JP2011168512A - Tricyclic chroman compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent for arrhythmia, i.e. to provide a novel tricyclic chroman compound that has an IKACh inhibitor activity and is useful for treating and/or preventing arrhythmia. <P>SOLUTION: A benzopyran derivative represented by formula (I) (wherein R<SP>1</SP>and R<SP>2</SP>are each 1C-6C alkyl group or the like; R<SP>3</SP>is hydroxyl group or the like; R<SP>4</SP>is hydrogen atom or the like; X is 1C-6C alkylene group or the like; R<SP>5</SP>is hydrogen atom or the like; R<SP>6</SP>is 1C-6C alkyl group, 3C-8C cycloalkyl group, 3C-8C cycloalkenyl group, 6C-14C aryl group, 2C-9C heteroaryl group, 2C-9C heterocyclyl group or the like; V is a substituent chosen from substituent group V<SP>1</SP>; m is an integer of 0-2; and A is a 5-, 6- or 7-membered ring that fuses with a benzene ring by sharing two carbon atoms) or a pharmaceutically acceptable salt thereof is provided. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a tricyclic chroman compound having an IKACh inhibitory action, and is used for the treatment and / or prevention of arrhythmia in mammals including humans.

Conventional antiarrhythmic drugs (for example, sotalol, which belongs to group III of the antiarrhythmic drug classification by Vaughan Williams) whose main mechanism is the refractory period prolongation action are rapid activation potassium channels existing in both atrial and ventricular muscles. In order to block mainly, induction of lethal arrhythmia based on the action of prolonging the refractory period of ventricular muscle is regarded as a problem. Acetylcholine-sensitive potassium channel (KACh channel) is a kind of potassium channel and is known to localize to atrial muscle, and is involved in the formation of a repolarization phase of resting membrane potential and action potential of atrial muscle (for example, non-patent literature) 1). Therefore, it has been suggested that inhibition of acetylcholine-sensitive potassium current (IKACh) may show an atrial-selective antiarrhythmic action, for example, for anti-atrial fibrillation, and it is actually a bee venom-derived peptide having a strong IKACh inhibitory action. A certain teltier pin does not affect the ventricle in dogs, and exhibits an atrial fibrillation stopping effect based on an atrial selective effective refractory period extending action (see, for example, Non-Patent Document 2).
Further, it is known that the onset of atrial fibrillation in patients with atrial fibrillation is deeply related to the vagal nerve tone through activation of the KACh channel (see, for example, Non-Patent Document 3). On the other hand, also in atrial myocytes of patients with persistent atrial fibrillation, an increase in IKACh (see, for example, Non-Patent Document 4) and activation of IKACh in the absence of acetylcholine (for example, see Non-Patent Document 5) are suggested.
Based on the above, IKACh inhibitors are expected to be effective against a wide range of pathological conditions of seizure and persistent atrial fibrillation, and development of new drugs is desired.

Nature. 1993: 364, p. 802-806 Pharmacol Res. 2006: 54, p. 136-141 Circulation. 1984: 70, p. 123-135 Cardiovasc Res. 1999: 44, p. 121-131 Circulation. 2005: 112, p. 3697-3706

  An object of the present invention is to provide a novel tricyclic chroman compound having IKCh inhibitory activity and useful for the treatment and / or prevention of arrhythmia.

〔式中、Ｒ^１及びＲ^２は、それぞれ独立して水素原子、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）、Ｃ_６−１４アリール基若しくはＣ_１−６アルコキシ基（該Ｃ_６−１４アリール基及びＣ_１−６アルコキシ基は無置換であるか又は１つ以上のハロゲン原子で置換されている。）、又は一緒になってＣ_３−８シクロアルキル基若しくはＣ_２−９ヘテロシクリル基を意味し、
Ｒ^３は、水酸基、若しくはＣ_１−６アルキルカルボニルオキシ基を意味するか、又はＲ^４と一緒になって結合を意味し、
Ｒ^４は水素原子を意味するか、又はＲ^３と一緒になって結合を意味し、
Ｘは単結合又はＣ_１−６アルキレン基（該Ｃ_１−６アルキレン基は無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されており、１つの炭素原子がＳ、Ｏ、ＳＯ_２又はＮＨで置換されていてもよい。）を意味し、
Ｒ^５は、水素原子又はＣ_１−６アルキル基（該アルキル基は無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）を意味し、
Ｒ^６は、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_３−８シクロアルケニル基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_３−８シクロアルケニル基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基及びＣ_２−９ヘテロシクリル基は無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）を意味し
Ｖは置換基群Ｖ^１より選ばれる置換基を意味し、
ｍは０から２の整数（ｍが２のとき、２つのＶは同一であっても異なっていてもよい）を意味し、
Ａはベンゼン環と二つの炭素原子を共有して縮環する５、６又は７員環（該５，６又は７員環は無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されており、ベンゼン環と共有する２つの炭素原子以外の環の構成原子として炭素原子、酸素原子、窒素原子又は硫黄原子を１〜３原子単独もしくは組み合わせて含むことができ、環内の不飽和結合の数は、縮合するベンゼン環の不飽和結合を含め、１、２又は３であり、環を構成する炭素原子のうちベンゼン環と共有する２つ以外の炭素原子は、カルボニル又はチオカルボニルであってもよい。）を意味し、
置換基群Ｖ^１は、カルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、モノＣ_１−６アルキルアミノカルボニル基、ジＣ_１−６アルキルアミノカルボニル基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基、Ｃ_２−９ヘテロシクリル基（該モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、モノＣ_１−６アルキルアミノカルボニル基、ジＣ_１−６アルキルアミノカルボニル基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基、及びＣ_２−９ヘテロシクリル基は無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、Ｃ_１−６アルキル基、ハロゲン置換Ｃ_１−３アルキル基、Ｃ_１−６アルコキシ基、ハロゲン置換Ｃ_１−３アルコキシ基、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、モノＣ_１−６アルキルアミノカルボニル基、ジＣ_１−６アルキルアミノカルボニル基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基、若しくはＣ_２−９ヘテロシクリル基（該Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基及びＣ_２−９ヘテロシクリル基は無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、Ｃ_１−６アルキル基、ハロゲン置換Ｃ_１−３アルキル基、Ｃ_１−６アルコキシ基、ハロゲン置換Ｃ_１−３アルコキシ基、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、モノＣ_１−６アルキルアミノカルボニル基（該モノＣ_１−６アルキルアミノカルボニル基は無置換であるか又は水酸基、Ｃ_６−１４アリール基、Ｃ_２−９ヘテロアリール基若しくはＣ_２−９ヘテロシクリル基より選ばれる１つ以上の置換基で置換されている。）、ジＣ_１−６アルキルアミノカルボニル基、Ｃ_１−６アルキルカルボニルアミノ基、Ｃ_１−６アルキルチオ基又はＣ_１−６アルキルスルホニル基で置換されている。）から単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）により構成される。］
で表されるベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＩＩ）
Ｒ^１及びＲ^２はそれぞれ独立してＣ_１−６アルキル基であり、Ｒ^３は水酸基又はＣ_１−６アルキルカルボニルオキシ基であり、Ｒ^４は水素原子であり、Ｒ^５は水素原子であるＩ）に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＩＩＩ）
Ｒ^１及びＲ^２がメチル基であり、Ｒ^３が水酸基であるＩＩ）に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＩＶ）
ＸがＣ_２−４アルキレン基（該Ｃ_２−４アルキレン基は無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）であり、Ｒ^６が、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_６−１４アリール基又はＣ_２−９ヘテロアリール基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_６−１４アリール基及びＣ_２−９ヘテロアリール基は無置換であるか又はハロゲン原子で置換されている。）であり、ｍが０であるＩ）乃至ＩＩＩ）の何れか一項に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
Ｖ）
ＸがＣ_２−４アルキレン基（該Ｃ_２−４アルキレン基は無置換であるか又は１つのメチル基若しくは水酸基で置換されている。）であり、Ｒ^６が、シクロヘキシル基又はフェニル基（該シクロヘキシル基及びフェニル基は無置換であるか又はハロゲン原子で置換されている。）であるＩＶ）に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＶＩ）
Ｘがエチレン基であり、Ｒ^６がフェニル基（該フェニル基は無置換であるか又はハロゲン原子で置換されている。）であるＶ）に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＶＩＩ）
Ａがベンゼン環と二つの炭素原子を共有して縮環するＣ_３−５ヘテロアリール基（該Ｃ_３−５ヘテロアリール基は無置換であるか又は１つ以上のＣ_１−６アルキル基（該アルキル基は無置換であるか、又は１つ以上のハロゲン原子、アミノ基若しくは水酸基で置換されている。）で置換されている。）であるＩ）乃至ＶＩ）のいずれか一項に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＶＩＩＩ）
Ａがベンゼン環と二つの炭素原子を共有して縮環するＣ_４−５ヘテロアリール基（該Ｃ_４−５ヘテロアリール基は無置換であるか又は１つ以上のＣ_１−３アルキル基（該アルキル基は無置換であるか、又は水酸基で置換されている。）で置換されている。）であるＶＩＩ）に記載のベンゾピラン化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
ＩＸ）
Ｉ）乃至ＶＩＩＩ）の何れか一項に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物を有効成分として含有するＩＫＡＣｈ阻害剤。
Ｘ）
ＩＸ）に記載のＩＫＡＣｈ阻害剤を有効成分として含有するＫＡＣｈチャネル阻害作用が有効な疾患の予防・治療・改善薬。
ＸＩ）
ＩＸ）に記載のＩＫＡＣｈ阻害剤を有効成分として含有する不整脈治療剤。
ＸＩＩ）
Ｉ）乃至ＶＩＩＩ）の何れか一項に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物を有効成分として含有する医薬。 The present inventors diligently studied to find a novel low molecular weight compound having IKCh inhibitory activity. As a result, they found that the compound of the present invention has a high inhibitory action, and completed the present invention. That is, this invention is comprised by the following.
I) Formula (I)

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is independent or different from the substituent group V ¹ Substituted with one or more selected substituents), a C _6-14 aryl group or a C _1-6 alkoxy group (whether the C _6-14 aryl group and the C _1-6 alkoxy group are unsubstituted) Or substituted with one or more halogen atoms), or taken together means a C _3-8 cycloalkyl group or a C _2-9 heterocyclyl group,
R ³ represents a hydroxyl group or a C _1-6 alkylcarbonyloxy group, or together with R ^{4 represents} a bond,
R ⁴ represents a hydrogen atom or together with R ^{3 represents} a bond,
X is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently; One carbon atom may be substituted with S, O, SO ₂ or NH),
R ⁵ represents a hydrogen atom or a C _1-6 alkyl group (the alkyl group is unsubstituted or substituted with one or more substituents selected from substituent group V ¹ alone or differently). Means
R ⁶ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, a C _6-14 aryl group, a C _2-9 heteroaryl group or a C _2-9 heterocyclyl group (this Is the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aryl group, C _2-9 heteroaryl group and C _2-9 heterocyclyl group unsubstituted? Or substituted with one or more substituents selected from the substituent group V ¹ singly or differently, and V represents a substituent selected from the substituent group V ¹ ;
m represents an integer of 0 to 2 (when m is 2, two Vs may be the same or different);
A is a 5-, 6-, or 7-membered ring that shares two carbon atoms with the benzene ring, and the 5-, 6-, or 7-membered ring is unsubstituted or selected alone or differently from the substituent group V ¹ 1 to 3 atoms alone or in combination as a constituent atom of a ring other than the two carbon atoms shared with the benzene ring. The number of unsaturated bonds in the ring is 1, 2 or 3, including the unsaturated bond of the condensed benzene ring, and the number of carbon atoms constituting the ring is other than two shared with the benzene ring. Carbon atom may be carbonyl or thiocarbonyl).
Substituent group V ¹ was a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group , Di C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, mono C _1-6 Alkylaminocarbonyl group, di-C _1-6 alkylaminocarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, C _6-14 aryl group, C _2-9 A heteroaryl group, a C _2-9 heterocyclyl group (the mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkyl) Group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, mono C _1-6 alkylaminocarbonyl group, di-C _1-6 alkylaminocarbonyl group , C _1-6 alkylcarbonylamino group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, C _6-14 aryl group, C _2-9 heteroaryl group, and C _2-9 heterocyclyl group are unsubstituted. Or a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a halogen-substituted C _1-3 alkyl group, C _1-6 alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, a hydroxyl group, an amino group, a mono _{C 1-6} alkylamino group, di _1-6 alkylamino group, a mono _{C 1-6} alkylaminocarbonyl group, di _{C 1-6} alkylaminocarbonyl _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkylthio _{group, C 1-6} alkylsulfonyl group , C _6-14 aryl group, C _2-9 heteroaryl group, or C _2-9 heterocyclyl group (the C _6-14 aryl group, C _2-9 heteroaryl group and C _2-9 heterocyclyl group are unsubstituted) Or a carboxyl group, carbamoyl group, sulfamoyl group, phosphono group, sulfo group, tetrazolyl group, formyl group, nitro group, cyano group, halogen atom, C _1-6 alkyl group, halogen-substituted C _1-3 alkyl group, C _C1-6 alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, a hydroxyl group, an amino group, a mono _{C 1-6} alkylamino Group, _{di-C 1-6} alkylamino group, or a hydroxyl group mono _{C 1-6} alkylaminocarbonyl group (the mono- _{C 1-6} alkylaminocarbonyl group is _{unsubstituted, C 6-14} aryl _{group, C 2-} It is substituted with one or more substituents selected from ₉ heteroaryl groups or C _2-9 heterocyclyl groups. ), A di C _1-6 alkylaminocarbonyl group, a C _1-6 alkylcarbonylamino group, a C _1-6 alkylthio group or a C _1-6 alkylsulfonyl group. ) Is substituted with one or more substituents selected singly or differently. ). ]
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
II)
R ¹ and R ² are each independently a C _1-6 alkyl group, R ³ is a hydroxyl group or a C _1-6 alkylcarbonyloxy group, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom. A benzopyran compound according to I), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
III)
The benzopyran compound according to II), wherein R ¹ and R ² are a methyl group, and R ³ is a hydroxyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .
IV)
X is a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). , R ⁶ is a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-14 aryl group, or a C _2-9 heteroaryl group (the C _1-6 alkyl group, C _3-8 cycloalkyl group) , The C _6-14 aryl group and the C _2-9 heteroaryl group are unsubstituted or substituted with a halogen atom.), And m is 0. The benzopyran compound described, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
V)
X is a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one methyl group or a hydroxyl group), and R ⁶ is a cyclohexyl group or a phenyl group (the The cyclohexyl group and the phenyl group are unsubstituted or substituted with a halogen atom.) The benzopyran compound according to IV), a tautomer, prodrug or pharmaceutically acceptable salt of the compound Or a solvate thereof.
VI)
A benzopyran compound according to V), wherein X is an ethylene group and R ⁶ is a phenyl group (the phenyl group is unsubstituted or substituted with a halogen atom), a tautomer of the compound, A prodrug or a pharmaceutically acceptable salt thereof or a solvate thereof.
VII)
A C _3-5 heteroaryl group in which A is condensed with a benzene ring sharing two carbon atoms (the C _3-5 heteroaryl group is unsubstituted or has one or more C _1-6 alkyl groups ( The alkyl group is unsubstituted or substituted with one or more halogen atoms, amino groups, or hydroxyl groups.))) Or any one of I) to VI). Benzopyran compounds, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
VIII)
A C _4-5 heteroaryl group in which A is fused with a benzene ring by sharing two carbon atoms (the C _4-5 heteroaryl group is unsubstituted or has one or more C _1-3 alkyl groups ( The alkyl group is unsubstituted or substituted with a hydroxyl group.)) Is substituted with a benzopyran compound according to VII), a tautomer, prodrug or pharmaceutical thereof Or a solvate thereof.
IX)
An IKACh inhibitor comprising the compound according to any one of I) to VIII), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.
X)
A preventive, therapeutic, or ameliorating agent for a disease having an effective KACh channel inhibitory effect, comprising the IKACh inhibitor according to IX) as an active ingredient.
XI)
A therapeutic agent for arrhythmia containing the IKCh inhibitor described in IX) as an active ingredient.
XII)
A medicament comprising the compound according to any one of I) to VIII), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.

  According to the present invention, a novel tricyclic chroman compound having excellent IKCh inhibitory activity and useful for the treatment and / or prevention of arrhythmia can be provided.

Hereinafter, the present invention will be described in more detail.
In the present invention, “n” is normal, “i” is iso, “s” is secondary, “t” or “tert” is tertiary, “c” is cyclo, “o” is ortho, and “m” is Meta, `` p '' means para, `` rac '' means racemic, `` Ph '' means phenyl, `` Py '' means pyridyl, `` Me '' means methyl, `` Et '' means ethyl, `` Pr '' means propyl, `` Bu “But” means tertiary butoxycarbonyl, “Ms” means methanesulfonyl, “Tf” means trifluoromethanesulfonyl, and “MOM” means methoxymethyl.

First, the substituents ^{R 1 ~R 6, V, X} , for the phrase in each substituent of A is described.

  Halogen atoms are fluorine, chlorine, bromine and iodine.

The C _1-3 alkyl group is an alkyl group having 1 to 3 carbon atoms, and may contain a linear, branched or C ₃ cycloalkyl group. Specific examples thereof include methyl, ethyl, n- And propyl, i-propyl and c-propyl.

The C _1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms, and may contain a linear, branched, or C _3-6 cycloalkyl group. n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, n-pentyl, 1-methyl-n-butyl, 2- Methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n- Propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n- Pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2- Ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl- n-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3- Ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4- Dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i- Propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, 1-ethyl-2-methyl- c-propyl, 2- Examples include ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl and 2-ethyl-3-methyl-c-propyl.

