JP4356504B2 - p38 MAP kinase inhibitor - Google Patents

Description

  The present invention relates to a p38 MAP kinase inhibitor comprising a novel 4-imidazolin-2-one compound and a pharmaceutical composition thereof.

Mitogen-activated protein (MAP) kinase is a type of serine-threonine kinase that transfers the γ-phosphate group of adenosine triphosphate (ATP) to the hydroxyl group of specific serine or threonine that constitutes the protein. It is involved in various cellular responses to signals. p38 MAP kinase is a protein of about 38 kDa cloned as a homologue of MAP kinase.
p38MAP kinase is activated by inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1), stress stimulation such as ultraviolet irradiation, and the like. In addition, p38 MAP kinase uses various transcription factor groups and kinase groups as substrates, and these transcription factor groups and kinase groups are activated by p38 MAP kinase, thereby being involved in various inflammatory reactions such as inflammatory cytokines. It has been clarified that it contributes to the promotion of transcription, post-transcriptional regulation (stabilization of mRNA and promotion of protein translation), protein stabilization, and the like. Therefore, p38 MAP kinase is deeply involved in various inflammatory reactions through the production of inflammatory cytokines and the control of receptor signaling, and inhibitors of p38 MAP kinase are used in various diseases such as inflammatory diseases. It is considered likely to be a therapeutic drug.
As an inhibitor of p38 MAP kinase, an imidazole derivative (Patent Document 1), a 1,3-thiazole derivative (Patent Document 2), a 1,3-thiazole derivative and a 1,3-oxazole derivative (Patent Document 3), Imidazole derivatives, pyrrole derivatives, furan derivatives, 3-pyrazolin-5-one derivatives, pyrazole derivatives, thiophene derivatives, and the like are known (Non-Patent Document 1), respectively. However, none of these describes any 4-imidazolin-2-one compounds.

JP 2000-503304 Gazette JP 2001-114690 A Japanese Patent Application Laid-Open No. 2001-11479 Expert Opinion on Therapeutic Patents, 2000, Vol. 10, No. 1, p.25-37

  It is an object of the present invention to provide a p38 MAP kinase inhibitor comprising a novel 4-imidazolin-2-one compound useful as a medicament and a pharmaceutical composition thereof.

〔式中、Ｇ^１は、ハロゲン原子もしくはアルコキシで置換されたアルキル、または式：

（式中、環Ｂは、ベンゼン環、ナフタレン環、単環性もしくは二環性芳香族複素環またはシクロアルカンを表し、該ベンゼン環、該ナフタレン環、該単環性もしくは二環性芳香族複素環および該シクロアルカンは、ハロゲン原子、ニトロ、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアミノ、置換されていてもよいカルバモイル、水酸基およびシアノより成る群から選ばれる同一または異なる１〜３個の基で置換されてもよい。Ｗは、単結合、または１もしくは２個のアルキルで置換されていてもよいＣ_１〜Ｃ_４アルキレンを表す。）
で表される基を表す。
Ｑ^１およびＱ^２は、同一でも異なっていてもよく、それぞれ、水素原子、ハロゲン原子またはアルキルを表す。
ｎは、０、１、２、３または４を表す。
Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル、置換されていてもよいフェニルまたは置換されていてもよい複素環式基を表す。
Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、同一でも異なっていてもよく、それぞれ、ＣＨまたはＮを表し、ただし、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４のうち３つ以上がＮになることはない。
Ｇ^２は、水素原子、−ＮＲ^３Ｒ^４、−ＯＲ^５、−ＳＲ^５、−ＣＯＲ^６、−ＣＨＲ^７Ｒ^８または複素環式基を表す。
Ｒ^３〜Ｒ^８は、互いに独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、水酸基、アルコキシ、置換されていてもよいアミノ、置換されていてもよいアルカノイル、置換されていてもよいカルバモイル、アルコキシオキサリル、アルキルスルホニル、置換されていてもよいシクロアルキル、置換されていてもよいフェニル、置換されていてもよい複素環式基、置換されていてもよいシクロアルキル置換カルボニル、置換されていてもよいフェニル置換カルボニルまたは置換されていてもよい複素環式基置換カルボニルを表す。〕
で示される化合物またはその薬理的に許容しうる塩からなる医薬。 As a result of intensive studies, the present inventors have found that the following 4-imidazolin-2-one compound has an excellent p38 MAP kinase inhibitory action and completed the present invention.
That is, the present invention is as follows.
1. Formula [I]:

[Wherein G ¹ represents an alkyl substituted with a halogen atom or alkoxy, or a group represented by the formula:

(In the formula, ring B represents a benzene ring, naphthalene ring, monocyclic or bicyclic aromatic heterocycle or cycloalkane, and the benzene ring, naphthalene ring, monocyclic or bicyclic aromatic heterocycle The ring and the cycloalkane are a group consisting of a halogen atom, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted carbamoyl, hydroxyl group and cyano. And W is a single bond or C ₁ -C ₄ alkylene which may be substituted with 1 or 2 alkyls.
Represents a group represented by
Q ¹ and Q ² may be the same or different and each represents a hydrogen atom, a halogen atom or alkyl.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and each represents CH or N, provided that three or more of Z ¹ , Z ² , Z ³ and Z ⁴ are N. Never become.
G ² represents a hydrogen atom, —NR ³ R ⁴ , —OR ⁵ , —SR ⁵ , —COR ⁶ , —CHR ⁷ R ^8, or a heterocyclic group.
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. ]
Or a pharmacologically acceptable salt thereof.

（式中、環Ａは、ベンゼン環または単環性芳香族複素環を表し、該ベンゼン環および該単環性芳香族複素環は、ハロゲン原子、ニトロ、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアミノ、置換されていてもよいカルバモイル、水酸基およびシアノより成る群から選ばれる同一または異なる１〜３個の基で置換されてもよい。
Ｑ^１は、水素原子、ハロゲン原子またはアルキルを表す。
Ｗは、単結合、または１もしくは２個のアルキルで置換されていてもよいＣ_１〜Ｃ_４アルキレンを表す。
ｎは、０、１、２、３または４を表す。
Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル、置換されていてもよいフェニルまたは置換されていてもよい複素環式基を表す。
Ｚは、ＣＨまたはＮを表す。
Ｒ^２は、水素原子、−ＮＲ^３Ｒ^４、−ＯＲ^５、−ＣＯＲ^６または−ＣＨＲ^７Ｒ^８を表す。
Ｒ^３〜Ｒ^８は、互いに独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、水酸基、アルコキシ、置換されていてもよいアミノ、置換されていてもよいアルカノイル、置換されていてもよいカルバモイル、アルコキシオキサリル、アルキルスルホニル、置換されていてもよいシクロアルキル、置換されていてもよいフェニル、置換されていてもよい複素環式基、置換されていてもよいシクロアルキル置換カルボニル、置換されていてもよいフェニル置換カルボニルまたは置換されていてもよい複素環式基置換カルボニルを表す。）
で示される化合物またはその薬理的に許容しうる塩からなる医薬。 2. Formula [Ia]:

(In the formula, ring A represents a benzene ring or a monocyclic aromatic heterocycle, and the benzene ring and the monocyclic aromatic heterocycle are a halogen atom, nitro, an optionally substituted alkyl, a substituted May be substituted with 1 to 3 identical or different groups selected from the group consisting of optionally substituted alkoxy, optionally substituted amino, optionally substituted carbamoyl, hydroxyl group and cyano.
Q ¹ represents a hydrogen atom, a halogen atom or alkyl.
W represents a single bond or C ₁ -C ₄ alkylene which may be substituted with 1 or 2 alkyls.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z represents CH or N.
R ² represents a hydrogen atom, —NR ³ R ⁴ , —OR ⁵ , —COR ⁶ or —CHR ⁷ R ⁸ .
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. )
Or a pharmacologically acceptable salt thereof.

