buffer was added. 4-NPA was used as the substrate. After reacting at 25 ° C. for 1 hour, the absorbance of 4-NP, which is a hydrolyzate of 4-NPA, was measured at a wavelength of 400 nm.

The hydrolysis rate was set to 100% as the measured value of the absorbance at a wavelength of 400 nm without the addition of the test compound (addition of DMSO), and the hydrolysis rate was calculated from the absorbance at each concentration of the test compound added, and the esterase activity was inhibited to 50%. The test compound concentration (IC ₅₀ ) was determined.
The results are shown in the "hCA-II inhibitory activity" column of Table 3.

Table 3

From the above, it was shown that the compound of the present invention has excellent adrenergic β ₂ receptor antagonist activity and carbonic anhydrase inhibitory activity.

The correspondence between the compounds of Examples 1 to 65 and the general formula (I) is shown below.

Since the compound represented by the general formula (I) of the present invention has adrenaline β ₂ receptor antagonist activity and carbonic anhydrase inhibitory activity, it is possible to reduce intraocular pressure. Therefore, the present invention is useful as a therapeutic or prophylactic agent for pathological conditions associated with intraocular pressure such as glaucoma and ocular hypertension.

Claims (24)

Equation (I):

[During the ceremony,
A represents a phenyl group or a 5- or 6-membered ring heteroaryl group (the phenyl group or the 5- or 6-membered ring heteroaryl group is represented by the <substituent group L> described later or the general formula: -Q-Ar. It may be substituted with 1 to 3 substituents selected from the represented groups);
here,
Q represents a single bond, a lower alkylene group, a lower alkenylene group or a lower alkynylene group (one or two or more methylene groups constituting the lower alkylene group independently form an oxygen atom, a sulfur atom, a sulfinyl group, and the like. a sulfonyl group, a carbonyl group or the general formula: -N (R ^N) - group represented by (R ^N represents a hydrogen atom or a lower alkyl group) may be the entire methylene group is replaced by, and / or , The hydrogen constituting the methylene group may be substituted with a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group);
Ar represents a phenyl group or a 5- or 6-membered ring heteroaryl group (the phenyl group or the 5- or 6-membered ring heteroaryl group is 1 to 3 selected from the <substituent group M> described later. It may be substituted with a substituent);
R ¹ and R ² independently represent a hydrogen atom or a lower alkyl group;
X ¹ represents a single bond or lower alkylene group
X ² represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, the general formula: -N (R ^N) - group represented by the general formula: represented by -N (R ^N) CO- group, the general formula: -CON (R ^N) -, a group represented by the general _{^{formula: -N (R N) SO 2}} - or the ^{_{formula: -SO 2 N (R N)}} - represents a group represented by (R ^N in each formula represents a hydrogen atom or a lower alkyl group);
B is
General formula:

(During the ceremony,
W ¹ represents a nitrogen atom or a methine group:
R ^b1 is a substituent or a phenyl group or a 5- or 6-membered ring heteroaryl group selected from the <substituent group N> described later (the phenyl group or the 5- or 6-membered ring heteroaryl group is It may be substituted with a lower alkyl group);
R ^b2 represents a hydrogen atom or a halogen atom), or a group represented by
General formula:

(During the ceremony,
W ² represents an oxygen atom or a sulfur atom;
W ³ represents a nitrogen atom or a methine group;
R ^b1 is a substituent or a phenyl group or a 5- or 6-membered ring heteroaryl group selected from the <substituent group N> described later (the phenyl group or the 5- or 6-membered ring heteroaryl group is It is a group represented by)), which may be substituted with a lower alkyl group;
<Substitute group L>, <Substitute group M> and <Substitute group N> are defined as follows.
<Substituent group L>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, Lower alkylsulfonylamino group and lower alkoxycarbonylamino group <substituent group M>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, cyclic amino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, lower alkanoylamino group, Lower alkylsulfonylamino group and lower alkoxycarbonylamino group <substituent group N>:
Halogen atom, hydroxyl group, nitro group, cyano group, amino group, lower alkyl group, cycloalkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl Group, lower alkanoyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylamino group, dilower alkylamino group, carbamoyl group, monolower alkylcarbamoyl group, dilower alkylcarbamoyl group, amino lower alkyl group, lower alkylamino lower Alkyl group and dilower alkylamino lower alkyl group]
The compound represented by or a pharmaceutically acceptable salt thereof. B is
General formula:

(In the formula, R ^b1 and R ^b2 are as defined above), or a group represented by
General formula:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a group represented by (in the formula, R ^{b1 is as defined above).} The compound according to claim 1 or 2, wherein R ^b1 is a halogen atom, a carbamoyl group, a monolower alkylcarbamoyl group, a dilower alkylcarbamoyl group, or a pyrazolyl group substituted with a lower alkyl group, or a pharmaceutical drug of the compound. Tolerant salt. A is the general formula:

(In each formula,
R ^a1 is a substituent selected from the <substituent group L> or the group represented by the general formula: −Q—Ar;
R ^a2 and R ^a3 are hydrogen atoms independently or substituents selected from <substituent group L>).
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is selected from the groups represented by. A is the general formula:

The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is (in the formula, R ^a1 , R ^a2 and R ^{a3 are as defined above).} A is the general formula:

The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is (in the formula, R ^a1 and R a ^{2 are as defined above).} The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R ^{a1 is a substituent selected from the <substituent group L>.} The compound according to claim 7, wherein R ^a1 is a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a mono-lower alkyl carbamoyl group, or a di-lower alkyl carbamoyl group, or pharmaceutically thereof. Acceptable salt. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R ^{a1 is a substituent represented by the general formula: −Q—Ar.} The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein Q is a single bond, a lower alkylene group, an oxygen atom, or a carbonyl group. Ar may be substituted with 1 to 3 substituents selected from <substituent group M>, phenyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, triazolyl group, 1 The compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof, which is a 3,4-oxadiazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, or a pyrimidinyl group. Claims 4 to 11, wherein R ^a2 is a substituent selected from a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a cycloalkyl group, a halo lower alkyl group, a lower alkoxy group, or a hydroxy lower alkyl group. The compound according to any one item or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 4 to 12, wherein R ^{a2 is a lower alkyl group, or a pharmaceutically acceptable salt thereof.} A is the general formula:

The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is (in the formula, ^{Ra1 is as defined above).} The compound according to claim 14, wherein R ^a1 is a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkylamino group, a dilower alkylamino group, a cyclic amino group, or a phenyl group, or a pharmaceutically acceptable compound thereof. salt. The formula (I) is the following formula (I-2):

The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which is represented by (A, R ¹ , R ^{2 and B are as defined above).} The following compounds (1) to (26):
(1) (S) -4- (2-{[3- (2-chloro-5-methylphenoxy) -2-hydroxypropyl] amino} propan-2-yl) -3-fluorobenzenesulfonamide,
(2) (S) -4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(3) (S) -4- (2-{[3- (2-chloro-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(4) (S) -4- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(5) (S) -4- (2-{[3- (2-cyano-5-methoxyphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(6) (S) -4- (2-{[3- (2-cyano-5-fluorophenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(7) (S) -4- (2-{[3- (2-cyano-3-fluorophenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(8) (S) -4- (2-{[3- (3-chloro-2-cyanophenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(9) (S) -4- (2-{[3- (2-cyano-3-ethylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3-fluorobenzenesulfonamide,
(10) (S) -3-fluoro-4- (2-{[3- (2-fluoro-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) benzenesulfonamide,
(11) (S) -3-fluoro-4- [2-({2-hydroxy-3-[(4-morpholino-1,2,5-thiadiazole-3-yl) oxy] propyl} amino) -2 -Methylpropyl] benzenesulfonamide,
(12) (S) -4- [2-({3-[(4-ethyl-1,2,5-thiadiazole-3-yl) oxy] -2-hydroxypropyl} amino) -2-methylpropyl] -3-Fluorobenzene sulfonamide,
(13) (S) -3-fluoro-4- [2-({2-hydroxy-3-[(4-isopropyl-1,2,5-thiadiazole-3-yl) oxy] propyl} amino) -2 -Methylpropyl] benzenesulfonamide,
(14) (S) -3-Fluoro-4- {2-[(2-Hydroxy-3-{[4- (piperidin-1-yl) -1,2,5-thiadiazole-3-yl] oxy} Propyl) amino] -2-methylpropyl} benzenesulfonamide,
(15) (S) -3-fluoro-4- [2-({2-hydroxy-3-[(4-phenyl-1,2,5-thiadiazole-3-yl) oxy] propyl} amino) -2 -Methylpropyl] benzenesulfonamide,
(16) (S) -4- [2-({3-[(4-Cyclopropyl-1,2,5-thiadiazole-3-yl) oxy] -2-hydroxypropyl} amino) -2-methylpropyl ] -3-Fluorobenzenesulfonamide,
(17) (S) -3-chloro -N ² - [2 - ({2-hydroxy-3 - [(4-morpholino-1,2,5-thiadiazol-3-yl) oxy] propyl} amino) ethyl ] Thiophene-2,5-disulfone amide,
(18) (S) -3- chloro ^{-N 2 - (2 - {[} 3- (2- cyano-5-methylphenoxy) -2-hydroxypropyl] amino} ethyl) thiophene-2,5-sulfonamide,
(19) (S) -3- chloro ^{-N 2 - [2 - ({} 3- (2- chloro-5-methylphenoxy) -2-hydroxypropyl} amino) ethyl] thiophene-2,5-sulfonamide,
(20) (S) -4-chloro-5-[(3-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} propyl) sulfonyl] thiophene-2-sulfonamide,
(21) (S) -3-bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) benzenesulfonamide,
(22) (S) -3-Bromo-4- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzenesulfon Amide,
(23) (S) -4-chloro-5- (2-{[3- (2-cyano-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) thiophene-2-sulfonamide ,
(24) (S) -4- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -3- (1-ethyl-1H-) Pyrazole-5-yl) benzenesulfonamide,
(25) (S) -3-Bromo-4- (2-{[3- (2-chloro-5-methylphenoxy) -2-hydroxypropyl] amino} -2-methylpropyl) -5-fluorobenzenesulfon Amide,
(26) (S) -N ^1- (2-{[3- (2-cyano-3-methylphenoxy) -2-hydroxypropyl] amino} ethyl) -2-fluorobenzene-1,4-disulfoneamide A compound according to claim 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating an eye disease, which comprises the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 18, wherein the eye disease is selected from the group consisting of glaucoma, ocular hypertension, increased intraocular pressure due to trauma, increased intraocular pressure due to inflammation, increased intraocular pressure due to a drug, and increased intraocular pressure after surgery. Stuff. The pharmaceutical composition according to claim 19, wherein the eye disease is glaucoma or ocular hypertension. An eye disease preventive agent or an eye disease therapeutic agent, which comprises the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. The preventive agent according to claim 21, wherein the eye disease is selected from the group consisting of glaucoma, ocular hypertension, increased intraocular pressure due to trauma, increased intraocular pressure due to inflammation, increased intraocular pressure due to a drug, and increased intraocular pressure after surgery. Or a remedy. The prophylactic or therapeutic agent according to claim 22, wherein the eye disease is glaucoma or ocular hypertension. An intraocular pressure-lowering agent comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.