The C _2-6 alkenyl group means a group in which any 1, 2 or 3 positions of the C _1-6 alkyl group (excluding the methyl group) shown above are converted to a double bond. , Branched and C _3-6 cycloalkenyl groups, specific examples include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-ethenyl, 1-butenyl, 2-butenyl, 3- Butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethylethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-n-propylethenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 2-ethyl-2-propenyl, 2-methyl-1- Butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3- Tenenyl, 1,1-dimethyl-2-propenyl, 1-i-propylethenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-c-pentenyl, 2-c- Pentenyl, 3-c-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3- Pentenyl, 1-methyl-4-pentenyl, 1-n-butylethenyl, 2-methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2- n-propyl-2-propenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 3-methyl-4-pentenyl, 3-ethyl-3-butenyl, 4- Methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1-methyl-2-ethyl-2-propenyl, 1-s-butylethenyl, 1 , 3-Dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 1-i-butylethenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl -1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 2-i-propyl-2-propenyl, 3,3-dimethyl-1-butenyl, 1-ethyl-1 -Butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-n-propyl-1-propenyl, 1-n-propyl-2-propenyl, 2-ethyl-1-butenyl, 2-ethyl 2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-t-butylethenyl, 1-methyl-1-ethyl-2-propenyl, 1-ethyl-2-methyl -1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-i-propyl-1-propenyl 1-i-propyl-2-propenyl, 1-methyl-2-c-pentenyl, 1-methyl-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3- Methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c- Examples include hexenyl, 2-c-hexenyl, and 3-c-hexenyl.

The C _2-6 alkynyl group is an alkynyl group having 2 to 6 carbon atoms, and may include linear, branched, and C ₆ cycloalkynyl. Specific examples include ethynyl, 1-propynyl. 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1 -Methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5 -Hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butyn Nyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 1-n-propyl-2-propynyl, 2-ethyl-3-butynyl, 1-methyl-1-ethyl-2-propynyl, 1-c-propyl-2-propynyl and 1- i-propyl-2-propynyl and the like can be mentioned.

C _3-8 cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms, and specific examples thereof include c-propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl. , C-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1 -Ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, c-heptyl, c-octyl, 1-methyl-c-hexyl, 2-methyl-c-hexyl, 3-methyl-c-hexyl 1,2-dimethyl-c-hexyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c -Pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2 -Dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i-propyl-c-propyl 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, 1-ethyl-2-methyl-c-propyl, 2 -Ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c-propyl and the like.

The C _3-8 cycloalkenyl group means a group in which any 1, 2 or 3 positions of the C _3-8 cycloalkyl group shown above are converted to a double bond, and specific examples include 1-c-pentenyl. 2-c-pentenyl, 3-c-pentenyl, 1-methyl-2-c-pentenyl, 1-methyl-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c -Pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl 3-methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1 -c-hexenyl, 2-c-hexenyl, 3-c-hexenyl, 1-c-heptynyl, 2-c-heptynyl, 3-c-heptynyl, 4-c-heptynyl, 1-c-octynyl, 2-c -Octynyl, 3-c-octynyl and 4-c-octini Etc. The.
Preferably, 1-c-pentenyl, 2-c-pentenyl, 3-c-pentenyl, 1-c-hexenyl, 2-c-hexenyl and 3-c-hexenyl are exemplified.

The halogen-substituted C _1-3 alkyl group, which alkyl group a C _1-3 alkyl group shown above is a fluorine atom, a chlorine atom, is 1 or more substituted with halogen atom such as bromine and / or iodine atom Specific examples include fluoromethyl group, difluoromethyl group, trifluoromethyl group, chlorofluoromethyl group, chlorodifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, Tribromomethyl group, iodomethyl group, diiodomethyl group, triiodomethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, tetrafluoroethyl group, pentafluoroethyl group, chloroethyl group, dichloroethyl group, trichloroethyl group, Tetrachloroethyl group, pentachrome Ethyl group, bromoethyl group, dibromoethyl group, tribromoethyl group, tetrabromoethyl group, pentabromoethyl group, perfluoro-n-propyl group, 2,2-difluoro-n-propyl group, 2,2,3, 3,3-pentafluoro-n-propyl group, perfluoro-i-propyl group, 2-fluoro-i-propyl group, 2,2,2,2,2,2-hexafluoro-i-propyl group, 2 , 2-difluoro-c-propyl group, 2,2,3,3-tetrafluoro-c-propyl group and the like.

The C _1-3 alkoxy group is an alkoxy group having 1 to 3 carbon atoms and may contain a linear, branched or C ₃ cycloalkoxy group. Specific examples thereof include methoxy, ethoxy, n- Examples include propoxy, i-propoxy and c-propoxy.

The halogen-substituted C _1-3 alkoxy group is a group in which one or more alkyl groups in the C _1-3 alkoxy group shown above are substituted with a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and / or an iodine atom. Specific examples include fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chlorofluoromethoxy group, chlorodifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, bromomethoxy group, dibromomethoxy. Group, tribromomethoxy group, iodomethoxy group, diiodomethoxy group, triiodomethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, tetrafluoroethoxy group, pentafluoroethoxy group, chloroethoxy group, dichloroethoxy Group, bird Loroethoxy, tetrachloroethoxy, pentachloroethoxy, bromoethoxy, dibromoethoxy, tribromoethoxy, tetrabromoethoxy, pentabromoethoxy, perfluoro-n-propoxy, 2,2-difluoro- n-propoxy group, 2,2,3,3,3-pentafluoro-n-propoxy group, perfluoro-i-propoxy group, 2-fluoro-i-propoxy group, 2,2,2,2,2, Examples include 2-hexafluoro-i-propoxy group, 2,2-difluoro-c-propoxy group and 2,2,3,3-tetrafluoro-c-propoxy group.

The C _1-6 alkoxy group is an alkoxy group having 1 to 6 carbon atoms, and may include linear, branched, and C _3-6 cycloalkoxy groups. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, 1-methyl-c-propoxy, 2-methyl-c-propoxy, n -Pentyloxy, 1-methyl-n-butoxy, 2-methyl-n-butoxy, 3-methyl-n-butoxy, 1,1-dimethyl-n-propoxy, 1,2-dimethyl-n-propoxy, 2, 2-dimethyl-n-propoxy, 1-ethyl-n-propoxy, c-pentyloxy, 1-methyl-c-butoxy, 2-methyl-c-butoxy, 3-methyl-c-butoxy, 1,2-dimethyl -c-propoxy, 2,3-dimethyl-c-propoxy, 1-ethyl-c-propoxy, 2-ethyl-c-propoxy, n-hexyloxy, 1- Tyl-n-pentyloxy, 2-methyl-n-pentyloxy, 3-methyl-n-pentyloxy, 4-methyl-n-pentyloxy, 1,1-dimethyl-n-butoxy, 1,2-dimethyl- n-butoxy, 1,3-dimethyl-n-butoxy, 2,2-dimethyl-n-butoxy, 2,3-dimethyl-n-butoxy, 3,3-dimethyl-n-butoxy, 1-ethyl-n- Butoxy, 2-ethyl-n-butoxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, 1-ethyl-1-methyl-n-propoxy, 1-ethyl- 2-methyl-n-propoxy, c-hexyloxy, 1-methyl-c-pentyloxy, 2-methyl-c-pentyloxy, 3-methyl-c-pentyloxy, 1-ethyl-c-butoxy, 2- Ethyl-c-butoxy, 3-ethyl-c-butoxy, 1,2-dimethyl-c-butoxy, 1,3-dimethyl-c-butoxy, 2,2-dimethyl-c-butoxy, 2,3-dimethyl- c-butoxy, 2,4-dimethyl-c-butoxy, 3,3-dimethyl-c- Toxi, 1-n-propyl-c-propoxy, 2-n-propyl-c-propoxy, 1-i-propyl-c-propoxy, 2-i-propyl-c-propoxy, 1,2,2-trimethyl- c-propoxy, 1,2,3-trimethyl-c-propoxy, 2,2,3-trimethyl-c-propoxy, 1-ethyl-2-methyl-c-propoxy, 2-ethyl-1-methyl-c- Examples include propoxy, 2-ethyl-2-methyl-c-propoxy and 2-ethyl-3-methyl-c-propoxy.

The C _1-6 alkylene group is a divalent group obtained by removing one hydrogen atom from the C _1-6 alkyl group shown above, and represents a linear, branched alkylene group or cyclic C _3-6 alkylene group. Specific examples include methylene, ethylene, 1-methylethane-1,2-diyl, propane-1,3-diyl, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl. , Butane-1,4-diyl, 1,1-dimethylethane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, pentane-1, 5-diyl, cyclopentane-1,3-diyl, hexane-1,6-diyl, cyclohexane-1,4-diyl, bicyclo [3.1.0] hexane-2,3-diyl and the like.

The C _2-4 alkylene group means a linear, branched alkylene group or cyclic C _3-4 alkylene group having 2 to 4 carbon atoms among the C _1-6 alkylene groups shown above. Examples include ethylene, 1-methylethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, 1,1-dimethylethane-1,2-diyl and the like.

The C _6-14 aryl group is an aryl group having 6 to 14 carbon atoms, and specific examples thereof include phenyl group, 1-indenyl group, 2-indenyl group, 3-indenyl group, 4-indenyl group, 5 -Indenyl group, 6-indenyl group, 7-indenyl group, α-naphthyl group, β-naphthyl group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthyl group, 5-tetrahydronaphthyl group, 6-tetrahydronaphthyl group, o- Biphenylyl, m-biphenylyl, p-biphenylyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9- Examples include a phenanthryl group.
The C _2-9 heteroaryl group is a 5- to 7-membered C _2-6 monocyclic heterocyclic group which can contain 1 to 3 atoms alone or in combination of oxygen, nitrogen and sulfur atoms, and constituent atoms This means a C _5-9 fused bicyclic heterocyclic aryl group having a number of 8 to 10, and when it contains a nitrogen atom, it also includes an N-oxide.
Specific examples of the 5- to 7-membered C _2-6 monocyclic heterocyclic group include 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, and 3-pyranyl. Group, 4-pyranyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group Group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group Group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4-pi Midinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group 5-1, 2, 4-oxadiazolyl group, 3-1, 2, 4-thiadiazolyl group, 5-1, 2, 4-thiadiazolyl group, 3-1, 2, 5-oxadiazolyl group, 3-1, 2 , 5-thiadiazolyl group, 3-4H-1,2,4-triazolyl group, 3-1H-1,2,4-triazolyl group, 5-1H-1,2,4-triazolyl group, 4-2H-1 , 2,3-triazolyl group, 5-2H-1,2,3-triazolyl group, 4-1H-1,2,3-triazolyl group, 5-1H-1,2,3-triazolyl group and the like. .
_Examples of the C _5-9 condensed bicyclic heterocyclic group having 8 to 10 constituent atoms include 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group. Group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5- Chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-indolidinyl group, 2-indolidinyl group, 3-indolidinyl group Group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indolyl group, 2-indolyl group Group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5-indazolyl group Group, 6-indazolyl group, 7-indazolyl group, 2- (7-aza) indazolyl group, 3- (7-aza) indazolyl group, 4- (7-aza) indazolyl group, 5- (7-aza) indazolyl Group, 6- (7-aza) indazolyl group, 2- (4-aza) indazolyl group, 3- (4-aza) indazolyl group 5- (4-aza) indazolyl group, 6- (4-aza) indazolyl group, 7- (4-aza) indazolyl group, 1-purinyl group, 2-purinyl group, 3-purinyl group, 6-prinyl group 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 1-2, 7-naphthyridinyl group, 3-2,7-naphthyridinyl group, 4-2,7-naphthyridinyl group, 1-2,6-naphthyridinyl group, 3-2,6-naphthyridinyl group, 4-2,6-naphth Lysinyl group, 2-1,8-naphthyridinyl group, 3-1,8-naphthyridinyl group, 4-1,8-naphthyridinyl group, 2-1,7-naphthyridinyl group, 3-1,7-naphthyridinyl group, 4- 1,7-naphthyridinyl group, 5-1,7-naphthyridinyl group, 6-1,7-naphthyridinyl group, 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, 3-1,6-naphthyridinyl group Group, 4-1,6-naphthyridinyl group, 5-1,6-naphthyridinyl group, 7-1,6-naphthyridinyl group, 8-1,6-naphthyridinyl group, 2-1,5-naphthyridinyl group, 3-1 , 5-naphthyridinyl group, 4-1,5-naphthyridinyl group, 6-1,5-naphthyridinyl group, 7-1,5-naphthyridinyl group, 8-1,5-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl Group, 6-ki Xalinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6- Examples include cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, and 7-pteridinyl group.

The C _3-5 heteroaryl group means an aromatic group composed of 3 to 5 carbon atoms and one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include furanyl group, thiophenyl group, pyrrolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group and pyrazinyl group.

The C _3-5 heteroaryl group fused ring sharing a benzene ring and two carbon atoms, a C _3-5 heteroaryl group described above, the C _3-5 heteroaryl group and the benzene ring 2 Two carbon atoms are condensed and shared, and the two carbon atoms are included in the number of 3 to 5 carbon atoms constituting the C _3-5 heteroaryl group. Specific examples thereof include, for example, a pyrazinyl group that is a partial structure of quinoxaline (consisting of 4 carbon atoms and 2 nitrogen atoms) or a pyridyl group that is a partial structure of quinoline (consisting of 5 carbon atoms and 1 nitrogen atom). Etc.).

The C _4-5 heteroaryl group means an aromatic group composed of 4 to 5 carbon atoms and one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include furanyl group, thiophenyl group, pyrrolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group and pyrazinyl group.

The C _4-5 heteroaryl group condensed with a benzene ring by sharing two carbon atoms is the above C _4-5 heteroaryl group, and the C _4-5 heteroaryl group is a benzene ring and 2 Two carbon atoms are condensed and shared, and the two carbon atoms are included in the number of 4 to 5 carbon atoms constituting the C _4-5 heteroaryl group. Specific examples thereof include, for example, a pyrazinyl group that is a partial structure of quinoxaline (consisting of 4 carbon atoms and 2 nitrogen atoms) or a pyridyl group that is a partial structure of quinoline (consisting of 5 carbon atoms and 1 nitrogen atom). Etc.).

The C _1-6 alkylcarbonyloxy group is an alkylcarbonyloxy group having 1 to 6 carbon atoms, and may contain a linear, branched or C _3-6 cycloalkylcarbonyloxy group. As methylcarbonyloxy group, ethylcarbonyloxy group, propylcarbonyloxy group, c-propylcarbonyloxy group, butylcarbonyloxy group, c-butylcarbonyloxy group, i-butylcarbonyloxy group, t-butylcarbonyloxy group, A pentylcarbonyloxy group, a c-pentylcarbonyloxy group, a hexylcarbonyloxy group, a c-hexylcarbonyloxy group and the like can be mentioned.

などの基が挙げられる。 The C _2-9 heterocyclyl group is a monocyclic or condensed bicyclic heterocyclic group composed of one or more atoms freely selected from a nitrogen atom, an oxygen atom and a sulfur atom and 2 to 9 carbon atoms. And the carbon atoms constituting the ring may be carbonyl or thiocarbonyl, specifically,

And the like.

The mono C _1-6 alkylamino group is an amino group having one C _1-6 alkyl group, which may include linear, branched, and C _3-6 cycloalkylamino groups. Is methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-methyl -c-propylamino, 2-methyl-c-propylamino, n-pentylamino, 1-methyl-n-butylamino, 2-methyl-n-butylamino, 3-methyl-n-butylamino, 1,1 -Dimethyl-n-propylamino, 1,2-dimethyl-n-propylamino, 2,2-dimethyl-n-propylamino, 1-ethyl-n-propylamino, c-pentylamino, 1-methyl-c- Butylamino, 2-methyl-c-butylamino, 3-methyl-c-butylamino, 1,2-dimethyl-c-propyl Pyramino, 2,3-dimethyl-c-propylamino, 1-ethyl-c-propylamino, 2-ethyl-c-propylamino, n-hexylamino, 1-methyl-n-pentylamino, 2-methyl-n -Pentylamino, 3-methyl-n-pentylamino, 4-methyl-n-pentylamino, 1,1-dimethyl-n-butylamino, 1,2-dimethyl-n-butylamino, 1,3-dimethyl- n-butylamino, 2,2-dimethyl-n-butylamino, 2,3-dimethyl-n-butylamino, 3,3-dimethyl-n-butylamino, 1-ethyl-n-butylamino, 2-ethyl -n-butylamino, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-propylamino, 1-ethyl-1-methyl-n-propylamino, 1-ethyl-2 -Methyl-n-propylamino, c-hexylamino, 1-methyl-c-pentylamino, 2-methyl-c-pentylamino, 3-methyl-c-pentylamino, 1-ethyl-c-butylamino, 2 - Til-c-butylamino, 3-ethyl-c-butylamino, 1,2-dimethyl-c-butylamino, 1,3-dimethyl-c-butylamino, 2,2-dimethyl-c-butylamino, 2 , 3-Dimethyl-c-butylamino, 2,4-dimethyl-c-butylamino, 3,3-dimethyl-c-butylamino, 1-n-propyl-c-propylamino, 2-n-propyl-c -Propylamino, 1-i-propyl-c-propylamino, 2-i-propyl-c-propylamino, 1,2,2-trimethyl-c-propylamino, 1,2,3-trimethyl-c-propyl Amino, 2,2,3-trimethyl-c-propylamino, 1-ethyl-2-methyl-c-propylamino, 2-ethyl-1-methyl-c-propylamino, 2-ethyl-2-methyl-c -Propylamino, 2-ethyl-3-methyl-c-propylamino and the like.