（式中、Ｒ^１１は、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_４アルキルおよびＣ_１〜Ｃ_４アルコキシより成る群から選ばれる基を表す。
ｋは１または２を表し、ｋが２のとき、２つのＲ^１１は同一でも異なっていてもよい。
Ｒ^１２は、（１）水酸基、アルコキシ、シアノ、アルキル置換されていてもよいカルバモイルおよびアミノより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、
（２）Ｃ_３〜Ｃ_４シクロアルキルメチル、
（３）カルバモイルメチル、
（４）シアノ、ハロゲン原子、Ｃ_１〜Ｃ_３アルコキシ、Ｃ_１〜Ｃ_３アルキルおよびハロゲン置換Ｃ_１〜Ｃ_３アルキルより成る群から選ばれる基で置換されていてもよいベンジル、
（５）テトラヒドロピラニル、または
（６）アルキル、アルカノイル、アルキルスルホニル、アルコキシカルボニルおよびアルキル置換されていてもよいカルバモイルアルキルより成る群から選ばれる基で置換されていてもよいピペリジルを表す。
Ｚ^５はＣＨまたはＮを表す。
Ｒ^１３は、（１）Ｃ_１〜Ｃ_６アルキル（該Ｃ_１〜Ｃ_６アルキルは、次の（ｉ）〜（ｘｉｉ）より成る群から選ばれる基で置換されていてもよい）：
（ｉ）次のａ）〜ｅ）より成る群から選ばれる基で置換されていてもよいＣ_５〜Ｃ_７シクロアルキル、
ａ）水酸基、
ｂ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいアミノ、
ｃ）Ｃ_１〜Ｃ_４アルカノイルアミノ、
ｄ）水酸基、アミノおよびＣ_１〜Ｃ_４アルキル置換されていてもよいカルバモイルより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、および
ｅ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル
（ｉｉ）水酸基、および
（ｉｉｉ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル、
（ｉｖ）アルキル、アルカノイル、アルキルスルホニルおよびオキソより成る群から選ばれる基で置換されていてもよいピペリジル、
（ｖ）アルキル、アルカノイル、アルキルスルホニルおよびオキソより成る群から選ばれる基で置換されていてもよいピロリジニル、
（ｖｉ）水酸基で置換されていてもよいテトラヒドロピラニル、
（ｖｉｉ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいイミダゾリニル、
（ｖｉｉｉ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいイミダゾリジニル、
（ｉｘ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいピペラジニル、
（ｘ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいヘキサヒドロピリミジニル、
（ｘｉ）アルキル置換されていてもよいピリジル、および
（ｘｉｉ）フリル
（２）Ｃ_５〜Ｃ_７シクロアルキル（該Ｃ_５〜Ｃ_７シクロアルキルは、次の（ｉ）〜（ｉｉｉ）より成る群から選ばれる基で置換されていてもよい）、
（ｉ）水酸基、
（ｉｉ）水酸基、アミノおよびＣ_１〜Ｃ_４アルキル置換されていてもよいカルバモイルより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、および
（ｉｉｉ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル、または
（３）複素環式基（該複素環式基は、次の（ｉ）〜（ｖｉ）より成る群から選ばれる基で置換されていてもよい）、
（ｉ）ハロゲン、アミノ、水酸基、フェニルおよびオキソから選ばれる基で置換されていてもよいアルキル、
（ｉｉ）アルキル置換されていてもよいアミノスルホニル、
（ｉｉｉ）ハロゲンで置換されていてもよいアルキルスルホニル、
（ｉｖ）アルキル置換されていてもよいカルバモイル、
（ｖ）水酸基、および
（ｖｉ）アルコキシカルボニルを表す。）
で示される化合物またはその薬理的に許容しうる塩からなる医薬。 3. Formula [Ib]

