JP2006316054A - High-conductance type calcium-sensitive k channel opening agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high-conductance type calcium-sensitive K channel opening agent. <P>SOLUTION: A medicine which is the high-conductance type calcium-sensitive K channel opening agent comprises a compound represented by formula (I) (wherein, R<SP>1</SP>and R<SP>3</SP>represent each a sulfonamide, a carbamoyl, an acyl, an amino or the like; m and n represent each 0-2; R<SP>2</SP>and R<SP>4</SP>represent each a cyano, a nitro, a hydroxy group, an alkoxy, a halogen or an alkyl; ring A represents a benzene or a heterocyclic ring; ring B represents a benzene, a heterocyclic ring, a cycloalkane or the like; and ring Q represents a pyrazole or an isoxazole) or a salt thereof as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a high conductance calcium sensitive K channel opener useful for the treatment of diseases such as pollakiuria, urinary incontinence, asthma, chronic obstructive pulmonary disease (COPD), cerebral infarction, and subarachnoid hemorrhage.

  Potassium is the most abundant cation in the cell and is very important for maintaining physiological homeostasis. Potassium channels are found in almost all vertebrate cells, and potassium influx from these channels is essential for maintaining the resting membrane potential of hyperpolarized cells.

  High conductance calcium-sensitive potassium channels (also referred to as BK channels or maxi-K channels) are expressed particularly in neurons and smooth muscle cells. Since the maxi-K channel is activated by an increase in intracellular calcium concentration and membrane depolarization, it has been considered to play an extremely important role in controlling calcium influx depending on the potential. Increases in intracellular calcium levels mediate many processes such as neurotransmitter release, smooth muscle contraction, cell proliferation and cell death. In fact, the opening of the maxi-K channel causes a strong membrane hyperpolarization, thereby suppressing these calcium-induced reactions. Therefore, a substance having an action of opening the maxi-K channel suppresses physiological reactions mediated by various depolarizations, thereby treating diseases such as cerebral infarction, subarachnoid hemorrhage, frequent urination and urinary incontinence. Useful for.

It has been reported that a drug that opens a BK channel has an action of suppressing airway contraction of a guinea pig airway specimen caused by electronic stimulation (Non-patent Document 1). Therefore, it is effective for the treatment of asthma, COPD, etc., for example. Further, it has been suggested that a drug that opens a BK channel can be a therapeutic drug for sexual dysfunction such as erectile dysfunction (Patent Document 1).
Examples of the high conductance calcium-sensitive K channel opener include pyrrole derivatives (for example, Patent Document 2), furan derivatives (for example, Patent Document 3), and nitrogen-containing 5 in which a nitrogen atom is substituted with a phenyl group or a benzyl group. Various reports have been made on member ring derivatives (for example, Patent Document 4) and diphenyltriazole derivatives (for example, Non-Patent Document 2).

On the other hand, cyclooxygenase 2 inhibitors such as celecoxib and valdecoxib have been used as therapeutic agents for inflammation-related diseases such as rheumatoid arthritis. No use has been reported (for example, Patent Document 5 and Patent Document 6).
As related compounds, pyrazole derivatives useful as neurotensin receptor antagonists and cyclooxygenase inhibitors are known (Patent Document 7, Patent Document 8, Non-Patent Document 3, Non-Patent Document 4).

WO 00/34244 WO 96/40634 JP2000-351773 WO 98/04135 Special table hei 09-506350 Special table flat 09-500372 11-504624 JP 63-022080 J. Pharmacol. Exp. Ther., (1998) 286: p.952-958 J. Med. Chem., 2000, 45, p.2942-2952 J. Am. Chem. Soc., 1997, 119, p.4882-4886 J. Med. Chem., 1997, 40, p.1347-1365

  The present invention provides a compound having an excellent high conductance calcium-sensitive K channel opening action and useful for the treatment of diseases such as frequent urination, urinary incontinence, asthma, COPD, cerebral infarction, and subarachnoid hemorrhage. is there.

As a result of intensive studies, the present inventors have found that the compound represented by the following formula has an excellent high conductance type calcium sensitive K channel opening action, and completed the present invention.
That is, the present invention is as follows.

〔式中、環Ａはベンゼンまたは複素環を示す。
環Ｂはベンゼン、複素環、シクロアルカンまたはシクロアルケンを示す。
環Ｑは下式から選ばれる基を示す。

Ｒ^１およびＲ^３は同一または異なって、それぞれ下式から選ばれる基を示す。

Ｒ^５およびＲ^６は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合されていてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、（５）置換されていてもよい複素環式基、もしくは（６）アルコキシカルボニルを示すか、または（７）Ｒ^５およびＲ^６が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。
Ｒ^７は（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合されていてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）アルコキシカルボニルを示す。
Ｒ^１４は水素、アルコキシ、水酸基、シアノまたは置換されていてもよいアルキルを示す。
ｍおよびｎは、同一または異なって、それぞれ０、１または２を示す。
Ｒ^２およびＲ^４は同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲン、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノまたは置換されていてもよいアルキルを示す。但し、ｍが２の時、２つのＲ^２は同一または異なっていてもよく、ｎが２の時、２つのＲ^４は同一または異なっていてもよい。
また、Ｒ^１とＲ^２がそれぞれ一緒になって、環Ａとともに、下式から選ばれる基を形成してもよい。

また、Ｒ^３とＲ^４がそれぞれ一緒になって、環Ｂとともに、下式から選ばれる基を形成してもよい。

ｐは１〜３の整数を示す。
Ｒ^１３は（１）置換されていてもよいアルキル、（２）シアノ、（３）水素、（４）ハロゲン、（５）置換されていてもよいアミノ、（６）アルケニル、（７）置換されていてもよいカルバモイル、（８）アルコキシカルボニル、（９）カルボキシ、（１０）複素環式基、（１１）水酸基または（１２）アルコキシを示す。〕
により表される化合物またはその製薬上許容し得る塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。 1. Formula (I)

[Wherein, ring A represents benzene or a heterocyclic ring.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
Ring Q represents a group selected from the following formulae.

R ¹ and R ³ are the same or different and each represents a group selected from the following formulae.

R ⁵ and R ⁶ are the same or different and are each (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, ( 4) represents an optionally substituted aryl, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl, or (7) R ⁵ and R ^{6 taken} together An optionally substituted heterocycle may be formed with the atom to which is bonded.
R ⁷ is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl Or (5) represents alkoxycarbonyl.
R ¹⁴ represents hydrogen, alkoxy, hydroxyl group, cyano or alkyl which may be substituted.
m and n are the same or different and each represents 0, 1 or 2.
R ² and R ⁴ are the same or different and are each oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted Good alkyl. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ⁴ may be the same or different.
R ¹ and R ² may be combined together to form a group selected from the following formula together with ring A:

R ³ and R ⁴ may be combined together to form a group selected from the following formula together with ring B:

p shows the integer of 1-3.
R ¹³ is (1) optionally substituted alkyl, (2) cyano, (3) hydrogen, (4) halogen, (5) optionally substituted amino, (6) alkenyl, (7) substituted. Carbamoyl, (8) alkoxycarbonyl, (9) carboxy, (10) heterocyclic group, (11) hydroxyl group or (12) alkoxy which may be optionally present. ]
Or a pharmaceutically acceptable salt thereof as an active ingredient.

〔式中、Ｒ^８およびＲ^９は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルコキシカルボニル、（６）置換されていてもよい複素環式基または（７）置換されていてもよいアリールを示すか、または（８）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。Ｒ^１０およびＲ^１１は、同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基を示す。Ｒ^１２は（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基を示す。〕 2. In the above 1 wherein the optionally substituted alkyl substituents in R ⁵ , R ⁶ and R ⁷ are 1 to 7 halogens independently selected and / or 1 to 3 groups selected from the following formulae: The described high conductance calcium sensitive K channel opener.

[Wherein R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. , (3) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8 ) R ⁸ and R ⁹ may be taken together with the atoms to which they are attached to form an optionally substituted heterocycle. R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3 ) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) The heterocyclic group which may be substituted is shown. ]

Ｒ^３が、下式から選ばれる基であり、

Ｒ^５が（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１〜３個の基で置換されていてもよいアルキル、

（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）置換されていてもよい複素環式基であり、
Ｒ^６が水素、アルキルまたはアルコキシカルボニルであるか、あるいはＲ^５およびＲ^６が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよく、
Ｒ^７が、水素、アルキルまたはアルコキシカルボニルであり、
Ｒ^８およびＲ^９が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）置換されていてもよい複素環式基、（６）置換されていてもよいアリールであるか、あるいは（７）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子とともに置換されていてもよい複素環を形成してもよく、
Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基であり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲンまたは置換されていてもよいアルキルである前記１記載の高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。 3. Ring B is benzene, heterocycle, cycloalkane or cycloalkene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae:

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 to 3 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen, alkyl or alkoxycarbonyl, or R ⁵ and R ⁶ together may form an optionally substituted heterocycle with the atoms to which they are attached;
R ⁷ is hydrogen, alkyl or alkoxycarbonyl;
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) optionally substituted heterocyclic group, (6) optionally substituted aryl, or (7) R ⁸ and R ⁹ together And may form a heterocyclic ring that may be substituted with the atoms to which they are attached,
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
^2. The high conductance calcium-sensitive K-channel opener according to 1 above, wherein R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, or optionally substituted alkyl.

Ｒ^３が下式から選ばれる基であり、

Ｒ^５が（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１または２個の基で置換されていてもよいアルキル、

（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）置換されていてもよい複素環式基であり、
Ｒ^６が水素またはアルキルであるか、あるいはＲ^５およびＲ^６が一緒になって、それらが結合している原子とともに、ヒドロキシアルキルで置換されていてもよい複素環を形成してもよく、
Ｒ^７が水素またはアルキルであり、
Ｒ^８およびＲ^９が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキルまたは（４）アルコキシアルキルであり、
Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲンまたは水酸基で置換されていてもよいアルキルであり、
Ｒ^１３は（１）水素、（２）ハロゲン、水酸基、置換されていてもよいアルコキシ、シアノ、カルボキシ、カルバモイル、アルコキシカルボニル、置換されていてもよいアミノおよび置換されていてもよいイミノから選ばれる基で置換されていてもよいアルキル、（３）アルケニル、または（４）複素環式基である前記１記載の高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。 4). Ring B is (1) benzene or (2) a thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, 2,3-dihydroindole, 2,3-dihydrobenzofuran and 1,4-benzodioxane or (3 ) Cyclohexene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ may be taken together with the atoms to which they are attached to form a heterocycle that may be substituted with hydroxyalkyl;
R ⁷ is hydrogen or alkyl,
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl or (4) alkoxyalkyl;
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl or (5) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl, alkoxy, halogen or alkyl optionally substituted with hydroxyl;
R ¹³ is selected from (1) hydrogen, (2) halogen, hydroxyl group, optionally substituted alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, optionally substituted amino and optionally substituted imino. 2. The high conductance calcium-sensitive K channel opener according to the above 1, which is an alkyl optionally substituted with a group, (3) alkenyl, or (4) a heterocyclic group.

Ｒ^３が下式から選ばれる基であり、

Ｒ^５は（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１または２個の基で置換されていてもよいアルキル、

（３）水酸基で置換されていてもよいアリールと縮合したシクロアルキル、または（４）複素環式基であり、
Ｒ^６が水素またはアルキルであるか、あるいはＲ^５およびＲ^６が一緒になって、ヒドロキシアルキルで置換されていてもよい複素環を形成してもよく、
Ｒ^７が水素またはアルキルであり、
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）置換されていてもよい複素環式基、または（６）置換されていてもよいアリールであり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれシアノ、ニトロ、水酸基、ハロゲン、アルキルまたはアルコキシであり、
Ｒ^１３が（１）水素、（２）ハロゲン、水酸基、ハロゲンおよびフェニルから選ばれる基で置換されていてもよいアルコキシ、シアノ、カルボキシ、カルバモイル、アルコキシカルボニル、フェニルで置換されていてもよいアミノならびにアルコキシおよび水酸基で置換されていてもよいイミノから選ばれる基で置換されていてもよいアルキル、（３）アルケニルまたは（４）４，５−ジヒドロオキサゾール−２−イルである前記１記載の高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。 5. Ring A is benzene, thiophene, pyridine or pyrazole,
Ring B is (1) benzene, (2) thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, a heterocyclic ring selected from 2,3-dihydroindole and 1,4-benzodioxane, or (3) cyclohexene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1-7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) a cycloalkyl fused with an aryl optionally substituted with a hydroxyl group, or (4) a heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form a heterocycle optionally substituted with hydroxyalkyl,
R ⁷ is hydrogen or alkyl,
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and each may be substituted with (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. Good alkyl, (3) hydroxyalkyl, (4) alkoxyalkyl, (5) an optionally substituted heterocyclic group, or (6) an optionally substituted aryl,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is cyano, nitro, hydroxyl, halogen, alkyl or alkoxy;
R ¹³ is (1) hydrogen, (2) amino optionally substituted with alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, phenyl optionally substituted with a group selected from halogen, hydroxyl, halogen and phenyl, and 2. The high conductance according to 1 above, which is alkyl optionally substituted with a group selected from alkoxy and imino optionally substituted with a hydroxyl group, (3) alkenyl or (4) 4,5-dihydrooxazol-2-yl Type calcium sensitive K channel opener.

6). The high conductance calcium-sensitive K channel opener according to any one of 1 to 5, wherein R ¹ is a group selected from the following formulae:

〔式中、環Ａはベンゼンまたは複素環を示す。
環Ｂはベンゼン、複素環、シクロアルカンまたはシクロアルケンを示す。
環Ｑは下式から選ばれる基を示す。

Ｒ^１ａは下式から選ばれる基を示す。

Ｒ^３は下式から選ばれる基を示す。

Ｒ^５およびＲ^６は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、（５）置換されていてもよい複素環式基、もしくは（６）アルコキシカルボニルを示すか、または（７）Ｒ^５およびＲ^６が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。
Ｒ^７は（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）アルコキシカルボニルを示す。
Ｒ^１４は水素、アルコキシ、水酸基、シアノまたは置換されていてもよいアルキルを示す。
ｍおよびｎは同一または異なって、それぞれ０、１または２を示す。
Ｒ^２およびＲ^４は同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲン、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノまたは置換されていてもよいアルキルを示す。但し、ｍが２の時、２つのＲ^２は同一または異なっていてもよく、ｎが２の時、２つのＲ^４は同一または異なっていてもよい。
また、Ｒ^１ａとＲ^２がそれぞれ一緒になって、環Ａとともに、下式の基を形成してもよい。

また、Ｒ^３とＲ^４がそれぞれ一緒になって、環Ｂとともに、下式から選ばれる基を形成してもよい。

ｐは１〜３の整数を示す。
Ｒ^１３は（１）置換されていてもよいアルキル、（２）シアノ、（３）水素、（４）ハロゲン、（５）置換されていてもよいアミノ、（６）アルケニル、（７）置換されていてもよいカルバモイル、（８）アルコキシカルボニル、（９）カルボキシ、（１０）複素環式基、（１１）水酸基または（１２）アルコキシを示す。
（ただし、（ｉ）環Ａおよび環Ｂがベンゼン環であり、
環Ｑが、

であり、
Ｒ^３が２位に置換した水酸基、アルコキシまたはシクロアルキルオキシであり、
Ｒ^４が６位に置換したメトキシであり、
Ｒ^１３がアルコキシカルボニルまたはカルボキシである化合物、
（ｉｉ）Ｎ−（３−イソプロポキシプロピル）−４−（３−メチル−５−フェニル−１Ｈ−ピラゾール−１−イル）ベンズアミド、
（ｉｉｉ）４−（１−（４−アミノスルホニルフェニル）−３−ジフルオロメチル−１Ｈ−ピラゾール−５−イル）ベンズアミド、および
（ｉｖ）４−〔５−（４−クロロフェニル）−３−（３−ヒドロキシプロピル）−１Ｈ−ピラゾール−１−イル〕−Ｎ−メチルベンゾヒドロキサム酸
を除く。）〕
により表される化合物またはその製薬上許容し得る塩。 7). Formula (Ia)

[Wherein, ring A represents benzene or a heterocyclic ring.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
Ring Q represents a group selected from the following formulae.

R ^1a represents a group selected from the following formulae.

R ³ represents a group selected from the following formulae.

R ⁵ and R ⁶ are the same or different and are each (1) hydrogen, (2) optionally substituted alkyl, (3) optionally fused to aryl, optionally substituted cycloalkyl, ( 4) represents an optionally substituted aryl, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl, or (7) R ⁵ and R ^{6 taken} together An optionally substituted heterocycle may be formed with the atom to which is bonded.
R ⁷ is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally fused to aryl, optionally substituted cycloalkyl, (4) optionally substituted aryl Or (5) represents alkoxycarbonyl.
R ¹⁴ represents hydrogen, alkoxy, hydroxyl group, cyano or alkyl which may be substituted.
m and n are the same or different and each represents 0, 1 or 2.
R ² and R ⁴ are the same or different and are each oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted Good alkyl. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ⁴ may be the same or different.
R ^1a and R ² may be combined to form a group of the following formula together with ring A.

R ³ and R ⁴ may be combined together to form a group selected from the following formula together with ring B:

p shows the integer of 1-3.
R ¹³ is (1) optionally substituted alkyl, (2) cyano, (3) hydrogen, (4) halogen, (5) optionally substituted amino, (6) alkenyl, (7) substituted. Carbamoyl, (8) alkoxycarbonyl, (9) carboxy, (10) heterocyclic group, (11) hydroxyl group or (12) alkoxy which may be optionally present.
(However, (i) Ring A and Ring B are benzene rings,
Ring Q is

And
R ³ is a hydroxyl group substituted at the 2-position, alkoxy or cycloalkyloxy,
R ⁴ is methoxy substituted at the 6-position,
A compound wherein R ¹³ is alkoxycarbonyl or carboxy;
(Ii) N- (3-isopropoxypropyl) -4- (3-methyl-5-phenyl-1H-pyrazol-1-yl) benzamide,
(Iii) 4- (1- (4-aminosulfonylphenyl) -3-difluoromethyl-1H-pyrazol-5-yl) benzamide, and (iv) 4- [5- (4-chlorophenyl) -3- (3 -Hydroxypropyl) -1H-pyrazol-1-yl] -N-methylbenzohydroxamic acid. )]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^８およびＲ^９は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルコキシカルボニル、（６）置換されていてもよい複素環式基または（７）置換されていてもよいアリールを示すか、または（８）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。Ｒ^１０およびＲ^１１は、同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基を示す。Ｒ^１２は（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基を示す。〕 8). In the above 7 wherein the optionally substituted alkyl substituents in R ⁵ , R ⁶ and R ⁷ are independently selected 1 to 7 halogens and / or 1 to 3 groups selected from the following formulae: The described compound or a pharmaceutically acceptable salt thereof.

[Wherein R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. , (3) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8 ) R ⁸ and R ⁹ may be taken together with the atoms to which they are attached to form an optionally substituted heterocycle. R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3 ) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) The heterocyclic group which may be substituted is shown. ]

Ｒ^３が、下式から選ばれる基であり、

Ｒ^５が（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１〜３個の基で置換されていてもよいアルキル、

（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）置換されていてもよい複素環式基であり、
Ｒ^６が水素またはアルキルであるか、あるいはＲ^５およびＲ^６が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよく、
Ｒ^７が、水素、アルキルまたはアルコキシカルボニルであり、
Ｒ^８およびＲ^９が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）置換されていてもよい複素環式基、（６）置換されていてもよいアリールであるか、あるいは（７）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子とともに置換されていてもよい複素環を形成してもよく、
Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基であり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲンまたは置換されていてもよいアルキルである前記７記載の化合物またはその製薬上許容し得る塩。 9. Ring B is benzene, heterocycle or cycloalkane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae:

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 to 3 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form an optionally substituted heterocycle with the atoms to which they are attached;
R ⁷ is hydrogen, alkyl or alkoxycarbonyl;
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) optionally substituted heterocyclic group, (6) optionally substituted aryl, or (7) R ⁸ and R ⁹ together And may form a heterocyclic ring that may be substituted with the atoms to which they are attached,
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
8. The compound according to 7 or a pharmaceutically acceptable salt thereof, wherein R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, or optionally substituted alkyl.

Ｒ^３が下式から選ばれる基であり、

Ｒ^５が（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１または２個の基で置換されていてもよいアルキル、

（３）アリールと縮合していてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）置換されていてもよい複素環式基であり、
Ｒ^６が水素またはアルキルであるか、あるいはＲ^５およびＲ^６が一緒になって、それらが結合している原子とともに、ヒドロキシアルキルで置換されていてもよい複素環を形成してもよく、
Ｒ^７が水素またはアルキルであり、
Ｒ^８およびＲ^９が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキルまたは（４）アルコキシアルキルであり、
Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲンまたは水酸基で置換されていてもよいアルキルであり、
Ｒ^１３は（１）水素、（２）ハロゲン、水酸基、置換されていてもよいアルコキシ、シアノ、カルボキシ、置換されていてもよいアミノおよび置換されていてもよいイミノから選ばれる基で置換されていてもよいアルキル、（３）アルケニル、または（４）複素環式基である前記７記載の化合物またはその製薬上許容し得る塩。 10. Ring B is a heterocyclic ring selected from (1) benzene or (2) thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, 2,3-dihydroindole, 2,3-dihydrobenzofuran and 1,4-benzodioxane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ may be taken together with the atoms to which they are attached to form a heterocycle that may be substituted with hydroxyalkyl;
R ⁷ is hydrogen or alkyl,
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl or (4) alkoxyalkyl;
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl or (5) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl, alkoxy, halogen or alkyl optionally substituted with hydroxyl;
R ¹³ is substituted with a group selected from (1) hydrogen, (2) halogen, hydroxyl group, optionally substituted alkoxy, cyano, carboxy, optionally substituted amino and optionally substituted imino. 8. The compound according to 7 or a pharmaceutically acceptable salt thereof, which may be alkyl, (3) alkenyl, or (4) a heterocyclic group.

Ｒ^３が下式から選ばれる基であり、

Ｒ^５は（１）水素、（２）独立に選ばれる１〜７個のハロゲンおよび／または下式から選ばれる１または２個の基で置換されていてもよいアルキル、

（３）水酸基で置換されていてもよいアリールと縮合したシクロアルキル、または（４）複素環式基であり、
Ｒ^６が水素またはアルキルであるか、あるいはＲ^５およびＲ^６が一緒になって、ヒドロキシアルキルで置換されていてもよい複素環を形成してもよく、
Ｒ^７が水素またはアルキルであり、
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）置換されていてもよい複素環式基、または（６）置換されていてもよいアリールであり、
Ｒ^１２が（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基であり、
ｍおよびｎが同一または異なって、それぞれ０、１または２であり、
Ｒ^２およびＲ^４が同一または異なって、それぞれシアノ、ニトロ、水酸基、ハロゲン、アルキルまたはアルコキシであり、
Ｒ^１３が（１）水素、（２）ハロゲン、水酸基、ハロゲンおよびフェニルから選ばれる基で置換されていてもよいアルコキシ、シアノ、カルボキシ、カルバモイル、アルコキシカルボニル、フェニルで置換されていてもよいアミノならびにアルコキシおよび水酸基で置換されていてもよいイミノから選ばれる基で置換されていてもよいアルキル、（３）アルケニルまたは（４）４，５−ジヒドロオキサゾール−２−イルである請求項７記載の化合物またはその製薬上許容し得る塩。 11. Ring A is benzene, thiophene, pyridine or pyrazole,
Ring B is (1) benzene, or (2) a heterocyclic ring selected from thiophene, pyridine, pyrimidine, pyrazine, benzothiophene and 1,4-benzodioxane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1-7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) a cycloalkyl fused with an aryl optionally substituted with a hydroxyl group, or (4) a heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form a heterocycle optionally substituted with hydroxyalkyl,
R ⁷ is hydrogen or alkyl,
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and each may be substituted with (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. Good alkyl, (3) hydroxyalkyl, (4) alkoxyalkyl, (5) an optionally substituted heterocyclic group, or (6) an optionally substituted aryl,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is cyano, nitro, hydroxyl, halogen, alkyl or alkoxy;
R ¹³ is (1) hydrogen, (2) amino optionally substituted with alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, phenyl optionally substituted with a group selected from halogen, hydroxyl, halogen and phenyl, and 8. The compound according to claim 7, which is an alkyl, (3) alkenyl, or (4) 4,5-dihydrooxazol-2-yl optionally substituted with a group selected from alkoxy and imino optionally substituted with a hydroxyl group. Or a pharmaceutically acceptable salt thereof.

  12 A medicament comprising the compound according to any one of 7 to 11 above or a pharmaceutically acceptable salt thereof.

  13. 13. The medicament according to 12 above, which is a high conductance calcium-sensitive K channel opener.

  14 14. The high conductance calcium-sensitive K channel opener according to any one of 1 to 5 and 13, which is a preventive and / or therapeutic agent for pollakiuria, urinary incontinence, asthma or COPD.

〔式中、環Ａはベンゼンまたは複素環を示す。
環Ｂはベンゼン、複素環、シクロアルカンまたはシクロアルケンを示す。
環Ｑは下式から選ばれる基を示す。

Ｒ^１およびＲ^３は同一または異なって、それぞれ下式から選ばれる基を示す。

Ｒ^５およびＲ^６は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合されていてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、（５）置換されていてもよい複素環式基、もしくは（６）アルコキシカルボニルを示すか、または（７）Ｒ^５およびＲ^６が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。
Ｒ^７は（１）水素、（２）置換されていてもよいアルキル、（３）アリールと縮合されていてもよく、置換されていてもよいシクロアルキル、（４）置換されていてもよいアリール、または（５）アルコキシカルボニルを示す。
Ｒ^１４は水素、アルコキシ、水酸基、シアノまたは置換されていてもよいアルキルを示す。
ｍおよびｎは、同一または異なって、それぞれ０、１または２を示す。
Ｒ^２およびＲ^４は同一または異なって、それぞれオキソ、シアノ、ニトロ、水酸基、アルコキシ、ハロゲン、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノまたは置換されていてもよいアルキルを示す。但し、ｍが２の時、２つのＲ^２は同一または異なっていてもよく、ｎが２の時、２つのＲ^４は同一または異なっていてもよい。
また、Ｒ^１とＲ^２がそれぞれ一緒になって、環Ａとともに、下式から選ばれる基を形成してもよい。

また、Ｒ^３とＲ^４がそれぞれ一緒になって、環Ｂとともに、下式から選ばれる基を形成してもよい。

ｐは１〜３の整数を示す。
Ｒ^１３は（１）置換されていてもよいアルキル、（２）シアノ、（３）水素、（４）ハロゲン、（５）置換されていてもよいアミノ、（６）アルケニル、（７）置換されていてもよいカルバモイル、（８）アルコキシカルボニル、（９）カルボキシ、（１０）複素環式基、（１１）水酸基または（１２）アルコキシを示す。
（ただし、環Ａはベンゼン環であり、
環Ｂはベンゼン環、ピリジンまたはシクロアルカンであり、
環Ｑは、

（式中、Ｒ^１３はハロゲン、アルキルまたはハロアルキルである。）であり、
Ｒ^１がスルファモイルまたはアルキルスルホニルであり、
Ｒ^３は水素、アルキルまたはアルコキシであり、
ｍが１であってＲ^２がハロゲンであるか、またはｍが０であり、
ｎが１であってＲ^４がハロゲン、アルコキシまたはアルキルであるか、またはｎが０である化合物を除く。）〕
により表される化合物またはその製薬上許容し得る塩。 15. Formula (I)

[Wherein, ring A represents benzene or a heterocyclic ring.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
Ring Q represents a group selected from the following formulae.

R ¹ and R ³ are the same or different and each represents a group selected from the following formulae.

R ⁵ and R ⁶ are the same or different and are each (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, ( 4) represents an optionally substituted aryl, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl, or (7) R ⁵ and R ^{6 taken} together An optionally substituted heterocycle may be formed with the atom to which is bonded.
R ⁷ is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl Or (5) represents alkoxycarbonyl.
R ¹⁴ represents hydrogen, alkoxy, hydroxyl group, cyano or alkyl which may be substituted.
m and n are the same or different and each represents 0, 1 or 2.
R ² and R ⁴ are the same or different and are each oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted Good alkyl. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ⁴ may be the same or different.
R ¹ and R ² may be combined together to form a group selected from the following formula together with ring A:

R ³ and R ⁴ may be combined together to form a group selected from the following formula together with ring B:

p shows the integer of 1-3.
R ¹³ is (1) optionally substituted alkyl, (2) cyano, (3) hydrogen, (4) halogen, (5) optionally substituted amino, (6) alkenyl, (7) substituted. Carbamoyl, (8) alkoxycarbonyl, (9) carboxy, (10) heterocyclic group, (11) hydroxyl group or (12) alkoxy which may be optionally present.
(However, ring A is a benzene ring,
Ring B is a benzene ring, pyridine or cycloalkane,
Ring Q is

Wherein R ¹³ is halogen, alkyl or haloalkyl.
R ¹ is sulfamoyl or alkylsulfonyl;
R ³ is hydrogen, alkyl or alkoxy;
m is 1 and R ² is halogen, or m is 0;
Excludes compounds where n is 1 and R ⁴ is halogen, alkoxy or alkyl, or n is 0. )]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^８およびＲ^９は同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルコキシカルボニル、（６）置換されていてもよい複素環式基または（７）置換されていてもよいアリールを示すか、または（８）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子とともに、置換されていてもよい複素環を形成してもよい。Ｒ^１０およびＲ^１１は、同一または異なって、それぞれ（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基を示す。Ｒ^１２は（１）水素、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基を示す。〕 16. In the above 15, wherein the optionally substituted alkyl substituents in R ⁵ , R ⁶ and R ⁷ are 1 to 7 halogens independently selected and / or 1 to 3 groups selected from the following formulae: The described compound or a pharmaceutically acceptable salt thereof.