The di-C _1-6 alkylamino group means an amino group having two C _1-6 alkyl groups, and the two alkyl groups may be symmetric or asymmetric. Symmetric diC _1-6 alkylamino groups may include linear, branched and C _3-6 cycloalkylamino groups, specific examples being dimethylamino, diethylamino, di-n-propylamino, di- -i-propylamino, di-c-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, di-c-butylamino, di- (1-methyl-c-propyl) amino, di- (2-methyl-c-propyl) amino, di-n-pentylamino, di- (1-methyl-n-butyl) amino, di- (2-methyl -n-butyl) amino, di- (3-methyl-n-butyl) amino, di- (1,1-dimethyl-n-propyl) amino, di- (1,2-dimethyl-n-propyl) amino, Di- (2,2-dimethyl-n-propyl) amino, di- (1-ethyl-n-propyl) amino, di-c-pentylamino, di- (1-methyl-c-butyl) amino, di- (2-Methyl-c-butyl) amino, di- (3-Methyl-c-butyl) amino, di- (1,2-dimethyl-c-propyl) amino, di- (2,3-dimethyl-c-propyl) amino, di- (1-ethyl-c- Propyl) amino, di- (2-ethyl-c-propyl) amino, di-n-hexylamino, di- (1-methyl-n-pentyl) amino, di- (2-methyl-n-pentyl) amino, Di- (3-methyl-n-pentyl) amino, di- (4-methyl-n-pentyl) amino, di- (1,1-dimethyl-n-butyl) amino, di- (1,2-dimethyl- n-butyl) amino, di- (1,3-dimethyl-n-butyl) amino, di- (2,2-dimethyl-n-butyl) amino, di- (2,3-dimethyl-n-butyl) amino , Di- (3,3-dimethyl-n-butyl) amino, di- (1-ethyl-n-butyl) amino, di- (2-ethyl-n-butyl) amino, di- (1,1,2 -Trimethyl-n-propyl) amino, di- (1,2,2-trimethyl-n-propyl) amino, di- (1-ethyl-1-methyl-n-propyl) amino, di- (1-ethyl- 2-Methyl-n-propyl) a Di-c-hexylamino, di- (1-methyl-c-pentyl) amino, di- (2-methyl-c-pentyl) amino, di- (3-methyl-c-pentyl) amino, di- (1-ethyl-c-butyl) amino, di- (2-ethyl-c-butyl) amino, di- (3-ethyl-c-butyl) amino, di- (1,2-dimethyl-c-butyl) Amino, di- (1,3-dimethyl-c-butyl) amino, di- (2,2-dimethyl-c-butyl) amino, di- (2,3-dimethyl-c-butyl) amino, di- ( 2,4-Dimethyl-c-butyl) amino, di- (3,3-dimethyl-c-butyl) amino, di- (1-n-propyl-c-propyl) amino, di- (2-n-propyl) -c-propyl) amino, di- (1-i-propyl-c-propyl) amino, di- (2-i-propyl-c-propyl) amino, di- (1,2,2-trimethyl-c- Propyl) amino, di- (1,2,3-trimethyl-c-propyl) amino, di- (2,2,3-trimethyl-c-propyl) amino, di- (1-ethyl-2-methyl-c) -Propyl) amino, di- (2-ethyl-1 -Methyl-c-propyl) amino, di- (2-ethyl-2-methyl-c-propyl) amino, di- (2-ethyl-3-methyl-c-propyl) amino and the like.
The asymmetric di C _1-6 alkylamino group may include linear, branched and C _3-6 cycloalkylamino groups. Specific examples include (methyl, ethyl) amino, (methyl, n-propyl). ) Amino, (methyl, i-propyl) amino, (methyl, c-propyl) amino, (methyl, n-butyl) amino, (methyl, i-butyl) amino, (methyl, s-butyl) amino, (methyl , T-butyl) amino, (methyl, n-pentyl) amino, (methyl, c-pentyl) amino, (methyl, n-hexyl) amino, (methyl, c-hexyl) amino, (ethyl, n-propyl) Amino, (ethyl, i-propyl) amino, (ethyl, c-propyl) amino, (ethyl, n-butyl) amino, (ethyl, i-butyl) amino, (ethyl, s-butyl) amino, (ethyl, t-butyl) amino, (ethyl, n- Pentyl) amino, (ethyl, c-pentyl) amino, (ethyl, n-hexyl) amino, (ethyl, c-hexyl) amino, (n-propyl, i-propyl) amino, (n-propyl, c-propyl) ) Amino, (n-propyl, n-butyl) amino, (n-propyl, i-butyl) amino, (n-propyl, s-butyl) amino, (n-propyl, t-butyl) amino, (n- Propyl, n-pentyl) amino, (n-propyl, c-pentyl) amino, (n-propyl, n-hexyl) amino, (n-propyl, c-hexyl) amino, (i-propyl, c-propyl) Amino, (i-propyl, n-butyl) amino, (i-propyl, i-butyl) amino, (i-propyl, s-butyl) amino, (i-propyl, t-butyl) amino, (i-propyl) , N-pentyl) amino, (i-propyl, c-pentyl) amino, (i-propyl) Pill, n-hexyl) amino, (i-propyl, c-hexyl) amino, (c-propyl, n-butyl) amino, (c-propyl, i-butyl) amino, (c-propyl, s-butyl) Amino, (c-propyl, t-butyl) amino, (c-propyl, n-pentyl) amino, (c-propyl, c-pentyl) amino, (c-propyl, n-hexyl) amino, (c-propyl) , C-hexyl) amino, (n-butyl, i-butyl) amino, (n-butyl, s-butyl) amino, (n-butyl, t-butyl) amino, (n-butyl, n-pentyl) amino , (N-butyl, c-pentyl) amino, (n-butyl, n-hexyl) amino, (n-butyl, c-hexyl) amino, (i-butyl, s-butyl) amino, (i-butyl, t-butyl) amino, (i-butyl, n-pentyl) amino, (i-butyl, c-pentyl) amino, (i-butyl, n-hexyl) amino , (I-butyl, c-hexyl) amino, (s-butyl, t-butyl) amino, (s-butyl, n-pentyl) amino, (s-butyl, c-pentyl) amino, (s-butyl, n-hexyl) amino, (s-butyl, c-hexyl) amino, (t-butyl, n-pentyl) amino, (t-butyl, c-pentyl) amino, (t-butyl, n-hexyl) amino, (T-butyl, c-hexyl) amino, (n-pentyl, c-pentyl) amino, (n-pentyl, n-hexyl) amino, (n-pentyl, c-hexyl) amino, (c-pentyl, n -Hexyl) amino, (c-pentyl, c-hexyl) amino, (n-hexyl, c-hexyl) amino and the like.

The C _1-6 alkylthio group is a thio group having a C _1-6 alkyl group, and may include linear, branched, and C _3-6 cycloalkylthio groups. Specific examples include methylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, c-butylthio, 1-methyl-c-propylthio, 2-methyl-c-propylthio, n- Pentylthio, 1-methyl-n-butylthio, 2-methyl-n-butylthio, 3-methyl-n-butylthio, 1,1-dimethyl-n-propylthio, 1,2-dimethyl-n-propylthio, 2,2- Dimethyl-n-propylthio, 1-ethyl-n-propylthio, c-pentylthio, 1-methyl-c-butylthio, 2-methyl-c-butylthio, 3-methyl-c-butylthio, 1,2-dimethyl-c- Propylthio, 2,3-dimethyl-c-propylthio, 1-ethyl-c-propylthio, 2- Tyl-c-propylthio, n-hexylthio, 1-methyl-n-pentylthio, 2-methyl-n-pentylthio, 3-methyl-n-pentylthio, 4-methyl-n-pentylthio, 1,1-dimethyl-n- Butylthio, 1,2-dimethyl-n-butylthio, 1,3-dimethyl-n-butylthio, 2,2-dimethyl-n-butylthio, 2,3-dimethyl-n-butylthio, 3,3-dimethyl-n- Butylthio, 1-ethyl-n-butylthio, 2-ethyl-n-butylthio, 1,1,2-trimethyl-n-propylthio, 1,2,2-trimethyl-n-propylthio, 1-ethyl-1-methyl- n-propylthio, 1-ethyl-2-methyl-n-propylthio, c-hexylthio, 1-methyl-c-pentylthio, 2-methyl-c-pentylthio, 3-methyl-c-pentylthio, 1-ethyl-c- Butylthio, 2-ethyl-c-butylthio, 3-ethyl-c-butylthio, 1,2-dimethyl-c-butylthio, 1,3-dimethyl-c-butylthio, 2,2-dimethyl-c-butylthio, 2 , 3-Dimethyl-c-butylthio, 2,4-dimethyl-c-butylthio, 3,3-dimethyl-c-butylthio, 1-n-propyl-c-propylthio, 2-n-propyl-c-propylthio, 1 -i-propyl-c-propylthio, 2-i-propyl-c-propylthio, 1,2,2-trimethyl-c-propylthio, 1,2,3-trimethyl-c-propylthio, 2,2,3-trimethyl -c-propylthio, 1-ethyl-2-methyl-c-propylthio, 2-ethyl-1-methyl-c-propylthio, 2-ethyl-2-methyl-c-propylthio, 2-ethyl-3-methyl-c -Propylthio and the like.

The C _1-6 alkylsulfonyl group is a sulfonyl group having a C _1-6 alkyl group, and may include linear, branched, and C _3-6 cycloalkylsulfonyl groups. , Ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, c-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, c-butylsulfonyl, 1-methyl-c- Propylsulfonyl, 2-methyl-c-propylsulfonyl, n-pentylsulfonyl, 1-methyl-n-butylsulfonyl, 2-methyl-n-butylsulfonyl, 3-methyl-n-butylsulfonyl, 1,1-dimethyl- n-propylsulfonyl, 1,2-dimethyl-n-propylsulfonyl, 2,2-dimethyl-n-propylsulfonyl, 1-ethyl-n-propylsulfonyl, c-pentylsulfonyl 1-methyl-c-butylsulfonyl, 2-methyl-c-butylsulfonyl, 3-methyl-c-butylsulfonyl, 1,2-dimethyl-c-propylsulfonyl, 2,3-dimethyl-c-propylsulfonyl, 1 -Ethyl-c-propylsulfonyl, 2-ethyl-c-propylsulfonyl, n-hexylsulfonyl, 1-methyl-n-pentylsulfonyl, 2-methyl-n-pentylsulfonyl, 3-methyl-n-pentylsulfonyl, 4 -Methyl-n-pentylsulfonyl, 1,1-dimethyl-n-butylsulfonyl, 1,2-dimethyl-n-butylsulfonyl, 1,3-dimethyl-n-butylsulfonyl, 2,2-dimethyl-n-butyl Sulfonyl, 2,3-dimethyl-n-butylsulfonyl, 3,3-dimethyl-n-butylsulfonyl, 1-ethyl-n-butylsulfonyl, 2-ethyl-n-butylsulfonyl, 1,1,2-trimethyl- n-propylsulfonyl, 1,2,2-trimethyl-n-propylsulfonyl, 1-ethyl-1- Tyl-n-propylsulfonyl, 1-ethyl-2-methyl-n-propylsulfonyl, c-hexylsulfonyl, 1-methyl-c-pentylsulfonyl, 2-methyl-c-pentylsulfonyl, 3-methyl-c-pentyl Sulfonyl, 1-ethyl-c-butylsulfonyl, 2-ethyl-c-butylsulfonyl, 3-ethyl-c-butylsulfonyl, 1,2-dimethyl-c-butylsulfonyl, 1,3-dimethyl-c-butylsulfonyl 2,2-dimethyl-c-butylsulfonyl, 2,3-dimethyl-c-butylsulfonyl, 2,4-dimethyl-c-butylsulfonyl, 3,3-dimethyl-c-butylsulfonyl, 1-n-propyl -c-propylsulfonyl, 2-n-propyl-c-propylsulfonyl, 1-i-propyl-c-propylsulfonyl, 2-i-propyl-c-propylsulfonyl, 1,2,2-trimethyl-c-propyl Sulfonyl, 1,2,3-trimethyl-c-propylsulfonyl, 2,2,3-trimethyl-c-propyl Ruphonyl, 1-ethyl-2-methyl-c-propylsulfonyl, 2-ethyl-1-methyl-c-propylsulfonyl, 2-ethyl-2-methyl-c-propylsulfonyl and 2-ethyl-3-methyl-c -Propylsulfonyl and the like.

The mono C _1-6 alkylaminocarbonyl group is an aminocarbonyl group having one C _1-6 alkyl group, and may include linear, branched, and C _3-6 cycloalkylaminocarbonyl groups, Specific examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, c-propylaminocarbonyl, n-butylaminocarbonyl, i-butylaminocarbonyl, s-butylaminocarbonyl, t- Butylaminocarbonyl, c-butylaminocarbonyl, 1-methyl-c-propylaminocarbonyl, 2-methyl-c-propylaminocarbonyl, n-pentylaminocarbonyl, 1-methyl-n-butylaminocarbonyl, 2-methyl- n-Butylaminocarbonyl, 3-methyl-n-butylamino, 1,1-dimethyl-n-propylaminocarbo 1,2-dimethyl-n-propylaminocarbonyl, 2,2-dimethyl-n-propylaminocarbonyl, 1-ethyl-n-propylaminocarbonyl, c-pentylaminocarbonyl, 1-methyl-c-butylamino Carbonyl, 2-methyl-c-butylaminocarbonyl, 3-methyl-c-butylaminocarbonyl, 1,2-dimethyl-c-propylaminocarbonyl, 2,3-dimethyl-c-propylaminocarbonyl, 1-ethyl- c-propylaminocarbonyl, 2-ethyl-c-propylaminocarbonyl, n-hexylaminocarbonyl, 1-methyl-n-pentylaminocarbonyl, 2-methyl-n-pentylaminocarbonyl, 3-methyl-n-pentylamino Carbonyl, 4-methyl-n-pentylaminocarbonyl, 1,1-dimethyl-n-butylaminocarbonyl, 1,2-dimethyl-n-butylaminocarbonyl, 1,3-dimethyl-n-butylaminocarbo 2,2-dimethyl-n-butylaminocarbonyl, 2,3-dimethyl-n-butylaminocarbonyl, 3,3-dimethyl-n-butylaminocarbonyl, 1-ethyl-n-butylaminocarbonyl, 2- Ethyl-n-butylaminocarbonyl, 1,1,2-trimethyl-n-propylaminocarbonyl, 1,2,2-trimethyl-n-propylaminocarbonyl, 1-ethyl-1-methyl-n-propylaminocarbonyl, 1-ethyl-2-methyl-n-propylaminocarbonyl, c-hexylaminocarbonyl, 1-methyl-c-pentylaminocarbonyl, 2-methyl-c-pentylaminocarbonyl, 3-methyl-c-pentylaminocarbonyl, 1-ethyl-c-butylaminocarbonyl, 2-ethyl-c-butylaminocarbonyl, 3-ethyl-c-butylaminocarbonyl, 1,2-dimethyl-c-butylaminocarbonyl, 1,3-dimethyl-c- Butylaminocarbonyl, 2,2-dimethyl Ru-c-butylaminocarbonyl, 2,3-dimethyl-c-butylaminocarbonyl, 2,4-dimethyl-c-butylaminocarbonyl, 3,3-dimethyl-c-butylaminocarbonyl, 1-n-propyl- c-propylaminocarbonyl, 2-n-propyl-c-propylaminocarbonyl, 1-i-propyl-c-propylaminocarbonyl, 2-i-propyl-c-propylaminocarbonyl, 1,2,2-trimethyl- c-propylaminocarbonyl, 1,2,3-trimethyl-c-propylaminocarbonyl, 2,2,3-trimethyl-c-propylaminocarbonyl, 1-ethyl-2-methyl-c-propylaminocarbonyl, 2- Examples include ethyl-1-methyl-c-propylaminocarbonyl, 2-ethyl-2-methyl-c-propylaminocarbonyl, 2-ethyl-3-methyl-c-propylaminocarbonyl and the like.