(In the formula, R ¹¹ represents a group selected from the group consisting of a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.
k represents 1 or 2, and when k is 2, two R ¹¹ may be the same or different.
R ¹² is (1) a C ₁ -C ₄ alkyl optionally substituted with a group selected from the group consisting of a hydroxyl group, alkoxy, cyano, an optionally substituted carbamoyl and amino;
₍₂₎ C 3 ~C ₄ cycloalkylmethyl,
(3) Carbamoylmethyl,
(4) cyano, halogen _atom, C 1 -C _{3 alkoxy,} C 1 -C ₃ alkyl and halogen-substituted _C 1 -C ₃ optionally substituted with a group selected from the group consisting of alkyl benzyl,
(5) represents tetrahydropyranyl, or (6) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl and optionally substituted carbamoylalkyl.
Z ⁵ represents CH or N.
R ¹³ is (1) C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with a group selected from the group consisting of the following (i) to (xii)):
(I) following a) may be substituted with a group selected from the group consisting of ~e) _C 5 ~C ₇ cycloalkyl,
a) a hydroxyl group,
_b) C 1 ~C ₄ alkyl optionally substituted amino,
_c) C 1 ~C ₄ alkanoylamino,
d) a hydroxyl group, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _e) C 1 -C ₄ alkyl-substituted An optionally substituted carbamoyl (ii) hydroxyl group, and (iii) a C ₁ -C ₄ alkyl optionally substituted carbamoyl,
(Iv) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(V) pyrrolidinyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(Vi) tetrahydropyranyl optionally substituted with a hydroxyl group,
(Vii) imidazolinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Viii) imidazolidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Ix) piperazinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(X) hexahydropyrimidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(Xi) an alkyl-substituted pyridyl, and (xii) furyl (2) C ₅ -C ₇ cycloalkyl (the C ₅ -C ₇ cycloalkyl is a group consisting of the following (i) to (iii): Optionally substituted with a group selected from:
(I) a hydroxyl group,
(Ii) hydroxyl, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _(iii) C 1 -C ₄ An optionally substituted carbamoyl, or (3) a heterocyclic group (which may be substituted with a group selected from the group consisting of the following (i) to (vi)):
(I) alkyl optionally substituted with a group selected from halogen, amino, hydroxyl group, phenyl and oxo,
(Ii) alkylsulfonyl-substituted aminosulfonyl,
(Iii) alkylsulfonyl optionally substituted with halogen,
(Iv) an optionally substituted carbamoyl,
(V) represents a hydroxyl group and (vi) alkoxycarbonyl. )
Or a pharmacologically acceptable salt thereof.

4). 4. The medicament according to any one of 1 to 3 above, which is a p38 MAP kinase inhibitor.
5. 5. The pharmaceutical according to any one of 1 to 4 above, which is a preventive or therapeutic agent for a disease involving p38 MAP kinase.
6). 5. The medicament according to any one of 1 to 4 above, which is a preventive or therapeutic agent for inflammatory diseases.
7). 5. The medicament according to any one of 1 to 4 above, which is a prophylactic or therapeutic agent for arthritis.