[Wherein R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. , (3) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8 ) R ⁸ and R ⁹ may be taken together with the atoms to which they are attached to form an optionally substituted heterocycle. R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3 ) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) The heterocyclic group which may be substituted is shown. ]

  17. 17. A high conductance calcium-sensitive K channel opener comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof according to 15 or 16 above.

18. 18. The high conductance calcium-sensitive K channel opener according to any one of 1 to 5 and 17, wherein R ¹ and R ³ are not hydrogen.

19. 17. The compound or a pharmaceutically acceptable salt thereof according to 15 or 16, wherein R ¹ and R ³ are not both hydrogen.

（式中、環Ａ^１および環Ｂ^１は同一または異なって、それぞれベンゼン、ピリジン、シクロヘキサンまたはシクロヘキセンであり、Ｒ^１ｂは下式から選ばれる基を示し、

他の記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。
〔ただし、Ｒ^１ｂは、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 20. formula

Wherein ring A ¹ and ring B ¹ are the same or different and are each benzene, pyridine, cyclohexane or cyclohexene, R ^1b represents a group selected from the following formulae,

Other symbols are as defined above. )
Or a pharmaceutically acceptable salt thereof as an active ingredient.
^{[However, R 1b} is preferably bonded to the m-position or p-position of ring ^{A 1,} more preferably it binds to p-position of the ring ^{A 1.} Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。
〔ただし、Ｒ^１ｂは、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 21. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof as an active ingredient.
^{[However, R 1b} is preferably bonded to the m-position or p-position of ring ^{A 1,} more preferably it binds to p-position of the ring ^{A 1.} Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。
〔ただし、Ｒ^１ｂは、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 22. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof as an active ingredient.
^{[However, R 1b} is preferably bonded to the m-position or p-position of ring ^{A 1,} more preferably it binds to p-position of the ring ^{A 1.} Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。
〔ただし、Ｒ^１ｂは、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 23. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof as an active ingredient.
^{[However, R 1b} is preferably bonded to the m-position or p-position of ring ^{A 1,} more preferably it binds to p-position of the ring ^{A 1.} Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩。
〔ただし、R⁵R⁶NCO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 24. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
[However, R ⁵ R ⁶ NCO- groups are preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩。
〔ただし、R⁵R⁶NCO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 25. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
[However, R ⁵ R ⁶ NCO- groups are preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩。
〔ただし、R⁵R⁶NCO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 26. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
[However, R ⁵ R ⁶ NCO- groups are preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容しうる塩。
〔ただし、R⁵R⁶NCO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 27. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
[However, R ⁵ R ⁶ NCO- groups are preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

28. 24. The high conductance calcium-sensitive K channel opener according to any one of 20 to 23, wherein R ³ is a group selected from the following formulae.

29. 28. The compound or a pharmaceutically acceptable salt thereof according to any one of the above 24 to 27, wherein R ³ is a group selected from the following formulae.

30. The high conductance type according to any one of the above 20 to 23, wherein R ⁵ is independently selected 1 to 7 halogens and / or alkyl optionally substituted by 1 to 3 groups selected from the following formulae: Calcium sensitive K channel opener.

31. 28. The compound according to any one of 24 to 27 above, wherein R ⁵ is independently selected 1 to 7 halogens and / or alkyl optionally substituted with 1 to 3 groups selected from the following formulae: A pharmaceutically acceptable salt.

（式中、各記号は前記１と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、環Ａ^１は好ましくはベンゼンまたはピリジンであり、環Ｑは、好ましくは、

である。〕 32. formula

(In the formula, each symbol has the same meaning as 1 above.)
Or a pharmaceutically acceptable salt thereof.
[Wherein ring A ¹ is preferably benzene or pyridine and ring Q is preferably

It is. ]

33. 33. The compound or a pharmaceutically acceptable salt thereof according to 32, wherein Ring A ¹ is benzene or pyridine.

34. 34. The compound according to 32 or 33 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen or methyl, m is 0, R ⁴ is methyl, and n is 1.

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。
〔ただし、環Ａ^１は好ましくはベンゼンまたはピリジンであり、環Ｑは、好ましくは、

である。〕 35. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof as an active ingredient.
[Wherein ring A ¹ is preferably benzene or pyridine and ring Q is preferably

It is. ]

（式中、ｑおよびｒはそれぞれ１〜６の整数を示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、[R¹²O(CH₂)_q][R¹²O(CH₂)_r]CHN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。２つのＲ^１２は同一または異なっていてもよい。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 36. formula

(In the formula, q and r each represent an integer of 1 to 6, and the other symbols are as defined above.)
Or a pharmaceutically acceptable salt thereof.
[However, [R ¹² O (CH ₂ ) _q ] [R ¹² O (CH ₂ ) _r ] CHN (R ⁶ ) CO— group is preferably bonded to the m-position or p-position of ring A ¹ , and more preferably binds to p-position of the ring ^{a 1.} Two R ¹² may be the same or different. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、[R¹²O(CH₂)_q](R¹²O)CH(CH₂)_rN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。２つのＲ^１２は同一または異なっていてもよい。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 37. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
[Wherein, [R ¹² O (CH ₂ ) _q ] (R ¹² O) CH (CH ₂ ) _r N (R ⁶ ) CO— group is preferably bonded to the m-position or p-position of ring A ¹ , preferably it binds to p-position of the ring a ^1. Two R ¹² may be the same or different. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、ｓおよびｔはそれぞれ０〜６の整数を示し、ＲおよびＲ’はそれぞれ水素またはアルキルを示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、R¹²O(CH₂)_tC(R)(R')(CH₂)_sN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 38. formula

(In the formula, s and t each represent an integer of 0 to 6, R and R ′ each represent hydrogen or alkyl, and other symbols are as defined above.)
Or a pharmaceutically acceptable salt thereof.
[Wherein R ¹² O (CH ₂ ) _t C (R) (R ′) (CH ₂ ) _s N (R ⁶ ) CO— group is preferably bonded to the m-position or p-position of ring A ¹ , preferably it binds to p-position of the ring a ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、R⁹R⁸NCO(CH₂)_qN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 39. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
^{[However, R 9 R 8 NCO (CH} 2) q N (R 6) CO- group is preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of ring A ¹ . Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、R⁹OCON(R⁸)(CH₂)_qN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 40. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
^{[However, R 9 OCON (R 8)} (CH 2) q N (R 6) CO- group is preferably bonded to the m-position or p-position of ring A ^1, more preferably in the p-position of ring A ¹ Join. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、Ｈｅｔは置換されていてもよい複素環式基を示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、Het(CH₂)_qN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 41. formula

(In the formula, Het represents an optionally substituted heterocyclic group, and other symbols are as defined above.)
Or a pharmaceutically acceptable salt thereof.
_{[However, Het (CH 2) q N} (R 6) CO- group is preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、HetN(R⁸)(CH₂)_qN(R⁶)CO-基は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 42. formula

(In the formula, each symbol has the same meaning as described above.)
Or a pharmaceutically acceptable salt thereof.
^{[However, HetN (R 8) (CH} 2) q N (R 6) CO- group is preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of ring A ¹ . Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、Ｚはアルキル、ハロゲン、置換されていてもよいアミノを示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。
〔ただし、Ｒ^１は、好ましくは環Ａ^１のｍ位またはｐ位に結合し、さらに好ましくは環Ａ^１のｐ位に結合する。また、環Ａ^１および環Ｂ^１はそれぞれ好ましくはベンゼンまたはピリジンである。〕 43. formula

(In the formula, Z represents alkyl, halogen, or optionally substituted amino, and other symbols are as defined above.)
Or a pharmaceutically acceptable salt thereof.
[However, R ¹ is preferably bonded to the m-position or p-position of ring A ^1, more preferably binds to p-position of the ring A ^1. Ring A ¹ and ring B ¹ are each preferably benzene or pyridine. ]

（式中、各記号は前記と同義である。） 44. 44. The compound or a pharmaceutically acceptable salt thereof according to 43, wherein R ¹ is a group selected from the following formulae:

(In the formula, each symbol has the same meaning as described above.)

〔式中、Ｒ^１ｃは下式から選ばれる基を示し、

他の記号は前記と同義である。〕
により表される化合物またはその製薬上許容し得る塩。 45. Formula (I-1)

[Wherein R ^1c represents a group selected from the following formulae,

Other symbols are as defined above. ]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^１ｄは下式から選ばれる基を示し、

他の記号は前記と同義である。〕
により表される化合物またはその製薬上許容し得る塩。 46. Formula (I-2)

[Wherein R ^1d represents a group selected from the following formulae,

Other symbols are as defined above. ]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^１ｅは下式から選ばれる基を示し、

他の記号は前記と同義である。〕
により表される化合物またはその製薬上許容し得る塩。 47. Formula (I-3)

[Wherein R ^1e represents a group selected from the following formulae,

Other symbols are as defined above. ]
Or a pharmaceutically acceptable salt thereof.

〔式中、Ｒ^１ｆは下式から選ばれる基を示し、

他の記号は前記と同義である。〕
により表される化合物またはその製薬上許容し得る塩。 48. Formula (I-4)

[Wherein R ^1f represents a group selected from the following formulae,

Other symbols are as defined above. ]
Or a pharmaceutically acceptable salt thereof.

（式中、各記号は前記と同義である。） 49. 45 to 45 above, wherein the optionally substituted alkyl substituents for R ⁵ , R ⁶ and R ⁷ are 1 to 7 halogens independently selected and / or 1 to 3 groups selected from the following formulae: 49. The compound according to any of 48, or a pharmaceutically acceptable salt thereof.

(In the formula, each symbol has the same meaning as described above.)

（式中、Ｒ^１ｇは下式から選ばれる基を示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩を有効線分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。

50. formula

(Wherein R ^1g represents a group selected from the following formulas, and other symbols are as defined above.)
A high-conductance calcium-sensitive K-channel opener containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an effective line segment.

（式中、各記号は前記と同義である。） 51. The high conductance calcium-sensitive K channel opener according to 50, wherein R ⁵ is a group selected from the following formulae:

(In the formula, each symbol has the same meaning as described above.)

（式中、Ｒ^１ｇは下式から選ばれる基を示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩。

52. formula

(Wherein R ^1g represents a group selected from the following formulas, and other symbols are as defined above.)
Or a pharmaceutically acceptable salt thereof.

（式中、各記号は前記と同義である。） 53. 53. The compound or a pharmaceutically acceptable salt thereof according to the above 52, wherein R ⁵ is a group selected from the following formulae:

(In the formula, each symbol has the same meaning as described above.)

（式中、Ｒ^１ｈは下式から選ばれる基を示し、他の記号は前記と同義である。）
により表される化合物またはその製薬上許容し得る塩を有効線分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。

54. formula

(Wherein R ^1h represents a group selected from the following formulae, and other symbols are as defined above.)
A high-conductance calcium-sensitive K-channel opener containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an effective line segment.

（式中、各記号は前記と同義である。） 55. 55. The high conductance calcium-sensitive K channel opener according to the above 54, wherein R ⁵ is a group selected from the following formulae.

(In the formula, each symbol has the same meaning as described above.)

  56. A pharmaceutical comprising the compound according to any one of 15, 16, 19, 24-27, 29, 31, 32-34, 36-49, 52 and 53 or a pharmaceutically acceptable salt thereof.

  57. 57. The medicament according to 56 above, which is a high conductance calcium-sensitive K channel opener.

  58. 58. The high conductance calcium-sensitive K channel opener according to 57 above, which is a preventive and / or therapeutic agent for frequent urination, urinary incontinence, asthma or COPD.

  59. 59. A pharmaceutical composition for opening a high conductance type calcium sensitive K channel comprising the compound according to any one of 1 to 58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Hereinafter, groups represented by symbols in this specification will be described.
Examples of the alkyl in “alkyl” and “alkoxyalkyl” and “alkylsulfonyl” include, for example, linear or branched C ₁ -C ₆ alkyl, preferably linear or branched C ₁ -C ₄ alkyl. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, pentyl, hexyl and the like.

Examples of the “hydroxyalkyl” include linear or branched C ₁ -C ₆ alkyl, preferably linear or branched C ₁ -C ₄ alkyl substituted with a hydroxyl group. Specifically, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl and the like can be mentioned.

Alkoxy in “alkoxy” and “alkoxyalkyl” and “alkoxycarbonyl” is, for example, linear or branched C ₁ -C ₆ alkoxy, preferably linear or branched C ₁ -C ₄ alkoxy. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

  “Halogen” includes fluorine, chlorine, bromine and iodine.

Examples of “alkanoyl” include linear or branched C ₁ -C ₆ alkanoyl, preferably linear or branched C ₁ -C ₄ alkanoyl, and specifically include formyl, acetyl Propionyl, butyryl, pentanoyl, hexanoyl and the like.

“Haloalkyl” includes, for example, C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl substituted with halogen, and specifically includes chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoro Examples include methyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl and the like.

“Haloalkoxy” includes, for example, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy substituted with halogen, and specifically includes chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trioxy Fluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 3-chloropropoxy, 3-fluoropropoxy, 4-chlorobutoxy, 4-fluorobutoxy and the like.

“Alkenyl” includes, for example, linear or branched C ₂ -C ₆ alkenyl, preferably linear or branched C ₂ -C ₄ alkenyl, specifically vinyl, allyl, Examples include 1-methyl-2-propenyl, 3-butenyl, 2-pentenyl, 3-hexenyl and the like.

“Aryl” includes, for example, monocyclic, bicyclic or tricyclic C ₆ -C ₁₄ aryl, preferably C ₆ -C ₁₀ aryl, and specifically includes phenyl, naphthyl, phenanthryl, anthryl. Among them, phenyl and naphthyl are particularly preferable.

“Aralkyl” is, for example, a linear or branched C ₁ -C ₆ alkyl, preferably a linear or branched C ₁ -C ₄ alkyl substituted with aryl, specifically Examples include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl and the like.

“Cycloalkyl” includes C ₃ -C ₈ cycloalkyl, preferably C ₃ -C ₆ cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. “Cycloalkyl fused with aryl” includes C ₃ -C ₈ cycloalkyl, preferably C ₃ -C ₆ cycloalkyl fused with aryl (preferably phenyl), specifically indanyl, tetralinyl. Etc. The “cycloalkyl” and “cycloalkyl condensed with aryl” may be substituted, and examples of the substituent include a hydroxyl group, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, and the like. A hydroxyl group. Specific examples of substituted aryl-fused cycloalkyl include 2-hydroxyindan-1-yl.

  The “heterocyclic group” is, for example, a 5 to 10-membered monocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be partially or fully saturated. And a heterocyclic group of formula or bicyclic. A monocyclic or bicyclic heterocyclic group which may be partially or fully saturated may be substituted with oxo.

  The monocyclic heterocyclic group includes 5 to 7-membered heterocyclic group, which contains 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and may be partially or fully saturated. A group is a preferred example. Specific examples include oxazolyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, thiazolyl, piperidyl, piperazinyl, morpholyl, tetrahydropyranyl, tetrahydrofuryl, imidazolidinyl, oxazolidinyl and the like.

  As the bicyclic heterocyclic group, a bicyclic heterocyclic group in which the above monocyclic heterocyclic groups are the same or different and condensed, or the above monocyclic heterocyclic group and a benzene ring are condensed. Preferred bicyclic heterocyclic groups are listed as preferred examples. Specific examples include dihydroindolyl, tetrahydroquinolyl and the like.

  Examples of the “heterocycle” in ring A and ring B include, for example, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and part or all of which may be saturated 5 to 10 Membered monocyclic or bicyclic heterocycles. Specifically, thiophene, furan, pyrrole, pyrazole, thiazole, imidazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine , Tetrahydropyridine, dihydropyridine, pyrrolidine, pyrroline, tetrahydroazepine, homopiperidine, morpholine, homopiperazine, tetrahydropyran, benzo [b] thiophene, benzo [b] furan, indole, 2,3-dihydroindole, 2,3-dihydro Benzo [b] furan, 1,4-benzodioxan, quinoline, 1,5-benzodioxepin, pyridooxazole, pyridoimidazole, benzisoxazole, benzothiazole, pyridothiophene, benzimidazo Le, and the like. Of these, pyridine, pyrazine, pyrimidine, pyridazine, thiazole, pyrazole, pyrrole, thiophene, quinoline and indole are preferable, and pyridine, thiophene and pyrazole are particularly preferable.

Examples of “cycloalkane” in ring B include C ₃ -C ₈ cycloalkane, preferably C ₃ -C ₆ cycloalkane. Specific examples include cyclopropane, cyclobutane, cyclopentane, and cyclohexane, with cyclopropane being preferred.

Examples of “cycloalkene” in ring B include C ₃ -C ₈ cycloalkene, preferably C ₃ -C ₆ cycloalkene. Specific examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene and the like, and cyclohexene is preferable.

“R ⁵ and R ⁶ together to form a heterocycle with the atoms to which they are attached” and “R ⁸ and R ⁹ together to form a heterocycle with the atoms to which they are attached. "Saturated 5-8 membered monocyclic heterocycle which may contain 1 to 2 heteroatoms (nitrogen atom, oxygen atom, sulfur atom, etc.), specifically Pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine and the like.

  The heterocyclic ring may be substituted, and the substituent may be (1) (i) halogen, (ii) hydroxyl group, (iii) haloalkoxy, (iv) halogen, alkyl, phenyl or the like. Good alkoxy, (v) carbamoyl optionally substituted by alkyl, etc., (vi) cyano, (vii) alkoxycarbonyl, (viii) carboxy, (ix) alkyl, phenyl optionally substituted amino, and (X) by alkyl, optionally substituted by a group selected from alkoxy, imino optionally substituted by hydroxyl, etc., (2) cyano, (3) halogen, (4) alkyl, alkanoyl, cycloalkyl, etc. Substituted with optionally substituted amino, (5) alkenyl, (6) alkoxy, hydroxyl, etc. Which may be imino, (7) alkyl, carbamoyl which may be substituted by an aralkyl or the like, (8) an alkoxycarbonyl or (9) a heterocyclic group, and the like.

  Among the substituted heterocycles, preferred substituents include alkyl substituted with a hydroxyl group, or 5 to 6 which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. It is a monocyclic heterocyclic group, and hydroxymethyl and pyrimidyl are particularly preferable.

As the substituent of the substituted aryl in R ⁵ , R ⁶ and R ⁷ , alkyl substituted with a hydroxyl group is preferable, and specific examples include 2-hydroxymethylphenyl.

（式中、各記号は前記と同義である。）
このうち、（Ａ）、（Ｆ）、（Ｈ）、（Ｉ）、（Ｍ）、（Ｏ）、（Ｐ）および（Ｑ）が好ましく、（Ａ）、（Ｆ）、（Ｈ）、（Ｍ）、（Ｐ）および（Ｑ）が特に好ましい。 Examples of the substituent of the substituted alkyl in R ⁵ , R ⁶ and R ⁷ include 1 to 7 halogens independently selected and / or 1 to 3 groups selected from the following formulae.

(In the formula, each symbol has the same meaning as described above.)
Of these, (A), (F), (H), (I), (M), (O), (P) and (Q) are preferred, and (A), (F), (H), ( M), (P) and (Q) are particularly preferred.

As the heterocyclic group which is a substituent of the substituted alkyl in R ⁵ , R ⁶ , R ⁷ and Het, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl, tetrazolyl and thiazolyl are preferable. The heterocyclic group may be substituted with alkyl, haloalkyl, hydroxyl, alkoxy and the like, preferably methyl, trifluoromethyl, hydroxyl, methoxy and the like.

Examples of the substituent of substituted aryl in R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² include halogen, hydroxyl group, alkoxy, alkyl, haloalkyl and the like.

The heterocyclic group in R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is preferably pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, tetrahydropyranyl, and the heterocyclic group is alkyl, haloalkyl, hydroxyl group, It may be substituted with alkoxy or the like. As the heterocyclic group for R ¹⁰ and R ¹¹ , pyridyl is particularly preferable. As the heterocyclic group for R ^12, pyrimidyl and tetrahydropyranyl are particularly preferable.

As the heterocyclic group for R ^13, 4,5-dihydrooxazole is preferable.

Examples of the substituent of substituted carbamoyl and substituted amino in R ² and R ⁴ include alkyl optionally substituted by halogen, hydroxyl group, alkoxy, amino, mono- or dialkylamino, respectively.

Examples of the substituent of the substituted alkyl in R ² and R ⁴ include a hydroxyl group, alkoxy, halogen and the like, and specific examples of the substituted alkyl include hydroxymethyl, 2-hydroxyethyl, methoxymethyl, trifluoromethyl and the like. It is done.

As the substituent of the substituted alkyl in R ¹³ , (1) halogen, (2) hydroxyl group, (3) haloalkoxy, (4) alkoxy optionally substituted by halogen, alkoxy, phenyl, etc., (5) alkyl, Carbamoyl optionally substituted by a hydroxyl group, (6) cyano, (7) alkoxycarbonyl, (8) carboxy, (9) amino optionally substituted by phenyl, phenyl, or (10) alkoxy, hydroxyl group And imino which may be substituted by the like. Among these, (1) halogen, (2) hydroxyl group, (4) alkoxy optionally substituted by halogen, alkoxy, phenyl, etc., (6) cyano, (8) carboxy, (9) alkyl, phenyl Examples thereof include amino optionally substituted by, etc., (10) alkoxy, imino optionally substituted by hydroxyl group and the like.

Examples of the substituent of substituted amino in R ¹³ include alkyl and phenyl.

Examples of the substituent of the substituted carbamoyl in R ¹³ include alkyl.

Examples of the substituent of the substituted alkyl in R ¹⁴ include cyano, halogen, hydroxyl group, alkoxy and the like.

  Examples of the substituent of substituted amino in Z include alkyl.

Examples of the pharmaceutically acceptable salt of the compound of the present invention include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citrate, Examples thereof include organic acid salts such as methanesulfonate, benzenesulfonate, tosylate, and maleate. In addition, when it has an acidic group such as carboxy, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt, an alkaline earth metal salt such as calcium salt, an organic base salt such as triethylamine salt, a lysine salt, etc. And amino acid salts thereof.
The compound of the present invention or a pharmaceutically acceptable salt thereof includes any solvate such as an inner salt or hydrate thereof.

  The compound (I) of the present invention may have optical isomers based on asymmetric carbon, but the compound (I) of the present invention includes any of these isomers and mixtures thereof. Further, when the compound (I) of the present invention has a double bond or cycloalkanediyl, there exist cis and trans isomers, and the compound (I) of the present invention has tautomers based on unsaturated bonds such as carbonyl. However, the compound (I) of the present invention includes any isomers and mixtures thereof.

を用いて以下の方法を説明するが、対応する原料を用いることにより、

の化合物も同様に製造することができる。
また、Ｒ^１に関する反応は、Ｒ^３についても同様に行うことができる。 The compound (I) of the present invention can be produced by the following method.
Unless otherwise specified, as pyrazole or isoxazole in ring Q,

The following method is explained using the corresponding raw material,

This compound can also be produced in the same manner.
Further, reactions for ^{R 1} can be performed similarly for ^{R 3.}

（式中、Ｒ^１３ａは置換されていてもよいアルキル、アルケニルまたは複素環式基を示し、Ｒ''はメトキシ、エトキシなどのアルコキシまたはイミダゾールを示し、他の記号は前記と同義である。）
化合物（II）と化合物（III）との反応は、J. Am. Chem. Soc., 72, 2948〜2952, 1950の方法に準じて、塩基（ナトリウムメトキシド、ナトリウムエトキシド、水素化ナトリウムなど）の存在下で行うことができる。
化合物（IV）を化合物（V）またはその塩（塩酸塩など）と溶媒（メタノール、エタノール、イソプロピルアルコール、エチレングリコール、ＤＭＦ、ＤＭＳＯ、酢酸、水またはそれらの混合物など）中、室温から溶媒の還流温度で、１〜２４時間反応させることにより、化合物（I-a）および化合物（VI）の混合物が得られる。得られた反応混合物を再結晶またはクロマトグラフィーに付すことによって、化合物（I-a）を単離することができる。 Method 1: A compound in which ring Q is pyrazole and R ¹³ is an optionally substituted alkyl, alkenyl, or heterocyclic group can be produced by the following method.

(Wherein R ^13a represents an optionally substituted alkyl, alkenyl or heterocyclic group, R ″ represents alkoxy such as methoxy or ethoxy or imidazole, and other symbols are as defined above.)
The reaction of the compound (II) with the compound (III) is carried out according to the method of J. Am. Chem. Soc., 72, 2948 to 2952, 1950, base (sodium methoxide, sodium ethoxide, sodium hydride, etc. ) In the presence of
Compound (IV) is refluxed from room temperature in compound (V) or a salt thereof (such as hydrochloride) and a solvent (such as methanol, ethanol, isopropyl alcohol, ethylene glycol, DMF, DMSO, acetic acid, water, or a mixture thereof). By reacting at temperature for 1 to 24 hours, a mixture of compound (Ia) and compound (VI) is obtained. Compound (Ia) can be isolated by subjecting the obtained reaction mixture to recrystallization or chromatography.

（式中、Ｒ'''はメチル、エチルなどのＣ_１−Ｃ_４アルキルを示し、Ｘはハロゲンまたは置換されていてもよいアルキルスルホニルオキシ（好ましくはトリフルオロメタンスルホニルオキシ）などの脱離基を示し、Ｙは-B(OH)₂、-B(OR^a)₂または-Sn(R^a)₃を示し、Ｒ^ａはアルキルを示し、他の記号は前記と同義である。）
化合物（VII）と化合物（V）との反応は、方法１における化合物（IV）と化合物（V）との反応と同様に行うことができる。
化合物（VIII）を常法によりハロゲン化剤（オキシ塩化リン、オキシ臭化リンなど）またはスルホニル化剤（無水トリフルオロメタンスルホン酸など）を用いて化合物（VIII-a）とした後、化合物（VIII-a）を化合物（IX）とパラジウム触媒の存在下で反応させることにより化合物（I-a）を製造することができる。パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（トリフェニルホスフィン）パラジウム（II）クロリド、パラジウム（II）アセテート等の０価または２価のパラジウム触媒を用いることができる。Ｙが-B(OH)₂または-B(OR)₂である化合物（IX）を用いる場合は、塩基を加えるのが好ましい。塩基としては、例えば炭酸アルカリ金属、水酸化アルカリ金属、リン酸アルカリ金属、フッ化アルカリ金属等の無機塩基や、トリエチルアミン等の有機塩基などを用いることができる。溶媒としては、反応に悪影響を及ぼさないものであればいかなるものを用いてもよく、例えばＤＭＥ、ＴＨＦ、ジオキサン、ＤＭＦ、ジメチルアセタミド、トルエン、ベンゼンまたはこれらの混合物があげられる。本反応の反応温度は、通常６０〜１５０℃、好ましくは８０〜１２０℃であり、反応時間は、通常１〜２４時間である。 Method 2: Compound (Ia) can also be produced by the following method.

Wherein R ′ ″ represents C ₁ -C ₄ alkyl such as methyl or ethyl, and X represents a leaving group such as halogen or optionally substituted alkylsulfonyloxy (preferably trifluoromethanesulfonyloxy). Y represents —B (OH) ₂ , —B (OR ^a ) ₂ or —Sn (R ^a ) ₃ , R ^a represents alkyl, and other symbols are as defined above.
The reaction between compound (VII) and compound (V) can be carried out in the same manner as the reaction between compound (IV) and compound (V) in Method 1.
Compound (VIII) is converted into Compound (VIII-a) by a conventional method using a halogenating agent (phosphorus oxychloride, phosphorus oxybromide, etc.) or a sulfonylating agent (such as trifluoromethanesulfonic anhydride), and then compound (VIII Compound (Ia) can be produced by reacting -a) with compound (IX) in the presence of a palladium catalyst. As the palladium catalyst, for example, a zero-valent or divalent palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate can be used. When using the compound (IX) in which Y is —B (OH) ₂ or —B (OR) _2, it is preferable to add a base. As the base, for example, an inorganic base such as alkali metal carbonate, alkali metal hydroxide, alkali metal phosphate, or alkali metal fluoride, or an organic base such as triethylamine can be used. Any solvent may be used as long as it does not adversely influence the reaction, and examples thereof include DME, THF, dioxane, DMF, dimethylacetamide, toluene, benzene, and mixtures thereof. The reaction temperature of this reaction is usually 60 to 150 ° C., preferably 80 to 120 ° C., and the reaction time is usually 1 to 24 hours.

（式中、Ｐ^１はtert−ブトキシカルボニルまたはベンジルオキシカルボニルなどを示し、各記号は前記と同義である。）
化合物（I-b）を溶媒（ＴＨＦ、ジエチルエーテル、エチレングリコールジメチルエーテル、ＤＭＦ、ＤＭＳＯ、ジオキサンなど）中、アルコール（tert−ブタノール、ベンジルアルコールなど）および塩基（トリエチルアミン、ジイソプロピルエチルアミンなど）の存在下、アジ化剤（ジフェニルリン酸アジドなど）と−２０〜１５０℃で３０分から１０時間反応させることにより、化合物（I-c）を製造することができる。なお、本反応において、アジ化反応は活性化剤（クロロ炭酸メチル、クロロ炭酸エチル、クロロ炭酸イソプロピル、クロロ炭酸イソブチル、クロロ炭酸フェニルなど）とアジ化ナトリウムを用いて行うこともできる。
化合物（I-c）を常法により酸（塩酸、トリフルオロ酢酸など）で処理するか、または接触還元に付すことにより、化合物（I-c'）が得られる。
化合物（I-c'）を溶媒（水、酢酸、塩酸、臭化水素酸、硝酸、希硫酸またはそれらの混合物）中、亜硝酸ナトリウム、亜硝酸、有機亜硝酸エステル（例えば、亜硝酸イソペンチル）などを用いてジアゾ化合物とした後、ジアゾ化合物を求核試薬（ホウフッ化水素酸、塩酸−塩化第一銅、臭化水素酸−臭化第一銅、ヨウ素、ヨウ化カリウム、ヨウ化ナトリウムなど）と反応させることにより、化合物（I-d）を製造することができる。本反応は、通常−２０〜１００℃で、通常１０分間から１０時間で進行する。 Method 3: A compound in which ring Q is pyrazole and R ¹³ is amino or halogen can be produced by the following method.