The di-C _1-6 alkylaminocarbonyl group, an aminocarbonyl group having two C _1-6 alkyl groups, the two alkyl groups may be symmetric or asymmetric. Symmetrical diC _1-6 alkylamino groups may include straight chain, branched and C _3-6 cycloalkylaminocarbonyl groups, specific examples being dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propyl. Aminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl , Di-c-butylaminocarbonyl, di- (1-methyl-c-propyl) aminocarbonyl, di- (2-methyl-c-propyl) aminocarbonyl, di-n-pentylaminocarbonyl, di- (1- Methyl-n-butyl) aminocarbonyl, di- (2-methyl-n-butyl) aminocarbonyl, di- (3-methyl-n-butyl) aminocarbonyl, di- (1,1-dimethyl-n-propyl) Aminocal Bonyl, di- (1,2-dimethyl-n-propyl) aminocarbonyl, di- (2,2-dimethyl-n-propyl) aminocarbonyl, di- (1-ethyl-n-propyl) aminocarbonyl, di- c-pentylaminocarbonyl, di- (1-methyl-c-butyl) aminocarbonyl, di- (2-methyl-c-butyl) aminocarbonyl, di- (3-methyl-c-butyl) aminocarbonyl, di- (1,2-dimethyl-c-propyl) aminocarbonyl, di- (2,3-dimethyl-c-propyl) aminocarbonyl, di- (1-ethyl-c-propyl) aminocarbonyl, di- (2-ethyl -c-propyl) aminocarbonyl, di-n-hexylaminocarbonyl, di- (1-methyl-n-pentyl) aminocarbonyl, di- (2-methyl-n-pentyl) aminocarbonyl, di- (3-methyl -n-pentyl) aminocarbonyl, di- (4-methyl-n-pentyl) aminocarbonyl, di- (1,1-dimethyl-n-butyl) aminocarbonyl, Di- (1,2-dimethyl-n-butyl) aminocarbonyl, di- (1,3-dimethyl-n-butyl) aminocarbonyl, di- (2,2-dimethyl-n-butyl) aminocarbonyl, di- (2,3-dimethyl-n-butyl) aminocarbonyl, di- (3,3-dimethyl-n-butyl) aminocarbonyl, di- (1-ethyl-n-butyl) aminocarbonyl, di- (2-ethyl) -n-butyl) aminocarbonyl, di- (1,1,2-trimethyl-n-propyl) aminocarbonyl, di- (1,2,2-trimethyl-n-propyl) aminocarbonyl, di- (1-ethyl) -1-methyl-n-propyl) aminocarbonyl, di- (1-ethyl-2-methyl-n-propyl) aminocarbonylcarbonyl, di-c-hexylaminocarbonyl, di- (1-methyl-c-pentyl) Aminocarbonyl, di- (2-methyl-c-pentyl) aminocarbonyl, di- (3-methyl-c-pentyl) aminocarbonyl, di- (1-ethyl-c-butyl) aminocarbonyl, di- (2- D Til-c-butyl) aminocarbonyl, di- (3-ethyl-c-butyl) aminocarbonyl, di- (1,2-dimethyl-c-butyl) aminocarbonyl, di- (1,3-dimethyl-c- Butyl) aminocarbonyl, di- (2,2-dimethyl-c-butyl) aminocarbonyl, di- (2,3-dimethyl-c-butyl) aminocarbonyl, di- (2,4-dimethyl-c-butyl) Aminocarbonyl, di- (3,3-dimethyl-c-butyl) aminocarbonyl, di- (1-n-propyl-c-propyl) aminocarbonyl, di- (2-n-propyl-c-propyl) aminocarbonyl , Di- (1-i-propyl-c-propyl) aminocarbonyl, di- (2-i-propyl-c-propyl) aminocarbonyl, di- (1,2,2-trimethyl-c-propyl) aminocarbonyl , Di- (1,2,3-trimethyl-c-propyl) aminocarbonyl, di- (2,2,3-trimethyl-c-propyl) aminocarbonyl, di- (1-ethyl-2-methyl-c- Propyl) aminocarbonyl Di- (2-ethyl-1-methyl-c-propyl) aminocarbonyl, di- (2-ethyl-2-methyl-c-propyl) aminocarbonyl, di- (2-ethyl-3-methyl-c-propyl) ) Aminocarbonyl and the like.
The asymmetric di C _1-6 alkylaminocarbonyl group may include linear, branched and C _3-6 cycloalkylaminocarbonyl groups. Specific examples include (methyl, ethyl) aminocarbonyl, (methyl, n-propyl) aminocarbonyl, (methyl, i-propyl) aminocarbonyl, (methyl, c-propyl) aminocarbonyl, (methyl, n-butyl) aminocarbonyl, (methyl, i-butyl) aminocarbonyl, (methyl, s-butyl) aminocarbonyl, (methyl, t-butyl) aminocarbonyl, (methyl, n-pentyl) aminocarbonyl, (methyl, c-pentyl) aminocarbonyl, (methyl, n-hexyl) aminocarbonyl, (methyl, c-hexyl) aminocarbonyl, (ethyl, n-propyl) aminocarbonyl, (ethyl, i-propyl) aminocarbonyl Rubonyl, (ethyl, c-propyl) aminocarbonyl, (ethyl, n-butyl) aminocarbonyl, (ethyl, i-butyl) aminocarbonyl, (ethyl, s-butyl) aminocarbonyl, (ethyl, t-butyl) amino Carbonyl, (ethyl, n-pentyl) aminocarbonyl, (ethyl, c-pentyl) aminocarbonyl, (ethyl, n-hexyl) aminocarbonyl, (ethyl, c-hexyl) aminocarbonyl, (n-propyl, i-propyl) ) Aminocarbonyl, (n-propyl, c-propyl) aminocarbonyl, (n-propyl, n-butyl) aminocarbonyl, (n-propyl, i-butyl) aminocarbonyl, (n-propyl, s-butyl) amino Carbonyl, (n-propyl, t-butyl) aminocarbonyl, (n-propyl, n-pentyl) aminocarbonyl, (n-pro , C-pentyl) aminocarbonyl, (n-propyl, n-hexyl) aminocarbonyl, (n-propyl, c-hexyl) aminocarbonyl, (i-propyl, c-propyl) aminocarbonyl, (i-propyl, n-butyl) aminocarbonyl, (i-propyl, i-butyl) aminocarbonyl, (i-propyl, s-butyl) aminocarbonyl, (i-propyl, t-butyl) aminocarbonyl, (i-propyl, n- Pentyl) aminocarbonyl, (i-propyl, c-pentyl) aminocarbonyl, (i-propyl, n-hexyl) aminocarbonyl, (i-propyl, c-hexyl) aminocarbonyl, (c-propyl, n-butyl) Aminocarbonyl, (c-propyl, i-butyl) aminocarbonyl, (c-propyl, s-butyl) aminocarbonyl, (c-propyl, t-butyl) aminocarbonyl, (c-propyl) Propyl, n-pentyl) aminocarbonyl, (c-propyl, c-pentyl) aminocarbonyl, (c-propyl, n-hexyl) aminocarbonyl, (c-propyl, c-hexyl) aminocarbonyl, (n-butyl, i-butyl) aminocarbonyl, (n-butyl, s-butyl) aminocarbonyl, (n-butyl, t-butyl) aminocarbonyl, (n-butyl, n-pentyl) aminocarbonyl, (n-butyl, c- Pentyl) aminocarbonyl, (n-butyl, n-hexyl) aminocarbonyl, (n-butyl, c-hexyl) aminocarbonyl, (i-butyl, s-butyl) aminocarbonyl, (i-butyl, t-butyl) Aminocarbonyl, (i-butyl, n-pentyl) aminocarbonyl, (i-butyl, c-pentyl) aminocarbonyl, (i-butyl, n-hexyl) aminocarbonyl, (i-butyl, c-hexyl) Minocarbonyl, (s-butyl, t-butyl) aminocarbonyl, (s-butyl, n-pentyl) aminocarbonyl, (s-butyl, c-pentyl) aminocarbonyl, (s-butyl, n-hexyl) aminocarbonyl , (S-butyl, c-hexyl) aminocarbonyl, (t-butyl, n-pentyl) aminocarbonyl, (t-butyl, c-pentyl) aminocarbonyl, (t-butyl, n-hexyl) aminocarbonyl, ( t-butyl, c-hexyl) aminocarbonyl, (n-pentyl, c-pentyl) aminocarbonyl, (n-pentyl, n-hexyl) aminocarbonyl, (n-pentyl, c-hexyl) aminocarbonyl, (c- Examples include pentyl, n-hexyl) aminocarbonyl, (c-pentyl, c-hexyl) aminocarbonyl, (n-hexyl, c-hexyl) aminocarbonyl and the like.

The C _1-6 alkylcarbonylamino group is a carbonylamino group having one C _1-6 alkylcarbonyl group, which may include linear, branched and C _3-6 cycloalkylcarbonyl groups. Examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, c-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butyl Carbonylamino, c-butylcarbonylamino, 1-methyl-c-propylcarbonylamino, 2-methyl-c-propylcarbonylamino, n-pentylcarbonylamino, 1-methyl-n-butylcarbonylamino, 2-methyl-n -Butylcarbonylamino, 3-methyl-n-butylcarbonylamino, 1,1-dimethyl-n-propyl carbonate Bonylamino, 1,2-dimethyl-n-propylcarbonylamino, 2,2-dimethyl-n-propylcarbonylamino, 1-ethyl-n-propylcarbonylamino, c-pentylcarbonylamino, 1-methyl-c-butylcarbonyl Amino, 2-methyl-c-butylcarbonylamino, 3-methyl-c-butylcarbonylamino, 1,2-dimethyl-c-propylcarbonylamino, 2,3-dimethyl-c-propylcarbonylamino, 1-ethyl- c-propylcarbonylamino, 2-ethyl-c-propylcarbonylamino, n-hexylcarbonylamino, 1-methyl-n-pentylcarbonylamino, 2-methyl-n-pentylcarbonylamino, 3-methyl-n-pentylcarbonyl Amino, 4-methyl-n-pentylcarbonylamino, 1,1-dimethyl-n-butylcarbonylamino, 1,2-dimethyl-n-butylcarbonylamino, 1,3-dimethyl-n-butyl carbonate Bonylamino, 2,2-dimethyl-n-butylcarbonylamino, 2,3-dimethyl-n-butylcarbonylamino, 3,3-dimethyl-n-butylcarbonylamino, 1-ethyl-n-butylcarbonylamino, 2- Ethyl-n-butylcarbonylamino, 1,1,2-trimethyl-n-propylcarbonylamino, 1,2,2-trimethyl-n-propylcarbonylamino, 1-ethyl-1-methyl-n-propylcarbonylamino, 1-ethyl-2-methyl-n-propylcarbonylamino, c-hexylcarbonylamino, 1-methyl-c-pentylcarbonylamino, 2-methyl-c-pentylcarbonylamino, 3-methyl-c-pentylcarbonylamino, 1-ethyl-c-butylcarbonylamino, 2-ethyl-c-butylcarbonylamino, 3-ethyl-c-butylcarbonylamino, 1,2-dimethyl-c-butylcarbonylamino, 1,3-dimethyl-c- Butylcarbonyl amino 2,2-dimethyl-c-butylcarbonylamino, 2,3-dimethyl-c-butylcarbonylamino, 2,4-dimethyl-c-butylcarbonylamino, 3,3-dimethyl-c-butylcarbonylamino, 1 -n-propyl-c-propylcarbonylamino, 2-n-propyl-c-propylcarbonylamino, 1-i-propyl-c-propylcarbonylamino, 2-i-propyl-c-propylcarbonylamino, 1,2 , 2-Trimethyl-c-propylcarbonylamino, 1,2,3-trimethyl-c-propylcarbonylamino, 2,2,3-trimethyl-c-propylcarbonylamino, 1-ethyl-2-methyl-c-propyl Examples include carbonylamino, 2-ethyl-1-methyl-c-propylcarbonylamino, 2-ethyl-2-methyl-c-propylcarbonylamino, 2-ethyl-3-methyl-c-propylcarbonylamino and the like.

Preferable specific examples of the substituents R ¹ and R ² each independently include a C _1-6 alkyl group.

A particularly preferred specific example of the substituents R ¹ and R ² is a methyl group.

Preferable specific examples of the substituent R ³ include a hydroxyl group or a C _1-6 alkylcarbonyloxy group.

Particularly preferred specific examples of the substituent R ³ include a hydroxyl group, a methylcarbonyloxy group, and a t-butylcarbonyloxy group.

More particularly preferred specific examples of the substituent R ³ include a hydroxyl group.

A particularly preferred specific example of the substituent R ⁴ includes a hydrogen atom.

Preferable specific examples of the substituent R ⁵ include a hydrogen atom or a C _1-6 alkyl group.

A particularly preferred specific example of the substituent R ⁵ includes a hydrogen atom.

Preferable specific examples of the substituent X include a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or one or more substituents selected from the substituent group V ¹ alone or differently). Substituted).

Particularly preferred specific examples of the substituent X include a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one hydroxyl group or a methyl group).

  More particularly preferred specific examples of the substituent X include an ethylene group.

Preferable specific examples of the substituent R ⁶ include a C _1-6 alkyl group, a C _3-8 cycloalkyl group, or a C _6-14 aryl group (the C _1-6 alkyl group, a C _3-8 cycloalkyl group, and C _{The 6-14} aryl group is unsubstituted or substituted with a halogen atom).

Particularly preferred specific examples of the substituent R ⁶ include a phenyl group (the phenyl group is unsubstituted or substituted with a halogen atom) or a cyclohexyl group.

More particularly preferred specific examples of the substituent R ⁶ include a phenyl group.

Preferable specific examples of V include a halogen atom, a cyano group, a nitro group, a carbamoyl group, a sulfamoyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group and C _1-6 alkoxy). The group is unsubstituted or substituted with a halogen atom) or a hydroxyl group.

  Specific preferred examples of V include a halogen atom, a methoxy group, and a hydroxyl group.

  A preferred specific example of m is 0 or 1.

  A particularly preferred specific example of m is 0.

Preferable specific examples of the substituent A include a C _3-5 heteroaryl group condensed with a benzene ring sharing two carbon atoms (the C _3-5 heteroaryl group is unsubstituted or has one or more A halogen atom, an amino group or a C _1-6 alkyl group (the alkyl group is unsubstituted or substituted by one or more hydroxyl groups, halogen atoms or amino groups). Is mentioned.

As a particularly preferred specific example of the substituent A, a C _4-5 heteroaryl group condensed with a benzene ring sharing two carbon atoms (the C _4-5 heteroaryl group is unsubstituted or has one It is substituted with the above halogen atom, amino group or C _1-6 alkyl group (the alkyl group is unsubstituted or substituted with one or more hydroxyl group, halogen atom or amino group). ).

More particularly preferred examples of the substituent A include pyridine, pyrazine or pyridazine which are condensed with a benzene ring sharing two carbon atoms (the pyridine, pyrazine and pyridazine are unsubstituted or have one or more halogen atoms). An atom, an amino group, or a C _1-6 alkyl group (the alkyl group is unsubstituted or substituted with one or more hydroxyl groups, halogen atoms, or amino groups). .
Examples of the compounds useful for the treatment and / or prevention of IKCh inhibitors and arrhythmias according to the present invention include the following.

1)
R ¹ and R ² are each independently a C _1-6 alkyl group, R ³ is a hydroxyl group or a C _1-6 alkylcarbonyloxy group, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom or C _1-6 alkyl group, and X is a C _2-4 alkylene group (the C _2-4 alkylene group is an unsubstituted group or one or more substituents selected independently or differently from substituent group V ¹⁾ And R ⁶ is a C _1-6 alkyl group, a C _3-8 cycloalkyl group, or a C _6-14 aryl group (the C _1-6 alkyl group, C _3-8 cycloalkyl group and C _6-14 aryl group is unsubstituted or substituted with a halogen atom.), And V is a halogen atom, cyano group, nitro group, carbamoyl group, sulfamoyl group, C _1-6 alkyl group, C _1-6 alkoxy Group (wherein the C _1-6 alkyl group and a C _1-6 alkoxy group is substituted with or halogen atom is unsubstituted.) Or a hydroxyl group, m is 0 or 1, A is a benzene ring C _3-5 heteroaryl fused together by sharing two carbon atoms (the C _3-5 heteroaryl group is unsubstituted or has one or more halogen atoms, amino groups or C _1-6 alkyl groups ( The alkyl group is unsubstituted or substituted with one or more hydroxyl groups, halogen atoms or amino groups.)) The compound represented by the formula (1): Tautomers, prodrugs or pharmaceutically acceptable salts thereof, or solvates thereof.

2)
A compound represented by the above 1), wherein R ⁵ is a hydrogen atom, a word variant of the compound, a prodrug or a pharmaceutically acceptable salt thereof, or a solvate thereof.

3)
R ¹ and R ² are methyl groups, and R ³ is a hydroxyl group, the compound represented by the above 1 or 2), a tautomer, prodrug or pharmaceutically acceptable salt of the compound Solvate.

4)
A compound represented by the above 1 to 3), wherein X is a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one hydroxyl group or methyl group), A tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

5)
The compound represented by the above 4), wherein X is an ethylene group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

6)
R ⁶ is a phenyl group (the phenyl group is unsubstituted or substituted with a halogen atom) or a cyclohexyl group described in 1 to 5) above, a tautomer, pro A drug or a pharmaceutically acceptable salt thereof or a solvate thereof.

7)
The compound represented by 6) above wherein R ⁶ is a phenyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

8)
C _4-5 heteroaryl in which A is fused with a benzene ring by sharing two carbon atoms (the C _4-5 heteroaryl group is unsubstituted or has one or more halogen atoms, amino groups or C ₁ 1) to 7) above, which is a _-6 alkyl group (the alkyl group is unsubstituted or substituted with one or more hydroxyl groups, halogen atoms or amino groups). The represented compound, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

9)
A pyridine, pyrazine or pyridazine in which A is fused with a benzene ring by sharing two carbon atoms (the pyridine, pyrazine and pyridazine are unsubstituted or one or more halogen atoms, amino groups or C _1-6 alkyls) A compound represented by 8) above, wherein the alkyl group is unsubstituted or substituted with one or more hydroxyl groups, halogen atoms or amino groups), A tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

10)
The compound represented by 9) above, wherein A is a pyrazine fused with a benzene ring by sharing two carbon atoms, a tautomer, prodrug or pharmaceutically acceptable salt of the compound, or their Solvate.

11)
The compound represented by the above 1) to 10), wherein V is a halogen atom or a C _1-3 alkoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

12)
The compound represented by the above 1) to 11), wherein m is 0, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

式（ＩＩＩ）

13)
Compounds in which R ¹ and R ² are methyl groups, R ³ is a hydroxyl group, R ⁴ is a hydrogen atom, and Q and T are the combinations shown in Table 1 below, tautomerism of the compounds Body, a prodrug or a pharmaceutically acceptable salt thereof, or a solvate thereof.
In addition, the symbol in Table 1 shows the following substituents, Q means Formula (II), and T means Formula (III).
Formula (II)

Formula (III)

Table 1
Q T Q T Q T Q T
------- ------- ---------------
Q1 T1 Q1 T2 Q1 T3 Q1 T4
Q1 T5 Q1 T6 Q1 T7 Q1 T8
Q1 T9 Q1 T10 Q1 T11 Q1 T12
Q1 T13 Q1 T14 Q1 T15 Q1 T16
Q1 T17 Q1 T18 Q1 T19 Q1 T20
Q1 T21 Q1 T22 Q1 T23 Q1 T24
Q1 T25 Q1 T26 Q1 T27 Q1 T28
Q1 T29 Q1 T30 Q1 T31 Q1 T32
Q1 T33 Q1 T34 Q1 T35 Q1 T36
Q1 T37 Q1 T38 Q1 T39 Q1 T40
Q1 T41 Q1 T42 Q1 T43 Q1 T44
Q1 T45 Q1 T46 Q1 T47 Q1 T48
Q1 T49 Q1 T50 Q1 T51 Q1 T52
Q1 T53
Q2 T1 Q2 T2 Q2 T3 Q2 T4
Q2 T5 Q2 T6 Q2 T7 Q2 T8
Q2 T9 Q2 T10 Q2 T11 Q2 T12
Q2 T13 Q2 T14 Q2 T15 Q2 T16
Q2 T17 Q2 T18 Q2 T19 Q2 T20
Q2 T21 Q2 T22 Q2 T23 Q2 T24
Q2 T25 Q2 T26 Q2 T27 Q2 T28
Q2 T29 Q2 T30 Q2 T31 Q2 T32
Q2 T33 Q2 T34 Q2 T35 Q2 T36
Q2 T37 Q2 T38 Q2 T39 Q2 T40
Q2 T41 Q2 T42 Q2 T43 Q2 T44
Q2 T45 Q2 T46 Q2 T47 Q2 T48
Q2 T49 Q2 T50 Q2 T51 Q2 T52
Q2 T53
Q3 T1 Q3 T2 Q3 T3 Q3 T4
Q3 T5 Q3 T6 Q3 T7 Q3 T8
Q3 T9 Q3 T10 Q3 T11 Q3 T12
Q3 T13 Q3 T14 Q3 T15 Q3 T16
Q3 T17 Q3 T18 Q3 T19 Q3 T20
Q3 T21 Q3 T22 Q3 T23 Q3 T24
Q3 T25 Q3 T26 Q3 T27 Q3 T28
Q3 T29 Q3 T30 Q3 T31 Q3 T32
Q3 T33 Q3 T34 Q3 T35 Q3 T36
Q3 T37 Q3 T38 Q3 T39 Q3 T40
Q3 T41 Q3 T42 Q3 T43 Q3 T44
Q3 T45 Q3 T46 Q3 T47 Q3 T48
Q3 T49 Q3 T50 Q3 T51 Q3 T52
Q3 T53
Q4 T1 Q4 T2 Q4 T3 Q4 T4
Q4 T5 Q4 T6 Q4 T7 Q4 T8
Q4 T9 Q4 T10 Q4 T11 Q4 T12
Q4 T13 Q4 T14 Q4 T15 Q4 T16
Q4 T17 Q4 T18 Q4 T19 Q4 T20
Q4 T21 Q4 T22 Q4 T23 Q4 T24
Q4 T25 Q4 T26 Q4 T27 Q4 T28
Q4 T29 Q4 T30 Q4 T31 Q4 T32
Q4 T33 Q4 T34 Q4 T35 Q4 T36
Q4 T37 Q4 T38 Q4 T39 Q4 T40
Q4 T41 Q4 T42 Q4 T43 Q4 T44
Q4 T45 Q4 T46 Q4 T47 Q4 T48
Q4 T49 Q4 T50 Q4 T51 Q4 T52
Q4 T53
Q5 T1 Q5 T2 Q5 T3 Q5 T4
Q5 T5 Q5 T6 Q5 T7 Q5 T8
Q5 T9 Q5 T10 Q5 T11 Q5 T12
Q5 T13 Q5 T14 Q5 T15 Q5 T16
Q5 T17 Q5 T18 Q5 T19 Q5 T20
Q5 T21 Q5 T22 Q5 T23 Q5 T24
Q5 T25 Q5 T26 Q5 T27 Q5 T28
Q5 T29 Q5 T30 Q5 T31 Q5 T32
Q5 T33 Q5 T34 Q5 T35 Q5 T36
Q5 T37 Q5 T38 Q5 T39 Q5 T40
Q5 T41 Q5 T42 Q5 T43 Q5 T44
Q5 T45 Q5 T46 Q5 T47 Q5 T48
Q5 T49 Q5 T50 Q5 T51 Q5 T52
Q5 T53
Q6 T1 Q6 T2 Q6 T3 Q6 T4
Q6 T5 Q6 T6 Q6 T7 Q6 T8
Q6 T9 Q6 T10 Q6 T11 Q6 T12
Q6 T13 Q6 T14 Q6 T15 Q6 T16
Q6 T17 Q6 T18 Q6 T19 Q6 T20
Q6 T21 Q6 T22 Q6 T23 Q6 T24
Q6 T25 Q6 T26 Q6 T27 Q6 T28
Q6 T29 Q6 T30 Q6 T31 Q6 T32
Q6 T33 Q6 T34 Q6 T35 Q6 T36
Q6 T37 Q6 T38 Q6 T39 Q6 T40
Q6 T41 Q6 T42 Q6 T43 Q6 T44
Q6 T45 Q6 T46 Q6 T47 Q6 T48
Q6 T49 Q6 T50 Q6 T51 Q6 T52
Q6 T53
Q7 T1 Q7 T2 Q7 T3 Q7 T4
Q7 T5 Q7 T6 Q7 T7 Q7 T8
Q7 T9 Q7 T10 Q7 T11 Q7 T12
Q7 T13 Q7 T14 Q7 T15 Q7 T16
Q7 T17 Q7 T18 Q7 T19 Q7 T20
Q7 T21 Q7 T22 Q7 T23 Q7 T24
Q7 T25 Q7 T26 Q7 T27 Q7 T28
Q7 T29 Q7 T30 Q7 T31 Q7 T32
Q7 T33 Q7 T34 Q7 T35 Q7 T36
Q7 T37 Q7 T38 Q7 T39 Q7 T40
Q7 T41 Q7 T42 Q7 T43 Q7 T44
Q7 T45 Q7 T46 Q7 T47 Q7 T48
Q7 T49 Q7 T50 Q7 T51 Q7 T52
Q7 T53
Q8 T1 Q8 T2 Q8 T3 Q8 T4
Q8 T5 Q8 T6 Q8 T7 Q8 T8
Q8 T9 Q8 T10 Q8 T11 Q8 T12
Q8 T13 Q8 T14 Q8 T15 Q8 T16
Q8 T17 Q8 T18 Q8 T19 Q8 T20
Q8 T21 Q8 T22 Q8 T23 Q8 T24
Q8 T25 Q8 T26 Q8 T27 Q8 T28
Q8 T29 Q8 T30 Q8 T31 Q8 T32
Q8 T33 Q8 T34 Q8 T35 Q8 T36
Q8 T37 Q8 T38 Q8 T39 Q8 T40
Q8 T41 Q8 T42 Q8 T43 Q8 T44
Q8 T45 Q8 T46 Q8 T47 Q8 T48
Q8 T49 Q8 T50 Q8 T51 Q8 T52
Q8 T53
Q9 T1 Q9 T2 Q9 T3 Q9 T4
Q9 T5 Q9 T6 Q9 T7 Q9 T8
Q9 T9 Q9 T10 Q9 T11 Q9 T12
Q9 T13 Q9 T14 Q9 T15 Q9 T16
Q9 T17 Q9 T18 Q9 T19 Q9 T20
Q9 T21 Q9 T22 Q9 T23 Q9 T24
Q9 T25 Q9 T26 Q9 T27 Q9 T28
Q9 T29 Q9 T30 Q9 T31 Q9 T32
Q9 T33 Q9 T34 Q9 T35 Q9 T36
Q9 T37 Q9 T38 Q9 T39 Q9 T40
Q9 T41 Q9 T42 Q9 T43 Q9 T44
Q9 T45 Q9 T46 Q9 T47 Q9 T48
Q9 T49 Q9 T50 Q9 T51 Q9 T52
Q9 T53
Q10 T1 Q10 T2 Q10 T3 Q10 T4
Q10 T5 Q10 T6 Q10 T7 Q10 T8
Q10 T9 Q10 T10 Q10 T11 Q10 T12
Q10 T13 Q10 T14 Q10 T15 Q10 T16
Q10 T17 Q10 T18 Q10 T19 Q10 T20
Q10 T21 Q10 T22 Q10 T23 Q10 T24
Q10 T25 Q10 T26 Q10 T27 Q10 T28
Q10 T29 Q10 T30 Q10 T31 Q10 T32
Q10 T33 Q10 T34 Q10 T35 Q10 T36
Q10 T37 Q10 T38 Q10 T39 Q10 T40
Q10 T41 Q10 T42 Q10 T43 Q10 T44
Q10 T45 Q10 T46 Q10 T47 Q10 T48
Q10 T49 Q10 T50 Q10 T51 Q10 T52
Q10 T53
Q11 T1 Q11 T2 Q11 T3 Q11 T4
Q11 T5 Q11 T6 Q11 T7 Q11 T8
Q11 T9 Q11 T10 Q11 T11 Q11 T12
Q11 T13 Q11 T14 Q11 T15 Q11 T16
Q11 T17 Q11 T18 Q11 T19 Q11 T20
Q11 T21 Q11 T22 Q11 T23 Q11 T24
Q11 T25 Q11 T26 Q11 T27 Q11 T28
Q11 T29 Q11 T30 Q11 T31 Q11 T32
Q11 T33 Q11 T34 Q11 T35 Q11 T36
Q11 T37 Q11 T38 Q11 T39 Q11 T40
Q11 T41 Q11 T42 Q11 T43 Q11 T44
Q11 T45 Q11 T46 Q11 T47 Q11 T48
Q11 T49 Q11 T50 Q11 T51 Q11 T52
Q11 T53
Q12 T1 Q12 T2 Q12 T3 Q12 T4
Q12 T5 Q12 T6 Q12 T7 Q12 T8
Q12 T9 Q12 T10 Q12 T11 Q12 T12
Q12 T13 Q12 T14 Q12 T15 Q12 T16
Q12 T17 Q12 T18 Q12 T19 Q12 T20
Q12 T21 Q12 T22 Q12 T23 Q12 T24
Q12 T25 Q12 T26 Q12 T27 Q12 T28
Q12 T29 Q12 T30 Q12 T31 Q12 T32
Q12 T33 Q12 T34 Q12 T35 Q12 T36
Q12 T37 Q12 T38 Q12 T39 Q12 T40
Q12 T41 Q12 T42 Q12 T43 Q12 T44
Q12 T45 Q12 T46 Q12 T47 Q12 T48
Q12 T49 Q12 T50 Q12 T51 Q12 T52
Q12 T53
Q13 T1 Q13 T2 Q13 T3 Q13 T4
Q13 T5 Q13 T6 Q13 T7 Q13 T8
Q13 T9 Q13 T10 Q13 T11 Q13 T12
Q13 T13 Q13 T14 Q13 T15 Q13 T16
Q13 T17 Q13 T18 Q13 T19 Q13 T20
Q13 T21 Q13 T22 Q13 T23 Q13 T24
Q13 T25 Q13 T26 Q13 T27 Q13 T28
Q13 T29 Q13 T30 Q13 T31 Q13 T32
Q13 T33 Q13 T34 Q13 T35 Q13 T36
Q13 T37 Q13 T38 Q13 T39 Q13 T40
Q13 T41 Q13 T42 Q13 T43 Q13 T44
Q13 T45 Q13 T46 Q13 T47 Q13 T48
Q13 T49 Q13 T50 Q13 T51 Q13 T52
Q13 T53
Q14 T1 Q14 T2 Q14 T3 Q14 T4
Q14 T5 Q14 T6 Q14 T7 Q14 T8
Q14 T9 Q14 T10 Q14 T11 Q14 T12
Q14 T13 Q14 T14 Q14 T15 Q14 T16
Q14 T17 Q14 T18 Q14 T19 Q14 T20
Q14 T21 Q14 T22 Q14 T23 Q14 T24
Q14 T25 Q14 T26 Q14 T27 Q14 T28
Q14 T29 Q14 T30 Q14 T31 Q14 T32
Q14 T33 Q14 T34 Q14 T35 Q14 T36
Q14 T37 Q14 T38 Q14 T39 Q14 T40
Q14 T41 Q14 T42 Q14 T43 Q14 T44
Q14 T45 Q14 T46 Q14 T47 Q14 T48
Q14 T49 Q14 T50 Q14 T51 Q14 T52
Q14 T53
Q15 T1 Q15 T2 Q15 T3 Q15 T4
Q15 T5 Q15 T6 Q15 T7 Q15 T8
Q15 T9 Q15 T10 Q15 T11 Q15 T12
Q15 T13 Q15 T14 Q15 T15 Q15 T16
Q15 T17 Q15 T18 Q15 T19 Q15 T20
Q15 T21 Q15 T22 Q15 T23 Q15 T24
Q15 T25 Q15 T26 Q15 T27 Q15 T28
Q15 T29 Q15 T30 Q15 T31 Q15 T32
Q15 T33 Q15 T34 Q15 T35 Q15 T36
Q15 T37 Q15 T38 Q15 T39 Q15 T40
Q15 T41 Q15 T42 Q15 T43 Q15 T44
Q15 T45 Q15 T46 Q15 T47 Q15 T48
Q15 T49 Q15 T50 Q15 T51 Q15 T52
Q15 T53
Q16 T1 Q16 T2 Q16 T3 Q16 T4
Q16 T5 Q16 T6 Q16 T7 Q16 T8
Q16 T9 Q16 T10 Q16 T11 Q16 T12
Q16 T13 Q16 T14 Q16 T15 Q16 T16
Q16 T17 Q16 T18 Q16 T19 Q16 T20
Q16 T21 Q16 T22 Q16 T23 Q16 T24
Q16 T25 Q16 T26 Q16 T27 Q16 T28
Q16 T29 Q16 T30 Q16 T31 Q16 T32
Q16 T33 Q16 T34 Q16 T35 Q16 T36
Q16 T37 Q16 T38 Q16 T39 Q16 T40
Q16 T41 Q16 T42 Q16 T43 Q16 T44
Q16 T45 Q16 T46 Q16 T47 Q16 T48
Q16 T49 Q16 T50 Q16 T51 Q16 T52
Q16 T53
Q17 T1 Q17 T2 Q17 T3 Q17 T4
Q17 T5 Q17 T6 Q17 T7 Q17 T8
Q17 T9 Q17 T10 Q17 T11 Q17 T12
Q17 T13 Q17 T14 Q17 T15 Q17 T16
Q17 T17 Q17 T18 Q17 T19 Q17 T20
Q17 T21 Q17 T22 Q17 T23 Q17 T24
Q17 T25 Q17 T26 Q17 T27 Q17 T28
Q17 T29 Q17 T30 Q17 T31 Q17 T32
Q17 T33 Q17 T34 Q17 T35 Q17 T36
Q17 T37 Q17 T38 Q17 T39 Q17 T40
Q17 T41 Q17 T42 Q17 T43 Q17 T44
Q17 T45 Q17 T46 Q17 T47 Q17 T48
Q17 T49 Q17 T50 Q17 T51 Q17 T52
Q17 T53
Q18 T1 Q18 T2 Q18 T3 Q18 T4
Q18 T5 Q18 T6 Q18 T7 Q18 T8
Q18 T9 Q18 T10 Q18 T11 Q18 T12
Q18 T13 Q18 T14 Q18 T15 Q18 T16
Q18 T17 Q18 T18 Q18 T19 Q18 T20
Q18 T21 Q18 T22 Q18 T23 Q18 T24
Q18 T25 Q18 T26 Q18 T27 Q18 T28
Q18 T29 Q18 T30 Q18 T31 Q18 T32
Q18 T33 Q18 T34 Q18 T35 Q18 T36
Q18 T37 Q18 T38 Q18 T39 Q18 T40
Q18 T41 Q18 T42 Q18 T43 Q18 T44
Q18 T45 Q18 T46 Q18 T47 Q18 T48
Q18 T49 Q18 T50 Q18 T51 Q18 T52
Q18 T53
Q19 T1 Q19 T2 Q19 T3 Q19 T4
Q19 T5 Q19 T6 Q19 T7 Q19 T8
Q19 T9 Q19 T10 Q19 T11 Q19 T12
Q19 T13 Q19 T14 Q19 T15 Q19 T16
Q19 T17 Q19 T18 Q19 T19 Q19 T20
Q19 T21 Q19 T22 Q19 T23 Q19 T24
Q19 T25 Q19 T26 Q19 T27 Q19 T28
Q19 T29 Q19 T30 Q19 T31 Q19 T32
Q19 T33 Q19 T34 Q19 T35 Q19 T36
Q19 T37 Q19 T38 Q19 T39 Q19 T40
Q19 T41 Q19 T42 Q19 T43 Q19 T44
Q19 T45 Q19 T46 Q19 T47 Q19 T48
Q19 T49 Q19 T50 Q19 T51 Q19 T52
Q19 T53
Q20 T1 Q20 T2 Q20 T3 Q20 T4
Q20 T5 Q20 T6 Q20 T7 Q20 T8
Q20 T9 Q20 T10 Q20 T11 Q20 T12
Q20 T13 Q20 T14 Q20 T15 Q20 T16
Q20 T17 Q20 T18 Q20 T19 Q20 T20
Q20 T21 Q20 T22 Q20 T23 Q20 T24
Q20 T25 Q20 T26 Q20 T27 Q20 T28
Q20 T29 Q20 T30 Q20 T31 Q20 T32
Q20 T33 Q20 T34 Q20 T35 Q20 T36
Q20 T37 Q20 T38 Q20 T39 Q20 T40
Q20 T41 Q20 T42 Q20 T43 Q20 T44
Q20 T45 Q20 T46 Q20 T47 Q20 T48
Q20 T49 Q20 T50 Q20 T51 Q20 T52
Q20 T53
Q21 T1 Q21 T2 Q21 T3 Q21 T4
Q21 T5 Q21 T6 Q21 T7 Q21 T8
Q21 T9 Q21 T10 Q21 T11 Q21 T12
Q21 T13 Q21 T14 Q21 T15 Q21 T16
Q21 T17 Q21 T18 Q21 T19 Q21 T20
Q21 T21 Q21 T22 Q21 T23 Q21 T24
Q21 T25 Q21 T26 Q21 T27 Q21 T28
Q21 T29 Q21 T30 Q21 T31 Q21 T32
Q21 T33 Q21 T34 Q21 T35 Q21 T36
Q21 T37 Q21 T38 Q21 T39 Q21 T40
Q21 T41 Q21 T42 Q21 T43 Q21 T44
Q21 T45 Q21 T46 Q21 T47 Q21 T48
Q21 T49 Q21 T50 Q21 T51 Q21 T52
Q21 T53
Q22 T1 Q22 T2 Q22 T3 Q22 T4
Q22 T5 Q22 T6 Q22 T7 Q22 T8
Q22 T9 Q22 T10 Q22 T11 Q22 T12
Q22 T13 Q22 T14 Q22 T15 Q22 T16
Q22 T17 Q22 T18 Q22 T19 Q22 T20
Q22 T21 Q22 T22 Q22 T23 Q22 T24
Q22 T25 Q22 T26 Q22 T27 Q22 T28
Q22 T29 Q22 T30 Q22 T31 Q22 T32
Q22 T33 Q22 T34 Q22 T35 Q22 T36
Q22 T37 Q22 T38 Q22 T39 Q22 T40