(Wherein P ¹ represents tert-butoxycarbonyl or benzyloxycarbonyl, etc., and each symbol has the same meaning as described above.)
Compound (Ib) in a solvent (THF, diethyl ether, ethylene glycol dimethyl ether, DMF, DMSO, dioxane, etc.) in the presence of an alcohol (tert-butanol, benzyl alcohol, etc.) and a base (triethylamine, diisopropylethylamine, etc.) Compound (Ic) can be produced by reacting with an agent (such as diphenyl phosphate azide) at -20 to 150 ° C. for 30 minutes to 10 hours. In this reaction, the azidation reaction can also be carried out using an activating agent (such as methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl chlorocarbonate) and sodium azide.
The compound (Ic) is obtained by treating the compound (Ic) with an acid (hydrochloric acid, trifluoroacetic acid, etc.) or subjecting it to catalytic reduction by a conventional method.
Compound (I-c ′) in a solvent (water, acetic acid, hydrochloric acid, hydrobromic acid, nitric acid, dilute sulfuric acid or a mixture thereof), sodium nitrite, nitrous acid, organic nitrite (eg, isopentyl nitrite) The diazo compound is converted into a diazo compound by using a nucleophilic reagent (borohydrofluoric acid, hydrochloric acid-cuprous chloride, hydrobromic acid-cuprous bromide, iodine, potassium iodide, sodium iodide, etc. ) To produce a compound (Id). This reaction usually proceeds at −20 to 100 ° C., usually 10 minutes to 10 hours.

Method 4: Compounds wherein ring Q is pyrazole and R ¹³ is carbamoyl, cyano or optionally substituted imino substituted methyl are described in J. Med. Chem., 40, 1347-1365, 1997 and It can be produced according to the method described in Table 9-506350.

（式中、各記号は前記と同義である。）
化合物（XI）は、化合物（X）をヒドロキシルアミンまたはその塩（塩酸塩など）と溶媒（水、メタノール、エタノールまたはそれらの混合物など）中で反応させることにより製造することができる。本反応は、通常０℃から溶媒の還流温度、好ましくは室温から５０℃で、通常１〜２４時間で進行する。なお、ヒドロキシルアミンの塩を用いる場合、アルカリ（炭酸水素ナトリウムなど）の存在下で行うことが好ましい。
化合物（XI）を溶媒（ＴＨＦ、ジエチルエーテルなど）中、塩基（ｎ−ブチルリチウム、リチウムジイソプロピルアミドなど）の存在下で、化合物（XII-a）、化合物（XII-b）または化合物（XII-c）と反応させることにより、化合物（XIII）が得られる。本反応は、通常−７８℃から氷冷下で、通常１〜２４時間で進行する。
化合物（XIII）を溶媒（メタノール、エタノール、ベンゼン、トルエン、キシレン、クロロホルムなど）中、酸（塩酸、硫酸、ｐ−トルエンスルホン酸など）と処理することにより化合物（I-e）が得られる。本反応は通常０℃から溶媒の還流温度で、通常１〜２４時間で進行する。 Method 5: Compound (Ie) in which ring Q is isoxazole and R ¹³ is an optionally substituted alkyl, alkenyl, or heterocyclic group can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (XI) can be produced by reacting compound (X) with hydroxylamine or a salt thereof (such as hydrochloride) in a solvent (such as water, methanol, ethanol, or a mixture thereof). This reaction proceeds usually from 0 ° C. to the reflux temperature of the solvent, preferably from room temperature to 50 ° C., usually for 1 to 24 hours. In addition, when using the salt of hydroxylamine, it is preferable to carry out in presence of an alkali (sodium hydrogencarbonate etc.).
Compound (XI) in a solvent (THF, diethyl ether, etc.) in the presence of a base (n-butyllithium, lithium diisopropylamide, etc.), compound (XII-a), compound (XII-b) or compound (XII- Compound (XIII) is obtained by reacting with c). This reaction usually proceeds from −78 ° C. under ice cooling, usually in 1 to 24 hours.
Compound (Ie) is obtained by treating compound (XIII) with an acid (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc.) in a solvent (methanol, ethanol, benzene, toluene, xylene, chloroform, etc.). This reaction usually proceeds from 0 ° C. to the reflux temperature of the solvent, usually in 1 to 24 hours.

（式中、各記号は前記と同義である。）
Chem. Commun., 1558-59, 2001に記載の方法に準じて製造できる化合物（XIV）と化合物（XV）との反応は、方法２における化合物（VIII-a）と化合物（IX）との反応と同様に行うことにより、化合物（I-f）を製造することができる。 Method 6: Compound (If) can also be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
The reaction of compound (XIV) and compound (XV), which can be produced according to the method described in Chem. Commun., 1558-59, 2001, is the reaction of compound (VIII-a) and compound (IX) in Method 2. The compound (If) can be produced by carrying out in the same manner as above.

（式中、各記号は前記と同義である。）
化合物（XIV-a）をハロゲン化剤（臭素、塩素、ヨウ素、Ｎ−ブロモコハク酸イミド等）を用いて常法によりハロゲン化することにより、化合物（XIV-b）を製造することができる。化合物（XIV-b）と化合物（XV-a）との反応は、化合物（VIII-a）と化合物（IX）との反応と同様に行うことができる。 Method 7: Compound (I) can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (XIV-b) can be produced by halogenating compound (XIV-a) by a conventional method using a halogenating agent (bromine, chlorine, iodine, N-bromosuccinimide, etc.). The reaction between compound (XIV-b) and compound (XV-a) can be carried out in the same manner as the reaction between compound (VIII-a) and compound (IX).

（式中、各記号は前記と同義である。）
化合物（I-g）を溶媒（クロロホルム、塩化メチレンなど）中、クロロ硫酸と氷冷下から溶媒の還流温度、好ましくは室温にて、１〜４８時間処理することにより、化合物（XVI）が得られる。
化合物（XVI）を化合物（XVII）と、必要に応じて塩基（トリエチルアミンなど）の存在下、または過剰量の化合物（XVII）を用いて、氷冷下から室温で１〜２４時間反応させることにより化合物（I-h）が得られる。 Method 8: A compound in which R ¹ is —SO ₂ N (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (XVI) is obtained by treating compound (Ig) in a solvent (chloroform, methylene chloride, etc.) with chlorosulfuric acid and ice-cooling to the reflux temperature of the solvent, preferably at room temperature for 1 to 48 hours.
Compound (XVI) is reacted with Compound (XVII) in the presence of a base (such as triethylamine) or an excess amount of Compound (XVII) as necessary at room temperature for 1 to 24 hours under ice cooling. Compound (Ih) is obtained.

（式中、各記号は前記と同義である。）
化合物（I-g）を溶媒（酢酸、無水酢酸、濃硫酸、クロロホルム、ジクロロメタン、二硫化炭素、ジクロロエタン、またはそれらの混合物など）中または無溶媒で、硝酸、混酸、硝酸アセチルなどと処理することにより化合物（XVIII）を製造することができる。本反応は、通常−２０〜１００℃で、通常３０分間から１２時間で進行する。
化合物（XVIII）を、溶媒（例えば、水、メタノール、エタノール、tert−ブチルアルコール、ＴＨＦ、ジオキサン、酢酸エチル、酢酸、キシレン、ＤＭＦ、ＤＭＳＯまたはそれらの混合物）中、還元することにより化合物（I-i）を製造することができる。還元反応は、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム等の還元剤を用いるか、金属（鉄、亜鉛、スズ等）を用いるか、または遷移金属（パラジウム−炭素、酸化白金、ラネーニッケル、ロジウム、ルテニウム等）を用いた接触還元などによっても行うことができる。なお、接触還元を行う場合、水素源はギ酸、ギ酸アンモニウム、１，４−シクロヘキサジエン等であってもよい。本反応は、通常−２０〜１５０℃で、通常３０分間から４８時間で進行する。 Method 9: A compound in which R ¹ is —NH ₂ can be produced by Method 6, 7 or the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (Ig) is treated with nitric acid, mixed acid, acetyl nitrate, etc. in a solvent (such as acetic acid, acetic anhydride, concentrated sulfuric acid, chloroform, dichloromethane, carbon disulfide, dichloroethane, or a mixture thereof) or without solvent. (XVIII) can be produced. This reaction usually proceeds at −20 to 100 ° C., usually 30 minutes to 12 hours.
Compound (Ii) by reducing Compound (XVIII) in a solvent (eg, water, methanol, ethanol, tert-butyl alcohol, THF, dioxane, ethyl acetate, acetic acid, xylene, DMF, DMSO or mixtures thereof) Can be manufactured. For the reduction reaction, for example, a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride or the like, a metal (iron, zinc, tin, etc.) or a transition metal (palladium-carbon, platinum oxide) is used. , Raney nickel, rhodium, ruthenium, etc.). When performing catalytic reduction, the hydrogen source may be formic acid, ammonium formate, 1,4-cyclohexadiene, or the like. This reaction usually proceeds at −20 to 150 ° C., usually 30 minutes to 48 hours.

（式中、各記号は前記と同義である。）
化合物（I-i）のＮ−アシル化反応またはＮ−スルホニル化反応は、溶媒中、塩基の存在下で行うことができる。溶媒としては、例えば、ＴＨＦ、ジオキサン、ジエチルエーテル、エチレングリコールジメチルエーテル、ベンゼン、ジクロロメタン、ジクロロエタン、クロロホルム、トルエン、キシレン、ＤＭＦ、ＤＭＳＯ、水またはそれらの混合物などがあげられる。塩基としては、例えば炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カリウム、トリエチルアミン、ジイソプロピルエチルアミン、１，８−ジアザビシクロ〔５．４．０〕ウンデカ−７−エン（ＤＢＵ）、ピリジン、４−ジメチルアミノピリジンがあげられる。本反応は、通常−８０〜１５０℃で、通常３０分から４８時間で進行する。 Method 10: Compounds in which R ¹ is —NHCOR ⁵ or —NHSO ₂ R ⁵ can be prepared by Method 6, 7 or the following method.

(In the formula, each symbol has the same meaning as described above.)
N-acylation reaction or N-sulfonylation reaction of compound (Ii) can be carried out in a solvent in the presence of a base. Examples of the solvent include THF, dioxane, diethyl ether, ethylene glycol dimethyl ether, benzene, dichloromethane, dichloroethane, chloroform, toluene, xylene, DMF, DMSO, water, or a mixture thereof. Examples of the base include potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU), pyridine, 4-dimethylaminopyridine. This reaction usually proceeds at −80 to 150 ° C., usually 30 minutes to 48 hours.

（式中、各記号は前記と同義である。）
化合物（XIX）を溶媒（アセトニトリル、ＤＭＳＯ、ＤＭＦまたはその混合物など）中、シアノ化剤（シアン化ナトリウム、シアン化第一銅など）と室温から１００℃で１から２４時間反応させることにより化合物（ＸＸ）を得ることができる。また、テトラキス（トリフェニルホスフィン）パラジウムなどのパラジウム触媒およびシアン化亜鉛、シアン化カリウムなどのシアノ化剤を用いることによっても化合物（XX）を得ることができる。
化合物（XX）を溶媒（水、メタノール、エタノール、イソプロピルアルコール、tert−ブチルアルコール、エチレングリコール、ジエチレングリコールまたはそれらの混合物など）中、酸（塩酸、硫酸など）またはアルカリ（水酸化ナトリウム、水酸化カリウムなど）で加水分解することにより、化合物（I-m）を得ることができる。本反応のは通常−２０〜１５０℃で、通常３０分〜４８時間で進行する。また、化合物（I-m）は方法６、７により製造することもできる。
化合物（I-o）または化合物（I-n）は次のいずれかの方法により製造することができる。
（１）化合物（I-m）をハロゲン化剤（塩化チオニルなど）と処理して酸ハライドに変換した後、化合物（XVII）または化合物（XXI）と塩基（炭酸水素ナトリウム、炭酸カリウム、トリエチルアミン、ピリジンなど）の存在下、−２０℃から室温で３０分から２４時間反応させることにより化合物（I-o）または化合物（I-n）が得られる。なお、化合物（XX）を溶媒（水、メタノール、エタノール、イソプロピルアルコール、tert−ブチルアルコール、エチレングリコール、ジエチレングリコールまたはそれらの混合物など）中、アルカリ（水酸化ナトリウム、水酸化カリウムなど）で加水分解することにより、Ｒ^５およびＲ^６が水素である化合物（I-o）を得ることができる。
（２）化合物（I-m）を必要に応じて溶媒（ＤＭＦ、ＴＨＦ、ジオキサンなど）中、縮合剤（１，３−ジシクロヘキシルカルボジイミド、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、カルボニルジイミダゾール、シアノリン酸ジエチルなど）の存在下で化合物（XVII）または化合物（XXI）と縮合させることにより化合物（I-o）または化合物（I-n）が得られる。本反応は通常０℃から１００℃で、通常３０分から２４時間で進行する。なお、縮合剤を用いる反応は、必要に応じて１−ヒドロキシベンズトリアゾール、Ｎ−ヒドロキシスクシンイミドなどの存在下で行うこともできる。
（３）化合物（I-m）を炭酸エステル（クロロ炭酸メチル、クロロ炭酸エチルなどとの混合酸無水物）に変換し、当該炭酸エステルを適当な溶媒（ＴＨＦ、トルエン、ニトロベンゼンあるいはこれらの混合溶媒など）中、塩基（トリエチルアミン、ピリジンなど）の存在下、室温から溶媒の還流温度で１から２４時間、化合物（XVII）または化合物（XXI）と縮合させることにより化合物（I-o）または化合物（I-n）が得られる。 Method 11: A compound in which R ¹ is —COOR ⁵ or —CON (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (XIX) is reacted with a cyanating agent (sodium cyanide, cuprous cyanide, etc.) in a solvent (acetonitrile, DMSO, DMF or a mixture thereof) at room temperature to 100 ° C. for 1 to 24 hours. XX) can be obtained. The compound (XX) can also be obtained by using a palladium catalyst such as tetrakis (triphenylphosphine) palladium and a cyanating agent such as zinc cyanide and potassium cyanide.
Compound (XX) in a solvent (water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, diethylene glycol, or a mixture thereof), acid (hydrochloric acid, sulfuric acid, etc.) or alkali (sodium hydroxide, potassium hydroxide) Etc.) to give compound (Im). This reaction is usually carried out at -20 to 150 ° C., usually in 30 minutes to 48 hours. Compound (Im) can also be produced by methods 6 and 7.
Compound (Io) or compound (In) can be produced by any of the following methods.
(1) Compound (Im) is treated with a halogenating agent (such as thionyl chloride) and converted to an acid halide, then compound (XVII) or compound (XXI) and a base (sodium hydrogen carbonate, potassium carbonate, triethylamine, pyridine, etc.) ) To -20 ° C. to room temperature for 30 minutes to 24 hours, compound (Io) or compound (In) is obtained. Compound (XX) is hydrolyzed with an alkali (sodium hydroxide, potassium hydroxide, etc.) in a solvent (water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, diethylene glycol, or a mixture thereof). Thus, a compound (Io) in which R ⁵ and R ⁶ are hydrogen can be obtained.
(2) In a solvent (DMF, THF, dioxane, etc.) as necessary, the compound (Im) is condensed in a condensing agent (1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, carbonyldiimide. Compound (Io) or compound (In) is obtained by condensation with compound (XVII) or compound (XXI) in the presence of imidazole, diethyl cyanophosphate, etc. This reaction usually proceeds at 0 ° C. to 100 ° C., usually 30 minutes to 24 hours. In addition, reaction using a condensing agent can also be performed in presence of 1-hydroxy benztriazole, N-hydroxysuccinimide, etc. as needed.
(3) Compound (Im) is converted into a carbonate ester (mixed acid anhydride with methyl chlorocarbonate, ethyl chlorocarbonate, etc.), and the carbonate ester is converted into an appropriate solvent (THF, toluene, nitrobenzene or a mixed solvent thereof). In the presence of a base (triethylamine, pyridine, etc.), compound (Io) or compound (In) is obtained by condensation with compound (XVII) or compound (XXI) from room temperature to the reflux temperature of the solvent for 1 to 24 hours. It is done.

（式中、各記号は前記と同義である。）
化合物（I-p)または化合物（I-r）を適当な溶媒（水、ＤＭＳＯ、ＤＭＦ、トルエン、ＴＨＦまたはそれらの混合溶媒など）中、塩基（水酸化ナトリウム、水素化ナトリウムなど）の存在下、化合物（XXII）と−２０℃から溶媒の還流温度で１から２４時間反応させることにより化合物（I-q）または化合物（I-s）を得ることができる。 Method 12: A compound in which R ¹ is —OR ⁵ or —SR ⁵ can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (Ip) or Compound (Ir) is compound (XXII) in the presence of a base (sodium hydroxide, sodium hydride, etc.) in an appropriate solvent (water, DMSO, DMF, toluene, THF, or a mixed solvent thereof). ) At −20 ° C. at the reflux temperature of the solvent for 1 to 24 hours, compound (Iq) or compound (Is) can be obtained.

（式中、各記号は前記と同義である。）
化合物（I-s）を適当な溶媒（酢酸、ジオキサン、クロロホルム、塩化メチレンまたはそれらの混合物など）中、酸化剤（メタクロロ過安息香酸、過酸化水素など）と０〜１００℃で３０分から２４時間反応させることにより、化合物（I-t）が得られる。 Method 13: A compound in which R ¹ is —SO ₂ —R ⁵ can be produced by Method 6, 7 or the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (Is) is reacted with an oxidizing agent (such as metachloroperbenzoic acid or hydrogen peroxide) in an appropriate solvent (such as acetic acid, dioxane, chloroform, methylene chloride, or a mixture thereof) at 0 to 100 ° C. for 30 minutes to 24 hours. Thus, compound (It) is obtained.

（式中、Halは塩素、臭素などのハロゲンを示し、他の記号は前記と同義である。）
化合物（XVI-a）または化合物（XXV）を化合物（XXIII）と適当な溶媒（水、酢酸エチル、ＤＭＦ、ＤＭＳＯ、クロロホルム、塩化メチレン、ＴＨＦまたはこれら混合物など）中、塩基（トリエチルアミン、炭酸水素ナトリウム、炭酸カリウムなど）の存在下で、氷冷下から溶媒の還流温度で１〜２４時間反応させることにより、化合物（I-u）または化合物（I-w）が得られる。
また、化合物（XVI-a）または化合物（XXV）を化合物（XXIV）と上記反応と同様に行うことにより、化合物（I-v）または化合物（I-x）が得られる。 Method 14: A compound in which R ¹ is —SO ₂ N (R ⁶ ) OR ⁵ or —CON (R ⁶ ) OR ⁵ , or R ¹ is —SO ₂ NHN (R ⁵ ) (R ⁶ ) or —CONHN (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, Hal represents halogen such as chlorine and bromine, and other symbols are as defined above.)
Compound (XVI-a) or compound (XXV) is mixed with compound (XXIII) and a suitable solvent (water, ethyl acetate, DMF, DMSO, chloroform, methylene chloride, THF or a mixture thereof) in a base (triethylamine, sodium bicarbonate). Compound (Iu) or Compound (Iw) is obtained by reacting for 1 to 24 hours at the reflux temperature of the solvent under ice-cooling in the presence of potassium carbonate or the like.
In addition, compound (Iv) or compound (Ix) can be obtained by performing compound (XVI-a) or compound (XXV) in the same manner as in the above reaction with compound (XXIV).

（式中、各記号は前記と同義である。）
化合物（I-y）を化合物（XXVI）と溶媒（ＴＨＦ、ジエチルエーテル、エチレングリコールジメチルエーテル、ベンゼン、トルエン、キシレン、ジオキサンなど）中、−２０〜１００℃で３０分〜２４時間グリニャール（Grignard）反応に付すことにより、化合物（XXVII）が得られる。
化合物（XXVII）を酸化剤〔クロム酸−硫酸、酸化クロム（VI）−硫酸−アセトン（ジョーンズ（Jones）試薬）、酸化クロム（VI）−ピリジン錯体（コリンズ（Collins）試薬）、二クロム酸塩（二クロム酸ナトリウム、二クロム酸カリウムなど）−硫酸、クロロクロム酸ピリジニウム（PCC）、二酸化マンガン、ジメチルスルホキシド−親電子活性化試薬（ジシクロヘキシルカルボジイミド、無水酢酸、五酸化リン、三酸化硫黄−ピリジン錯体、無水トリフルオロ酢酸、塩化オキサリル、ハロゲン）、次亜塩素酸ナトリウム、次亜塩素酸カリウム、亜臭素酸ナトリウムなど〕と−２０〜１００℃で３０分〜２４時間反応させることにより、化合物（I-z）が得られる。 Method 15: A compound in which R ¹ is —COR ⁵ can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (Iy) is subjected to a Grignard reaction in Compound (XXVI) and a solvent (THF, diethyl ether, ethylene glycol dimethyl ether, benzene, toluene, xylene, dioxane, etc.) at -20 to 100 ° C for 30 minutes to 24 hours. Thus, compound (XXVII) is obtained.
Compound (XXVII) as an oxidizing agent (chromic acid-sulfuric acid, chromium oxide (VI) -sulfuric acid-acetone (Jones reagent), chromium oxide (VI) -pyridine complex (Collins reagent), dichromate (Sodium dichromate, potassium dichromate, etc.)-Sulfuric acid, pyridinium chlorochromate (PCC), manganese dioxide, dimethyl sulfoxide-electrophilic activator (dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine Complex, trifluoroacetic anhydride, oxalyl chloride, halogen), sodium hypochlorite, potassium hypochlorite, sodium bromate, etc.] at −20 to 100 ° C. for 30 minutes to 24 hours to give a compound ( Iz) is obtained.

（式中、各記号は前記と同義である。）
化合物（I-i’）を化合物（XXVIII）と方法１１と同様に反応させることにより、化合物（I-aa’）が得られる。 Method 16: A compound in which R ¹ is —NHSO ₂ N (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (I-aa ′) is obtained by reacting compound (I-i ′) with compound (XXVIII) in the same manner as in Method 11.

（式中、各記号は前記と同義である。）
化合物（I-p）を化合物（XXIX）と方法１１と同様に反応させることにより、化合物（I-bb）が得られる。 Method 17: A compound in which R ¹ is —OCON (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (I-bb) is obtained by reacting compound (Ip) with compound (XXIX) in the same manner as in Method 11.

（式中、Ｐｈはフェニルを示し、他の記号は前記と同義である。）
化合物（I-z’）を化合物（XXX）と−２０〜１５０℃で３０分〜２４時間、ウィッティッヒ（Wittig）反応に付すことにより、化合物（I-cc）が得られる。本反応に用いられる溶媒としては、水、メタノール、エタノール、tert−ブチルアルコール、ＴＨＦ、ジエチルエーテル、エチレングリコールジメチルエーテル、ＤＭＦ、ＤＭＳＯ、ベンゼン、トルエン、キシレン、ジオキサン、塩化メチレン、クロロホルム、ジクロロエタン、アセトニトリル等があげられる。本反応に用いられる塩基としては、ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシド、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、ブチルリチウム、リチウムヘキサメチルジシラザン、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ＤＢＵなどがあげられる。 Method 18: A compound in which R ¹ is —C (R ⁷ ) ═C (R ⁵ ) (R ⁶ ) can be produced by the following method.

(In the formula, Ph represents phenyl, and other symbols are as defined above.)
Compound (I-cc) is obtained by subjecting compound (I-z ′) to Wittig reaction with compound (XXX) at −20 to 150 ° C. for 30 minutes to 24 hours. Solvents used in this reaction include water, methanol, ethanol, tert-butyl alcohol, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, DMSO, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile, and the like. Can be given. Examples of the base used in this reaction include sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine, pyridine, DBU etc. are mentioned.

（式中、Ｙ^１は-B(OR^a)₂または-Sn(R^a)₃を示し、Ｒ^ａはアルキルを示し、Ｒ^１３ｂは置換されていてもよいアルキルを示し、他の記号は前記と同義である。）
化合物（XXXI-a）をハロゲン化剤（塩素、Ｎ−クロロコハク酸イミド、次亜塩素酸ナトリウム等）を用いて常法によりハロゲン化することにより、化合物（XXXI-b）を製造することができる。
化合物（XXXI-b）を化合物（XXXII）と溶媒（ジエチルエーテル、ジイソプロピルエーテル、ＴＨＦ、ジオキサン、アセトン、メチルエチルケトン、塩化メチレン、１，２−ジクロロエタン、四塩化炭素、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＳＯ、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、酢酸エチル、水またはそれらの混合物など）中、塩基（炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、ピリジン、トリエチルアミンなど）の存在下で反応させることにより、化合物（XXXIII）を製造することができる。本反応は、通常−２０〜１５０℃、好ましくは０〜１００℃で、通常１〜２４時間で進行する。
なお、Acta Chemica Scandinavica, 48, 61-67, 1994の方法に準じて、化合物（XXXI-a）をハロゲン化剤および化合物（XXXII）と反応をさせることにより、化合物（XXXI-b）を単離することなく、化合物（XXXIII）を製造することもできる。
得られた化合物（XXXIII）を方法２における化合物（VIII-a）と化合物（IX）との反応と同様に反応させることにより、化合物（I-dd）を製造することができる。 Method 19: Compound (I-dd) in which ring Q is isoxazole and R ¹³ is optionally substituted alkyl can be produced by the following method.

Wherein Y ¹ represents —B (OR ^a ) ₂ or —Sn (R ^a ) ₃ ; R ^a represents alkyl; R ^13b represents optionally substituted alkyl; Is synonymous with.)
Compound (XXXI-b) can be produced by halogenating compound (XXXI-a) with a halogenating agent (chlorine, N-chlorosuccinimide, sodium hypochlorite, etc.) by a conventional method. .
Compound (XXXI-b) and compound (XXXII) and solvent (diethyl ether, diisopropyl ether, THF, dioxane, acetone, methyl ethyl ketone, methylene chloride, 1,2-dichloroethane, carbon tetrachloride, benzene, toluene, xylene, DMF, DMSO , Methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, water or mixtures thereof) in the presence of a base (sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, pyridine, triethylamine, etc.) To make compound (XXXIII). This reaction usually proceeds at -20 to 150 ° C, preferably 0 to 100 ° C, and usually proceeds for 1 to 24 hours.
According to the method of Acta Chemica Scandinavica, 48, 61-67, 1994, compound (XXXI-b) is isolated by reacting compound (XXXI-a) with a halogenating agent and compound (XXXII). The compound (XXXIII) can also be produced without this.
Compound (I-dd) can be produced by reacting the obtained compound (XXXIII) in the same manner as in the reaction of compound (VIII-a) and compound (IX) in Method 2.

（式中、Ｐ^１はＢｏｃ等のアミノ保護基を、ｘは０または１を、ｙは１または２を示し、他の記号は前記と同義である。）
化合物（XXXIV）を適当な溶媒（ＴＨＦ、ジオキサン、ジメチルエーテル、ＤＭＥ等）中、−７８℃から室温で塩基（ブチルリチウム、リチウムジイソピロピルアミド等）と処理してリチオ化合物とし、次いで化合物（XXXV）と１〜２４時間反応させることにより、化合物（XXXVI）を製造することができる。
化合物（XXXVI）を酸〔ポリリン酸トリメチルシリルエステル（PPSE）など〕と反応させるか、または化合物（XXXVI）をハロゲン化物やスルホン酸エステルに変換した後、塩基（ピリジン、ＤＢＵ等）と処理し、脱保護することにより、化合物（XXXVII）を製造することができる。本反応は、適当な溶媒（塩化メチレン、クロロホルム、ＴＨＦ、ジオキサン、ＤＭＦ、ＤＭＳＯ等）中、０℃から溶媒の還流温度で１〜２４時間で実施することができる。
得られた化合物（XXXVII）を適当な溶媒（塩化メチレン、クロロホルム、ＴＨＦ、ジオキサン、ＤＭＦ、ＤＭＳＯ等）中、トリホスゲンおよびHN(R⁵)(R⁶)と氷冷下から室温で１〜２４時間反応させることにより、化合物（I-ee）を製造することができる。なお、本反応は、トリホスゲンおよびHN(R⁵)(R⁶)に代えて、(R⁵)(R⁶)NCOHalまたは(R⁵)(R⁶)NCOおよび塩基（ピリジン、トリエチルアミン等）を用いて実施することもできる。
また、得られた化合物（XXXVI）の水酸基をOC(=S)SMeに変換した後、トリブチル錫ヒドリドおよびラジカル開始剤〔２，２’−アゾビスイソブチロニトリル（AIBN）など〕と処理することにより、環Ａがピロリジン、ピペリジンまたはホモピペリジンの化合物を製造することができる。 Method 20: Compound (I-ee) in which ring Q is isoxazole, R ¹ is CON (R ⁵ ) (R ⁶ ), R ² is hydrogen, and ring A is pyrroline, tetrahydropyridine or tetrahydroazepine. It can be produced by the following method.