Q22 T41 Q22 T42 Q22 T43 Q22 T44
Q22 T45 Q22 T46 Q22 T47 Q22 T48
Q22 T49 Q22 T50 Q22 T51 Q22 T52
Q22 T53
Q23 T1 Q23 T2 Q23 T3 Q23 T4
Q23 T5 Q23 T6 Q23 T7 Q23 T8
Q23 T9 Q23 T10 Q23 T11 Q23 T12
Q23 T13 Q23 T14 Q23 T15 Q23 T16
Q23 T17 Q23 T18 Q23 T19 Q23 T20
Q23 T21 Q23 T22 Q23 T23 Q23 T24
Q23 T25 Q23 T26 Q23 T27 Q23 T28
Q23 T29 Q23 T30 Q23 T31 Q23 T32
Q23 T33 Q23 T34 Q23 T35 Q23 T36
Q23 T37 Q23 T38 Q23 T39 Q23 T40
Q23 T41 Q23 T42 Q23 T43 Q23 T44
Q23 T45 Q23 T46 Q23 T47 Q23 T48
Q23 T49 Q23 T50 Q23 T51 Q23 T52
Q23 T53
Q24 T1 Q24 T2 Q24 T3 Q24 T4
Q24 T5 Q24 T6 Q24 T7 Q24 T8
Q24 T9 Q24 T10 Q24 T11 Q24 T12
Q24 T13 Q24 T14 Q24 T15 Q24 T16
Q24 T17 Q24 T18 Q24 T19 Q24 T20
Q24 T21 Q24 T22 Q24 T23 Q24 T24
Q24 T25 Q24 T26 Q24 T27 Q24 T28
Q24 T29 Q24 T30 Q24 T31 Q24 T32
Q24 T33 Q24 T34 Q24 T35 Q24 T36
Q24 T37 Q24 T38 Q24 T39 Q24 T40
Q24 T41 Q24 T42 Q24 T43 Q24 T44
Q24 T45 Q24 T46 Q24 T47 Q24 T48
Q24 T49 Q24 T50 Q24 T51 Q24 T52
Q24 T53
Q25 T1 Q25 T2 Q25 T3 Q25 T4
Q25 T5 Q25 T6 Q25 T7 Q25 T8
Q25 T9 Q25 T10 Q25 T11 Q25 T12
Q25 T13 Q25 T14 Q25 T15 Q25 T16
Q25 T17 Q25 T18 Q25 T19 Q25 T20
Q25 T21 Q25 T22 Q25 T23 Q25 T24
Q25 T25 Q25 T26 Q25 T27 Q25 T28
Q25 T29 Q25 T30 Q25 T31 Q25 T32
Q25 T33 Q25 T34 Q25 T35 Q25 T36
Q25 T37 Q25 T38 Q25 T39 Q25 T40
Q25 T41 Q25 T42 Q25 T43 Q25 T44
Q25 T45 Q25 T46 Q25 T47 Q25 T48
Q25 T49 Q25 T50 Q25 T51 Q25 T52
Q25 T53
Q26 T1 Q26 T2 Q26 T3 Q26 T4
Q26 T5 Q26 T6 Q26 T7 Q26 T8
Q26 T9 Q26 T10 Q26 T11 Q26 T12
Q26 T13 Q26 T14 Q26 T15 Q26 T16
Q26 T17 Q26 T18 Q26 T19 Q26 T20
Q26 T21 Q26 T22 Q26 T23 Q26 T24
Q26 T25 Q26 T26 Q26 T27 Q26 T28
Q26 T29 Q26 T30 Q26 T31 Q26 T32
Q26 T33 Q26 T34 Q26 T35 Q26 T36
Q26 T37 Q26 T38 Q26 T39 Q26 T40
Q26 T41 Q26 T42 Q26 T43 Q26 T44
Q26 T45 Q26 T46 Q26 T47 Q26 T48
Q26 T49 Q26 T50 Q26 T51 Q26 T52
Q26 T53
Q27 T1 Q27 T2 Q27 T3 Q27 T4
Q27 T5 Q27 T6 Q27 T7 Q27 T8
Q27 T9 Q27 T10 Q27 T11 Q27 T12
Q27 T13 Q27 T14 Q27 T15 Q27 T16
Q27 T17 Q27 T18 Q27 T19 Q27 T20
Q27 T21 Q27 T22 Q27 T23 Q27 T24
Q27 T25 Q27 T26 Q27 T27 Q27 T28
Q27 T29 Q27 T30 Q27 T31 Q27 T32
Q27 T33 Q27 T34 Q27 T35 Q27 T36
Q27 T37 Q27 T38 Q27 T39 Q27 T40
Q27 T41 Q27 T42 Q27 T43 Q27 T44
Q27 T45 Q27 T46 Q27 T47 Q27 T48
Q27 T49 Q27 T50 Q27 T51 Q27 T52
Q27 T53
Q28 T1 Q28 T2 Q28 T3 Q28 T4
Q28 T5 Q28 T6 Q28 T7 Q28 T8
Q28 T9 Q28 T10 Q28 T11 Q28 T12
Q28 T13 Q28 T14 Q28 T15 Q28 T16
Q28 T17 Q28 T18 Q28 T19 Q28 T20
Q28 T21 Q28 T22 Q28 T23 Q28 T24
Q28 T25 Q28 T26 Q28 T27 Q28 T28
Q28 T29 Q28 T30 Q28 T31 Q28 T32
Q28 T33 Q28 T34 Q28 T35 Q28 T36
Q28 T37 Q28 T38 Q28 T39 Q28 T40
Q28 T41 Q28 T42 Q28 T43 Q28 T44
Q28 T45 Q28 T46 Q28 T47 Q28 T48
Q28 T49 Q28 T50 Q28 T51 Q28 T52
Q28 T53
Q29 T1 Q29 T2 Q29 T3 Q29 T4
Q29 T5 Q29 T6 Q29 T7 Q29 T8
Q29 T9 Q29 T10 Q29 T11 Q29 T12
Q29 T13 Q29 T14 Q29 T15 Q29 T16
Q29 T17 Q29 T18 Q29 T19 Q29 T20
Q29 T21 Q29 T22 Q29 T23 Q29 T24
Q29 T25 Q29 T26 Q29 T27 Q29 T28
Q29 T29 Q29 T30 Q29 T31 Q29 T32
Q29 T33 Q29 T34 Q29 T35 Q29 T36
Q29 T37 Q29 T38 Q29 T39 Q29 T40
Q29 T41 Q29 T42 Q29 T43 Q29 T44
Q29 T45 Q29 T46 Q29 T47 Q29 T48
Q29 T49 Q29 T50 Q29 T51 Q29 T52
Q29 T53
Q30 T1 Q30 T2 Q30 T3 Q30 T4
Q30 T5 Q30 T6 Q30 T7 Q30 T8
Q30 T9 Q30 T10 Q30 T11 Q30 T12
Q30 T13 Q30 T14 Q30 T15 Q30 T16
Q30 T17 Q30 T18 Q30 T19 Q30 T20
Q30 T21 Q30 T22 Q30 T23 Q30 T24
Q30 T25 Q30 T26 Q30 T27 Q30 T28
Q30 T29 Q30 T30 Q30 T31 Q30 T32
Q30 T33 Q30 T34 Q30 T35 Q30 T36
Q30 T37 Q30 T38 Q30 T39 Q30 T40
Q30 T41 Q30 T42 Q30 T43 Q30 T44
Q30 T45 Q30 T46 Q30 T47 Q30 T48
Q30 T49 Q30 T50 Q30 T51 Q30 T52
Q30 T53
Q31 T1 Q31 T2 Q31 T3 Q31 T4
Q31 T5 Q31 T6 Q31 T7 Q31 T8
Q31 T9 Q31 T10 Q31 T11 Q31 T12
Q31 T13 Q31 T14 Q31 T15 Q31 T16
Q31 T17 Q31 T18 Q31 T19 Q31 T20
Q31 T21 Q31 T22 Q31 T23 Q31 T24
Q31 T25 Q31 T26 Q31 T27 Q31 T28
Q31 T29 Q31 T30 Q31 T31 Q31 T32
Q31 T33 Q31 T34 Q31 T35 Q31 T36
Q31 T37 Q31 T38 Q31 T39 Q31 T40
Q31 T41 Q31 T42 Q31 T43 Q31 T44
Q31 T45 Q31 T46 Q31 T47 Q31 T48
Q31 T49 Q31 T50 Q31 T51 Q31 T52
Q31 T53
Q32 T1 Q32 T2 Q32 T3 Q32 T4
Q32 T5 Q32 T6 Q32 T7 Q32 T8
Q32 T9 Q32 T10 Q32 T11 Q32 T12
Q32 T13 Q32 T14 Q32 T15 Q32 T16
Q32 T17 Q32 T18 Q32 T19 Q32 T20
Q32 T21 Q32 T22 Q32 T23 Q32 T24
Q32 T25 Q32 T26 Q32 T27 Q32 T28
Q32 T29 Q32 T30 Q32 T31 Q32 T32
Q32 T33 Q32 T34 Q32 T35 Q32 T36
Q32 T37 Q32 T38 Q32 T39 Q32 T40
Q32 T41 Q32 T42 Q32 T43 Q32 T44
Q32 T45 Q32 T46 Q32 T47 Q32 T48
Q32 T49 Q32 T50 Q32 T51 Q32 T52
Q32 T53
Q33 T1 Q33 T2 Q33 T3 Q33 T4
Q33 T5 Q33 T6 Q33 T7 Q33 T8
Q33 T9 Q33 T10 Q33 T11 Q33 T12
Q33 T13 Q33 T14 Q33 T15 Q33 T16
Q33 T17 Q33 T18 Q33 T19 Q33 T20
Q33 T21 Q33 T22 Q33 T23 Q33 T24
Q33 T25 Q33 T26 Q33 T27 Q33 T28
Q33 T29 Q33 T30 Q33 T31 Q33 T32
Q33 T33 Q33 T34 Q33 T35 Q33 T36
Q33 T37 Q33 T38 Q33 T39 Q33 T40
Q33 T41 Q33 T42 Q33 T43 Q33 T44
Q33 T45 Q33 T46 Q33 T47 Q33 T48
Q33 T49 Q33 T50 Q33 T51 Q33 T52
Q33 T53
Q34 T1 Q34 T2 Q34 T3 Q34 T4
Q34 T5 Q34 T6 Q34 T7 Q34 T8
Q34 T9 Q34 T10 Q34 T11 Q34 T12
Q34 T13 Q34 T14 Q34 T15 Q34 T16
Q34 T17 Q34 T18 Q34 T19 Q34 T20
Q34 T21 Q34 T22 Q34 T23 Q34 T24
Q34 T25 Q34 T26 Q34 T27 Q34 T28
Q34 T29 Q34 T30 Q34 T31 Q34 T32
Q34 T33 Q34 T34 Q34 T35 Q34 T36
Q34 T37 Q34 T38 Q34 T39 Q34 T40
Q34 T41 Q34 T42 Q34 T43 Q34 T44
Q34 T45 Q34 T46 Q34 T47 Q34 T48
Q34 T49 Q34 T50 Q34 T51 Q34 T52
Q34 T53
Q35 T1 Q35 T2 Q35 T3 Q35 T4
Q35 T5 Q35 T6 Q35 T7 Q35 T8
Q35 T9 Q35 T10 Q35 T11 Q35 T12
Q35 T13 Q35 T14 Q35 T15 Q35 T16
Q35 T17 Q35 T18 Q35 T19 Q35 T20
Q35 T21 Q35 T22 Q35 T23 Q35 T24
Q35 T25 Q35 T26 Q35 T27 Q35 T28
Q35 T29 Q35 T30 Q35 T31 Q35 T32
Q35 T33 Q35 T34 Q35 T35 Q35 T36
Q35 T37 Q35 T38 Q35 T39 Q35 T40
Q35 T41 Q35 T42 Q35 T43 Q35 T44
Q35 T45 Q35 T46 Q35 T47 Q35 T48
Q35 T49 Q35 T50 Q35 T51 Q35 T52
Q35 T53
Q36 T1 Q36 T2 Q36 T3 Q36 T4
Q36 T5 Q36 T6 Q36 T7 Q36 T8
Q36 T9 Q36 T10 Q36 T11 Q36 T12
Q36 T13 Q36 T14 Q36 T15 Q36 T16
Q36 T17 Q36 T18 Q36 T19 Q36 T20
Q36 T21 Q36 T22 Q36 T23 Q36 T24
Q36 T25 Q36 T26 Q36 T27 Q36 T28
Q36 T29 Q36 T30 Q36 T31 Q36 T32
Q36 T33 Q36 T34 Q36 T35 Q36 T36
Q36 T37 Q36 T38 Q36 T39 Q36 T40
Q36 T41 Q36 T42 Q36 T43 Q36 T44
Q36 T45 Q36 T46 Q36 T47 Q36 T48
Q36 T49 Q36 T50 Q36 T51 Q36 T52
Q36 T53
Q37 T1 Q37 T2 Q37 T3 Q37 T4
Q37 T5 Q37 T6 Q37 T7 Q37 T8
Q37 T9 Q37 T10 Q37 T11 Q37 T12
Q37 T13 Q37 T14 Q37 T15 Q37 T16
Q37 T17 Q37 T18 Q37 T19 Q37 T20
Q37 T21 Q37 T22 Q37 T23 Q37 T24
Q37 T25 Q37 T26 Q37 T27 Q37 T28
Q37 T29 Q37 T30 Q37 T31 Q37 T32
Q37 T33 Q37 T34 Q37 T35 Q37 T36
Q37 T37 Q37 T38 Q37 T39 Q37 T40
Q37 T41 Q37 T42 Q37 T43 Q37 T44
Q37 T45 Q37 T46 Q37 T47 Q37 T48
Q37 T49 Q37 T50 Q37 T51 Q37 T52
Q37 T53
Q38 T1 Q38 T2 Q38 T3 Q38 T4
Q38 T5 Q38 T6 Q38 T7 Q38 T8
Q38 T9 Q38 T10 Q38 T11 Q38 T12
Q38 T13 Q38 T14 Q38 T15 Q38 T16
Q38 T17 Q38 T18 Q38 T19 Q38 T20
Q38 T21 Q38 T22 Q38 T23 Q38 T24
Q38 T25 Q38 T26 Q38 T27 Q38 T28
Q38 T29 Q38 T30 Q38 T31 Q38 T32
Q38 T33 Q38 T34 Q38 T35 Q38 T36
Q38 T37 Q38 T38 Q38 T39 Q38 T40
Q38 T41 Q38 T42 Q38 T43 Q38 T44
Q38 T45 Q38 T46 Q38 T47 Q38 T48
Q38 T49 Q38 T50 Q38 T51 Q38 T52
Q38 T53
Q39 T1 Q39 T2 Q39 T3 Q39 T4
Q39 T5 Q39 T6 Q39 T7 Q39 T8
Q39 T9 Q39 T10 Q39 T11 Q39 T12
Q39 T13 Q39 T14 Q39 T15 Q39 T16
Q39 T17 Q39 T18 Q39 T19 Q39 T20
Q39 T21 Q39 T22 Q39 T23 Q39 T24
Q39 T25 Q39 T26 Q39 T27 Q39 T28
Q39 T29 Q39 T30 Q39 T31 Q39 T32
Q39 T33 Q39 T34 Q39 T35 Q39 T36
Q39 T37 Q39 T38 Q39 T39 Q39 T40
Q39 T41 Q39 T42 Q39 T43 Q39 T44
Q39 T45 Q39 T46 Q39 T47 Q39 T48
Q39 T49 Q39 T50 Q39 T51 Q39 T52
Q39 T53
Q40 T1 Q40 T2 Q40 T3 Q40 T4
Q40 T5 Q40 T6 Q40 T7 Q40 T8
Q40 T9 Q40 T10 Q40 T11 Q40 T12
Q40 T13 Q40 T14 Q40 T15 Q40 T16
Q40 T17 Q40 T18 Q40 T19 Q40 T20
Q40 T21 Q40 T22 Q40 T23 Q40 T24
Q40 T25 Q40 T26 Q40 T27 Q40 T28
Q40 T29 Q40 T30 Q40 T31 Q40 T32
Q40 T33 Q40 T34 Q40 T35 Q40 T36
Q40 T37 Q40 T38 Q40 T39 Q40 T40
Q40 T41 Q40 T42 Q40 T43 Q40 T44
Q40 T45 Q40 T46 Q40 T47 Q40 T48
Q40 T49 Q40 T50 Q40 T51 Q40 T52
Q40 T53
Q41 T1 Q41 T2 Q41 T3 Q41 T4
Q41 T5 Q41 T6 Q41 T7 Q41 T8
Q41 T9 Q41 T10 Q41 T11 Q41 T12
Q41 T13 Q41 T14 Q41 T15 Q41 T16
Q41 T17 Q41 T18 Q41 T19 Q41 T20
Q41 T21 Q41 T22 Q41 T23 Q41 T24
Q41 T25 Q41 T26 Q41 T27 Q41 T28
Q41 T29 Q41 T30 Q41 T31 Q41 T32
Q41 T33 Q41 T34 Q41 T35 Q41 T36
Q41 T37 Q41 T38 Q41 T39 Q41 T40
Q41 T41 Q41 T42 Q41 T43 Q41 T44
Q41 T45 Q41 T46 Q41 T47 Q41 T48
Q41 T49 Q41 T50 Q41 T51 Q41 T52
Q41 T53
Q42 T1 Q42 T2 Q42 T3 Q42 T4
Q42 T5 Q42 T6 Q42 T7 Q42 T8
Q42 T9 Q42 T10 Q42 T11 Q42 T12
Q42 T13 Q42 T14 Q42 T15 Q42 T16
Q42 T17 Q42 T18 Q42 T19 Q42 T20
Q42 T21 Q42 T22 Q42 T23 Q42 T24
Q42 T25 Q42 T26 Q42 T27 Q42 T28
Q42 T29 Q42 T30 Q42 T31 Q42 T32
Q42 T33 Q42 T34 Q42 T35 Q42 T36
Q42 T37 Q42 T38 Q42 T39 Q42 T40
Q42 T41 Q42 T42 Q42 T43 Q42 T44
Q42 T45 Q42 T46 Q42 T47 Q42 T48
Q42 T49 Q42 T50 Q42 T51 Q42 T52
Q42 T53
Q43 T1 Q43 T2 Q43 T3 Q43 T4
Q43 T5 Q43 T6 Q43 T7 Q43 T8
Q43 T9 Q43 T10 Q43 T11 Q43 T12
Q43 T13 Q43 T14 Q43 T15 Q43 T16
Q43 T17 Q43 T18 Q43 T19 Q43 T20
Q43 T21 Q43 T22 Q43 T23 Q43 T24
Q43 T25 Q43 T26 Q43 T27 Q43 T28
Q43 T29 Q43 T30 Q43 T31 Q43 T32
Q43 T33 Q43 T34 Q43 T35 Q43 T36
Q43 T37 Q43 T38 Q43 T39 Q43 T40
Q43 T41 Q43 T42 Q43 T43 Q43 T44
Q43 T45 Q43 T46 Q43 T47 Q43 T48
Q43 T49 Q43 T50 Q43 T51 Q43 T52
Q43 T53
Q44 T1 Q44 T2 Q44 T3 Q44 T4
Q44 T5 Q44 T6 Q44 T7 Q44 T8
Q44 T9 Q44 T10 Q44 T11 Q44 T12
Q44 T13 Q44 T14 Q44 T15 Q44 T16
Q44 T17 Q44 T18 Q44 T19 Q44 T20
Q44 T21 Q44 T22 Q44 T23 Q44 T24
Q44 T25 Q44 T26 Q44 T27 Q44 T28
Q44 T29 Q44 T30 Q44 T31 Q44 T32
Q44 T33 Q44 T34 Q44 T35 Q44 T36
Q44 T37 Q44 T38 Q44 T39 Q44 T40
Q44 T41 Q44 T42 Q44 T43 Q44 T44
Q44 T45 Q44 T46 Q44 T47 Q44 T48
Q44 T49 Q44 T50 Q44 T51 Q44 T52
Q44 T53

14)
The compound according to 13) above, wherein R ₁ and R ₂ are ethyl groups.

15)
The compound according to 13) above, wherein R ₁ is a methyl group and R ₂ is an ethyl group.

16)
The compound according to any one of 13) to 15) above, wherein R ₃ is a methylcarbonyloxy group.

17)
Compounds according to 13) to 16) above, wherein R _{5 in} formula Q is a methyl group

18)
The IKACh inhibitor which contains the compound as described in said 1) thru | or 17), the tautomer of this compound, a prodrug, its pharmaceutically acceptable salt, or those solvates as an active ingredient.

19)
A prophylactic / therapeutic / ameliorating agent for a disease having an effective IKACh inhibitory activity, which comprises the IKACh inhibitor according to 18) as an active ingredient.

20)
A therapeutic agent for arrhythmia comprising the IKCh inhibitor according to 18) as an active ingredient.

21)
The pharmaceutical which contains the compound as described in said 1) thru | or 17), the tautomer of this compound, a prodrug, its pharmaceutically acceptable salt, or those solvates as an active ingredient.

  In the present invention, in addition to the compound represented by the formula (I) of the present invention being present via, for example, tautomerism or geometrical isomerism regardless of whether in the ring or outside the ring, It also exists as a mixture of isomers. In addition, when an asymmetric center is present, or when an asymmetric center is formed as a result of isomerization, this includes the presence of a mixture of each optical isomer and an arbitrary ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.

  The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can exist as an arbitrary crystal form depending on production conditions, and can exist as an arbitrary hydrate. And hydrates and mixtures thereof are also included within the scope of the present invention. Moreover, although it may exist as a solvate containing organic solvents, such as acetone, ethanol, and tetrahydrofuran, all of these forms are contained in the scope of the present invention.

The compound represented by the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt or can be liberated from the formed salt, if necessary. Examples of the pharmaceutically acceptable salt of the present invention include salts with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. In addition, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) Other salts are also possible.
A prodrug is a derivative of the present invention having a group that can be chemically or metabolically decomposed, and becomes a compound that forms the present invention pharmacologically active by solvolysis or in vivo under physiological conditions It is. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985) (Design of Prodrugs (Elsevier, Amsterdam 1985)). In the case of the present invention, when it has a hydroxyl group, a prodrug such as an acyloxy derivative produced by reacting the compound with an appropriate acyl halide or an appropriate acid anhydride is exemplified. -OCOC ₂ H ₅ is particularly preferred acyloxy as _{prodrugs, -OCO (t-Bu),} - OCOC 15 H 31, -OCO (m-CO 2 Na-Ph), - OCOCH 2 CH 2 CO 2 Na, - OCOCH (NH ₂ ) CH ₃ , —OCOCH ₂ N (CH ₃ ) _{2 and the} like can be mentioned. In the case where the compound forming the present invention has an amino group, a prodrug such as an amide derivative produced by reacting a compound having an amino group with an appropriate acid halide or an appropriate mixed acid anhydride is exemplified. Is done. Particularly preferred amides as prodrugs include —NHCO (CH ₂ ) ₂₀ OCH ₃ , —NHCOCH (NH ₂ ) CH _{3 and the} like.

  A preventive / treating / ameliorating agent for a disease having an IKACh inhibitory action effective comprising the IKCh inhibitor of the present invention as an active ingredient is usually an orally administered agent such as a tablet, capsule, powder, granule, pill, syrup, etc. It can be administered as a rectal administration agent, a transdermal absorption agent or an injection. The agent can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used for oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared with water or other suitable solvent prior to use. Good. The liquid preparation may contain conventional additives such as suspending agents, perfumes, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives, etc. as necessary Can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used.

  When the drug of the present invention is administered to humans, the dosage is determined depending on the age and condition of the patient. In general, in the case of adults, 0.1 to 1000 mg / human / day for oral or rectal administration, injection 0.05 mg to 500 mg / person / day. These numerical values are merely examples, and the dosage is determined according to the symptoms of the patient.

  As a scene using this invention, the scene which can expect improvement of a disease state is mentioned by using the compound which has IKACh inhibitory activity. Specifically, related to atrial arrhythmia, such as seizure, persistence, chronic, pre-operation, during surgery, prevention and treatment of atrial fibrillation after surgery, atrial flutter, prevention and treatment of atrial tachycardia, Prevention of progression to embolism based on atrial arrhythmia, prevention of ventricular arrhythmia or transition to tachycardia due to atrial arrhythmia or tachycardia, ventricular arrhythmia or atrial arrhythmia or tachycardia that can transition to tachycardia Although the scene which prevents the life prognosis deterioration based on a preventive action is assumed, it is not limited to these.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

  The compound of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), high performance liquid chromatography-mass spectrometry (LC / MS), etc. For example, a high purity product can be obtained by recrystallization or washing with a solvent.

Examples of the base in the description of the general production method of the compound of the present invention include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, lithium hydride. Alkali metal salts such as sodium amide, t-butoxy potassium, t-butoxy sodium, n-butyl lithium, lithium diisopropylamide, amines such as pyridine, triethylamine, diisopropylethylamine, pyrrolidine, N-methylpiperidine, hexamethyldisilazane And silane reagents, sodium acetate, and potassium acetate.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, dimethyl sulfoxide is representative. Sulfoxide solvents, amide solvents typified by dimethylformamide or dimethylacetamide, ether solvents typified by ethyl ether, dimethoxyethane or tetrahydrofuran, dioxane, cyclopentylmethyl ether, halogens typified by dichloromethane, chloroform, dichloroethane Solvent, acetonitrile, nitrile solvent represented by propionitrile, aromatic hydrocarbon solvent represented by benzene, toluene, hydrocarbon solvent represented by hexane, heptane, Ester solvents such as ethyl, methanol, ethanol, 1-propanol, 2-propanol, alcoholic solvents such as ethylene glycol, water. In addition, the reaction can be carried out under conditions where the above-mentioned solvents are arbitrarily mixed or without solvent.
The reaction temperature in the general production method of the compound of the present invention can be selected from an appropriate temperature in the range of -78 ° C. to the boiling point of the solvent used in the reaction, and this production method is conducted under atmospheric pressure, under pressure, and microwave irradiation. It can be implemented in the lower class.

  In the following general production method of the compound of the present invention, general formulas of intermediates and final products in each step are shown, and these intermediates and final products also include their precursors. Here, the precursor means a compound that can be derived into a target product by hydrolysis, deprotection group, reduction, oxidation, alkylation, etc., if necessary. Includes those protected with an acceptable protecting group. Protection and deprotection may be performed using commonly known protection / deprotection reactions (eg, Protective Groups in Organic Synthesis, Fourth edition), Green (T.W. Greene), John Wiley & Sons Inc. (2006), etc.).

  Starting material compounds (1) -I, (1) -II, (2) -II, (3) -I, (4) -I, (4) -II described in the general synthesis method shown below, As (5) -IV, (5) -V and (5) -VI, commercially available reagents or those which can be easily synthesized by those skilled in the art can be used.

（１）−Ｉで示されるエポキシ化合物を溶媒中、（１）−ＩＩで表されるアミン化合物と必要に応じて過塩素酸リチウム、臭化リチウム等の酸触媒及び／又はトリエチルアミン等の塩基を用い、必要に応じて加熱して反応させることにより、目的物又はその前駆体を得ることができる。 Among the compounds represented by the formula (I), a compound in which R ³ is a hydroxyl group and R ⁴ is a hydrogen atom can be synthesized by, for example, the following production method (formula 1).

(1) An epoxy compound represented by -I in a solvent, an amine compound represented by (1) -II and an acid catalyst such as lithium perchlorate and lithium bromide and / or a base such as triethylamine as necessary. The target product or a precursor thereof can be obtained by using and reacting by heating as necessary.

（２）−Ｉで示されるアミノ化合物を溶媒中、（２）−ＩＩで表されるアルデヒド化合物と必要に応じて酸触媒及び／又はトリエチルアミン等の塩基とモレキュラーシーブス又は無水硫酸マグネシウム等の脱水剤を用い、必要に応じて加熱下、水素化ホウ素ナトリウム又はピコリンボラン等の還元剤を反応させることにより、目的物又はその前駆体を得ることができる。 Among the compounds represented by the formula (I), the compound represented by (2) -III can be synthesized, for example, by the production method of the following (Formula 2).

(2) An amino compound represented by -I in a solvent, an aldehyde compound represented by (2) -II and, if necessary, an acid catalyst and / or a base such as triethylamine and a dehydrating agent such as molecular sieves or anhydrous magnesium sulfate The target product or a precursor thereof can be obtained by reacting a reducing agent such as sodium borohydride or picoline borane with heating as necessary.

Of the compounds represented by formula (I), a compound in which R ³ is a C _1-6 alkylcarbonyloxy group is obtained by using a compound in which R ³ is a hydroxyl group in a solvent, using a base such as triethylamine as necessary. Accordingly, the target product or its precursor can be obtained by reacting the corresponding alkyl chloroformate or the corresponding acid anhydride under heating.

Among the compounds represented by the formula (I), compounds in which R ³ and R ⁴ together represent a bond are the production methods described in JP-A-52-91866 and JP-A-10-87650, etc. The target product or a precursor thereof can be obtained by a similar method.

(1) The epoxy compound represented by -I can be synthesized by, for example, the following production method (formula 3).

(3) The alkene compound represented by -I is converted into a halohydrin by reacting with a halogen, NBS or an equivalent thereof under heating in a solvent, if necessary, using a base such as triethylamine, if necessary. The target product or a precursor thereof can be obtained by reacting with a base such as sodium hydroxide.
Or (3) The alkene compound represented by -I is reacted with a peroxide such as metachloroperbenzoic acid in a solvent, if necessary, using a base such as triethylamine, if necessary, under heating, to obtain the desired product Or its precursor can be obtained.

The compounds represented by (1) -I and (3) -I can be achieved by referring to the following synthesis method.
-General synthesis of fused-pyran rings
Known methods (JM Evans et al., J. Med. Chem. 1984, 27, 1127, J. Med. Chem. 1986, 29, 2194, JT North et al. J. Org. Chem. 1995, 60, 3397, and JP-A-56-57785, JP-A-56-57786, JP-A-58-188880, JP-A-2-141, JP-A-10-87650, JP-A-11-209366, etc. Can be synthesized according to the method described.
○ General method for coumarin ring synthesis Known methods (M. Narayana et al., J. Org. Chem., 1962, 27, 4704, RG Harvey et al., J. Org. Chem., 1988, 53, 3936, RS Mali et al., Synthesis , 1977, 464, F. Effenberger et al., Chem. Ber., 1987, 120, 373, and J. Sakakibara et al., Chem. Pharm. Bull., 1987, 35, 1796, Synthesis, 1986, 1026, etc. ) Can be synthesized.
○ Indole, oxindole
T. Sakamoto, et al., Heterocycles, 1986, 24, 31.
M. Belley, et.al., Synthesis, 2001, 222.
AD Cross, et al., J. Chem. Soc., 1961, 2714.
○ Imidazolinone
J. Kitteringham, et.al., Synthetic Commun., 2000, 30, 1937.
○ Quinoline
S. Imor, et al., Synthetic Commun., 1996, 26, 2197.
Y. Kitahara, et al., Tetrahedron, 1997, 53, 6001.
AG Osborne, et al., J. Chem. Soc. Perkin Trans. 1, 1993, 181.
RT Shuman, et al., J. Org. Chem., 1990, 55, 738.
T. Sakamoto, et al., Chem. Pharm. Bull., 1981, 29, 2485.
Y. Tsuji, et al., J. Org. Chem., 1987, 52, 1673.
Z. Song, et al., J. Heterocyclic Chem., 1993, 30, 17.
○ Quinolinone
MR Sabol, et al., Synthetic Commun., 2000, 30, 427.
ZY.Yang, et al., Tetrahedron Lett., 1999, 40, 4505.
HB Sun, et al., Synthesis, 1997, 1249.
A. Guiotto, et al., J. Heterocyclic Chem. 1989, 26, 917.
K. Konno, et al., Heterocycles 1986, 24, 2169.
E. Fernandez, et al., Synthesis 1995, 1362.
○ benzothiazole, triazole,
NBAmbati, et al., Synthetic Commun., 1997, 27, 1487.
DE Burton., Et al., J. Chem. Soc (C). 1968, 1268.
○ Quinoxaline, quinoxalinone
JH Liu, et al., J. Org. Chem., 2000, 65, 3395.
JJLi, et al., Tetrahedron Lett., 1999, 40, 4507.
Y. Ahmed, et al., Bull. Chem. Soc. Jpn., 1987, 60, 1145.
○ Benzoxazinone
GH Jones, et al., J. Med. Chem., 1987, 30, 295.
JL Wright, et al., J. Med. Chem., 2000, 43, 3408.
M. Kluge, et al., J. Heterocyclic Chem., 1995, 32, 395.
・ Pyranothiophene
Sanfilippo Pauline J., et al., Journal of Medicinal Chemistry, 35 (23), 4425-33; 1992
Eur. Pat. Appl., 360621, 28 Mar 1990
○ Pyranopyridine
Lee Sunkyung, et al., Bulletin of the Korean Chemical Society, 26 (4), 619-628; 2005
Al-Sehaibani Hamed A. Asian Journal of Chemistry, 11 (4), 1483-1487; 1999
Evans John M., et al., Synthetic Communications, 18 (10), 1111-18; 1988
Burrell Gordon, et al., Journal of Medicinal Chemistry, 33 (11), 3023-7; 1990
Cotterill W. David, et al., Journal of Chemical Research, Synopses, (1), 12-13; 1995
○ Pyranoisoquinoline
Al-Sehaibani Hamed A., Asian Journal of Chemistry, 11 (4), 1483-1487; 1999
Jpn. Kokai Tokkyo Koho, 02311479, 27 Dec 1990, Heisei
○ Pyranoquinoxaline
Ames Donald E., et al., Journal of Chemical Research, Synopses, (5), 144-5; 1985
○ Pyranoquinolinone
Wang Xue, et al., Synthesis, (19), 3044-3050; 2007
Suresh T., et al., Heterocyclic Communications, 11 (1), 79-84; 2005
○ Pyranopyridazine
Nie Aihua, et al., Zhongguo Yaowu Huaxue Zazhi, 14 (1), 9-13; 2004
○ Pyranopyrimidinone
Ahluwalia VK, et al., Synthetic Communications, 17 (12), 1435-40; 1987
○ Pyranopyrazole
Matsugo Seiichi, et al., Chemical & Pharmaceutical Bulletin, 32 (6), 2146-53; 1984
Matsugo Seiichi, et al., Synthesis, (6), 482-3; 1983

(3) Of the compounds represented by -I, A is a pyridine structure in which A is condensed via a benzene ring and two carbon atoms (4) -III or (4) -IV (wherein W is V and A compound represented by the following formula (4) represents the same meaning, n represents 0, 1, 2 or 3, and when n is 2 or 3, W may be the same or different. ).

  By using the compound represented by (4) -I or (4) -II, a target product or a precursor thereof can be obtained by the same method as the production method described in WO2004-084605.

Of the compounds represented by (I), (2) -I or (3) -I, (5) -I, (5) is a pyrazine structure in which A is condensed via a benzene ring and two carbon atoms. A compound represented by -II or (5) -III (wherein W represents the same meaning as V, n represents 0, 1 or 2, and when n is 2, W is the same or different) Can be synthesized, for example, by the production method of the following formula (5).

  Using the compound represented by (5) -IV, (5) -V or (5) -VI, the target product or a precursor thereof can be obtained by the same method as the production method described in WO2004-084605.

  Of the compounds represented by the general formula (I), an optically active form is synthesized by a method of optically resolving the racemic form (I) or 2- (I) (JP-A-3-141286, US Pat. No. 5,970,037 and European This is achieved by utilizing Japanese Patent No. 409165).