(In the formula, P ¹ represents an amino protecting group such as Boc, x represents 0 or 1, y represents 1 or 2, and other symbols are as defined above.)
Compound (XXXIV) is treated with a base (butyllithium, lithium diisopropylpyramide, etc.) at −78 ° C. to room temperature in a suitable solvent (THF, dioxane, dimethyl ether, DME, etc.) to give a lithio compound, and then compound ( Compound (XXXVI) can be produced by reacting with XXXV) for 1 to 24 hours.
The compound (XXXVI) is reacted with an acid (such as polyphosphoric acid trimethylsilyl ester (PPSE)) or the compound (XXXVI) is converted into a halide or sulfonic acid ester and then treated with a base (pyridine, DBU, etc.) to remove the compound. By protecting, compound (XXXVII) can be produced. This reaction can be carried out in a suitable solvent (methylene chloride, chloroform, THF, dioxane, DMF, DMSO, etc.) at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours.
The obtained compound (XXXVII) is mixed with triphosgene and HN (R ⁵ ) (R ⁶ ) in an appropriate solvent (methylene chloride, chloroform, THF, dioxane, DMF, DMSO, etc.) at room temperature for 1 to 24 hours under ice cooling. The compound (I-ee) can be produced by reacting. In this reaction, instead of triphosgene and HN (R ⁵ ) (R ⁶ ), (R ⁵ ) (R ⁶ ) NCOHal or (R ⁵ ) (R ⁶ ) NCO and a base (pyridine, triethylamine, etc.) are used. Can also be implemented.
Moreover, after converting the hydroxyl group of the obtained compound (XXXVI) to OC (= S) SMe, it is treated with tributyltin hydride and a radical initiator [2,2′-azobisisobutyronitrile (AIBN) etc.]. Thus, a compound in which ring A is pyrrolidine, piperidine or homopiperidine can be produced.

（式中、各記号は前記と同義である。）
化合物（I-ff）を化合物（XXXVIII）または化合物（XXXIX）と塩基（炭酸水素ナトリウム、炭酸カリウム、トリエチルアミン、ピリジン等）の存在下、−２０℃から室温で３０分から２４時間反応させることにより、化合物（I-gg）または化合物（I-hh）が得られる。 Method 21: A compound in which R ¹ is —CON (R ⁶ ) COR ⁵ or —CON (R ⁶ ) SO ₂ R ⁵ can be produced by the following method.

(In the formula, each symbol has the same meaning as described above.)
By reacting Compound (I-ff) with Compound (XXXVIII) or Compound (XXXIX) in the presence of a base (sodium hydrogen carbonate, potassium carbonate, triethylamine, pyridine, etc.) at −20 ° C. to room temperature for 30 minutes to 24 hours, Compound (I-gg) or compound (I-hh) is obtained.

（式中、Ｒ^１３ｃはハロゲンで置換されたアルキルを示し、Alkはアルキルを示し、他の記号は前記と同義である。）
本反応は、Drug Development Research 51, 273-286 (2000)に記載の方法に準じて実施することができる。
化合物（XL）を化合物（XLI）と適当な溶媒（ベンゼン、トルエン、キシレン、無水酢酸など）中、塩基（トリエチルアミン、ジイソプロピルエチルアミン、ピリジンなど）の存在下、溶媒の還流温度で１〜４８時間反応させることにより、化合物（XLII-a）を得ることができる。
化合物（XLII-a）を方法１１に準じて、アルコール（メタノールなど）を用いてエステル化し、化合物（XLII-b）を化合物（XLIII）と適当な溶媒（ＤＭＥ、ＴＨＦなど）中、触媒（フッ化セシウムなど）の存在下、０℃〜１００℃で１〜２４時間反応させた後、適当な酸（塩酸、硫酸など）を加えて１〜２４時間反応させることにより、化合物（XLIV）を得ることができる。
化合物（XLIV）をヒドロキシルアミン塩酸塩と適当な溶媒（メタノール、エタノール、イソプロパノールなど）中、塩基（酢酸ナトリウム、トリエチルアミン、炭酸ナトリウム、炭酸水素ナトリウムなど）の存在下、溶媒の還流温度で１〜２４時間反応させることにより、化合物（XLV）を得ることができる。
化合物（XLV）を適当な溶媒（ＴＨＦ、ジエチルエーテル、ジオキサン、水またはその混合物など）中、遮光下、ハロゲン化剤（ヨウ素−ヨウ化カリウムなど）および炭酸水素ナトリウムを用いて、溶媒の還流温度で１〜２４時間閉環反応に付すことにより、化合物（I-ii）を得ることができる。 Method 22: A compound in which ring Q is isoxazole and R ¹³ is alkyl substituted with halogen can be produced by the following method.

(Wherein R ^13c represents alkyl substituted with halogen, Alk represents alkyl, and other symbols are as defined above.)
This reaction can be carried out according to the method described in Drug Development Research 51, 273-286 (2000).
Compound (XL) is reacted with compound (XLI) in an appropriate solvent (benzene, toluene, xylene, acetic anhydride, etc.) in the presence of a base (triethylamine, diisopropylethylamine, pyridine, etc.) for 1 to 48 hours at the reflux temperature of the solvent. Compound (XLII-a) can be obtained.
Compound (XLII-a) is esterified with alcohol (such as methanol) according to Method 11, and compound (XLII-b) is converted into compound (XLIII) and a suitable solvent (such as DME and THF) using a catalyst (fluorinated). In the presence of cesium chloride, etc.), the reaction is carried out at 0-100 ° C. for 1-24 hours, and then an appropriate acid (hydrochloric acid, sulfuric acid, etc.) is added and reacted for 1-24 hours to obtain compound (XLIV). be able to.
Compound (XLIV) in hydroxylamine hydrochloride and a suitable solvent (methanol, ethanol, isopropanol, etc.) in the presence of a base (sodium acetate, triethylamine, sodium carbonate, sodium hydrogencarbonate, etc.) at 1-24 at the reflux temperature of the solvent. Compound (XLV) can be obtained by reacting for a period of time.
Compound (XLV) is refluxed in a suitable solvent (THF, diethyl ether, dioxane, water or a mixture thereof) using a halogenating agent (iodine-potassium iodide, etc.) and sodium hydrogen carbonate under light shielding. The compound (I-ii) can be obtained by subjecting to a ring closure reaction for 1 to 24 hours.

Method 23: A compound in which R ¹³ is a hydroxyl group or alkoxy can be produced according to Synthesis, 1989, 275-279 and Tetrahedron Lett., 1984, 25, 4587-4590.

Method 24:
(1) In the above method, when the compound of the present invention or the raw material compound has a functional group (hydroxyl group, amino, carboxy, etc.), the reaction is carried out by protecting the functional group with a protective group usually used in organic synthetic chemistry. The target compound can be obtained by removing the protecting group after the reaction. Examples of the hydroxyl protecting group include tetrahydropyranyl and TMS. Examples of the amino protecting group include Boc and benzyloxycarbonyl. Examples of the carboxyl protecting group include alkyl such as methyl and ethyl. Examples include benzyl.
(2) In the above method, when the compound of the present invention or the starting compound has amino, after protecting the amino as necessary, (i) in the presence of a base (sodium hydride, triethylamine, sodium carbonate, potassium carbonate, etc.) in halogenated alkyl (wherein the alkyl corresponds to the alkyl may be substituted in R ^5, R ^6.) and is reacted, or (ii) an alcohol (wherein the alkyl portion is substituted in R ^5, R ⁶ By subjecting it to a Mitsunobu reaction using dialkyl azodicarboxylate and triphenylphosphine, and deprotecting as necessary, so that the optionally substituted alkyl is mono- or di-substituted. Can be obtained.
(3) In the above method, when the compound of the present invention or the raw material compound has amino, the reaction is carried out using an acyl halide in the same manner as the reaction from compound (Ii) to compound (Ik) in Method 11, and the corresponding amide is obtained. Can be converted.
(4) In the above method, when the compound of the present invention or the starting compound has carboxy, the reaction is carried out using an amine in the same manner as in the reaction from compound (Im) to compound (Io) in method 12 to convert it to the corresponding carbamoyl. can do.
(5) In the above method, when the compound of the present invention or the raw material compound has a double bond, it is converted to a corresponding single bond by catalytic reduction using a transition metal (platinum, palladium, rhodium, ruthenium, nickel) catalyst. Can do.
(6) In the above method, when the compound of the present invention or the starting compound has an ester group, it can be converted to the corresponding carboxy by hydrolysis with an alkali (sodium hydroxide, potassium hydroxide, etc.).
(7) In the above method, when the compound of the present invention or the raw material compound has carbamoyl, it can be converted to the corresponding nitrile by reacting with trifluoroacetic anhydride.
(8) In the above method, when the compound of the present invention or the starting compound has carboxy, it is converted to the corresponding 4,5-dihydrooxazol-2-yl by reacting with 2-haloethylamine in the presence of a condensing agent. be able to.
(9) In the above method, when the compound of the present invention or the raw material compound has a hydroxyl group, it can be converted to a corresponding halogen by treatment with a halogenating agent. Moreover, when this invention compound or a raw material compound has a halogen, it can convert into corresponding alkoxy by processing with alcohol.
(10) In the above method, when the compound of the present invention or the starting compound has an ester, it is reduced using a reducing agent (metal reducing reagent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane, etc.). Thus, it can be converted into a corresponding hydroxyl group.
(11) In the above method, when the compound of the present invention or the raw material compound has a hydroxyl group, it can be converted into an aldehyde, a ketone or carboxy by oxidation using an oxidizing agent (similar to the oxidizing agent in Method 15).
(12) In the above method, when the compound of the present invention or the raw material compound has carbonyl or aldehyde, a reductive amination reaction is performed in the presence of an amine compound and a reducing agent (sodium borohydride, sodium cyanoborohydride, etc.). Can be converted to aminomethyl which may be mono- or di-substituted.
(13) In the above method, when the compound of the present invention or the raw material compound has carbonyl or aldehyde, it can be converted to a double bond by subjecting it to a Wittig reaction.
(14) In the above method, when the compound of the present invention or the raw material compound has a sulfonamide, the corresponding sulfonamide is obtained by treating with an alkali (sodium hydroxide, potassium hydroxide, etc.) in an alcohol (methanol, ethanol, etc.). Can be converted to the salt of (sodium salt, potassium salt, etc.).
(15) In the above method, when the compound of the present invention or the starting compound has an aldehyde, it is reacted with hydroxylamine or O-alkylhydroxylamine in an alcohol (methanol, ethanol, etc.) in the presence of a base (sodium hydrogencarbonate, etc.). Can be converted to the corresponding oxime.
(16) In the above method, when the compound of the present invention or the starting compound has a halogen, it can be converted to a corresponding cyano group by treatment with a cyanating agent (similar to the cyanating agent in Method 12).
(17) In the above method, when the compound of the present invention or the raw material compound has a halogen, it can be converted into a corresponding amine by reacting according to the method described in Tetrahedron, 2041-2075, 2002.
(18) In the above method, when the compound of the present invention or the raw material compound has alkoxycarbonyl, it can be condensed with N-hydroxysuccinimide to give a succinimide ester and then converted to the corresponding carbamoyl by reacting with an amine compound. it can. Further, the succinimide ester can be converted to the corresponding hydroxymethyl by treating with a reducing agent (such as sodium borohydride).
(19) In the above method, when the compound of the present invention or the raw material compound has benzylamine, it can be converted into the corresponding amine according to Synthesis, 1985, 770-773.

  In the above production, each produced compound and each intermediate can be purified by a usual method such as column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketone solvents such as acetone, and hydrocarbons such as hexane. A solvent, water, etc., or these mixed solvents are mentioned. In addition, the compound of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method, followed by recrystallization and the like.

  Compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), A lubricant (magnesium stearate, talc, polyethylene glycol, silica), a disintegrant (potato starch), a wetting agent (sodium lauryl sulfate) and the like can be mentioned.

Compound (I) or a pharmaceutically acceptable salt thereof of the present invention can be administered orally or parenterally, and can be used as an appropriate pharmaceutical preparation. Examples of suitable pharmaceutical preparations for oral administration include solid preparations such as tablets, granules, capsules, powders, solution preparations, suspension preparations, and emulsion preparations. Appropriate pharmaceutical preparations for parenteral administration include suppositories, injections or infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution, or inhalants.
The dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition or type / degree of disease, but is usually about 0.1 per day. It is preferably about 50 mg / kg, particularly about 0.1 to 30 mg / kg.

  The compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent high conductance type calcium sensitive K channel opening action and hyperpolarizes the membrane electrical potential of the cell, so that, for example, hypertension, premature labor, hypersensitivity Bowel syndrome, chronic heart failure, angina pectoris, myocardial infarction, cerebral infarction, subarachnoid hemorrhage, cerebrovascular spasm, cerebral hypoxia, peripheral vascular disorder, anxiety, male baldness, erectile dysfunction, diabetes, diabetic peripheral neuropathy , Other diabetic complications, infertility, urinary stones and associated pain, frequent urination, urinary incontinence, nocturnal enuresis, asthma, chronic obstructive pulmonary disease (COPD), cough associated with asthma or COPD, stroke, cerebral ischemia It is useful as an agent for preventing, reducing and / or treating traumatic brain injury.

EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention in detail, this invention is not limited at all by these.
In addition, the symbol used in an Example and a reference example represents the following meaning, respectively.
THF: Tetrahydrofuran DMF: N, N-dimethylformamide DMSO: Dimethyl sulfoxide DME: 1,2-dimethoxyethane Me: Methyl Et: Ethyl t-Bu: tert-butyl TMS: Trimethylsilyl Tf: Trifluoromethanesulfonyl Boc: tert-butoxycarbonyl Bn: benzyl Ph: phenyl

４，４，４−トリフルオロ−１−（４−メチルフェニル）ブタン−１，３−ジオン（230mg,1.00mmol）と３−メチルフェニルヒドラジン塩酸塩（174mg,1.10mmol）のエタノール（5ml）溶液を２０時間加熱還流した。反応液を冷却後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→９０：１０）で精製することにより、１−（３−メチルフェニル）−５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール（298mg,94％）を粉末として得た。
ＭＳ：３１７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 1

A solution of 4,4,4-trifluoro-1- (4-methylphenyl) butane-1,3-dione (230 mg, 1.00 mmol) and 3-methylphenylhydrazine hydrochloride (174 mg, 1.10 mmol) in ethanol (5 ml) Was heated to reflux for 20 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 90: 10) to give 1- (3-methylphenyl) -5- (4-methylphenyl) -3- (trifluoromethyl ) -1H-pyrazole (298 mg, 94%) was obtained as a powder.
MS: 317 [M + H] ⁺ , APCI (MeOH)

Examples 2-6
The following compounds were obtained by reacting and treating in the same manner as in Example 1.

５−（４−メチルフェニル）−１−（４−ニトロフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール（2.40g,6.91mmol）のＴＨＦ（50ml）とエタノール（50ml）溶液に１０％パラジウム炭素（250mg）を加え、水素雰囲気下、混合物を室温で２時間攪拌した。不溶物を濾別し、ＴＨＦで洗浄後、濾液と洗液を合せて減圧濃縮することにより、｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝アミン（2.14g,98％）を固体として得た。
ＭＳ：３１８［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 8

10% of 5- (4-methylphenyl) -1- (4-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazole (2.40 g, 6.91 mmol) in a solution of THF (50 ml) and ethanol (50 ml). Palladium on carbon (250 mg) was added and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Insoluble matter was filtered off, washed with THF, and the filtrate and washings were combined and concentrated under reduced pressure to give {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazole- 1-yl] phenyl} amine (2.14 g, 98%) was obtained as a solid.
MS: 318 [M + H] ⁺ , APCI (MeOH)

｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝アミン（101mg,0.32mmol）とトリエチルアミン（0.066ml,0.47mmol）の塩化メチレン（5ml）溶液にプロピオン酸クロリド（0.030ml,0.35mmol）を滴下後、混合物を室温で３日間攪拌した。反応液に希塩酸を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、芒硝で乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝９０：１０→８０：２０）で精製することにより、Ｎ−｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝プロパンアミド（92mg,77％）を粉末として得た。
ＭＳ：３７４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 9

Methylene chloride of {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} amine (101 mg, 0.32 mmol) and triethylamine (0.066 ml, 0.47 mmol) After adding dropwise propionic acid chloride (0.030 ml, 0.35 mmol) to the (5 ml) solution, the mixture was stirred at room temperature for 3 days. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 90: 10 → 80: 20) to give N- {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H -Pyrazol-1-yl] phenyl} propanamide (92 mg, 77%) was obtained as a powder.
MS: 374 [M + H] ⁺ , APCI (MeOH)

Example 10
The following compounds were obtained by reacting and treating in the same manner as in Example 9.

４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（6.93g,18.2mmol）のジクロロメタン（70ml）懸濁液に、ジメチルアミノピリジン（0.22g,1.82mmol）とトリエチルアミン（3.80ml,27.3mmol）を室温で加えた。そこに、ジ−tert−ブチルジカルボネート（4.76g,21.8mmol）のジクロロメタン（70ml）溶液を室温で滴下し、混合物を一晩攪拌した。反応液を減圧濃縮し、酢酸エチルおよび２０％蓚酸水溶液を加え、有機層を分離した。有機層を２回水洗し、飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１→３：１）で精製し、tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメート（7.64g,87％）を粉末として得た。
ＭＳ：４９９［Ｍ＋ＮＨ_４］^＋，ＡＰＣＩ（１０ｍＭ−ＡｃＯＮＨ_４／ＭｅＯＨ） Example 11

To a suspension of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (6.93 g, 18.2 mmol) in dichloromethane (70 ml) was added dimethylamino. Pyridine (0.22 g, 1.82 mmol) and triethylamine (3.80 ml, 27.3 mmol) were added at room temperature. Thereto was added dropwise a solution of di-tert-butyl dicarbonate (4.76 g, 21.8 mmol) in dichloromethane (70 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and 20% aqueous oxalic acid solution were added, and the organic layer was separated. The organic layer was washed twice with water, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) and tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H -Pyrazol-1-yl] phenyl} sulfonyl) carbamate (7.64 g, 87%) was obtained as a powder.
MS: 499 [M + NH ₄ ] ⁺ , APCI (10 mM-AcONH ₄ / MeOH)

Example 12
The following compounds were obtained by reacting and treating in the same manner as in Example 11.

tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメート（661mg,1.37mmol）のＤＭＦ（3ml）溶液に、炭酸カリウム（949mg,6.87mmol）を室温で加えた後、ブロモ酢酸tert−ブチル（321mg,1.65mmol）を室温で加え、混合物を５時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した後、抽出液を水および飽和食塩水で洗浄した。芒硝で乾燥した後、減圧濃縮して、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１２：１）で精製し、tert−ブチル Ｎ−（tert−ブトキシカルボニル）−Ｎ−（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）グリシネート（441mg,54％）を粉末として得た。
ＭＳ：６１３［Ｍ＋ＮＨ_４］^＋，ＡＰＣＩ（１０ｍＭ−ＡｃＯＮＨ_４／ＭｅＯＨ） Example 13

tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) carbamate (661 mg, 1.37 mmol) in DMF (3 ml) To the mixture was added potassium carbonate (949 mg, 6.87 mmol) at room temperature, tert-butyl bromoacetate (321 mg, 1.65 mmol) was added at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water and saturated brine. After drying over sodium sulfate, the residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 12: 1), and tert-butyl N- (tert-butoxycarbonyl) -N-({4- [ 5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) glycinate (441 mg, 54%) was obtained as a powder.
^{_{MS: 613 [M + NH 4}} ] +, APCI (10mM-AcONH 4 / MeOH)

Examples 14-21
The following compounds were obtained by reacting and treating in the same manner as in Example 13.

tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメート（200mg,0.42mmol）のＴＨＦ（3ml）溶液に、トリフェニルホスフィン（131mg,0.50mmol）、２−（２−ピリミジルオキシ）エタノール（70mg,0.50mmol）を室温で加えた後、ジエチルアゾジカルボキシラート（87mg,0.50mmol）を室温でゆっくり滴下した。反応液を室温で一晩攪拌した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→５０：５０）で精製し、tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）［２−（ピリミジン−２−イルオキシ）エチル］カルバメート（128mg,51％）を液体として得た。
ＭＳ：６０４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（１０ｍＭ−ＡｃＯＮＨ_４／ＭｅＯＨ） Example 22

tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) carbamate (200 mg, 0.42 mmol) in THF (3 ml) Triphenylphosphine (131 mg, 0.50 mmol) and 2- (2-pyrimidyloxy) ethanol (70 mg, 0.50 mmol) were added at room temperature, and then diethyl azodicarboxylate (87 mg, 0.50 mmol) was slowly added dropwise at room temperature. . The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 50: 50) and tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H -Pyrazol-1-yl] phenyl} sulfonyl) [2- (pyrimidin-2-yloxy) ethyl] carbamate (128 mg, 51%) was obtained as a liquid.
MS: 604 [M + H] ⁺ , APCI (10 mM-AcONH ₄ / MeOH)

Examples 23-28
The following compounds were obtained by reacting and treating in the same manner as in Example 22.

tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）［２−（ピリミジン−２−イルオキシ）エチル］カルバメート（150mg,0.25mmol）をトリフルオロ酢酸（3ml）に溶解し、室温で２日間攪拌した後、飽和重曹水に注いだ。混合物を酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→０：１００）で精製し、４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］−Ｎ−［２−（ピリミジン−２−イルオキシ）エチル］ベンゼンスルホンアミド（31mg,25％）を液体として得た。
ＭＳ：５０４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 29

tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) [2- (pyrimidin-2-yloxy) ethyl] carbamate (150 mg, 0.25 mmol) was dissolved in trifluoroacetic acid (3 ml), stirred at room temperature for 2 days, and poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 0: 100) to give 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazole-1- Iil] -N- [2- (pyrimidin-2-yloxy) ethyl] benzenesulfonamide (31 mg, 25%) was obtained as a liquid.
MS: 504 [M + H] ⁺ , APCI (MeOH)

Examples 30-42
The following compounds were obtained by reacting and treating in the same manner as in Example 29.

tert−ブチル （｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメート（130mg,0.27mmol）およびジメチルアミノエチルクロリド塩酸塩（58nmg,0.40mmol）を用いて、実施例１３と同様に反応を行い、粗生成物tert−ブチル ［２−（ジメチルアミノ）エチル］（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメートを得た。得られた粗生成物を単離せず、ひき続いて実施例２８と同様に反応を行った後、反応液を飽和重曹水に注いで酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮して残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）で精製した。得られた生成物を塩酸−ジオキサン溶液に溶かし、ジエチルエーテルを加えて撹拌した後、析出する固体を濾取してＮ−［２−（ジメチルアミノ）エチル］−４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド塩酸塩（98mg,74％）を固体として得た。
ＭＳ：４５３［Ｍ＋ＮＨ_４］^＋，ＡＰＣＩ（１０ｍＭ−ＡｃＯＮＨ_４／ＭｅＯＨ） Example 43

tert-butyl ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) carbamate (130 mg, 0.27 mmol) and dimethylaminoethyl chloride hydrochloride The reaction was carried out in the same manner as in Example 13 using the salt (58 nmg, 0.40 mmol) and the crude product tert-butyl [2- (dimethylamino) ethyl] ({4- [5- (4-methylphenyl)- 3- (Trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) carbamate was obtained. The obtained crude product was not isolated, and subsequently reacted in the same manner as in Example 28, and then the reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1). The obtained product was dissolved in a hydrochloric acid-dioxane solution, diethyl ether was added and stirred, and then the precipitated solid was collected by filtration to give N- [2- (dimethylamino) ethyl] -4- [5- (4- Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide hydrochloride (98 mg, 74%) was obtained as a solid.
^{_{MS: 453 [M + NH 4}} ] +, APCI (10mM-AcONH 4 / MeOH)

５−（４−メチルフェニル）−１−フェニル−３−（トリフルオロメチル）−１Ｈ−ピラゾール（0.99g,3.3mmol）のクロロホルム（5.0ml）溶液にクロロ硫酸（4.36ml,65.5mmol）を室温で加え、２４時間撹拌した。反応液を氷水に注ぎ、クロロホルム抽出した。有機層を水洗した後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→８０：２０）で精製し、２−メチル−５−［１−フェニル−３−（トリフルオロメチル）−１Ｈ−ピラゾール−５−イル］ベンゼンスルホニルクロリド（1.17g,89％）を粉末として得た。
ＭＳ：４０１／４０３［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 44
(1)

To a solution of 5- (4-methylphenyl) -1-phenyl-3- (trifluoromethyl) -1H-pyrazole (0.99 g, 3.3 mmol) in chloroform (5.0 ml) was added chlorosulfuric acid (4.36 ml, 65.5 mmol) at room temperature. And stirred for 24 hours. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with water and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 80: 20) to give 2-methyl-5- [1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl. Benzenesulfonyl chloride (1.17 g, 89%) was obtained as a powder.
MS: 401/403 [M + H] ⁺ , APCI (MeOH)

２−メチル−５−［１−フェニル−３−（トリフルオロメチル）−１Ｈ−ピラゾール−５−イル］ベンゼンスルホニルクロリド（100mg,0.25mmol）のＴＨＦ（5.0ml）溶液に氷冷下、３０％アンモニア水（2ml）を加えた。同温で４時間攪拌した後、反応液を酢酸エチル／水に注いだ。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→０：１００）で精製し、２−メチル−５−［１−フェニル−３−（トリフルオロメチル）−１Ｈ−ピラゾール−５−イル］ベンゼンスルホンアミド（86.0mg,90％）を粉末として得た。
ＭＳ：３８２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） (2)

2-Methyl-5- [1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonyl chloride (100 mg, 0.25 mmol) in THF (5.0 ml) solution under ice-cooling, 30% Aqueous ammonia (2 ml) was added. After stirring at the same temperature for 4 hours, the reaction solution was poured into ethyl acetate / water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 0: 100) to give 2-methyl-5- [1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl. Benzenesulfonamide (86.0 mg, 90%) was obtained as a powder.
MS: 382 [M + H] ⁺ , APCI (MeOH)

Example 45
The following compound was obtained by reacting and treating the compound of Example 1 in the same manner as in Examples 44 (1) and (2).

Example 46
The following compound was obtained by reacting and treating the compound of Example 44 (1) in the same manner as in Example 44 (2).

水素化アルミニウムリチウム（53.2mg,1.4mmol）のＴＨＦ（3ml）懸濁液に５−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］−１，２−ベンズイソチアゾール−３（２Ｈ）−オン １，１−ジオキシド（160mg,0.4mmol）を−７８℃で加え、反応液を室温まで昇温し、４時間攪拌した。反応液に氷、１０％塩酸水および酢酸エチルを加え、有機層を分離した。有機層を水洗し、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７０：３０→５０：５０）で精製し、２−（ヒドロキシメチル）−４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（77mg,47％）を固体として得た。
ＭＳ：４１２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 47

5- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -1 in a suspension of lithium aluminum hydride (53.2 mg, 1.4 mmol) in THF (3 ml) , 2-Benzisothiazol-3 (2H) -one 1,1-dioxide (160 mg, 0.4 mmol) was added at −78 ° C., and the reaction solution was warmed to room temperature and stirred for 4 hours. Ice, 10% aqueous hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 → 50: 50) to give 2- (hydroxymethyl) -4- [5- (4-methylphenyl) -3- (trifluoromethyl). -1H-pyrazol-1-yl] benzenesulfonamide (77 mg, 47%) was obtained as a solid.
MS: 412 [M + H] ⁺ , APCI (MeOH)

Ｎ−（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）グリシン（60mg,0.14mmol）のジクロロメタン（2ml）懸濁液に塩化オキサリル（23mg,0.18mmol）およびＤＭＦ１滴を加え、３時間攪拌した。反応液を減圧濃縮し、残渣をＴＨＦ（2ml）に溶解した後、氷冷下、５０％ジメチルアミン水溶液（2ml）／酢酸エチル（2ml）に撹拌しながら加えた。混合物を同温で２時間攪拌した後、酢酸エチル／水に注いだ。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→０：１００）で精製し、Ｎ，Ｎ−ジメチル−２−（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）アセタミド（55mg,86％）を液体として得た。
ＭＳ：４６７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 48

Suspension of N-({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) glycine (60 mg, 0.14 mmol) in dichloromethane (2 ml) To the solution were added oxalyl chloride (23 mg, 0.18 mmol) and 1 drop of DMF, and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in THF (2 ml), and then added to 50% aqueous dimethylamine solution (2 ml) / ethyl acetate (2 ml) with stirring under ice cooling. The mixture was stirred at the same temperature for 2 hours and then poured into ethyl acetate / water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 0: 100), and N, N-dimethyl-2-({4- [5- (4-methylphenyl) -3- (tri Fluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) acetamide (55 mg, 86%) was obtained as a liquid.
MS: 467 [M + H] ⁺ , APCI (MeOH)

Example 49
The following compound was obtained by reacting and treating the compound of Example 4 in the same manner as in Example 48.

Examples 50-57
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

Ｎ−（２−メチルアミノエチル）−４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（52.0mg,0.12mmol）のピリジン（2ml）溶液にクロロ炭酸メチル（16mg,0.14mmol）を加え、混合物を一晩攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→０：１００）で精製して、メチル Ｎ−メチル−｛２−［（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）アミノ］エチル｝カルバメート（50.4mg,86％）を固体として得た。
ＭＳ：４９７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 58

N- (2-methylaminoethyl) -4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (52.0 mg, 0.12 mmol) in pyridine To the (2 ml) solution was added methyl chlorocarbonate (16 mg, 0.14 mmol) and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 0: 100) to give methyl N-methyl- {2-[({4- [5- (4 -Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) amino] ethyl} carbamate (50.4 mg, 86%) was obtained as a solid.
MS: 497 [M + H] ⁺ , APCI (MeOH)

tert−ブチル ［２−（tert−ブトキシカルボニルアミノ）エチル］（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）カルバメート（87.8mg,0.14mmol）を用いて、実施例２８と同様に反応を行った。得られた粗生成物を単離せず、ひき続いて、クロロ炭酸メチル（16mg,0.14mmol）を用いて実施例５８と同様に反応を行った。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→０：１００）で精製してメチル ｛２−［（｛４−［５−（４−メチルフェニル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］フェニル｝スルホニル）アミノ］エチル｝カルバメート（33.5mg,50％）を固体として得た。
ＭＳ：４８１［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 59

tert-butyl [2- (tert-butoxycarbonylamino) ethyl] ({4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) carbamate (87.8 mg, 0.14 mmol) was used, and the reaction was carried out in the same manner as in Example 28. The obtained crude product was not isolated, and subsequently reacted in the same manner as in Example 58 using methyl chlorocarbonate (16 mg, 0.14 mmol). After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 0: 100) to give methyl {2-[({4- [5- (4-methylphenyl)]. -3- (Trifluoromethyl) -1H-pyrazol-1-yl] phenyl} sulfonyl) amino] ethyl} carbamate (33.5 mg, 50%) was obtained as a solid.
MS: 481 [M−H] ⁻ , ESI (MeOH)

アルゴン雰囲気下、４−［５−ヒドロキシ−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（23.6g,76.7mmol）および２，６−ジ−tert−ブチル−４−メチルピリジン（24.6g,119.9mmol）のジクロロメタン（750ml）懸濁液に、無水トリフルオロメタンスルホン酸（15.5ml,92.1mmol）を−２０℃で滴下した。混合物を０℃に昇温し、同温で３０分撹拌した後、氷冷下、反応液を飽和重曹水に注いだ。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、約200mlまで減圧濃縮した。沈殿物を濾取した後、ジクロロメタンで洗浄し、１−［４−（アミノスルホニル）フェニル］−３−（トリフルオロメチル）−１Ｈ−ピラゾール−５−イル トリフルオロメタンスルホネート（23.6g,70％）を固体として得た。
融点：１１４−１１５℃ Example 60
(1)

Under an argon atmosphere, 4- [5-hydroxy-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (23.6 g, 76.7 mmol) and 2,6-di-tert-butyl-4- To a suspension of methylpyridine (24.6 g, 119.9 mmol) in dichloromethane (750 ml), trifluoromethanesulfonic anhydride (15.5 ml, 92.1 mmol) was added dropwise at −20 ° C. The mixture was warmed to 0 ° C. and stirred at the same temperature for 30 minutes, and then the reaction mixture was poured into saturated aqueous sodium bicarbonate under ice cooling. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to about 200 ml. The precipitate was collected by filtration, washed with dichloromethane, and 1- [4- (aminosulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazol-5-yl trifluoromethanesulfonate (23.6 g, 70%) Was obtained as a solid.
Melting point: 114-115 ° C

１−［４−（アミノスルホニル）フェニル］−３−（トリフルオロメチル）−１Ｈ−ピラゾール−５−イル トリフルオロメタンスルホネート（220mg,0.50mmol）、１，４−ベンゾジオキサン−６−ボロン酸（108mg,0.60mmol）、炭酸カリウム（346mg,2.50mmol）およびジクロロビス（トリフェニルホスフィン）パラジウム（70mg,0.10mmol）を１，４−ジオキサン（3ml）で懸濁し、６時間加熱還流した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→２５：７５）およびリサイクルＨＰＬＣで精製し、４−［５−（２，３−ジヒドロ−１，４−ベンソジオキサン−６−イル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（103mg,48％）を固体として得た。
ＭＳ：４２６［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） (2)

1- [4- (Aminosulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazol-5-yl trifluoromethanesulfonate (220 mg, 0.50 mmol), 1,4-benzodioxan-6-boronic acid (108 mg , 0.60 mmol), potassium carbonate (346 mg, 2.50 mmol) and dichlorobis (triphenylphosphine) palladium (70 mg, 0.10 mmol) were suspended in 1,4-dioxane (3 ml) and heated to reflux for 6 hours. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 25: 75) and recycle HPLC to give 4- [5- (2,3-dihydro-1,4-benzodioxane-6-yl. ) -3- (Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (103 mg, 48%) was obtained as a solid.
MS: 426 [M + H] ⁺ , APCI (MeOH)

ジメチル １，３−アセトンジカルボキシレート（13.8g,79.0mmol）と４−スルホンアミドフェニルヒドラジン塩酸塩（17.6g,79.0 mmol）を１００℃で２時間加熱撹拌した。反応液を冷却後、飽和重曹水を加えてＴＨＦ−酢酸エチルで洗浄した。水層に１０％塩酸を加え、ｐＨを４とし、混合物をＴＨＦ−酢酸エチルで２回抽出した。抽出液を硫酸マグネシウムで乾燥し、減圧濃縮した。残渣にジエチルエーテル−酢酸エチルを加えて撹拌した後、得られた固体を濾取して、メチル ｛１−［４−（アミノスルホニル）フェニル］−５−オキソ−４，５−ジヒドロ−１Ｈ−ピラゾール−３−イル｝アセテート（12.85g,52％）を固体として得た。
ＭＳ：３１２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 61
(1)

Dimethyl 1,3-acetone dicarboxylate (13.8 g, 79.0 mmol) and 4-sulfonamidophenylhydrazine hydrochloride (17.6 g, 79.0 mmol) were heated and stirred at 100 ° C. for 2 hours. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate was added, and the mixture was washed with THF-ethyl acetate. 10% hydrochloric acid was added to the aqueous layer to adjust the pH to 4, and the mixture was extracted twice with THF-ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. Diethyl ether-ethyl acetate was added to the residue and stirred, and then the resulting solid was collected by filtration to give methyl {1- [4- (aminosulfonyl) phenyl] -5-oxo-4,5-dihydro-1H- Pyrazol-3-yl} acetate (12.85 g, 52%) was obtained as a solid.
MS: 312 [M + H] ⁺ , APCI (MeOH)

(2) The following compounds were obtained by reacting and treating in the same manner as in Example 60 (1).

(3) The following compounds were obtained by reacting and treating in the same manner as in Example 60 (2).

Example 62
The following compounds were obtained by reacting and treating in the same manner as in Example 61 (1) and Examples 60 (1) and (2). The obtained compound was converted into a sodium salt according to a conventional method.

Examples 63-67
The following compounds were obtained by reacting and treating in the same manner as in Example 60 (2).

Example 67
(1) The following compounds were obtained by reacting and treating in the same manner as in Example 62 (1).

(2) The following compound was obtained by reacting and treating in the same manner as in Example 62 (2).

４−［５−（１Ｈ−インドール−５−イル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（300mg,0.74mmol）の酢酸（4ml）溶液に、水素化シアノホウ素ナトリウム（186mg,2.95mmol）を室温で加えた後、室温で４時間攪拌した。氷冷下、反応液を飽和重曹水で塩基性にした後、酢酸エチルで抽出した。抽出液を水洗し、飽和食塩水で洗浄した後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→２５：７５）で精製し、４−［５−（２，３−ジヒドロ−１Ｈ−インドール−５−イル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（155mg,51％）を粉末として得た。
ＭＳ：４０９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 68

Hydrogenation of 4- [5- (1H-indol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (300 mg, 0.74 mmol) in acetic acid (4 ml) Sodium cyanoboron (186 mg, 2.95 mmol) was added at room temperature, followed by stirring at room temperature for 4 hours. Under ice-cooling, the reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 25: 75) to give 4- [5- (2,3-dihydro-1H-indol-5-yl) -3- (trifluoro Methyl) -1H-pyrazol-1-yl] benzenesulfonamide (155 mg, 51%) was obtained as a powder.
MS: 409 [M + H] ⁺ , APCI (MeOH)

氷冷下、４−［５−（２，３−ジヒドロ−１Ｈ−インドール−５−イル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（102mg,0.25mmol）のメタノール（3ml）溶液に、水素化シアノホウ素ナトリウム（32mg,0.50mmol）を加えた後、１％塩酸水溶液でｐＨを４とし、ホルマリン水溶液（30％,1ml）を加えた。反応液を室温で一晩攪拌した後、減圧濃縮した。残渣を３０％アンモニア水で塩基性とし、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→２５：７５）で精製し、Ｎ−メチル−４−［５−（１−メチル−２，３−ジヒドロ−１Ｈ−インドール−５−イル）−３−（トリフルオロメチル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（98mg,90％）を粉末として得た。
ＭＳ：４３７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 69

4- [5- (2,3-dihydro-1H-indol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (102 mg, 0.25 mmol) under ice cooling After adding sodium cyanoborohydride (32 mg, 0.50 mmol) to a methanol (3 ml) solution, the pH was adjusted to 4 with a 1% aqueous hydrochloric acid solution and a formalin aqueous solution (30%, 1 ml) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was basified with 30% aqueous ammonia and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 25: 75) to give N-methyl-4- [5- (1-methyl-2,3-dihydro-1H-indole-5 Yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (98 mg, 90%) was obtained as a powder.
MS: 437 [M + H] ⁺ , APCI (MeOH)

メチル ［１−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−イル］アセテート（3.30g,8.56mmol）のメタノール（33ml）溶液に２Ｎ水酸化ナトリウム溶液（12.8ml,25.6ml）を加え、３０分加熱還流した。反応液を冷却後、減圧濃縮し、１０％塩酸を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣にヘキサンを加えて撹拌した後、減圧濃縮し、［１−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−イル］酢酸（2.8g,87％）を粉末として得た。
ＭＳ：３７０[Ｍ−Ｈ]⁻，ＥＳＩ Example 70

To a solution of methyl [1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazol-3-yl] acetate (3.30 g, 8.56 mmol) in methanol (33 ml) was added 2N sodium hydroxide. The solution (12.8 ml, 25.6 ml) was added and heated to reflux for 30 minutes. The reaction mixture was cooled, concentrated under reduced pressure, 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the residue and stirred, followed by concentration under reduced pressure, and [1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazol-3-yl] acetic acid (2.8 g, 87 %) As a powder.
MS: 370 [M−H] ⁻ , ESI

Example 71
The following compounds were obtained by reacting and treating in the same manner as in Example 70.

氷冷下、２−［１−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−イル］アセタミド（126mg,0.34mmol）およびピリジン（108mg,1.36mmol）のクロロホルム（4ml）懸濁液に無水トリフルオロ酢酸（143mg,0.68mmol）を滴下した後、混合物を室温で一晩攪拌した。反応液に１０％水酸化ナトリウム水溶液を加えた後、３０分間撹拌し、酢酸エチル／水を加えた。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１→２０：１）で精製し、４−［３−（シアノメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（20mg,17％）を粉末として得た。
ＭＳ：３５１［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 72

Under ice cooling, 2- [1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazol-3-yl] acetamide (126 mg, 0.34 mmol) and pyridine (108 mg, 1.36 mmol) ) In chloroform (4 ml) was added dropwise trifluoroacetic anhydride (143 mg, 0.68 mmol), and the mixture was stirred overnight at room temperature. A 10% aqueous sodium hydroxide solution was added to the reaction solution, followed by stirring for 30 minutes, and ethyl acetate / water was added. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1 → 20: 1), and 4- [3- (cyanomethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzene Sulfonamide (20 mg, 17%) was obtained as a powder.
MS: 351 [M−H] ⁻ , ESI (MeOH)

メチル １−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−カルボキシレート（55.7g,0.15mol）のＴＨＦ（１．５リットル）溶液に室温で水素化アルミニウムリチウム（8.54g,0.23mol）を数回に分けて加えた後、２時間加熱還流した。反応液を氷冷後、１０％塩酸をゆっくりと加えた。混合物を攪拌後、酢酸エチル（500ml）および水（500ml）を加え、分液した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣にメタノール−ジエチルエーテル−ヘキサンを加えて攪拌した後、得られた結晶を濾取した。ジエチルエーテルおよびヘキサンで洗浄後、乾燥することにより４−［３−（ヒドロキシメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（42.8g,83％）を結晶として得た。融点：１７３−１７４℃
ＭＳ：３４４[Ｍ＋Ｈ]^＋，ＡＰＣＩ（ＭｅＯＨ） Example 73

Methyl 1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazole-3-carboxylate (55.7 g, 0.15 mol) in THF (1.5 liter) in hydrogen at room temperature Lithium aluminum halide (8.54 g, 0.23 mol) was added in several portions, and then heated under reflux for 2 hours. The reaction solution was ice-cooled, and 10% hydrochloric acid was slowly added. After stirring the mixture, ethyl acetate (500 ml) and water (500 ml) were added and the layers were separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Methanol-diethyl ether-hexane was added to the residue and stirred, and then the resulting crystals were collected by filtration. After washing with diethyl ether and hexane, 4- [3- (hydroxymethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (42.8 g, 83%) was obtained by drying. Obtained as crystals. Melting point: 173-174 ° C
MS: 344 [M + H] ⁺ , APCI (MeOH)

４−［３−（ヒドロキシメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（1.03g,3.00mmol）のＴＨＦ（20ml）溶液に塩化チオニル（0.33ml,4.52mmol）を加えた後、１時間加熱還流した。反応液を冷却し、減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）で精製し、４−［３−（クロロメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（242mg,38％）および４−［３−［（４−クロロブトキシ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（457mg,60％）をそれぞれ粉末として得た。
４−［３−（クロロメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド
ＭＳ：３６２／３６４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
４−［３−［（４−クロロブトキシ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド
ＭＳ：４３４／４３６［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 74

To a solution of 4- [3- (hydroxymethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (1.03 g, 3.00 mmol) in THF (20 ml) was added thionyl chloride (0.33 ml, 4.52 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give 4- [3- (chloromethyl) -5- (4-methylphenyl) -1H. -Pyrazol-1-yl] benzenesulfonamide (242 mg, 38%) and 4- [3-[(4-chlorobutoxy) methyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzene Sulfonamides (457 mg, 60%) were obtained as powders.
4- [3- (Chloromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide MS: 362/364 [M + H] ⁺ , APCI (MeOH)
4- [3-[(4-Chlorobutoxy) methyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide MS: 434/436 [M + H] ⁺ , APCI (MeOH)

４−［３−（クロロメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（90mg,0.25mmol）とベンジルアルコール（81mg,0.75mmol）のＴＨＦ（3ml）溶液に水素化ナトリウム（60％,30mg,0.75mmol）を加えた後、一晩加熱還流した。反応液を冷却後、１０％塩酸を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：２→１：１）で精製することにより、４−［３−［（ベンジルオキシ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（37mg,33％）を液体として得た。
ＭＳ：４３４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 75

4- [3- (Chloromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (90 mg, 0.25 mmol) and benzyl alcohol (81 mg, 0.75 mmol) in THF (3 ml) Sodium hydride (60%, 30 mg, 0.75 mmol) was added to the solution, and then heated under reflux overnight. The reaction mixture was cooled, 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 1: 1) to give 4- [3-[(benzyloxy) methyl] -5- (4-methylphenyl) -1H— Pyrazol-1-yl] benzenesulfonamide (37 mg, 33%) was obtained as a liquid.
MS: 434 [M + H] ⁺ , APCI (MeOH)

Example 76
The following compounds were obtained by reacting and treating in the same manner as in Example 75.

１−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−カルボン酸（357mg,1.0mmol）、２−ブロモエチルアミン臭酸塩（287mg,1.40mmol），Ｎ−ヒドロキシベンゾトリアゾール（203mg,1.50mmol）、トリエチルアミン（0.42ml,3.00mmol）および１−エチル−３−（３’−ジメチルアミノプロピル）カルボジイミド塩酸塩（288mg,1.50mmol）のＤＭＦ（5ml）溶液を室温で一晩攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→３０：１）で精製することにより、４−［３−（４，５−ジヒドロ−１，３−オキサゾール−２−イル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（170mg,45％）を粉末として得た。
ＭＳ：３８３［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 77

1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazole-3-carboxylic acid (357 mg, 1.0 mmol), 2-bromoethylamine bromide (287 mg, 1.40 mmol), A solution of N-hydroxybenzotriazole (203 mg, 1.50 mmol), triethylamine (0.42 ml, 3.00 mmol) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (288 mg, 1.50 mmol) in DMF (5 ml) Was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1) to give 4- [3- (4,5-dihydro-1,3-oxazol-2-yl) -5- (4-Methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (170 mg, 45%) was obtained as a powder.
MS: 383 [M + H] ⁺ , APCI (MeOH)

４−［３−（ヒドロキシメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（7.0g,0.020mol)と二酸化マンガン（35g,0.10mol）のＴＨＦ（140ml）懸濁液を１時間加熱還流した。反応液を冷却後、不溶物を濾別し、酢酸エチルにて洗浄した後、濾液と洗液を合せて減圧濃縮した。残渣をジエチルエーテルで粉末化し、４−［３−ホルミル−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（4.8g,68％）を粉末として得た。
ＭＳ：３４０［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 78

4- [3- (hydroxymethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (7.0 g, 0.020 mol) and manganese dioxide (35 g, 0.10 mol) in THF (140 ml) ) The suspension was heated to reflux for 1 hour. After cooling the reaction solution, the insoluble material was filtered off and washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to give 4- [3-formyl-5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (4.8 g, 68%) as a powder.
MS: 340 [M−H] ⁻ , ESI (MeOH)

４−［３−ホルミル−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（341mg,1.00mmol）のＴＨＦ（4ml）溶液にジエチル（シアノメチル）ホスフォナート（0.16ml,1.2mmol）およびカリウムtert−ブトキシド（135mg,1.2mmol）を加え、室温で一晩攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→３０：１）で精製し、４−［３−［（Ｅ）−２−シアノビニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（316mg,87％）を粉末として得た。
ＭＳ：３６５［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 79

4- (3-Formyl-5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (341 mg, 1.00 mmol) in THF (4 ml) in diethyl (cyanomethyl) phosphonate (0.16 ml, 1.2 mmol) and potassium tert-butoxide (135 mg, 1.2 mmol) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1) to give 4- [3-[(E) -2-cyanovinyl] -5- (4-methylphenyl) -1H-pyrazole. -1-yl] benzenesulfonamide (316 mg, 87%) was obtained as a powder.
MS: 365 [M + H] ⁺ , APCI (MeOH)

Examples 80 and 81
The following compounds were obtained by reacting and treating in the same manner as in Example 79.

４−［３−［（Ｅ）−２−シアノビニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（250mg,0.69mmol）と５％パラジウム炭素（500mg）のメタノール（8ml）懸濁液を水素雰囲気下、室温にて一晩攪拌した。不溶物を濾別し、メタノールで洗浄後、濾液と洗液を合せて減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→３０：１）で精製し、４−［３−（２−シアノエチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（169mg,79％）を粉末として得た。
ＭＳ：３６７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 82

4- [3-[(E) -2-cyanovinyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (250 mg, 0.69 mmol) and 5% palladium on carbon (500 mg) The methanol (8 ml) suspension was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble material was filtered off, washed with methanol, the filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1), and 4- [3- (2-cyanoethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl Benzenesulfonamide (169 mg, 79%) was obtained as a powder.
MS: 367 [M + H] ⁺ , APCI (MeOH)

４−［３−ホルミル−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（171mg,0.50mmol）とアニリン（0.055ml,0.60mmol）のＴＨＦ（4ml）溶液に室温でトリアセトキシ水素化ホウ素ナトリウム（223mg,1.0mmol）を加え、一晩攪拌した。反応液に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。抽出液を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→３０：１）で精製し、４−［３−（アニリノメチル）−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（157mg,75％）を粉末として得た。
ＭＳ：４１９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 83

4- [3-Formyl-5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (171 mg, 0.50 mmol) and aniline (0.055 ml, 0.60 mmol) in THF (4 ml) at room temperature. Added sodium triacetoxyborohydride (223 mg, 1.0 mmol) and stirred overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1) to give 4- [3- (anilinomethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzene. Sulfonamide (157 mg, 75%) was obtained as a powder.
MS: 419 [M + H] ⁺ , APCI (MeOH)

４−［３−ホルミル−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（341mg,1.0mmol）、Ｏ−メチルヒドロキシルアミン塩酸塩（125mg,1.5mmol）および炭酸ナトリウム（79mg,0.75mmol）のエタノール（3ml）および水（3ml）混合液を３時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→３０：１）で精製し、粉末の４−［３−［（Ｅ）−（メトキシイミノ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（トランス；280mg,75％）および固体の４−［３−［（Ｚ）−（メトキシイミノ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド（シス；93mg,25％）を得た。
４−［３−［（Ｅ）−（メトキシイミノ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド
ＭＳ：３７１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
４−［３−［（Ｚ）−（メトキシイミノ）メチル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−１−イル］ベンゼンスルホンアミド
ＭＳ：３７１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 84

4- [3-Formyl-5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (341 mg, 1.0 mmol), O-methylhydroxylamine hydrochloride (125 mg, 1.5 mmol) and sodium carbonate A mixture of (79 mg, 0.75 mmol) ethanol (3 ml) and water (3 ml) was heated to reflux for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1), and powdered 4- [3-[(E)-(methoxyimino) methyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (trans; 280 mg, 75%) and solid 4- [3-[(Z)-(methoxyimino) methyl] -5- (4-methylphenyl) -1H -Pyrazol-1-yl] benzenesulfonamide (cis; 93 mg, 25%) was obtained.
4- [3-[(E)-(methoxyimino) methyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide MS: 371 [M + H] ⁺ , APCI (MeOH)
4- [3-[(Z)-(methoxyimino) methyl] -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide MS: 371 [M + H] ⁺ , APCI (MeOH)

Example 85
The following compounds were obtained by reacting and treating in the same manner as in Example 84.

４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゼンスルホニルクロリド（200mg,0.60mmol）をＴＨＦ（3ml）に溶解し−７８℃に冷却した。この溶液にＳ−（−）−プロリノール（182mg,1.80mmol）を加えた後、徐々に室温に戻し、室温で６時間攪拌した。酢酸エチル（8ml）を加え、水（3ml）、続いて飽和食塩水（2ml）で洗浄した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製し、（（２Ｓ）−１−｛［４−（５−メチル−３−フェニルイソキサゾール−４−イル）フェニル］スルホニル｝ピロリジン−２−イル）メタノール（232mg,97％）を液体として得た。
ＭＳ：３９９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 86

4- (5-Methyl-3-phenylisoxazol-4-yl) benzenesulfonyl chloride (200 mg, 0.60 mmol) was dissolved in THF (3 ml) and cooled to -78 ° C. After adding S-(-)-prolinol (182 mg, 1.80 mmol) to this solution, it was gradually returned to room temperature and stirred at room temperature for 6 hours. Ethyl acetate (8 ml) was added, and the mixture was washed with water (3 ml), followed by saturated brine (2 ml), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) and ((2S) -1-{[4- (5-methyl-3-phenylisoxazol-4-yl). ) Phenyl] sulfonyl} pyrrolidin-2-yl) methanol (232 mg, 97%) was obtained as a liquid.
MS: 399 [M + H] ⁺ , APCI (MeOH)

Examples 87-108
The following compounds were obtained by reacting and treating in the same manner as in Example 86.

Ｎ−［（１Ｒ）−３−ヒドロキシ−１−メチルプロピル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゼンスルホンアミド（100mg,0.26mmol）をメタノール（3ml）に溶解し、これにナトリウムメチラート（０．５Ｍメタノール溶液，0.51ml,0.255mmol）を室温で加えた。１０分間攪拌した後、反応液を減圧濃縮した。残渣にアセトンを加えて撹拌した後、析出した固体を濾取することにより、Ｎ−［（１Ｒ）−３−ヒドロキシ−１−メチルプロピル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゼンスルホンアミド・ナトリウム塩（96mg,98％）を固体として得た。
ＭＳ：３８５［Ｍ−Ｎａ］⁻，ＥＳＩ（ＭｅＯＨ） Example 109

N-[(1R) -3-hydroxy-1-methylpropyl] -4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide (100 mg, 0.26 mmol) in methanol (3 ml) After dissolution, sodium methylate (0.5 M methanol solution, 0.51 ml, 0.255 mmol) was added thereto at room temperature. After stirring for 10 minutes, the reaction solution was concentrated under reduced pressure. Acetone was added to the residue and stirred, and then the precipitated solid was collected by filtration to give N-[(1R) -3-hydroxy-1-methylpropyl] -4- (5-methyl-3-phenylisoxazole). -4-yl) benzenesulfonamide sodium salt (96 mg, 98%) was obtained as a solid.
MS: 385 [M-Na] ^- , ESI (MeOH)

Examples 110-113
The following compounds were obtained by reacting and treating in the same manner as in Example 109.

Example 113
The following compounds were obtained by reacting and treating in the same manner as in Example 70.

tert−ブチル （｛４−［３−（４−ブロモフェニル）−５−メチルイソキサゾール−４−イル］フェニル｝スルホニル）メチル カルバメート（450mg,1.14mmol）、トリス（ジベンジリデンアセトン）ジパラジウム（110mg,0.12mmol）、２−ジシクロヘキシルホスフィノ−２’−（Ｎ，Ｎ−ジメチルアミノ）ビフェニル（90mg,0.23mmol）およびナトリウムtert−ブトキシド（220mg,2.29mmol）のトルエン（15ml）懸濁液にジメチルアミンのＴＨＦ溶液（２Ｍ，2.9ml,5.80mmol）を室温で加えた。混合物を封管中８０℃に加熱して２０時間攪拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を分離した。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→５０：５０）で精製し、４−｛３−［４−（ジメチルアミノ）フェニル］−５−メチルイソキサゾール−４−イル｝−Ｎ−メチルベンゼンスルホンアミド（154mg,47％）を固体として得た。
ＭＳ：３７２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 114

tert-butyl ({4- [3- (4-bromophenyl) -5-methylisoxazol-4-yl] phenyl} sulfonyl) methyl carbamate (450 mg, 1.14 mmol), tris (dibenzylideneacetone) dipalladium ( 110 mg, 0.12 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (90 mg, 0.23 mmol) and sodium tert-butoxide (220 mg, 2.29 mmol) in a toluene (15 ml) suspension. Dimethylamine in THF (2M, 2.9 ml, 5.80 mmol) was added at room temperature. The mixture was heated to 80 ° C. in a sealed tube and stirred for 20 hours. The suspension was poured into ethyl acetate / water and the organic layer was separated. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 50: 50), and 4- {3- [4- (dimethylamino) phenyl] -5-methylisoxazol-4-yl} -N-methylbenzenesulfonamide (154 mg, 47%) was obtained as a solid.
MS: 372 [M + H] ⁺ , APCI (MeOH)

Example 115
The following compounds were obtained by reacting and treating in the same manner as in Example 114.

４−［３−（４−ブロモフェニル）−５−メチルイソキサゾール−４−イル］ベンゼンスルホンアミド（3.70g,9.4mmol）およびアセトニルアセトン（4.4ml,37.5mmol）のトルエン（100ml）懸濁液にｐ−トルエンスルホン酸一水和物（0.18g,0.9mmol）を室温で加えた。Dean-Stark水分離器を取り付けた還流冷却管を装着し、混合物を１５時間加熱還流した。放冷後、反応液に酢酸エチル（100ml）を加え、飽和重曹水および飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製し、３−（４−ブロモフェニル）−４−｛４−［（２，５−ジメチル−１Ｈ−ピロール−１−イル）スルホニル］フェニル｝−５−メチルイソキサゾール（3.11g,70％）を固体として得た。
ＭＳ：４７１／４７３［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 116

4- [3- (4-Bromophenyl) -5-methylisoxazol-4-yl] benzenesulfonamide (3.70 g, 9.4 mmol) and acetonylacetone (4.4 ml, 37.5 mmol) in toluene (100 ml) P-Toluenesulfonic acid monohydrate (0.18 g, 0.9 mmol) was added to the suspension at room temperature. A reflux condenser fitted with a Dean-Stark water separator was attached and the mixture was heated to reflux for 15 hours. After allowing to cool, ethyl acetate (100 ml) was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3- (4-bromophenyl) -4- {4-[(2,5-dimethyl-1H-pyrrol-1-yl). Sulfonyl] phenyl} -5-methylisoxazole (3.11 g, 70%) was obtained as a solid.
MS: 471/473 [M + H] ⁺ , APCI (MeOH)

３−（４−ブロモフェニル）−４−｛４−［（２，５−ジメチル−１Ｈ−ピロール−１−イル）スルホニル］フェニル｝−５−メチルイソキサゾール（200mg,0.42mmol）、トリス（ジベンジリデンアセトン）ジパラジウム（40mg,0.04mmol）、２−ジシクロヘキシルホスフィノ−２’−（Ｎ，Ｎ−ジメチルアミノ）ビフェニル（35mg,0.09mmol）および炭酸セシウム（280mg,0.86mmol）の１，４−ジオキサン（4ml）およびtert−ブチルアルコール（2ml）懸濁液にＮ−（２−メトキシエチル）メチルアミン（60mg,0.67mmol）を室温で加えた後、マイクロウェーブ照射下、１００℃に加熱して１時間半撹拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→６５：３５）で精製し、固体を得た。この固体をトリフルオロ酢酸（3ml）および水（1ml）に溶解し、６０℃に加熱して６時間攪拌した。放冷後、反応液を飽和重曹水（25ml）に注ぎ、酢酸エチルで抽出した（３×10ml）。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→３０：７０）で精製し、液体を得た。この液体のメタノール（0.5ml）溶液に４Ｎ塩酸−ジオキサン溶液（2.0ml）を室温で加えた後、２０分間攪拌した。反応液を濃縮し４−（３−｛４−［（２−メトキシエチル）（メチル）アミノ］フェニル｝−５−メチルイソキサゾール−４−イル）ベンゼンスルホンアミド・塩酸塩（92mg,54％）を固体として得た。
ＭＳ：４０２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 117

3- (4-Bromophenyl) -4- {4-[(2,5-dimethyl-1H-pyrrol-1-yl) sulfonyl] phenyl} -5-methylisoxazole (200 mg, 0.42 mmol), tris ( 1,4 of dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (35 mg, 0.09 mmol) and cesium carbonate (280 mg, 0.86 mmol) -N- (2-methoxyethyl) methylamine (60 mg, 0.67 mmol) was added to a suspension of dioxane (4 ml) and tert-butyl alcohol (2 ml) at room temperature and then heated to 100 ° C under microwave irradiation. And stirred for 1.5 hours. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 65: 35) to obtain a solid. This solid was dissolved in trifluoroacetic acid (3 ml) and water (1 ml), heated to 60 ° C. and stirred for 6 hours. After allowing to cool, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (25 ml) and extracted with ethyl acetate (3 × 10 ml). The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 30: 70) to obtain a liquid. To this liquid methanol (0.5 ml) solution was added 4N hydrochloric acid-dioxane solution (2.0 ml) at room temperature, followed by stirring for 20 minutes. The reaction mixture was concentrated to 4- (3- {4-[(2-methoxyethyl) (methyl) amino] phenyl} -5-methylisoxazol-4-yl) benzenesulfonamide hydrochloride (92 mg, 54% ) Was obtained as a solid.
MS: 402 [M + H] ⁺ , APCI (MeOH)

Examples 118 and 119
The following compounds were obtained by reacting and treating in the same manner as in Example 117.