  Of the compounds represented by the general formula (I), the optically active compound is synthesized by a method of asymmetric synthesis of the compound represented by (1) -1 (Japanese Unexamined Patent Publication No. 5-507645, Japanese Patent Laid-Open No. 5-301878, Japanese Patent Laid-Open No. 7). -285983, EP535377, US 5420314, WO2000-278993, WO2004-048842 and WO2004-084605).

The present invention will be described in more detail with reference synthesis examples, synthesis examples, test examples, and formulation examples below, but the present invention is not limited to these examples.
In Examples, NMR means nuclear magnetic resonance spectrum, MS means mass spectrometry, LC / MS means liquid chromatography mass spectrometry, and (v / v) means (volume / volume). ¹ H-NMR was measured at 300 MHz, and LC / MS was measured under the following conditions.
LC / MS condition column: Waters SunFire C18 (3.5μm, 4.6x30mm)
Eluent: acetonitrile / 0.1% formic acid aqueous solution (10/90 → 85/15 (v / v))

Ｎ−｛３−ヒドロキシ−２，２−ジメチル−７−ニトロ−４−［２−フェニルエチルアミノ］−３，４−ジヒドロ−２Ｈ−クロマン−８−イル}アセトアミド

該化合物は文献記載の方法（Babu, K. Suresh et al. Heterocyclic Communications (2003), 9(5), 519-526.）に準じて、Ｎ−（２−ヒドロキシ−６−ニトロフェニル）アセトアミドより合成したＮ−（２，２−ジメチル−７−ニトロ−２Ｈ−クロマン−８−イル}アセトアミドより、ＷＯ２００５／０９０３５７記載の方法により合成した。 Synthesis example 1
Synthesis of 9,9-dimethyl-7-7- (2-phenylethylamino) -8,9-dihydro-7H-pyrano [2,3-f] quinoxalin-8-ol 1 maleate

N- {3-hydroxy-2,2-dimethyl-7-nitro-4- [2-phenylethylamino] -3,4-dihydro-2H-chroman-8-yl} acetamide

The compound was obtained from N- (2-hydroxy-6-nitrophenyl) acetamide according to a method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (2003), 9 (5), 519-526.). It was synthesized from the synthesized N- (2,2-dimethyl-7-nitro-2H-chroman-8-yl} acetamide by the method described in WO2005 / 090357.

N- {3-hydroxy-2,2-dimethyl-7-nitro-4- [2-phenylethylamino] -3,4-dihydro-2H-chroman-8-yl} acetamide

Shape: Light yellow amorphous
¹ H-NMR (CDCl ₃ ) δ; 1.20 (s, 3H), 1.52 (s, 3H), 2.18 (s, 3H), 2.71-2.93 (m, 5H), 3.53 (d, J = 10.0 Hz, 1H ), 3.69 (d, J = 10.0 Hz, 1H), 6.89 (dd, J = 8.6, 1.1 Hz, 1H), 7.19-7.39 (m, 6H), 7.51 (br, 1H).
MS (FAB) m / z; 400 [M + H] ⁺

8-Amino-2,2-dimethyl-7-nitro-4-[(2-phenylethyl) amino] -3,4-dihydro-2H-chroman-3-ol

  Of N- {3-hydroxy-2,2-dimethyl-7-nitro-4- [2-phenylethylamino] -3,4-dihydro-2H-chroman-8-yl} acetamide (66 mg, 0.17 mmol) 6M Hydrochloric acid (0.2 mL) was added to the ethanol (0.5 mL) solution, and the mixture was stirred at 90 ° C. for 3.5 hours. After cooling, the mixture is neutralized with 1M aqueous sodium hydroxide solution (1.6 mL) and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, Was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the desired product (yield: 79%).

８−アミノ−２，２−ジメチル−７−ニトロ−４−［（２−フェニルエチル）アミノ］−３，４−ジヒドロ−２Ｈ−クロマン−３−オール（35mg, 0.098mmol）と5％パラジウム−炭素（AERタイプ, 2 mg）のエタノール溶液を水素雰囲気（１気圧）で3時間室温で攪拌した。窒素雰囲気下に置換後、４０％グリオキサール水溶液（14 mg, 0.098 mmol）を加え、30分間攪拌した。反応終了後、反応液をろ過し、飽和食塩水を加え、酢酸エチルで抽出、有機相を無水硫酸ナトリウムで乾燥、減圧濃縮し、得られた残渣を、シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、目的物（40mg, 定量的）を得た。
形状：淡黄色油状物
¹H-NMR(CDCl₃)δ; 1.30 (d, 3H), 1.72 (s, 3H), 2.0-2.3 (br s, 2H), 2.7-3.0 (m, 4H), 3.73 (d, J= 9.9 Hz, 1H), 3.86 (d, J = 9.9 Hz, 1H), 7.2-7.4 (m, 5H), 7.44 (d, J= 9.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H).

９，９−ジメチル−７−７−（２−フェニルエチルアミノ）−８，９−ジヒドロ−７H−ピラノ[2,3−f]キノキサリン−８−オール １マレイン酸塩

９，９−ジメチル−７−７−（２−フェニルエチルアミノ）−８，９−ジヒドロ−７H−ピラノ[2,3−f]キノキサリン−８−オール(40 mg, 0.114 mmol)のエタノール溶液（0.2 mL）に室温でマレイン酸（15 mg, 0.125 mmol）、続いて、ヘキサン(0.8 mL)を加え、5分間攪拌した。得られた固形物をろ取して、エタノール−ヘキサン混合溶媒で洗浄、乾燥して目的物 (16 mg, 30% 収率)を得た。
形状：無色固体
¹H-NMR(DMSO-d6)δ;1.20 (s, 3H), 1.59 (s, 3H), 2.9-3.1 (m, 4H), 4.09 (br d, J = 9.9Hz, 1H), 4.58 (br s, 1H), 6.06 (s, 2H), 6.25 (br s, 1H), 7.2-7.35 (m, 5H), 7.71 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.97 (d, J = 1.7 Hz, 1H).
LC/MS： 保持時間1.62分
LC/MS(ESI⁺) m/z; 350 [M+1]⁺ Shape: Light brown amorphous
¹ H-NMR (CDCl ₃ ) δ; 1.18 (s, 3H), 1.55 (s, 3H), 2.74-2.92 (m, 5H), 3.58 (ABq, J = 9.9 Hz, 2H), 6.30 (d, J = 9.2 Hz, 1H), 6.38 (br, 2H), 7.19-7.35 (m, 5H), 7.62 (d, J = 9.2 Hz, 1H).
MS (FAB) m / z; 358 [M + H] ⁺

9,9-Dimethyl-7-7- (2-phenylethylamino) -8,9-dihydro-7H-pyrano [2,3-f] quinoxalin-8-ol

8-Amino-2,2-dimethyl-7-nitro-4-[(2-phenylethyl) amino] -3,4-dihydro-2H-chroman-3-ol (35 mg, 0.098 mmol) and 5% palladium- An ethanol solution of carbon (AER type, 2 mg) was stirred at room temperature for 3 hours in a hydrogen atmosphere (1 atm). After substitution in a nitrogen atmosphere, 40% glyoxal aqueous solution (14 mg, 0.098 mmol) was added and stirred for 30 minutes. After completion of the reaction, the reaction mixture is filtered, saturated brine is added, extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (ethyl acetate). The target product (40 mg, quantitative) was obtained.
Shape: pale yellow oil
¹ H-NMR (CDCl ₃ ) δ; 1.30 (d, 3H), 1.72 (s, 3H), 2.0-2.3 (br s, 2H), 2.7-3.0 (m, 4H), 3.73 (d, J = 9.9 Hz, 1H), 3.86 (d, J = 9.9 Hz, 1H), 7.2-7.4 (m, 5H), 7.44 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H).

9,9-Dimethyl-7-7- (2-phenylethylamino) -8,9-dihydro-7H-pyrano [2,3-f] quinoxalin-8-ol 1 maleate

Ethanol solution of 9,9-dimethyl-7-7- (2-phenylethylamino) -8,9-dihydro-7H-pyrano [2,3-f] quinoxalin-8-ol (40 mg, 0.114 mmol) ( 0.2 mL) was added maleic acid (15 mg, 0.125 mmol), followed by hexane (0.8 mL) at room temperature and stirred for 5 minutes. The obtained solid was collected by filtration, washed with an ethanol-hexane mixed solvent, and dried to obtain the desired product (16 mg, 30% yield).
Shape: colorless solid
¹ H-NMR (DMSO-d6) δ; 1.20 (s, 3H), 1.59 (s, 3H), 2.9-3.1 (m, 4H), 4.09 (br d, J = 9.9Hz, 1H), 4.58 (br s, 1H), 6.06 (s, 2H), 6.25 (br s, 1H), 7.2-7.35 (m, 5H), 7.71 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.97 (d, J = 1.7 Hz, 1H).
LC / MS: Retention time 1.62 minutes
LC / MS (ESI ⁺ ) m / z; 350 [M + 1] ⁺

Pharmacological Analysis Test Example 1 Measurement of IKACh Inhibitory Activity GIRK1 and GIRK4 constituting the KACh channel were cloned from a human heart cDNA library, and GIRK1 and GIRK4 cRNA were prepared using mMESSAGE mMACHINE In Vitro Transcription T7 Kit (Ambion). did.
An oocyte mass is collected from a mature female Xenopus laevis and treated with collagenase (10 ml ND96 buffer (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 5 mM HEPES, pH 7.5)). The oocytes isolated by mg collagenase, 90 minutes at room temperature) were allowed to stand at 17 ° C. for 1 day. The isolated oocytes were injected with GIRK1 and GIRK4 cRNA (each 10 ng / oocyte) and cultured at 17 ° C. for 3-5 days. Thereafter, the membrane potential of the oocyte was fixed at −80 mV in ND96 buffer using two microelectrodes filled with 3M KCl. GIRK1 / 4 current was induced with high potassium buffer (2 mM NaCl, 96 mM KCl, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 5 mM HEPES, pH 7.5), and the drugs were applied cumulatively in an incremental fashion. 3 mM BaCl ₂ was applied after drug application to confirm maximum response. The inhibition rate was calculated from the equation (1), and the IC50 value was determined by linear regression of the concentration response curve.
(1) Inhibition rate (%) = (I ₀ -I) / (I ₀ -I _BaCl2 ) x 100
(I ₀ : current value before drug application, I: current value after drug application, I _BaCl2 : current value after BaCl ₂ application)
The IC50 value of the compound of Synthesis Example 1 was 6.1 μM.

Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
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1000mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. Add low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution to the mixed powder, knead and granulate (extruded granulation pore size 0.5-1mm), then dry. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (I) 10 mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
----------------------------------
100mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. Fill 10 mg powder into a No. 5 hard gelatin capsule.

Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Component Compound represented by formula (I) 15 mg
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
----------------------------------
150mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granule is sieved with a vibrating screen (12/60 mesh) and the size is adjusted, and 150 mg of the dried granule is filled into a No. 4 hard gelatin capsule.

Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
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150mg total
The compound represented by the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 5
The intravenous formulation is produced as follows.
Compound represented by formula (I) 100 mg
Saturated fatty acid glyceride 1000mL
A solution of the above components is usually administered intravenously to the patient at a rate of 1 mL per minute.

  Since the compound of the present invention inhibits IKCh, it can be used as a prophylactic / therapeutic / ameliorating agent for diseases in which suppression of IKCh is effective, particularly a therapeutic agent useful for the treatment and / or prevention of arrhythmia, and is useful as a pharmaceutical. .

Claims (12)

Formula (I)

[Wherein, R ¹ and R ² are each independently a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is independent or different from the substituent group V ¹ Substituted with one or more selected substituents), a C _6-14 aryl group or a C _1-6 alkoxy group (whether the C _6-14 aryl group and the C _1-6 alkoxy group are unsubstituted) Or substituted with one or more halogen atoms), or taken together means a C _3-8 cycloalkyl group or a C _2-9 heterocyclyl group,
R ³ represents a hydroxyl group or a C _1-6 alkylcarbonyloxy group, or together with R ^{4 represents} a bond,
R ⁴ represents a hydrogen atom or together with R ^{3 represents} a bond,
X is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently; One carbon atom may be substituted with S, O, SO ₂ or NH),
R ⁵ represents a hydrogen atom or a C _1-6 alkyl group (the alkyl group is unsubstituted or substituted with one or more substituents selected from substituent group V ¹ alone or differently). Means
R ⁶ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, a C _6-14 aryl group, a C _2-9 heteroaryl group or a C _2-9 heterocyclyl group (this Is the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aryl group, C _2-9 heteroaryl group and C _2-9 heterocyclyl group unsubstituted? Or substituted with one or more substituents selected from the substituent group V ¹ singly or differently, and V represents a substituent selected from the substituent group V ¹ ;
m represents an integer of 0 to 2 (when m is 2, two Vs may be the same or different);
A is a 5-, 6-, or 7-membered ring that shares two carbon atoms with the benzene ring, and the 5-, 6-, or 7-membered ring is unsubstituted or selected alone or differently from the substituent group V ¹ 1 to 3 atoms alone or in combination as a constituent atom of a ring other than the two carbon atoms shared with the benzene ring. The number of unsaturated bonds in the ring is 1, 2 or 3, including the unsaturated bond of the condensed benzene ring, and the number of carbon atoms constituting the ring is other than two shared with the benzene ring. Carbon atom may be carbonyl or thiocarbonyl).
Substituent group V ¹ was a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group , Di C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, mono C _1-6 Alkylaminocarbonyl group, di-C _1-6 alkylaminocarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, C _6-14 aryl group, C _2-9 A heteroaryl group, a C _2-9 heterocyclyl group (the mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkyl) Group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, mono C _1-6 alkylaminocarbonyl group, di-C _1-6 alkylaminocarbonyl group , C _1-6 alkylcarbonylamino group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, C _6-14 aryl group, C _2-9 heteroaryl group, and C _2-9 heterocyclyl group are unsubstituted. Or a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a halogen-substituted C _1-3 alkyl group, C _1-6 alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, a hydroxyl group, an amino group, a mono _{C 1-6} alkylamino group, di _1-6 alkylamino group, a mono _{C 1-6} alkylaminocarbonyl group, di _{C 1-6} alkylaminocarbonyl _{group, C 1-6} alkylcarbonylamino _{group, C 1-6} alkylthio _{group, C 1-6} alkylsulfonyl group , C _6-14 aryl group, C _2-9 heteroaryl group, or C _2-9 heterocyclyl group (the C _6-14 aryl group, C _2-9 heteroaryl group and C _2-9 heterocyclyl group are unsubstituted) Or a carboxyl group, carbamoyl group, sulfamoyl group, phosphono group, sulfo group, tetrazolyl group, formyl group, nitro group, cyano group, halogen atom, C _1-6 alkyl group, halogen-substituted C _1-3 alkyl group, C _C1-6 alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, a hydroxyl group, an amino group, a mono _{C 1-6} alkylamino Group, _{di-C 1-6} alkylamino group, or a hydroxyl group mono _{C 1-6} alkylaminocarbonyl group (the mono- _{C 1-6} alkylaminocarbonyl group is _{unsubstituted, C 6-14} aryl _{group, C 2-} It is substituted with one or more substituents selected from ₉ heteroaryl groups or C _2-9 heterocyclyl groups. ), A di C _1-6 alkylaminocarbonyl group, a C _1-6 alkylcarbonylamino group, a C _1-6 alkylthio group or a C _1-6 alkylsulfonyl group. ) Is substituted with one or more substituents selected singly or differently. ). ]
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. R ¹ and R ² are each independently a C _1-6 alkyl group, R ³ is a hydroxyl group or a C _1-6 alkylcarbonyloxy group, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom. The benzopyran compound according to claim 1, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. The benzopyran compound according to claim 2, wherein R ¹ and R ² are a methyl group, and R ³ is a hydroxyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. object. X is a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). , R ⁶ is a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-14 aryl group, or a C _2-9 heteroaryl group (the C _1-6 alkyl group, C _3-8 cycloalkyl group) And the C _6-14 aryl group and the C _2-9 heteroaryl group are unsubstituted or substituted with a halogen atom), and m is 0. 4. The benzopyran compound described, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. X is a C _2-4 alkylene group (the C _2-4 alkylene group is unsubstituted or substituted with one methyl group or a hydroxyl group), and R ⁶ is a cyclohexyl group or a phenyl group (the The cyclohexyl group and the phenyl group are unsubstituted or substituted with a halogen atom.) The benzopyran compound according to claim 4, a tautomer, prodrug or pharmaceutically acceptable salt of the compound Salts or solvates thereof. ^6. The benzopyran compound according to claim 5, wherein X is an ethylene group, and R ⁶ is a phenyl group (the phenyl group is unsubstituted or substituted with a halogen atom), a tautomer of the compound , Prodrugs or pharmaceutically acceptable salts thereof, or solvates thereof. A C _3-5 heteroaryl group in which A is condensed with a benzene ring sharing two carbon atoms (the C _3-5 heteroaryl group is unsubstituted or has one or more C _1-6 alkyl groups ( The alkyl group is unsubstituted or substituted with one or more halogen atoms, amino groups or hydroxyl groups.)). Benzopyran compounds, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof. A C _4-5 heteroaryl group in which A is condensed with a benzene ring sharing two carbon atoms (the C _4-5 heteroaryl group is unsubstituted or has one or more C _1-3 alkyl groups ( The alkyl group is unsubstituted or substituted with a hydroxyl group. Acceptable salts or solvates thereof.   An IKACh inhibitor comprising as an active ingredient the compound according to any one of claims 1 to 8, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.   A prophylactic / therapeutic / ameliorating agent for a disease having an effective KACh channel inhibitory effect, comprising the IKCh inhibitor according to claim 9 as an active ingredient.   The arrhythmia therapeutic agent which contains the IKCh inhibitor of Claim 9 as an active ingredient.   A pharmaceutical comprising the compound according to any one of claims 1 to 8, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.