３−（４−ブロモフェニル）−５−メチル−４−フェニルイソキサゾール（200mg,0.64mmol）、トリス（ジベンジリデンアセトン）ジパラジウム（60mg,0.07mmol）、２−ジシクロヘキシルホスフィノ−２’−（Ｎ，Ｎ−ジメチルアミノ）ビフェニル（50mg,0.13mmol）、tert−ブチルカーバメート（115mg,0.98mmol）のトルエン（5ml）懸濁液にナトリウム フェノキシド（115mg,0.99mmol）を室温で加えた後、マイクロウェーブ照射下、１００℃に加熱して１時間撹拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→７５：２５）で精製し固体を得た。この固体を４Ｎ塩酸−ジオキサン溶液（5ml）に溶解し、室温で１６時間攪拌した。反応液を飽和重曹水（50ml）に注ぎ、酢酸エチルで抽出した（３×10ml）。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→５０：５０）で精製し、［４−（５−メチル−４−フェニルイソキサゾール−３−イル）フェニル］アミン（116mg,73％）を固体として得た。
ＭＳ：２５１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 120

3- (4-Bromophenyl) -5-methyl-4-phenylisoxazole (200 mg, 0.64 mmol), tris (dibenzylideneacetone) dipalladium (60 mg, 0.07 mmol), 2-dicyclohexylphosphino-2′- After adding sodium phenoxide (115 mg, 0.99 mmol) to a toluene (5 ml) suspension of (N, N-dimethylamino) biphenyl (50 mg, 0.13 mmol) and tert-butyl carbamate (115 mg, 0.98 mmol) at room temperature, Under microwave irradiation, the mixture was heated to 100 ° C. and stirred for 1 hour. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 75: 25) to obtain a solid. This solid was dissolved in 4N hydrochloric acid-dioxane solution (5 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (50 ml) and extracted with ethyl acetate (3 × 10 ml). The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 50: 50) to give [4- (5-methyl-4-phenylisoxazol-3-yl) phenyl] amine (116 mg, 73 %) As a solid.
MS: 251 [M + H] ⁺ , APCI (MeOH)

４−ブロモ−５−メチル−３−フェニルイソキサゾール（200mg,0.84mmol）、４−アセチルフェニルホウ酸（210mg,1.28mmol）、ジクロロビス（トリフェニルホスフィン）パラジウム（60mg,0.09mmol）のＤＭＥ（5ml）懸濁液に炭酸ナトリウム水溶液（２Ｍ，1.3ml,2.60mmol）を室温で加えた後、マイクロウェーブ照射下、１００℃に加熱して２時間半撹拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９８：２→６５：３５）で精製し、１−［４−（５−メチル−３−フェニルイソキサゾール−４−イル）フェニル］エタノン（189mg,81％）を液体として得た。
ＭＳ：２７８［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 121

4-bromo-5-methyl-3-phenylisoxazole (200 mg, 0.84 mmol), 4-acetylphenylboric acid (210 mg, 1.28 mmol), dichlorobis (triphenylphosphine) palladium (60 mg, 0.09 mmol) in DME ( 5 ml) A sodium carbonate aqueous solution (2 M, 1.3 ml, 2.60 mmol) was added to the suspension at room temperature, followed by heating to 100 ° C. under microwave irradiation and stirring for 2.5 hours. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 → 65: 35) to give 1- [4- (5-methyl-3-phenylisoxazol-4-yl) phenyl] ethanone (189 mg , 81%) as a liquid.
MS: 278 [M + H] ⁺ , APCI (MeOH)

Examples 122-134
The following compounds were obtained by reacting and treating in the same manner as in Example 121.

４−（５−メチル−３−フェニルイソキサゾール−４−イル）安息香酸（100mg,0.36mmol）、Ｎ−ヒドロキシスクシンイミド（72mg,0.38mmol）をＤＭＦ（3ml）に溶解し、１−エチル−３−（３’−ジメチルアミノプロピル）カルボジイミド塩酸塩（45mg,0.39mmol）を０℃で加えた。反応液を徐々に室温に戻し室温で一晩攪拌した。反応液に酢酸エチル（100ml）を加え、飽和重曹水および水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をヘキサンで結晶化し、濾取した。この結晶をＤＭＦ（3ml）に溶解し−７８℃に冷却した。この溶液にＳ−アラニノール（30mg,0.4mmol）を加えた後、反応液を徐々に室温に戻し室温で一晩攪拌した。反応液に酢酸エチル（20ml）を加え１０％クエン酸水溶液および水で洗浄し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→８０：２０）で精製し、Ｎ−［（１Ｓ）−２−ヒドロキシ−１−メチルエチル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（105mg,87％）を固体として得た。
ＭＳ：３３７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 135

4- (5-Methyl-3-phenylisoxazol-4-yl) benzoic acid (100 mg, 0.36 mmol) and N-hydroxysuccinimide (72 mg, 0.38 mmol) were dissolved in DMF (3 ml), and 1-ethyl- 3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (45 mg, 0.39 mmol) was added at 0 ° C. The reaction solution was gradually returned to room temperature and stirred at room temperature overnight. Ethyl acetate (100 ml) was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane and collected by filtration. The crystals were dissolved in DMF (3 ml) and cooled to -78 ° C. After adding S-alaninol (30 mg, 0.4 mmol) to this solution, the reaction solution was gradually returned to room temperature and stirred at room temperature overnight. Ethyl acetate (20 ml) was added to the reaction solution, washed with 10% aqueous citric acid solution and water, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 80: 20), and N-[(1S) -2-hydroxy-1-methylethyl] -4- (5-methyl-3- Phenylisoxazol-4-yl) benzamide (105 mg, 87%) was obtained as a solid.
MS: 337 [M + H] ⁺ , APCI (MeOH)

Examples 136-148
The following compounds were obtained by reacting and treating in the same manner as in Example 135.

３−（４−ブロモフェニル）−５−メチル−４−フェニルイソキサゾール（5.00g,15.9mmol）、シアン化亜鉛（1.88g,16.0mmol）、テトラキス（トリフェニルホスフィン）パラジウム（1.85g,1.60mmol）のＤＭＦ（80ml）懸濁液をマイクロウェーブ照射下、１７５℃に加熱して５分間撹拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝６：１）で精製し、４−（５−メチル−４−フェニルイソキサゾール−３−イル）ベンゾニトリル（2.95mg,71％）を粉末として得た。
ＭＳ：２６１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 149

3- (4-Bromophenyl) -5-methyl-4-phenylisoxazole (5.00 g, 15.9 mmol), zinc cyanide (1.88 g, 16.0 mmol), tetrakis (triphenylphosphine) palladium (1.85 g, 1.60) mmol) in DMF (80 ml) was heated to 175 ° C. under microwave irradiation and stirred for 5 minutes. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) and 4- (5-methyl-4-phenylisoxazol-3-yl) benzonitrile (2.95 mg, 71%) as a powder Obtained.
MS: 261 [M + H] ⁺ , APCI (MeOH)

４−（５−メチル−４−フェニルイソキサゾール−３−イル）ベンゾニトリル（2.00g,7.7mmol）と粉末水酸化カリウム（2.40g,42.8mmol）の１−プロパノール（50ml）懸濁液を１４時間加熱還流した。反応液を冷却後、減圧濃縮した。残渣に１Ｎ塩酸を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、４−（５−メチル−４−フェニルイソキサゾール−３−イル）安息香酸（2.01g,94％）を粉末として得た。
ＭＳ：２７８［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 150

A suspension of 4- (5-methyl-4-phenylisoxazol-3-yl) benzonitrile (2.00 g, 7.7 mmol) and powdered potassium hydroxide (2.40 g, 42.8 mmol) in 1-propanol (50 ml) was added. The mixture was heated to reflux for 14 hours. The reaction mixture was cooled and concentrated under reduced pressure. 1N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 4- (5-methyl-4-phenylisoxazol-3-yl) benzoic acid (2.01 g, 94%) as a powder. It was.
MS: 278 [M−H] ⁻ , ESI (MeOH)

４−（５−メチル−３−フェニルイソキサゾール−４−イル）フェノール（150mg,0.60mmol）をＤＭＦ（3ml）に溶解し、６０％水素化ナトリウム（27mg,0.68mmol）を室温で加えた。１０分後、２−（２−ブロモエトキシ）テトラヒドロ−２Ｈ−ピラン（137mg,0.66mmol）を室温で加え、混合物を一晩攪拌した。反応液に酢酸エチル（200ml）を加え、水で洗浄した後、芒硝で乾燥した。溶媒を減圧留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→７０：３０）で精製することにより、５−メチル−３−フェニル−４−｛４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ］フェニル｝イソキサゾール（141mg,62％）を油状物として得た。
ＭＳ：３８０［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 151

4- (5-Methyl-3-phenylisoxazol-4-yl) phenol (150 mg, 0.60 mmol) was dissolved in DMF (3 ml) and 60% sodium hydride (27 mg, 0.68 mmol) was added at room temperature. . After 10 minutes, 2- (2-bromoethoxy) tetrahydro-2H-pyran (137 mg, 0.66 mmol) was added at room temperature and the mixture was stirred overnight. Ethyl acetate (200 ml) was added to the reaction mixture, washed with water, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 70: 30) to give 5-methyl-3-phenyl-4- {4- [2- (Tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} isoxazole (141 mg, 62%) was obtained as an oil.
MS: 380 [M + H] ⁺ , APCI (MeOH)

５−メチル−３−フェニル−４−｛４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ］フェニル｝イソキサゾール（140mg,0.37mmol）をトリフルオロ酢酸（4ml）に溶解し、室温で６時間攪拌した。反応液を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→０：１００）で精製することにより、２−［４−（５−メチル−３−フェニルイソキサゾール−４−イル）フェノキシ］エタノール（52mg,47％）を粉末として得た。
ＭＳ：２９６［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 152

5-Methyl-3-phenyl-4- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} isoxazole (140 mg, 0.37 mmol) was dissolved in trifluoroacetic acid (4 ml) at room temperature. For 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 0: 100) to give 2- [4- (5-methyl-3-phenylisoxazole- 4-yl) phenoxy] ethanol (52 mg, 47%) was obtained as a powder.
MS: 296 [M + H] ⁺ , APCI (MeOH)

２−メトキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゾニトリル（109mg,0.377mmol）のtert−ブタノール溶液（4.0ml）に、粉末水酸化カリウム（197mg,3.50mmol）を加え、５時間加熱還流した。反応液を冷却後、飽和食塩水を加え、酢酸エチルで抽出した。有機層を芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２）で精製し、２−メトキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（273mg,73％）を固体として得た。
ＭＳ：３０９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 153

To a solution of 2-methoxy-4- (5-methyl-3-phenylisoxazol-4-yl) benzonitrile (109 mg, 0.377 mmol) in tert-butanol (4.0 ml) was added powdered potassium hydroxide (197 mg, 3.50 mmol). ) And heated to reflux for 5 hours. The reaction mixture was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 2-methoxy-4- (5-methyl-3-phenylisoxazol-4-yl) benzamide (273 mg, 73%). Obtained as a solid.
MS: 309 [M + H] ⁺ , APCI (MeOH)

Example 154
The following compounds were obtained by reacting and treating in the same manner as in Example 153.

２−メトキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（45mg,0.146mmol）に塩化ピリジニウム（270mg,2.34mmol）を加え、混合物を２時間１９０℃で加熱した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、２−ヒドロキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（34.9mg,81％）を固体として得た。
ＭＳ：２９３［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 155

To 2-methoxy-4- (5-methyl-3-phenylisoxazol-4-yl) benzamide (45 mg, 0.146 mmol) was added pyridinium chloride (270 mg, 2.34 mmol) and the mixture was heated at 190 ° C. for 2 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2-hydroxy-4- (5-methyl-3-phenylisoxazol-4-yl) benzamide (34.9 mg, 81%) Was obtained as a solid.
MS: 293 [M−H] ⁻ , ESI (MeOH)

５−メチル−３−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イソキサゾール（605mg,2.12mmol）、４−ブロモ−２−メトキシベンゾニトリル（300mg,1.415mmol）、酢酸パラジウム（31.7mg,0.142mmol）、２−ジシクロヘキシルホスフィノ−２’−（Ｎ，Ｎ−ジメチルアミノ）ビフェニル（111mg,0.283mmol）、リン酸カリウム（901mg,4.245mmol）のトルエン（7.0ml）懸濁液を、２４時間加熱しながら攪拌した。懸濁液を酢酸エチル／水に注いだ後、有機層を飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）で精製し、２−メトキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゾニトリル（188mg,46％）を固体として得た。
ＭＳ：２９１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 156

5-methyl-3-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole (605 mg, 2.12 mmol), 4-bromo-2-methoxybenzo Nitrile (300 mg, 1.415 mmol), palladium acetate (31.7 mg, 0.142 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (111 mg, 0.283 mmol), potassium phosphate (901 mg, 4.245) mmol) in toluene (7.0 ml) was stirred with heating for 24 hours. The suspension was poured into ethyl acetate / water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-methoxy-4- (5-methyl-3-phenylisoxazol-4-yl) benzonitrile (188 mg, 46%) Was obtained as a solid.
MS: 291 [M + H] ⁺ , APCI (MeOH)

Example 157
The following compounds were obtained by reacting and treating in the same manner as in Example 156.

メチル−Ｎ−［４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゾイル］グリシネート(138mg,0.39mmol)をメタノール（1ml）に溶解し、１Ｎ水酸化ナトリウム水溶液（945μl）を加え室温で２時間攪拌した。反応液を減圧濃縮し、１０％塩酸−酢酸エチルを加えた。有機層を分離し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮して、Ｎ−［４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゾイル］グリシンの粗生成物を得た。得られた粗生成物を単離せず、塩化チオニルを加えて２時間還流した。反応液を濃縮し、ジクロロメタン（2ml）に希釈した。それを３−アミノ−１−プロパノール（59mg,79mmol）とトリエチルアミン（80mg,79mmol）のジクロロメタン溶液に−７８℃で滴下し、混合物をさらに室温で一晩攪拌した。反応液を濃縮し、残渣を精製することにより、Ｎ−［（３−ヒドロキシプロピルアミノ）カルボニルメチル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（56mg,36％）を粉末として得た。
ＭＳ：３９４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 158

Methyl-N- [4- (5-methyl-3-phenylisoxazol-4-yl) benzoyl] glycinate (138 mg, 0.39 mmol) was dissolved in methanol (1 ml), and 1N aqueous sodium hydroxide solution (945 μl) was added. The mixture was further stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 10% hydrochloric acid-ethyl acetate was added. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude N- [4- (5-methyl-3-phenylisoxazol-4-yl) benzoyl] glycine. The product was obtained. The obtained crude product was not isolated, and thionyl chloride was added and refluxed for 2 hours. The reaction was concentrated and diluted in dichloromethane (2 ml). It was added dropwise to a solution of 3-amino-1-propanol (59 mg, 79 mmol) and triethylamine (80 mg, 79 mmol) in dichloromethane at −78 ° C., and the mixture was further stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified to give N-[(3-hydroxypropylamino) carbonylmethyl] -4- (5-methyl-3-phenylisoxazol-4-yl) benzamide (56 mg, 36 %) As a powder.
MS: 394 [M + H] ⁺ , APCI (MeOH)

１−［４−（アミノスルホニル）フェニル］−５−（４−メチルフェニル）−１Ｈ−ピラゾール−３−カルボン酸（2.14g,6mmol）、ジフェニルホスホニルアジド（1.55ml,7.2mmol）およびトリエチルアミン（1.00ml,7.2mmol）のtert−ブタノール（30ml）および１，４−ジオキサン（30ml）溶液を１６時間加熱還流した。反応液を氷冷後、酢酸エチルおよび水を加えた。有機層を分離し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１→２０：１）で精製し、１−(４−アミノスルホニルフェニル)−３−（tert−ブトキシカルボニルアミノ）−５−（４−メチルフェニル）−１Ｈ−ピラゾール（569mg,22％）を固体として得た。
ＭＳ：４２９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（１０ｍＭ−ＡｃＯＮＨ_４／ＭｅＯＨ） Example 159

1- [4- (aminosulfonyl) phenyl] -5- (4-methylphenyl) -1H-pyrazole-3-carboxylic acid (2.14 g, 6 mmol), diphenylphosphonyl azide (1.55 ml, 7.2 mmol) and triethylamine ( A solution of 1.00 ml, 7.2 mmol) of tert-butanol (30 ml) and 1,4-dioxane (30 ml) was heated to reflux for 16 hours. The reaction mixture was ice-cooled, and ethyl acetate and water were added. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 20: 1) to give 1- (4-aminosulfonylphenyl) -3- (tert-butoxycarbonylamino) -5- (4-methylphenyl). ) -1H-pyrazole (569 mg, 22%) was obtained as a solid.
MS: 429 [M + H] ⁺ , APCI (10 mM-AcONH ₄ / MeOH)

１−(４−アミノスルホニルフェニル)−３−（tert−ブトキシカルボニルアミノ）−５−（４−メチルフェニル）−１Ｈ−ピラゾール（510mg,1.19mmol）のクロロホルム溶液（5ml）にトリフルオロ酢酸（2ml）を加えて攪拌した。反応液に酢酸エチルおよび飽和重曹水を加えた。有機層を分離し、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮した。残渣にジエチルエーテルを加えて、析出した固体を濾取することにより、３−アミノ−１−(４−アミノスルホニルフェニル)−５−（４−メチルフェニル）−１Ｈ−ピラゾール（295mg,75％）を固体として得た。
ＭＳ：３２９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 160

To a chloroform solution (5 ml) of 1- (4-aminosulfonylphenyl) -3- (tert-butoxycarbonylamino) -5- (4-methylphenyl) -1H-pyrazole (510 mg, 1.19 mmol) was added trifluoroacetic acid (2 ml). ) Was added and stirred. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give 3-amino-1- (4-aminosulfonylphenyl) -5- (4-methylphenyl) -1H-pyrazole (295 mg, 75%). Was obtained as a solid.
MS: 329 [M + H] ⁺ , APCI (MeOH)

３−アミノ−１−(４−アミノスルホニルフェニル)−５−（４−メチルフェニル）−１Ｈ−ピラゾール（66mg,0.2mmol）に水（2ml）および４８％HBr水溶液（1ml）を加えた。混合物に亜硝酸ナトリウム（17mg,0.24mmol）の水溶液（0.5ml）およびアセトニトリル（2ml）を氷冷下加え、１０分攪拌した。得られた反応液にCuBr（43mg,0.3mmol）の４８％HBr水溶液（0.5ml）を室温で加えた後、８０℃で３０分攪拌した。反応液に酢酸エチルおよび水を加えた。有機層を分離し、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）で精製し、１−［４−（アミノスルホニル）フェニル］−３−ブロモ−５−（４−メチルフェニル）−１Ｈ−ピラゾール（33mg,39％）を得た。
ＭＳ：３９２／３９４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 161

To 3-amino-1- (4-aminosulfonylphenyl) -5- (4-methylphenyl) -1H-pyrazole (66 mg, 0.2 mmol) was added water (2 ml) and 48% aqueous HBr (1 ml). An aqueous solution (0.5 ml) of sodium nitrite (17 mg, 0.24 mmol) and acetonitrile (2 ml) were added to the mixture under ice-cooling, and the mixture was stirred for 10 minutes. A 48% aqueous solution of HBr (0.5 ml) of CuBr (43 mg, 0.3 mmol) was added to the resulting reaction solution at room temperature, and then stirred at 80 ° C. for 30 minutes. Ethyl acetate and water were added to the reaction solution. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give 1- [4- (aminosulfonyl) phenyl] -3-bromo-5- (4-methylphenyl) -1H-pyrazole (33 mg, 39%).
MS: 392/394 [M + H] ⁺ , APCI (MeOH)

２−（４−ブロモフェニル）−１−ピリジン−３−イルエタノン（8.00g,27.5mmol）、塩酸ヒドロキシルアミン（2.00g,28.8mmol）および炭酸水素ナトリウム（2.45g,29.2mmol）のエタノール（70ml）および水（10ml）の懸濁液を、６０℃で３時間攪拌した。溶媒を減圧留去した後、残渣に酢酸エチル／水を注いだ。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製することにより、２−（４−ブロモフェニル）−１−ピリジン−３−イルエタノン オキシム（7.95g,94％）を粉末として得た。
ＭＳ：２９１／２９３［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 162
(1)

2- (4-Bromophenyl) -1-pyridin-3-ylethanone (8.00 g, 27.5 mmol), hydroxylamine hydrochloride (2.00 g, 28.8 mmol) and sodium bicarbonate (2.45 g, 29.2 mmol) in ethanol (70 ml) And a suspension of water (10 ml) was stirred at 60 ° C. for 3 hours. After evaporating the solvent under reduced pressure, ethyl acetate / water was poured into the residue. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2- (4-bromophenyl) -1-pyridin-3-ylethanone oxime (7.95 g, 94%) as a powder. It was.
MS: 291/293 [M + H] ⁺ , APCI (MeOH)

２−（４−ブロモフェニル）−１−ピリジン−３−イルエタノン オキシム（4.0g,13.7mmol）をＴＨＦ（40ml）に溶解し、−６０℃にてリチウムジイソプロピルアミド２Ｍ溶液（ヘプタン／ＴＨＦ／エチルベンゼン溶液）（15.1ml,30.2mmol）を滴下した。滴下後、反応液を−３０℃に昇温し、無水酢酸（1.55,16.4mmol）を一気に加えた。混合物を室温で１時間攪拌後、反応液を酢酸エチル／水に注いだ。有機層を分離し、飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製することにより、４−（４−ブロモフェニル）−５−メチル−３−ピリジン−３−イル−４，５−ジヒドロイソキサゾール−５−オール（2.54g,56％）を粉末として得た。
ＭＳ：３３３／３３５［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） (2)

2- (4-Bromophenyl) -1-pyridin-3-ylethanone oxime (4.0 g, 13.7 mmol) was dissolved in THF (40 ml), and lithium diisopropylamide 2M solution (heptane / THF / ethylbenzene solution) at −60 ° C. ) (15.1 ml, 30.2 mmol) was added dropwise. After the addition, the temperature of the reaction solution was raised to −30 ° C., and acetic anhydride (1.55, 16.4 mmol) was added all at once. After the mixture was stirred at room temperature for 1 hour, the reaction solution was poured into ethyl acetate / water. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4- (4-bromophenyl) -5-methyl-3-pyridin-3-yl-4,5-dihydroisoxa. Zol-5-ol (2.54 g, 56%) was obtained as a powder.
MS: 333/335 [M + H] ⁺ , APCI (MeOH)

４−（４−ブロモフェニル）−５−メチル−３−ピリジン−３−イル−４，５−ジヒドロイソキサゾール−５−オール（2.5g,7.6mmol）およびｐ−トルエンスルホン酸一水和物（1.7g,9.1mmol）のメタノール（25ml）懸濁液を、２４時間加熱還流した。冷却後、反応液を減圧濃縮し、酢酸エチル／飽和重曹水を加えた。有機層を分離し、飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）で精製し、３−［４−（４−ブロモフェニル）−５−メチルイソキサゾール−３−イル］ピリジン（1.9g,78％）を液体として得た。
ＭＳ：３１５／３１７［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） (3)

4- (4-Bromophenyl) -5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-ol (2.5 g, 7.6 mmol) and p-toluenesulfonic acid monohydrate A suspension of (1.7 g, 9.1 mmol) in methanol (25 ml) was heated to reflux for 24 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and ethyl acetate / saturated aqueous sodium bicarbonate was added. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3- [4- (4-bromophenyl) -5-methylisoxazol-3-yl] pyridine (1.9 g, 78% ) Was obtained as a liquid.
MS: 315/317 [M + H] ⁺ , APCI (MeOH)

上記（３）で得られた化合物を実施例１４９と同様に反応・処理することにより、４−（５−メチル−３−（３−ピリジル）イソキサゾール−４−イル）ベンゾニトリルを得た。
ＭＳ：２６２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（５）

上記（４）で得られた化合物を実施例１４９と同様の反応・処理を行った後、実施例１５０において水酸化カリウムの代わりに６Ｎ塩酸を用いて同様に反応・処理することにより、４−（５−メチル−３−（３−ピリジル）イソキサゾール−４−イル）安息香酸を塩酸塩として得た。
ＭＳ：２７９［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） (4)

The compound obtained in (3) above was reacted and treated in the same manner as in Example 149 to give 4- (5-methyl-3- (3-pyridyl) isoxazol-4-yl) benzonitrile.
MS: 262 [M + H] ⁺ , APCI (MeOH)
(5)

The compound obtained in (4) above was subjected to the same reaction and treatment as in Example 149, and then reacted and treated in the same manner using Example 6 with 6N hydrochloric acid instead of potassium hydroxide. (5-Methyl-3- (3-pyridyl) isoxazol-4-yl) benzoic acid was obtained as the hydrochloride salt.
MS: 279 [M−H] ⁻ , ESI (MeOH)

  The following compounds were obtained by reacting and treating in the same manner as in the above examples, or by a commonly used known method.

Example 173
The following compounds were obtained by reacting and treating in the same manner as in Example 72.

  Example 174: Compounds described in Journal of Medicinal Chemistry, 40, 1347-1365 (1997)

Examples 175 and 176
The following compounds were obtained by reacting and treating in the same manner as in Example 121 using 4-bromo-5-methyl-3-phenylisoxazole.

[３−（５−メチル−３−フェニルイソオキサゾール−４−イル）フェニル]アミン（500mg, 2.00mmol）を１,４−ジオキサン（5ml）に溶解し、ジ−ｔ−ブチルジカーボネートを室温で添加し、混合物を９０℃で６時間攪拌した。反応液を室温まで冷却し、１０％クエン酸溶液（15ml）を加えて酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１→３：１）で精製することにより、ｔ−ブチル [３−（５−メチル−３−フェニルイソオキサゾール−４−イル）フェニル]カルバメート（553mg, 82％）を固体として得た。
ＭＳ：３５１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（１０ｍＭ-ＡｃＯＮＨ_４/ＭｅＯＨ） Example 177

[3- (5-Methyl-3-phenylisoxazol-4-yl) phenyl] amine (500 mg, 2.00 mmol) was dissolved in 1,4-dioxane (5 ml) and di-tert-butyl dicarbonate was dissolved at room temperature. And the mixture was stirred at 90 ° C. for 6 hours. The reaction mixture was cooled to room temperature, 10% citric acid solution (15 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 3: 1) to give t-butyl [3- (5-methyl-3-phenylisoxazol-4-yl) phenyl] carbamate (553 mg, 82%) was obtained as a solid.
MS: 351 [M + H] ⁺ , APCI (10 mM-AcONH ₄ / MeOH)

Example 178
The following compounds were obtained by reacting and treating the compounds obtained in Example 177 in the same manner as in Example 151.

Examples 179 and 180
The following compounds were obtained by reacting and treating the compounds obtained in Examples 176 and 178 in the same manner as in Example 29.

Examples 181 to 184
The following compound was obtained by reacting and treating the compound obtained in Example 44 (1) in the same manner as in Example 44 (2).

Examples 185-187
Reaction and treatment in the same manner as in Example 156 using 5-methyl-3-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole Gave the following compounds:

Examples 188 and 189
The following compounds were obtained by reacting and treating the compounds obtained in Example 156 and Example 185 in the same manner as in Example 150.

Examples 190 and 191
The following compounds were obtained by reacting and treating the compounds obtained in Examples 185 and 186 in the same manner as in Example 153.

Examples 192-222
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

Examples 223 and 224
The following compounds were obtained by reacting and treating the compounds of Example 187 and Example 194 in the same manner as in Example 70.

メチル（３Ｒ）−３−｛［（４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンゾイル）アミノ］ブタノエート（952mg, 2.52mmol）をメタノール（5ml）に溶解し、１Ｎ水酸化ナトリウム水溶液（3ml,3.0mmol）を０℃で添加し、２時間室温で攪拌した。反応液を濃縮後、水（60ml）を加え、ジエチルエーテルで洗浄した。水層を１０％塩酸でｐＨ３とし、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣にＤＭＦ（3ml）を加え、続いてＮ−ヒドロキシスクシンイミド（290mg,2.52mmol）および１−エチル−３−（３’−ジメチルアミノプロピル）カルボジイミド塩酸塩（482mg,2.52mmol）を０℃で加えた。混合物を徐々に室温に戻して室温で一晩攪拌した。これに酢酸エチル（100ml）を加え、飽和重曹水および水で洗浄し、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をヘキサンで結晶化して濾取し、Ｎ−｛（１Ｒ）−３−［（２，５−ジオキソピロリジン−１−イル）オキシ］−１−メチル−３−オキソプロピル｝−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（875mg,75％）を固体として得た。
ＭＳ：４６２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 225

Methyl (3R) -3-{[(4- (5-methyl-3-phenylisoxazol-4-yl) benzoyl) amino] butanoate (952 mg, 2.52 mmol) was dissolved in methanol (5 ml) and 1N water was added. Aqueous sodium oxide solution (3 ml, 3.0 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, water (60 ml) was added, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added DMF (3 ml), followed by N-hydroxysuccinimide (290 mg, 2.52 mmol) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (482 mg, 2.52 mmol) at 0 ° C. It was. The mixture was gradually warmed to room temperature and stirred overnight at room temperature. Ethyl acetate (100 ml) was added thereto, washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from hexane and collected by filtration, and N-{(1R) -3-[(2,5-dioxopyrrolidin-1-yl) oxy] -1-methyl-3-oxopropyl} -4- ( 5-Methyl-3-phenylisoxazol-4-yl) benzamide (875 mg, 75%) was obtained as a solid.
MS: 462 [M + H] ⁺ , APCI (MeOH)

Example 226
The following compounds were obtained by reacting and treating in the same manner as in Example 225.

Ｎ−｛（１Ｒ）−３−［（２，５−ジオキソピロリジン−１−イル）オキシ］−１−メチル−３−オキソプロピル｝−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（100mg,0.22mmol）をＴＨＦ（5ml）に溶解し、氷冷下、３０％アンモニア水（1ml）を加えた。室温で一晩攪拌した後、反応液を酢酸エチル／水に注いだ。有機層を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７５：２５→０：１００）で精製し、Ｎ−［（１Ｒ）−３−アミノ−１−メチル−３−オキシプロピル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（875mg,75％）を固体として得た。
ＭＳ：３６４［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 227

N-{(1R) -3-[(2,5-dioxopyrrolidin-1-yl) oxy] -1-methyl-3-oxopropyl} -4- (5-methyl-3-phenylisoxazole- 4-yl) benzamide (100 mg, 0.22 mmol) was dissolved in THF (5 ml), and 30% aqueous ammonia (1 ml) was added under ice cooling. After stirring overnight at room temperature, the reaction mixture was poured into ethyl acetate / water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 75: 25 → 0: 100), and N-[(1R) -3-amino-1-methyl-3-oxypropyl] -4- (5- Methyl-3-phenylisoxazol-4-yl) benzamide (875 mg, 75%) was obtained as a solid.
MS: 364 [M + H] ⁺ , APCI (MeOH)

Examples 228-230
The following compounds were obtained by reacting and treating in the same manner as in Example 227.

Ｎ−｛（１Ｒ）−３−［（２，５−ジオキソピロリジン−１−イル）オキシ］−１−メチル−３−オキソプロピル｝−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（100mg,0.22mmol）をＴＨＦ（5ml）に溶解し、水素化ホウ素ナトリウム（16mg,0.42mmol）を０℃で加え、３時間室温で攪拌した。反応液に飽和塩化アンモニウム水溶液（2ml）を０℃で加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１→１：１）で精製することにより、Ｎ−［（１Ｒ）−３−ヒドロキシ−１−メチルプロピル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（75mg,99％）を固体として得た。
ＭＳ：３５１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 231

N-{(1R) -3-[(2,5-dioxopyrrolidin-1-yl) oxy] -1-methyl-3-oxopropyl} -4- (5-methyl-3-phenylisoxazole- 4-yl) benzamide (100 mg, 0.22 mmol) was dissolved in THF (5 ml), sodium borohydride (16 mg, 0.42 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution (2 ml) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to give N-[(1R) -3-hydroxy-1-methylpropyl] -4- (5-methyl- 3-Phenylisoxazol-4-yl) benzamide (75 mg, 99%) was obtained as a solid.
MS: 351 [M + H] ⁺ , APCI (MeOH)

Example 232
Example The following compound was obtained by reacting and treating in the same manner as in Example 231.

Example 233
The following compounds were obtained by reacting and treating in the same manner as in Example 44 (2).

Examples 234-248
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

Example 249
The following compounds were obtained by reacting and treating in the same manner as in Example 121.

３−フェニルイソキサゾール（840mg,5.787mmol）の酢酸（15.0ml）溶液に、臭素（6.0ml,117.1mmol）を加え、攪拌しながら９０℃で９６時間加熱した。反応液を冷却し、飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を１５％チオ硫酸ナトリウム水溶液、続いて飽和食塩水で洗浄し、芒硝で乾燥させ、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→９０：１０）で精製し、４−ブロモ−３−フェニルイソキサゾール（1290mg,99％）を固体として得た。
ＭＳ：２２４／２２６［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 250
(1)

Bromine (6.0 ml, 117.1 mmol) was added to a solution of 3-phenylisoxazole (840 mg, 5.787 mmol) in acetic acid (15.0 ml), and the mixture was heated at 90 ° C. for 96 hours with stirring. The reaction mixture was cooled, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with 15% aqueous sodium thiosulfate solution followed by saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 90: 10) to give 4-bromo-3-phenylisoxazole (1290 mg, 99%) as a solid.
MS: 224/226 [M + H] ⁺ , APCI

(2) The following compound was obtained by reacting and treating in the same manner as in Example 121 using 4-bromo-3-phenylisoxazole.

Examples 251 and 252
The following compounds were obtained by reacting and treating in the same manner as in Example 135.

Examples 253 and 254
The following compounds were obtained by reacting and treating in the same manner as in Example 150.

Examples 255 and 256
The following compounds were obtained by reacting and treating in the same manner as in Example 151.

Example 257
The following compounds were obtained by reacting and treating in the same manner as in Example 152.

Example 258
The following compounds were obtained by reacting and treating in the same manner as in Example 153.

Examples 259 and 260
The following compounds were obtained by reacting and treating in the same manner as in Example 156.

Example 261
The following compounds were obtained by reacting and treating in the same manner as in Example 158.

Example 262
The following compounds were obtained by reacting and treating in the same manner as in Example 162 (2) and (3).

Example 263
The following compounds were obtained by reacting and treating in the same manner as in Example 162 (4).

Examples 264-266
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

Examples 267 and 268
The following compounds were obtained by reacting and treating in the same manner as in Example 150.

Examples 269-271
The following compounds were obtained by reacting and treating in the same manner as in Example 153.

Examples 272 and 273
The following compounds were obtained by reacting and treating in the same manner as in Example 156.

Example 274
The following compounds were obtained by reacting and treating in the same manner as in Example 162 (5).

Examples 275-289
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

Example 290
The following compounds were obtained by reacting and treating in the same manner as in Example 70.

２−ピリジンカルボヒドロキシモイルクロリド（500mg,3.19mmol）およびトリブチル（1−プロピン−１−イル）スタナン（1.94ml,6.38mmol）のＴＨＦ（10ml）溶液に、氷冷下、トリエチルアミン（1.00ml,7.18mmol）を１５分かけて滴下した。一晩放置し室温に戻した後、反応液を濃縮しヘキサンで希釈した。不溶物を濾過し、濾液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（ヘキサン）で精製し、２−［５−メチル−４−（トリブチルスタニル）イソキサゾール−３−イル］ピリジン（554mg,39％）を油状物として得た。
ＭＳ：４４７／４４９／４５１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 291
(1)

To a solution of 2-pyridinecarbohydroxymoyl chloride (500 mg, 3.19 mmol) and tributyl (1-propyn-1-yl) stannane (1.94 ml, 6.38 mmol) in THF (10 ml) was added triethylamine (1.00 ml, 7.18) under ice cooling. mmol) was added dropwise over 15 minutes. After allowing to stand overnight and returning to room temperature, the reaction solution was concentrated and diluted with hexane. Insoluble matter was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane) to give 2- [5-methyl-4- (tributylstannyl) isoxazol-3-yl]. Pyridine (554 mg, 39%) was obtained as an oil.
MS: 447/449/451 [M + H] ⁺ , APCI (MeOH)

２−［５−メチル−４−（トリブチルスタニル）イソキサゾール−３−イル］ピリジン（100mg,0.223mmol）、４−ブロモベンゾニトリル（61mg,0.325mmol）、テトラキス（トリフェニルホスフィン）パラジウム（30mg,0.026mmol）およびヨウ化銅（Ｉ）（5mg,0.026mmol）のジオキサン溶液（3ml）を一晩加熱還流した。放冷後、反応液を酢酸エチルで希釈し、飽和フッ化カリウム水溶液を加えて、室温で２時間攪拌した。沈殿をろ過した後、濾液を飽和食塩水で洗浄し、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→６５：３５）で精製することにより、２−［５−メチル−４−（４−シアノフェニル）イソキサゾール―３−イル］ピリジン（48mg,83％）を粉末として得た。
ＭＳ：２６２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） (2)

2- [5-Methyl-4- (tributylstannyl) isoxazol-3-yl] pyridine (100 mg, 0.223 mmol), 4-bromobenzonitrile (61 mg, 0.325 mmol), tetrakis (triphenylphosphine) palladium (30 mg, 0.026 mmol) and copper (I) iodide (5 mg, 0.026 mmol) in dioxane (3 ml) were heated to reflux overnight. The reaction liquid was diluted with ethyl acetate after standing_to_cool, saturated potassium fluoride aqueous solution was added, and it stirred at room temperature for 2 hours. After filtering the precipitate, the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 65: 35) to give 2- [5-methyl-4- (4-cyanophenyl) isoxazol-3-yl] pyridine (48 mg , 83%) as a powder.
MS: 262 [M + H] ⁺ , APCI (MeOH)

Examples 292 and 293
(1) The following compounds were obtained by reacting and treating in the same manner as in Example 291 (1) and (2).

Examples 294-299
The following compounds were obtained by reacting and treating in the same manner as in Example 48.

４−ブロモ−５−メチル−３−フェニルイソキサゾール（7.14g,0.30mmol）のＴＨＦ（100ml）溶液にドライアイス−アセトン冷却下、１．６Ｎ ｎ−ブチルリチウムヘキサン溶液（21ml,33mmol）を加えた。同温で３０分攪拌した後、１−tert−ブトキシカルボニルピペリジン−４−オン（6.8g,34.3mmol）を加えた。反応液を室温まで昇温し、水を加えて酢酸エチル抽出をした。有機層を飽和食塩水洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製した後、得られた残渣をジエチルエーテル−ヘキサンから結晶化し、tert−ブチル ４−ヒドロキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ピペリジン−１−カルボキシレート（5.83g, 54％）を得た。
ＭＳ：３５９［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（２）

tert−ブチル ４−ヒドロキシ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ピペリジン−１−カルボキシレートをＰＰＳＥ ジクロロベンゼン溶液（40ml）に溶解して１４０℃で一晩加熱した。冷却後、反応液を水に注ぎ、重曹で中和し、酢酸エチル抽出した。有機層を飽和食塩水洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、４−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，３，６−テトラヒドロピリジン（193mg, 16％）を得た。
ＭＳ：２４１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
ＰＰＳＥ ジクロロベンゼン溶液の調整：ビス（トリメチルシリル）エーテル（0.5L）およびｏ−ジクロロベンゼン（1L）を１５０℃に加熱し、五酸化ニリン（200g）を少しずつ加えた。同温で１０分放置し、得られた溶液を室温まで冷却しＰＰＳＥ ジクロロベンゼン溶液を得た。
（３）

トリホスゲン（41.2mg,0.14mmol）の塩化メチレン（2ml）溶液に氷冷下、２−メトキシ−１−エチルアミン（37μl, 0.42mmol）、次いで、トリエチルアミン（120μl, 0.84mmol）を加え、同温で１５分攪拌した。これに４−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，３，６−テトラヒドロピリジン（95mg,0.39mmol）を加え、室温で２日間攪拌した。反応液をシリカゲルカラムシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９７：３）で精製することにより、Ｎ−（２−メトキシエチル）−４−（５−メチル−３−フェニルイソキサゾール−４−イル）−３，６−ジヒドロピリジン−１（２Ｈ）−カルボキサミド（121mg, 91％）を得た。
ＭＳ：３４２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 300
(1)

To a solution of 4-bromo-5-methyl-3-phenylisoxazole (7.14 g, 0.30 mmol) in THF (100 ml) was added 1.6N n-butyllithium hexane solution (21 ml, 33 mmol) under dry ice-acetone cooling. added. After stirring at the same temperature for 30 minutes, 1-tert-butoxycarbonylpiperidin-4-one (6.8 g, 34.3 mmol) was added. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), the obtained residue was crystallized from diethyl ether-hexane to give tert-butyl 4-hydroxy-4- (5-methyl-3- Phenylisoxazol-4-yl) piperidine-1-carboxylate (5.83 g, 54%) was obtained.
MS: 359 [M + H] ⁺ , APCI (MeOH)
(2)

tert-Butyl 4-hydroxy-4- (5-methyl-3-phenylisoxazol-4-yl) piperidine-1-carboxylate was dissolved in PPSE dichlorobenzene solution (40 ml) and heated at 140 ° C. overnight. . After cooling, the reaction solution was poured into water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to give 4- (5-methyl-3-phenylisoxazol-4-yl) -1,2,3,6-tetrahydropyridine (193 mg, 16 %).
MS: 241 [M + H] ⁺ , APCI (MeOH)
Preparation of PPSE dichlorobenzene solution: Bis (trimethylsilyl) ether (0.5 L) and o-dichlorobenzene (1 L) were heated to 150 ° C., and niline pentoxide (200 g) was added little by little. The solution was allowed to stand at the same temperature for 10 minutes, and the resulting solution was cooled to room temperature to obtain a PPSE dichlorobenzene solution.
(3)

To a solution of triphosgene (41.2 mg, 0.14 mmol) in methylene chloride (2 ml) was added 2-methoxy-1-ethylamine (37 μl, 0.42 mmol) and then triethylamine (120 μl, 0.84 mmol) under ice-cooling. Stir for minutes. 4- (5-Methyl-3-phenylisoxazol-4-yl) -1,2,3,6-tetrahydropyridine (95 mg, 0.39 mmol) was added thereto, and the mixture was stirred at room temperature for 2 days. The reaction solution was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 97: 3) to give N- (2-methoxyethyl) -4- (5-methyl-3-phenylisoxazole). -4-yl) -3,6-dihydropyridine-1 (2H) -carboxamide (121 mg, 91%) was obtained.
MS: 342 [M + H] ⁺ , APCI (MeOH)

（１）４−ブロモフェニル酢酸（15.0g、7.0mmol）、ニコチンアルデヒド（7.47g,7.0mmol）およびトリエチルアミン（9.7ml,7.0mmol）を無水酢酸（60ml）に溶解し２０時間加熱還流した。混合物を１１０℃まで冷却後、水（30ml）を撹拌しながら徐々に加えた。３０分後、反応液を室温まで冷却し、析出した結晶を濾取し、水およびジエチルエーテルで洗浄し乾燥後、（２Ｅ）−２−（４−ブロモフェニル）−３−ピリジン−３−イルアクリル酸（11.1g,52％）を固体として得た。
ＭＳ：３０２／３０４［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ）
（２）メタノール（150ml）に塩化チオニル（2.9ml,4.0mmol）を−１０℃で滴下して２０分撹拌した。これに（２Ｅ）−２−（４−ブロモフェニル）−３−ピリジン−３−イルアクリル酸（11.0g,3.6mmol）を加えた後、混合物を徐々に室温に戻し、その後７０℃で１４時間撹拌した。メタノールを減圧留去後、飽和重曹水を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製することにより、メチル （２Ｅ）−２−（４−ブロモフェニル）−３−ピリジン−３−イルアクリレート（8.78g,76％）を液体として得た。
ＭＳ：３１８／３２０［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（３）メチル （２Ｅ）−２−（４−ブロモフェニル）−３−ピリジン−３−イルアクリレート（14.14g,44.4mmol）およびフッ化セシウム（70mg,0.46mmol）のＤＭＥ（100ml）溶液にトリフルオロメチルトリメチルシラン（8.23ml,55.7mmol）を室温で加えた。１時間後、４Ｎ塩酸（100ml）を加え、混合物を室温で３時間撹拌した。これに飽和重曹水を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、芒硝で乾燥し、減圧濃縮して、定量的に粗生成物の（３Ｅ）−３−（４−ブロモフェニル）−１，１，１−トリフルオロ−４−ピリジン−３−イルブタ−３−エン−２−オンを液体として得た。
ＭＳ：３５６／３５８［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（４）（３Ｅ）−３−（４−ブロモフェニル）−１，１，１−トリフルオロ−４−ピリジン−３−イルブタ−３−エン−２−オン（15.0g,42.1mmol）、塩酸ヒドロキシルアミン（3.22g,46.3mmol）および酢酸ナトリウム（3.80g,46.3mmol）の無水エタノール（400ml）混合物を１時間加熱還流した。反応液を冷却し、減圧濃縮した後、酢酸エチルを加えた。混合物を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製することにより、３−（４−ブロモフェニル）−１，１，１−トリフルオロ−４−（ヒドロキシアミノ）−４−ピリジン−３−イルブタン−２−オン（8.80g,54％）を粉末として得た。
ＭＳ：３８９／３９１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（５）３−（４−ブロモフェニル）−１，１，１−トリフルオロ−４−（ヒドロキシアミノ）−４−ピリジン−３−イルブタン−２−オン（8.80g,22.6mmol）、ヨウ素（5.74g,22.6mmol）、ヨウ化カリウム（37.5g,226mmol）および炭酸水素ナトリウム（19.0g,226mmol）のＴＨＦ（200ml）および水（100ml）の混合物を、遮光下で７時間還流し、さらに室温で一晩撹拌した。混合物を減圧濃縮した後、酢酸エチルを加えた。混合物を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製することにより、３−［４−（４−ブロモフェニル）−５−（トリフルオロメチル）イソキサゾール−３−イル］ピリジン（6.05g,73％）を油状物として得た。
ＭＳ：３６９／３７１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 301

(1) 4-Bromophenylacetic acid (15.0 g, 7.0 mmol), nicotinaldehyde (7.47 g, 7.0 mmol) and triethylamine (9.7 ml, 7.0 mmol) were dissolved in acetic anhydride (60 ml) and heated to reflux for 20 hours. After the mixture was cooled to 110 ° C., water (30 ml) was gradually added with stirring. After 30 minutes, the reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration, washed with water and diethyl ether, dried, and then (2E) -2- (4-bromophenyl) -3-pyridin-3-yl. Acrylic acid (11.1 g, 52%) was obtained as a solid.
MS: 302/304 [M−H] ⁻ , ESI (MeOH)
(2) Thionyl chloride (2.9 ml, 4.0 mmol) was added dropwise to methanol (150 ml) at −10 ° C. and stirred for 20 minutes. To this was added (2E) -2- (4-bromophenyl) -3-pyridin-3-ylacrylic acid (11.0 g, 3.6 mmol), and then the mixture was gradually warmed to room temperature and then at 70 ° C. for 14 hours. Stir. Methanol was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to give methyl (2E) -2- (4-bromophenyl) -3-pyridin-3-yl acrylate (8.78 g, 76%) was obtained as a liquid.
MS: 318/320 [M + H] ⁺ , APCI (MeOH)
(3) Methyl (2E) -2- (4-bromophenyl) -3-pyridin-3-yl acrylate (14.14 g, 44.4 mmol) and cesium fluoride (70 mg, 0.46 mmol) in a DME (100 ml) solution Fluoromethyltrimethylsilane (8.23 ml, 55.7 mmol) was added at room temperature. After 1 hour, 4N hydrochloric acid (100 ml) was added and the mixture was stirred at room temperature for 3 hours. To this was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and quantitatively analyzed as crude product (3E) -3- (4-bromophenyl) -1,1,1-trifluoro-4. -Pyridin-3-ylbut-3-en-2-one was obtained as a liquid.
MS: 356/358 [M + H] ⁺ , APCI (MeOH)
(4) (3E) -3- (4-Bromophenyl) -1,1,1-trifluoro-4-pyridin-3-ylbut-3-en-2-one (15.0 g, 42.1 mmol), hydroxyl hydrochloride A mixture of amine (3.22 g, 46.3 mmol) and sodium acetate (3.80 g, 46.3 mmol) in absolute ethanol (400 ml) was heated to reflux for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and then ethyl acetate was added. The mixture was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to give 3- (4-bromophenyl) -1,1,1-trifluoro-4- (hydroxyamino) -4-Pyridin-3-ylbutan-2-one (8.80 g, 54%) was obtained as a powder.
MS: 389/391 [M + H] ⁺ , APCI (MeOH)
(5) 3- (4-Bromophenyl) -1,1,1-trifluoro-4- (hydroxyamino) -4-pyridin-3-ylbutan-2-one (8.80 g, 22.6 mmol), iodine (5.74 g, 22.6 mmol), potassium iodide (37.5 g, 226 mmol) and sodium hydrogen carbonate (19.0 g, 226 mmol) in THF (200 ml) and water (100 ml) were refluxed for 7 hours in the dark and further at room temperature. Stir overnight. After the mixture was concentrated under reduced pressure, ethyl acetate was added. The mixture was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to give 3- [4- (4-bromophenyl) -5- (trifluoromethyl) isoxazol-3-yl ] Pyridine (6.05 g, 73%) was obtained as an oil.
MS: 369/371 [M + H] ⁺ , APCI (MeOH)

４−［３−ピリジン−３−イル−５−（トリフルオロメチル）イソキサゾール−４−イルベンゾニトリル（1.60g,5.08mmol）の６Ｎ塩酸（10ml）混合物を４日間加熱還流した。混合物を冷却後、減圧濃縮して４−［３−ピリジン−３−イル−５−（トリフルオロメチル）イソキサゾール−４−イル］安息香酸・塩酸塩（1.71g,91％）を粉末として得た。
ＭＳ：３３３［Ｍ−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ） Example 302

A mixture of 4- [3-pyridin-3-yl-5- (trifluoromethyl) isoxazol-4-ylbenzonitrile (1.60 g, 5.08 mmol) in 6N hydrochloric acid (10 ml) was heated to reflux for 4 days. The mixture was cooled and concentrated under reduced pressure to give 4- [3-pyridin-3-yl-5- (trifluoromethyl) isoxazol-4-yl] benzoic acid / hydrochloride (1.71 g, 91%) as a powder. .
MS: 333 [M−H] ⁻ , ESI (MeOH)

（１）２−メトキシニコチンアルデヒド オキシム（1350mg,8.87mmol）、トリブチル（1−プロピン―１−イル）スタナン（2.97ml,9.76mmol）、炭酸水素カリウム（1780mg,17.74mmol）および水（１滴）の酢酸エチル（10ml）懸濁液に、N−クロロスクシンイミド（1320mg,9.76mmol）を氷冷下加え、室温で一晩攪拌した。反応液を酢酸エチルで希釈し、不溶物を塩基性シリカゲルで濾別した後、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：１→３０：１）で精製することにより、２−メトキシ−３−［５−メチル−４−（トリブチルスタニル）イソキサゾール―３−イル］ピリジン（1820mg,43％）を油状物として得た。
ＭＳ：４７７／４７９／４８１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（２）２−メトキシ−３−［５−メチル−４−（トリブチルスタニル）イソキサゾール―３−イル］ピリジン（373mg,0.778mmol）、４−ブロモベンズアミド（120mg,0.600mmol）およびジクロロビス（トリフェニルホスフィン）パラジウム（II）（42mg,0.060mmol）の１，４−ジオキサン（6ml）溶液を一晩加熱還流した。反応液を冷却した後、酢酸エチルで希釈し、１０％フッ化カリウム水溶液を加えて室温で３０分間攪拌した。沈殿をろ過した後、濾液を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９９：１→９３：７）で精製することにより、４−［３−（２−メトキシピリジン−３−イル）−５−メチルイソキサゾール−４−イル］ベンズアミド（64mg,35％）を泡状物として得た。
ＭＳ：３１０［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 303

(1) 2-methoxynicotinaldehyde oxime (1350 mg, 8.87 mmol), tributyl (1-propyn-1-yl) stannane (2.97 ml, 9.76 mmol), potassium bicarbonate (1780 mg, 17.74 mmol) and water (1 drop) To an ethyl acetate (10 ml) suspension, N-chlorosuccinimide (1320 mg, 9.76 mmol) was added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off with basic silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 → 30: 1) to give 2-methoxy-3- [5-methyl-4- (tributylstannyl) isoxazol-3-yl] Pyridine (1820 mg, 43%) was obtained as an oil.
MS: 477/479/481 [M + H] ⁺ , APCI (MeOH)
(2) 2-methoxy-3- [5-methyl-4- (tributylstannyl) isoxazol-3-yl] pyridine (373 mg, 0.778 mmol), 4-bromobenzamide (120 mg, 0.600 mmol) and dichlorobis (triphenyl) A solution of phosphine) palladium (II) (42 mg, 0.060 mmol) in 1,4-dioxane (6 ml) was heated to reflux overnight. The reaction mixture was cooled, diluted with ethyl acetate, 10% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 30 min. The precipitate was filtered, and the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 99: 1 → 93: 7) to give 4- [3- (2-methoxypyridin-3-yl) -5-methylisoxazole-4 -Il] benzamide (64 mg, 35%) was obtained as a foam.
MS: 310 [M + H] ⁺ , APCI (MeOH)

Examples 304-341
The following compounds were obtained by reacting and treating in the same manner as in the above examples using the corresponding starting compounds.

２−クロロ−４−（５−メチル−３−フェニルイソキサゾール−４−イル）安息香酸（78mg,0.25mmol）、（Ｓ）−１−アミノ−２−プロパノール（0.039ml,0.49mmol
、Ｎ−ヒドロキシベンゾトリアゾール（40mg,0.30mmol）および１−エチル−３−（３’−ジメチルアミノプロピル）カルボジイミド塩酸塩（100mg,0.52ml）のＤＭＦ（2ml）溶液を室温で一晩撹拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：３→１：０）で精製することにより、２−クロロ−Ｎ−［（２Ｓ）−２−ヒドロキシプロピル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（84mg,91％）を粉末として得た。
ＭＳ：３７１／３７３［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 342

2-Chloro-4- (5-methyl-3-phenylisoxazol-4-yl) benzoic acid (78 mg, 0.25 mmol), (S) -1-amino-2-propanol (0.039 ml, 0.49 mmol)
, N-hydroxybenzotriazole (40 mg, 0.30 mmol) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (100 mg, 0.52 ml) in DMF (2 ml) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 0) to give 2-chloro-N-[(2S) -2-hydroxypropyl] -4- (5-methyl- 3-Phenylisoxazol-4-yl) benzamide (84 mg, 91%) was obtained as a powder.
MS: 371/373 [M + H] ⁺ , APCI

３−クロロペルオキシ安息香酸（85％純度,13mg,0.0640mmol）および１Ｍ塩化鉄（II）水溶液（0.030ml,0.030mmol）をドライアイス−アセトン冷却下、Ｎ−［（４−ベンジルモルホリン−２−イル）メチル］−４−（５−メチル−３−フェニルイソキサゾール−４−イル）ベンズアミド（30mg,0.0642mmol）のジクロロメタン（2ml）溶液に順次加えた。反応液を室温で３日間撹拌し、希アンモニア水を加えた。混合物をクロロホルムで抽出し、抽出液を飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をＮＨシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９５：５）で精製することにより、４−（５−メチル−３−フェニルイソキサゾール−４−イル）−Ｎ−（モルホリン−２−イルメチル）ベンズアミド（13mg,53％）をカラメルとして得た。
ＭＳ：３７８［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 343

3-Chloroperoxybenzoic acid (85% purity, 13 mg, 0.0640 mmol) and 1M aqueous solution of iron (II) chloride (0.030 ml, 0.030 mmol) were added with N-[(4-benzylmorpholine-2-one) under dry ice-acetone cooling. Yl) methyl] -4- (5-methyl-3-phenylisoxazol-4-yl) benzamide (30 mg, 0.0642 mmol) was added sequentially to a solution of dichloromethane (2 ml). The reaction was stirred at room temperature for 3 days and diluted aqueous ammonia was added. The mixture was extracted with chloroform, and the extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) to give 4- (5-methyl-3-phenylisoxazol-4-yl) -N- (morpholine- 2-ylmethyl) benzamide (13 mg, 53%) was obtained as caramel.
MS: 378 [M + H] ⁺ , APCI

（１）臭素（49.4g,309mmol）をメチル ５−メチルイソキサゾール−３−カルボキシレート（30g,206mmol）のクロロホルム（103ml）溶液に室温で加え、３時間還流した。冷却後、反応液を飽和炭酸カリウム水溶液−飽和チオ硫酸ナトリウム水溶液に注ぎ、クロロホルムで２回抽出した。合わせた有機層を飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、メチル ４−ブロモ−５−メチルイソキサゾール−３−カルボキシレート（27.3g,60％）を固体として得た。
ＭＳ：２２０／２２２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（２）水酸化ナトリウム水溶液（4N,20.5ml,81.8mmol）を氷冷下、メチル ４−ブロモ−５−メチルイソキサゾール−３−カルボキシレート（15.0g,68.2mmol）のメタノール（150ml）溶液に加え、室温で２時間撹拌した。塩酸（6N,13.6ml,81.8mmol）を加え、減圧濃縮した。残渣を酢酸エチルに溶解し、芒硝で乾燥後、セライト濾過し、減圧濃縮した。残渣をジイソプロピルエーテルで粉末化して、４−ブロモ−５−メチルイソキサゾール−３−カルボン酸（12.1g,86％）を固体として得た。
ＭＳ：１６０／１６２［Ｍ−ＣＯ_２−Ｈ］⁻，ＥＳＩ（ＭｅＯＨ）
（３）塩化オキザリル（616mg,4.86mmol）を４−ブロモ−５−メチルイソキサゾール−３−カルボン酸（500mg,2.43mmol）およびＤＭＦ（17.7mg,0.243mmol）のクロロホルム（10ml）懸濁液に室温で加え、３０分間撹拌した。反応液を減圧濃縮した。残渣をクロロホルム（5ml）に溶解し、氷冷下、３−アミノ−４−ヒドロキシピリジン塩酸塩（533mg,3.64mmol）およびピリジン（960mg,12.1mmol）のクロロホルム（5ml）懸濁液に加えた。混合物を室温で２時間撹拌し、水を加えて酢酸エチルで２回抽出した。合わせた有機層を芒硝で乾燥し、濾過した後、減圧濃縮した。残渣をジイソプロピルエーテルで粉末化して、４−ブロモ−Ｎ−（４−ヒドロキシピリジン−３−イル）−５−メチルイソキサゾール−３−カルボキサミド（574mg,79％）を固体として得た。
ＭＳ：２９８／３００［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（４）４−ブロモ−Ｎ−（４−ヒドロキシピリジン−３−イル）−５−メチルイソキサゾール−３−カルボキサミド（572mg,1.92mmol）およびポリリン酸（5.72g）の混合物を１５０℃で１時間撹拌した。冷却後、反応液を水で希釈し、１５％水酸化ナトリウム水溶液で塩基性にした後、酢酸エチルで２回抽出した。合わせた有機層を芒硝で乾燥し、濾過した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル＝５：１）で精製することにより、２−（４−ブロモ−５−メチルイソキサゾール−３−イル）［１，３］オキサゾロ［４，５−ｃ］ピリジン（331mg,61％）を固体として得た。
ＭＳ：２８０／２８２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（５）２−（４−ブロモ−５−メチルイソキサゾール−３−イル）［１，３］オキサゾロ［４，５−ｃ］ピリジンを実施例１２１と同様に反応・処理することにより、４−［５−メチル−３−（［１，３］オキサゾロ［４，５−ｃ］ピリジン−２−イル）イソキサゾール−４−イル］ベンズアミドを得た。
ＭＳ：３２１［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 344

(1) Bromine (49.4 g, 309 mmol) was added to a solution of methyl 5-methylisoxazole-3-carboxylate (30 g, 206 mmol) in chloroform (103 ml) at room temperature and refluxed for 3 hours. After cooling, the reaction solution was poured into a saturated aqueous potassium carbonate solution-saturated aqueous sodium thiosulfate solution, and extracted twice with chloroform. The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give methyl 4-bromo-5-methylisoxazole-3-carboxylate (27.3 g, 60%) as a solid. .
MS: 220/222 [M + H] ⁺ , APCI (MeOH)
(2) Methanol (150 ml) solution of methyl 4-bromo-5-methylisoxazole-3-carboxylate (15.0 g, 68.2 mmol) under ice-cooling aqueous sodium hydroxide solution (4N, 20.5 ml, 81.8 mmol) And stirred at room temperature for 2 hours. Hydrochloric acid (6N, 13.6 ml, 81.8 mmol) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered through celite, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 4-bromo-5-methylisoxazole-3-carboxylic acid (12.1 g, 86%) as a solid.
^{_{MS: 160/162 [M-CO 2}} -H] -, ESI (MeOH)
(3) A suspension of oxalyl chloride (616 mg, 4.86 mmol) in 4-bromo-5-methylisoxazole-3-carboxylic acid (500 mg, 2.43 mmol) and DMF (17.7 mg, 0.243 mmol) in chloroform (10 ml) At room temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform (5 ml) and added to a suspension of 3-amino-4-hydroxypyridine hydrochloride (533 mg, 3.64 mmol) and pyridine (960 mg, 12.1 mmol) in chloroform (5 ml) under ice cooling. The mixture was stirred at room temperature for 2 hours, water was added and extracted twice with ethyl acetate. The combined organic layers were dried with mirabilite, filtered, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 4-bromo-N- (4-hydroxypyridin-3-yl) -5-methylisoxazole-3-carboxamide (574 mg, 79%) as a solid.
MS: 298/300 [M + H] ⁺ , APCI (MeOH)
(4) A mixture of 4-bromo-N- (4-hydroxypyridin-3-yl) -5-methylisoxazole-3-carboxamide (572 mg, 1.92 mmol) and polyphosphoric acid (5.72 g) Stir for hours. After cooling, the reaction mixture was diluted with water, basified with 15% aqueous sodium hydroxide solution, and extracted twice with ethyl acetate. The combined organic layers were dried with mirabilite, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give 2- (4-bromo-5-methylisoxazol-3-yl) [1,3] oxazolo [4,5 -C] Pyridine (331 mg, 61%) was obtained as a solid.
MS: 280/282 [M + H] ⁺ , APCI (MeOH)
(5) By reacting and treating 2- (4-bromo-5-methylisoxazol-3-yl) [1,3] oxazolo [4,5-c] pyridine in the same manner as in Example 121, 4 -[5-Methyl-3-([1,3] oxazolo [4,5-c] pyridin-2-yl) isoxazol-4-yl] benzamide was obtained.
MS: 321 [M + H] ⁺ , APCI

（１）３−アミノ−２−ヒドロキシピリジンを用いて、４−ブロモ−５−メチルイソキサゾール−３−カルボン酸を実施例３４４（３）と同様に反応・処理することにより、４−ブロモ−Ｎ−（２−ヒドロキシピリジン−３−イル）−５−メチルイソキサゾール−３−カルボキサミドを得た。
（２）４−ブロモ−Ｎ−（２−ヒドロキシピリジン−３−イル）−５−メチルイソキサゾール−３−カルボキサミド（512mg,1.72mmol）およびオキシ塩化リン（8.42g）の混合物を一晩還流した。冷却後、反応液を水に注ぎ、１５％水酸化ナトリウム水溶液で塩基性にした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、芒硝で乾燥し、濾過した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９３：７→１７：３）で精製することにより、２−（４−ブロモ−５−メチルイソキサゾール−３−イル）［１，３］オキサゾロ［５，４−ｂ］ピリジン（101mg,21％）を固体として得た。
ＭＳ：２８０／２８２［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（３）２−（４−ブロモ−５−メチルイソキサゾール−３−イル）［１，３］オキサゾロ［５，４−ｂ］ピリジンを実施例１２１と同様に反応・処理することにより、４−［５−メチル−３−（［１，３］オキサゾロ［５，４−ｂ］ピリジン−２−イル）イソキサゾール−４−イル］ベンズアミドを得た。
ＭＳ：３２１［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 345

(1) 4-bromo-5-methylisoxazole-3-carboxylic acid was reacted and treated in the same manner as in Example 344 (3) using 3-amino-2-hydroxypyridine to give 4-bromo -N- (2-hydroxypyridin-3-yl) -5-methylisoxazole-3-carboxamide was obtained.
(2) A mixture of 4-bromo-N- (2-hydroxypyridin-3-yl) -5-methylisoxazole-3-carboxamide (512 mg, 1.72 mmol) and phosphorus oxychloride (8.42 g) was refluxed overnight. did. After cooling, the reaction solution was poured into water, made basic with a 15% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7 → 17: 3) to give 2- (4-bromo-5-methylisoxazol-3-yl) [1,3] oxazolo [5,4-b] pyridine (101 mg, 21%) was obtained as a solid.
MS: 280/282 [M + H] ⁺ , APCI (MeOH)
(3) By reacting and treating 2- (4-bromo-5-methylisoxazol-3-yl) [1,3] oxazolo [5,4-b] pyridine in the same manner as in Example 121, 4 -[5-Methyl-3-([1,3] oxazolo [5,4-b] pyridin-2-yl) isoxazol-4-yl] benzamide was obtained.
MS: 321 [M + H] ⁺ , APCI

（１）アセチルヒドラジンを用いて、４−ブロモ−５−メチルイソキサゾール−３−カルボン酸を実施例３４４（３）と同様に反応・処理することにより、Ｎ’−アセチル−４−ブロモ−５−メチルイソキサゾール−３−カルボヒドラジドを得た。
（２）トリエチルアミン（586mg,5.79mmol）を氷冷下、Ｎ’−アセチル−４−ブロモ−５−メチルイソキサゾール−３−カルボヒドラジド（506mg,1.931mmol）および２−クロロ−１，３−ジメチルイミダゾリニウムクロリド（490mg,2.90mmol）のクロロホルム（15ml）溶液に加えた。混合物を室温で一晩撹拌し、さらに５時間還流した。冷却後、水を加え、クロロホルムで抽出し、有機層を減圧濃縮した。残渣を１，２−ジクロロエタン（5ml）に溶解し、混合物を一晩還流した。冷却後、反応液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→４：１）で精製することにより、２−（４−ブロモ−５−メチルイソキサゾール−３−イル）−５−メチル−１，３，４−オキサジアゾール（62mg,13％）を固体として得た。
ＭＳ：２４４／２４６［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ）
（３）２−（４−ブロモ−５−メチルイソキサゾール−３−イル）−５−メチル−１，３，４−オキサジアゾールを実施例１２１と同様に反応・処理することにより、４−［５−メチル−３−（５−メチル−１，３，４−オキサジアゾール−２−イル）イソキサゾール−４−イル］ベンズアミドを得た。
ＭＳ：２８５［Ｍ＋Ｈ］^＋，ＡＰＣＩ Example 346

(1) Using acetylhydrazine, 4-bromo-5-methylisoxazole-3-carboxylic acid was reacted and treated in the same manner as in Example 344 (3), so that N′-acetyl-4-bromo- 5-Methylisoxazole-3-carbohydrazide was obtained.
(2) Triethylamine (586 mg, 5.79 mmol) was cooled with ice while N′-acetyl-4-bromo-5-methylisoxazole-3-carbohydrazide (506 mg, 1.931 mmol) and 2-chloro-1,3- Dimethylimidazolinium chloride (490 mg, 2.90 mmol) was added to a chloroform (15 ml) solution. The mixture was stirred at room temperature overnight and refluxed for an additional 5 hours. After cooling, water was added, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The residue was dissolved in 1,2-dichloroethane (5 ml) and the mixture was refluxed overnight. After cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1) to give 2- (4-bromo-5-methylisoxazol-3-yl) -5-methyl-1 , 3,4-oxadiazole (62 mg, 13%) was obtained as a solid.
MS: 244/246 [M + H] ⁺ , APCI (MeOH)
(3) By reacting and treating 2- (4-bromo-5-methylisoxazol-3-yl) -5-methyl-1,3,4-oxadiazole in the same manner as in Example 121, 4 -[5-Methyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) isoxazol-4-yl] benzamide was obtained.
MS: 285 [M + H] ⁺ , APCI

３−（クロロメチル）−５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール（100mg,0.36mmol）のＤＭＦ（2ml）溶液に、酢酸ナトリウム（44mg,0.54mmol）を室温で加え、６０℃で３時間撹拌した。混合物を冷却後、水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、［５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール−３−イル］メチル アセテート（87.4mg,81％）を固体として得た。
ＭＳ：３００［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 347

To a solution of 3- (chloromethyl) -5- (5-methyl-3-phenylisoxazol-4-yl) -1,2,4-oxadiazole (100 mg, 0.36 mmol) in DMF (2 ml) was added acetic acid. Sodium (44 mg, 0.54 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give [5- (5-methyl-3-phenylisoxazol-4-yl) -1,2,4-oxadi Azol-3-yl] methyl acetate (87.4 mg, 81%) was obtained as a solid.
MS: 300 [M + H] ⁺ , APCI (MeOH)

［５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール−３−イル］メチル アセテート（86.2mg,0.29mmol）のメタノール溶液に水（0.5ml）、引き続いて炭酸カリウム（199mg,1.44mmol）を室温で加え、同温度で１時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、芒硝で乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１→１：１）で精製することにより、［５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール−３−イル］メタノール（67.8mg,91％）を固体として得た。
ＭＳ：２５８［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 348

[5- (5-Methyl-3-phenylisoxazol-4-yl) -1,2,4-oxadiazol-3-yl] methyl acetate (86.2 mg, 0.29 mmol) in methanol (0.5% ml), and subsequently potassium carbonate (199 mg, 1.44 mmol) was added at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 1: 1) to give [5- (5-methyl-3-phenylisoxazol-4-yl) -1,2, 4-Oxadiazol-3-yl] methanol (67.8 mg, 91%) was obtained as a solid.
MS: 258 [M + H] ⁺ , APCI (MeOH)

［５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール−３−イル］メタノール（67.8mg,0.26mmol）のアセトン溶液に、２，２，６，６−テトラメチルピペリジン−１−オキシル（41mg,0.26mmol）および炭酸水素ナトリム（50mg）の水溶液（1ml）、続いて臭化カリウム（3.6mg,0.03mmol）を室温で加えた。溶液を０℃に冷却し、次亜塩素酸ナトリウム水溶液（0.9ml,0.58mmol）を加え、室温で一晩撹拌した。反応液を減圧濃縮した。残渣を１０％塩酸に注ぎ、酢酸エチルで抽出した。有機層を芒硝で乾燥した後、減圧濃縮し、残渣をジクロロメタンに溶解した。これに塩化オキザリル（0.026ml,0.29mmol）およびＤＭＦ（0.015ml）を室温で加えた。反応液を同温で１時間撹拌し、３０％アンモニア水（2ml）に注ぎ、クロロホルムで抽出した。有機層を芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１→１：１）で精製することにより、５−（５−メチル−３−フェニルイソキサゾール−４−イル）−１，２，４−オキサジアゾール−３−カルボキサミド（33.1mg,47％）を固体として得た。
ＭＳ：２７１［Ｍ＋Ｈ］^＋，ＡＰＣＩ（ＭｅＯＨ） Example 349

To a solution of [5- (5-methyl-3-phenylisoxazol-4-yl) -1,2,4-oxadiazol-3-yl] methanol (67.8 mg, 0.26 mmol) in acetone, , 6,6-tetramethylpiperidine-1-oxyl (41 mg, 0.26 mmol) and aqueous sodium bicarbonate (50 mg) (1 ml) were added at room temperature followed by potassium bromide (3.6 mg, 0.03 mmol). The solution was cooled to 0 ° C., aqueous sodium hypochlorite (0.9 ml, 0.58 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was poured into 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was dissolved in dichloromethane. To this was added oxalyl chloride (0.026 ml, 0.29 mmol) and DMF (0.015 ml) at room temperature. The reaction solution was stirred at the same temperature for 1 hour, poured into 30% aqueous ammonia (2 ml), and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 1: 1) to give 5- (5-methyl-3-phenylisoxazol-4-yl) -1,2,4 -Oxadiazole-3-carboxamide (33.1 mg, 47%) was obtained as a solid.
MS: 271 [M + H] ⁺ , APCI (MeOH)

Example 350
The following compounds were obtained in the same manner as in Example 344 or 345 using the corresponding starting compounds.

Examples 351-419
The following compounds were obtained by reacting and treating in the same manner as in the above examples using the corresponding starting compounds.

Experimental example 1
[Relaxation of potassium-induced contraction in rabbit isolated bladder specimens]
The bladder was removed from a male NZW rabbit (weight: 2.0-3.5 kg) and ice-cooled Krebs-bicarbonate solution (unit: 118 NaCl, 4.7 KCl, 2.55 CaCl ₂ , 1.18 MgSO ₄ , 1.18 KH ₂ PO ₄ , 24.88) NaHCO ₃ and 11.1 glucose). The urinary bladder was cut after removing the mucosal layer to form strips in the longitudinal direction (total length 5 mm, width 3 to 4 mm).
The specimen was immersed in an organ bath filled with 10 ml of Krebs solution heated to 37 ° C. and aerated with a mixed gas of 95% O ₂ /5% CO ₂ . The specimens were stretched so that the static tension was 2.0 ± 1.0 g, and the change in isometric contraction was measured with a force-displacement transducer. Change the organ bath solution to Krebs solution (unit: 118 NaCl, 4.7 KCl, 2.55 CaCl ₂ , 1.18 MgSO ₄ , 1.18 KH ₂ PO ₄ , 24.88 NaHCO ₃ and 11.1 glucose) in high concentration potassium ion (30 mM). Pre-shrink.
Test specimens were cumulatively added to the organ bath (10 ⁻⁸ M−10 ⁻⁴ M) on specimens that showed stable contraction. The effect of the drug was expressed as a percentage with the maximum relaxation due to the addition of 10 ⁻⁴ M papaverine as 100%. The concentration (IC ₅₀ ) at which the relaxation rate was 50% was calculated, and the IC ₅₀ value range (μM) of the selected compound of the present invention was shown in the following Table 68 by the rank of A, B or C. These ranges are as follows.
3 μM ≧ C> 1 μM ≧ B> 0.5 μM ≧ A

Experimental example 2
[Inhibitory effect on substance P-induced rhythmic bladder contraction in anesthetized rats]
In the experiment, female Sprague-Dawley rats (9-12 weeks old) weighing 200-300 g were used. After urethane anesthesia (1.2 g / kg, subcutaneous administration), the left and right femoral veins were cannulated. One catheter was used for intravenous administration of the drug, and the other catheter was used for injecting substance P (0.33 μg / kg / min). A catheter was also inserted into the ureter to secure the urinary tract. A polyethylene catheter was inserted into the carotid artery for continuous measurement of arterial pressure and heart rate. For continuous infusion, a transurethral bladder catheter was inserted into the bladder from the urethra and fixed with a ligature around the urethral closure. One end of the catheter was connected to a pressure transducer for measurement of intravesical pressure. The other end of the catheter was used to inject saline into the bladder. After the blood pressure and heart rate were stabilized and the bladder was emptied, about 0.6 ml of physiological saline was slowly loaded to measure the intravesical pressure. About 10 minutes later, continuous infusion of substance P into the vein (0.33 μg / kg / min) was started to stabilize the bladder contraction. After confirming that the onset of rhythmic contraction lasted for about 15 minutes, the test compound was administered. All test compounds were dissolved or suspended in physiological saline containing 0.5% Tween 80 and administered intravenously (0.1 ml / kg). Rhythmic bladder contraction and intravesical pressure were observed up to 35 minutes after test compound administration.
As a result, the compound of the present invention suppressed the development of rhythmic bladder contraction without affecting the bladder contractile force. In addition, the time (minutes) during which the frequency of rhythmic contraction was suppressed 100% by administration of 0.25 mg / kg of the drug was determined. The 100% inhibition time (minutes) of selected compounds in the present invention is shown in Table 69 below.

Further, pre-administration of iberiotoxin (0.15 mg / kg, intravenous administration), which is a specific inhibitor of high conductance type calcium sensitive K channel, attenuated the rhythmic bladder contraction expression inhibitory effect of the compound of the present invention. Therefore, it was suggested that the compound of the present invention has a detrusor relaxation activity through a high conductance type calcium sensitive K channel opening action.
Thus, it was shown that the compound of the present invention is useful as a preventive and therapeutic agent for frequent urination, urinary incontinence, etc. via the high conductance type calcium sensitive K channel opening action.

The active ingredient compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent high conductance calcium-sensitive K channel opening action, and hyperpolarizes the cell's membrane electric potential. Therefore, frequent urination, urinary incontinence, asthma It is useful as a preventive, alleviating and / or therapeutic agent for chronic obstructive pulmonary disease (COPD).

Claims (12)

Formula (I) for producing a high conductance calcium sensitive K channel opener

[Wherein, ring A represents benzene or a heterocyclic ring.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
Ring Q represents a group selected from the following formulae.

R ¹ and R ³ are the same or different and each represents a group selected from the following formulae.

R ⁵ and R ⁶ are the same or different and are each (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, ( 4) represents an optionally substituted aryl, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl, or (7) R ⁵ and R ^{6 taken} together An optionally substituted heterocycle may be formed with the atom to which is bonded.
R ⁷ is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl Or (5) represents alkoxycarbonyl.
R ¹⁴ represents hydrogen, alkoxy, hydroxyl group, cyano or alkyl which may be substituted.
m and n are the same or different and each represents 0, 1 or 2.
R ² and R ⁴ are the same or different and are each oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted Good alkyl. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ⁴ may be the same or different.
R ¹ and R ² may be combined together to form a group selected from the following formula together with ring A:

R ³ and R ⁴ may be combined together to form a group selected from the following formula together with ring B:

p shows the integer of 1-3.
R ¹³ is (1) optionally substituted alkyl, (2) cyano, (3) hydrogen, (4) halogen, (5) optionally substituted amino, (6) alkenyl, (7) substituted. Carbamoyl, (8) alkoxycarbonyl, (9) carboxy, (10) heterocyclic group, (11) hydroxyl group or (12) alkoxy which may be optionally present.
(However, ring A is a benzene ring,
Ring B is a benzene ring, pyridine or cycloalkane,
Ring Q is

Wherein R ¹³ is halogen, alkyl or haloalkyl.
R ¹ is sulfamoyl or alkylsulfonyl;
R ³ is hydrogen, alkyl or alkoxy;
m is 1 and R ² is halogen, or m is 0;
Excludes compounds where n is 1 and R ⁴ is halogen, alkoxy or alkyl, or n is 0. )]
Or a pharmaceutically acceptable salt thereof. The optionally substituted alkyl substituents for R ⁵ , R ⁶ and R ⁷ are independently selected 1 to 7 halogens and / or 1 to 3 groups selected from the following formulae: Use as described in.

[Wherein R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. , (3) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8 ) R ⁸ and R ⁹ may be taken together with the atoms to which they are attached to form an optionally substituted heterocycle. R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3 ) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) The heterocyclic group which may be substituted is shown. ] Ring B is benzene, heterocycle, cycloalkane or cycloalkene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae:

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 to 3 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen, alkyl or alkoxycarbonyl, or R ⁵ and R ⁶ together may form an optionally substituted heterocycle with the atoms to which they are attached;
R ⁷ is hydrogen, alkyl or alkoxycarbonyl;
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) optionally substituted heterocyclic group, (6) optionally substituted aryl, or (7) R ⁸ and R ⁹ together And may form a heterocyclic ring that may be substituted with the atoms to which they are attached,
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
The use according to claim 1, wherein R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl, alkoxy, halogen or optionally substituted alkyl. Ring B is (1) benzene or (2) a thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, 2,3-dihydroindole, 2,3-dihydrobenzofuran and 1,4-benzodioxane or (3 ) Cyclohexene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ may be taken together with the atoms to which they are attached to form a heterocycle that may be substituted with hydroxyalkyl;
R ⁷ is hydrogen or alkyl,
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl or (4) alkoxyalkyl;
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl or (5) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl, alkoxy, halogen or alkyl optionally substituted with hydroxyl;
R ¹³ is selected from (1) hydrogen, (2) halogen, hydroxyl group, optionally substituted alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, optionally substituted amino and optionally substituted imino. The use according to claim 1, which is an alkyl, (3) alkenyl, or (4) heterocyclic group optionally substituted with a group. Ring A is benzene, thiophene, pyridine or pyrazole,
Ring B is (1) benzene, (2) thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, a heterocyclic ring selected from 2,3-dihydroindole and 1,4-benzodioxane, or (3) cyclohexene,
R ¹ is a group selected from the following formulae:

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1-7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) a cycloalkyl fused with an aryl optionally substituted with a hydroxyl group, or (4) a heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form a heterocycle optionally substituted with hydroxyalkyl,
R ⁷ is hydrogen or alkyl,
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and each may be substituted with (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. Good alkyl, (3) hydroxyalkyl, (4) alkoxyalkyl, (5) an optionally substituted heterocyclic group, or (6) an optionally substituted aryl,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is cyano, nitro, hydroxyl, halogen, alkyl or alkoxy;
R ¹³ is (1) hydrogen, (2) amino optionally substituted with alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, phenyl optionally substituted with a group selected from halogen, hydroxyl, halogen and phenyl, and The use according to claim 1, which is an alkyl, (3) alkenyl, or (4) 4,5-dihydrooxazol-2-yl optionally substituted with a group selected from alkoxy and imino optionally substituted with a hydroxyl group. . The use according to any one of claims 1 to 5, wherein R ¹ is a group selected from the following formulae.

Formula (Ia) for producing a high conductance calcium sensitive K channel opener

[Wherein, ring A represents benzene or a heterocyclic ring.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
Ring Q represents a group selected from the following formulae.

R ^1a represents a group selected from the following formulae.

R ³ represents a group selected from the following formulae.

R ⁵ and R ⁶ are the same or different and are each (1) hydrogen, (2) optionally substituted alkyl, (3) optionally fused to aryl, optionally substituted cycloalkyl, ( 4) represents an optionally substituted aryl, (5) an optionally substituted heterocyclic group, or (6) an alkoxycarbonyl, or (7) R ⁵ and R ^{6 taken} together An optionally substituted heterocycle may be formed with the atom to which is bonded.
R ⁷ is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally fused to aryl, optionally substituted cycloalkyl, (4) optionally substituted aryl Or (5) represents alkoxycarbonyl.
R ¹⁴ represents hydrogen, alkoxy, hydroxyl group, cyano or alkyl which may be substituted.
m and n are the same or different and each represents 0, 1 or 2.
R ² and R ⁴ are the same or different and are each oxo, cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted Good alkyl. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ⁴ may be the same or different.
R ^1a and R ² may be combined to form a group of the following formula together with ring A.

R ³ and R ⁴ may be combined together to form a group selected from the following formula together with ring B:

p shows the integer of 1-3.
R ¹³ is (1) optionally substituted alkyl, (2) cyano, (3) hydrogen, (4) halogen, (5) optionally substituted amino, (6) alkenyl, (7) substituted. Carbamoyl, (8) alkoxycarbonyl, (9) carboxy, (10) heterocyclic group, (11) hydroxyl group or (12) alkoxy which may be optionally present.
(However, (i) Ring A and Ring B are benzene rings,
Ring Q is

And
R ³ is a hydroxyl group substituted at the 2-position, alkoxy or cycloalkyloxy,
R ⁴ is methoxy substituted at the 6-position,
A compound wherein R ¹³ is alkoxycarbonyl or carboxy;
(Ii) N- (3-isopropoxypropyl) -4- (3-methyl-5-phenyl-1H-pyrazol-1-yl) benzamide,
(Iii) 4- (1- (4-aminosulfonylphenyl) -3-difluoromethyl-1H-pyrazol-5-yl) benzamide, and (iv) 4- [5- (4-chlorophenyl) -3- (3 -Hydroxypropyl) -1H-pyrazol-1-yl] -N-methylbenzohydroxamic acid. )]
Or a pharmaceutically acceptable salt thereof. The optionally substituted alkyl substituent in R ⁵ , R ⁶ and R ⁷ is independently selected from 1 to 7 halogens and / or 1 to 3 groups selected from the following formulae: Use as described in.

[Wherein R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. , (3) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8 ) R ⁸ and R ⁹ may be taken together with the atoms to which they are attached to form an optionally substituted heterocycle. R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3 ) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) The heterocyclic group which may be substituted is shown. ] Ring B is benzene, heterocycle or cycloalkane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae:

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 to 3 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form an optionally substituted heterocycle with the atoms to which they are attached;
R ⁷ is hydrogen, alkyl or alkoxycarbonyl;
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) optionally substituted heterocyclic group, (6) optionally substituted aryl, or (7) R ⁸ and R ⁹ together And may form a heterocyclic ring that may be substituted with the atoms to which they are attached,
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and the use of each oxo, cyano, nitro, hydroxyl, alkoxy, claim 7, wherein the halogen or alkyl which may be substituted. Ring B is a heterocyclic ring selected from (1) benzene or (2) thiophene, pyridine, pyrimidine, pyrazine, benzothiophene, 2,3-dihydroindole, 2,3-dihydrobenzofuran and 1,4-benzodioxane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1 to 7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) an optionally substituted cycloalkyl, optionally substituted cycloalkyl, (4) optionally substituted aryl, or (5) an optionally substituted heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ may be taken together with the atoms to which they are attached to form a heterocycle that may be substituted with hydroxyalkyl;
R ⁷ is hydrogen or alkyl,
R ⁸ and R ⁹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl or (4) alkoxyalkyl;
R ¹⁰ and R ¹¹ are the same or different and are each (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) Hydroxyalkyl, (4) alkoxyalkyl or (5) an optionally substituted heterocyclic group,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is oxo, cyano, nitro, hydroxyl, alkoxy, halogen or alkyl optionally substituted with hydroxyl;
R ¹³ is substituted with a group selected from (1) hydrogen, (2) halogen, hydroxyl group, optionally substituted alkoxy, cyano, carboxy, optionally substituted amino and optionally substituted imino. 8. Use according to claim 7, which is optionally alkyl, (3) alkenyl, or (4) a heterocyclic group. Ring A is benzene, thiophene, pyridine or pyrazole,
Ring B is (1) benzene, or (2) a heterocyclic ring selected from thiophene, pyridine, pyrimidine, pyrazine, benzothiophene and 1,4-benzodioxane,
R ^1a is a group selected from the following formulae,

R ³ is a group selected from the following formulae,

R ⁵ is (1) hydrogen, (2) 1-7 halogens independently selected and / or alkyl optionally substituted with 1 or 2 groups selected from the following formulae,

(3) a cycloalkyl fused with an aryl optionally substituted with a hydroxyl group, or (4) a heterocyclic group,
R ⁶ is hydrogen or alkyl, or R ⁵ and R ⁶ together may form a heterocycle optionally substituted with hydroxyalkyl,
R ⁷ is hydrogen or alkyl,
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and each may be substituted with (1) hydrogen, (2) optionally substituted aryl, or optionally substituted heterocyclic group. Good alkyl, (3) hydroxyalkyl, (4) alkoxyalkyl, (5) an optionally substituted heterocyclic group, or (6) an optionally substituted aryl,
R ¹² is (1) hydrogen, (2) optionally substituted aryl or optionally substituted heterocyclic group, (3) hydroxyalkyl, (4) alkoxyalkyl or (5) is an optionally substituted heterocyclic group,
m and n are the same or different and are each 0, 1 or 2;
R ² and R ⁴ are the same or different and each is cyano, nitro, hydroxyl, halogen, alkyl or alkoxy;
R ¹³ is (1) hydrogen, (2) amino optionally substituted with alkoxy, cyano, carboxy, carbamoyl, alkoxycarbonyl, phenyl optionally substituted with a group selected from halogen, hydroxyl, halogen and phenyl, and The use according to claim 7, which is alkyl optionally substituted with a group selected from alkoxy and imino optionally substituted with hydroxyl group, (3) alkenyl or (4) 4,5-dihydrooxazol-2-yl. . The use according to any one of claims 1 to 11, wherein the high conductance calcium-sensitive K channel opener is a preventive and / or therapeutic agent for pollakiuria, urinary incontinence, asthma or chronic obstructive pulmonary disease.