〔式中、Ｇ^１は、ハロゲン原子もしくはアルコキシで置換されたアルキル、または式：

（式中、環Ｂは、ベンゼン環、ナフタレン環、単環性もしくは二環性芳香族複素環またはシクロアルカンを表し、該ベンゼン環、該ナフタレン環、該単環性もしくは二環性芳香族複素環および該シクロアルカンは、ハロゲン原子、ニトロ、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアミノ、置換されていてもよいカルバモイル、水酸基およびシアノより成る群から選ばれる同一または異なる１〜３個の基で置換されてもよい。Ｗは、単結合、または１もしくは２個のアルキルで置換されていてもよいＣ_１〜Ｃ_４アルキレンを表す。）
で表される基を表す。
Ｑ^１およびＱ^２は、同一でも異なっていてもよく、それぞれ、水素原子、ハロゲン原子またはアルキルを表す。
ｎは、０、１、２、３または４を表す。
Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル、置換されていてもよいフェニルまたは置換されていてもよい複素環式基を表す。
Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、同一でも異なっていてもよく、それぞれ、ＣＨまたはＮを表し、ただし、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４のうち３つ以上がＮになることはない。
Ｇ^２は、水素原子、−ＮＲ^３Ｒ^４、−ＯＲ^５、−ＳＲ^５、−ＣＯＲ^６、−ＣＨＲ^７Ｒ^８または複素環式基を表す。
Ｒ^３〜Ｒ^８は、互いに独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、水酸基、アルコキシ、置換されていてもよいアミノ、置換されていてもよいアルカノイル、置換されていてもよいカルバモイル、アルコキシオキサリル、アルキルスルホニル、置換されていてもよいシクロアルキル、置換されていてもよいフェニル、置換されていてもよい複素環式基、置換されていてもよいシクロアルキル置換カルボニル、置換されていてもよいフェニル置換カルボニルまたは置換されていてもよい複素環式基置換カルボニルを表す。〕
で示される化合物またはその薬理的に許容しうる塩、および薬理学的に許容される担体からなる医薬組成物。 8). Formula [I]:

[Wherein G ¹ represents an alkyl substituted with a halogen atom or alkoxy, or a group represented by the formula:

(In the formula, ring B represents a benzene ring, naphthalene ring, monocyclic or bicyclic aromatic heterocycle or cycloalkane, and the benzene ring, naphthalene ring, monocyclic or bicyclic aromatic heterocycle The ring and the cycloalkane are a group consisting of a halogen atom, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted carbamoyl, hydroxyl group and cyano. And W is a single bond or C ₁ -C ₄ alkylene which may be substituted with 1 or 2 alkyls.
Represents a group represented by
Q ¹ and Q ² may be the same or different and each represents a hydrogen atom, a halogen atom or alkyl.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and each represents CH or N, provided that three or more of Z ¹ , Z ² , Z ³ and Z ⁴ are N. Never become.
G ² represents a hydrogen atom, —NR ³ R ⁴ , —OR ⁵ , —SR ⁵ , —COR ⁶ , —CHR ⁷ R ^8, or a heterocyclic group.
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. ]
Or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

（式中、環Ａは、ベンゼン環または単環性芳香族複素環を表し、該ベンゼン環および該単環性芳香族複素環は、ハロゲン原子、ニトロ、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアミノ、置換されていてもよいカルバモイル、水酸基およびシアノより成る群から選ばれる同一または異なる１〜３個の基で置換されてもよい。
Ｑ^１は、水素原子、ハロゲン原子またはアルキルを表す。
Ｗは、単結合、または１もしくは２個のアルキルで置換されていてもよいＣ_１〜Ｃ_４アルキレンを表す。
ｎは、０、１、２、３または４を表す。
Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル、置換されていてもよいフェニルまたは置換されていてもよい複素環式基を表す。
Ｚは、ＣＨまたはＮを表す。
Ｒ^２は、水素原子、−ＮＲ^３Ｒ^４、−ＯＲ^５、−ＣＯＲ^６または−ＣＨＲ^７Ｒ^８を表す。
Ｒ^３〜Ｒ^８は、互いに独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、水酸基、アルコキシ、置換されていてもよいアミノ、置換されていてもよいアルカノイル、置換されていてもよいカルバモイル、アルコキシオキサリル、アルキルスルホニル、置換されていてもよいシクロアルキル、置換されていてもよいフェニル、置換されていてもよい複素環式基、置換されていてもよいシクロアルキル置換カルボニル、置換されていてもよいフェニル置換カルボニルまたは置換されていてもよい複素環式基置換カルボニルを表す。）
で示される化合物またはその薬理的に許容しうる塩、および薬理学的に許容される担体からなる医薬組成物。 9. Formula [Ia]:

(In the formula, ring A represents a benzene ring or a monocyclic aromatic heterocycle, and the benzene ring and the monocyclic aromatic heterocycle are a halogen atom, nitro, an optionally substituted alkyl, a substituted May be substituted with 1 to 3 identical or different groups selected from the group consisting of optionally substituted alkoxy, optionally substituted amino, optionally substituted carbamoyl, hydroxyl group and cyano.
Q ¹ represents a hydrogen atom, a halogen atom or alkyl.
W represents a single bond or C ₁ -C ₄ alkylene which may be substituted with 1 or 2 alkyls.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z represents CH or N.
R ² represents a hydrogen atom, —NR ³ R ⁴ , —OR ⁵ , —COR ⁶ or —CHR ⁷ R ⁸ .
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. )
Or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

（式中、Ｒ^１１は、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_４アルキルおよびＣ_１〜Ｃ_４アルコキシより成る群から選ばれる基を表す。
ｋは１または２を表し、ｋが２のとき、２つのＲ^１１は同一でも異なっていてもよい。
Ｒ^１２は、（１）水酸基、アルコキシ、シアノ、アルキル置換されていてもよいカルバモイルおよびアミノより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、
（２）Ｃ_３〜Ｃ_４シクロアルキルメチル、
（３）カルバモイルメチル、
（４）シアノ、ハロゲン原子、Ｃ_１〜Ｃ_３アルコキシ、Ｃ_１〜Ｃ_３アルキルおよびハロゲン置換Ｃ_１〜Ｃ_３アルキルより成る群から選ばれる基で置換されていてもよいベンジル、
（５）テトラヒドロピラニル、または
（６）アルキル、アルカノイル、アルキルスルホニル、アルコキシカルボニルおよびアルキル置換されていてもよいカルバモイルアルキルより成る群から選ばれる基で置換されていてもよいピペリジルを表す。
Ｚ^５はＣＨまたはＮを表す。
Ｒ^１３は、（１）Ｃ_１〜Ｃ_６アルキル（該Ｃ_１〜Ｃ_６アルキルは、次の（ｉ）〜（ｘｉｉ）より成る群から選ばれる基で置換されていてもよい）：
（ｉ）次のａ）〜ｅ）より成る群から選ばれる基で置換されていてもよいＣ_５〜Ｃ_７シクロアルキル、
ａ）水酸基、
ｂ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいアミノ、
ｃ）Ｃ_１〜Ｃ_４アルカノイルアミノ、
ｄ）水酸基、アミノおよびＣ_１〜Ｃ_４アルキル置換されていてもよいカルバモイルより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、および
ｅ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル
（ｉｉ）水酸基、および
（ｉｉｉ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル、
（ｉｖ）アルキル、アルカノイル、アルキルスルホニルおよびオキソより成る群から選ばれる基で置換されていてもよいピペリジル、
（ｖ）アルキル、アルカノイル、アルキルスルホニルおよびオキソより成る群から選ばれる基で置換されていてもよいピロリジニル、
（ｖｉ）水酸基で置換されていてもよいテトラヒドロピラニル、
（ｖｉｉ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいイミダゾリニル、
（ｖｉｉｉ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいイミダゾリジニル、
（ｉｘ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいピペラジニル、
（ｘ）アルキルおよびオキソより成る群から選ばれる基で置換されていてもよいヘキサヒドロピリミジニル、
（ｘｉ）アルキル置換されていてもよいピリジル、および
（ｘｉｉ）フリル
（２）Ｃ_５〜Ｃ_７シクロアルキル（該Ｃ_５〜Ｃ_７シクロアルキルは、次の（ｉ）〜（ｉｉｉ）より成る群から選ばれる基で置換されていてもよい）、
（ｉ）水酸基、
（ｉｉ）水酸基、アミノおよびＣ_１〜Ｃ_４アルキル置換されていてもよいカルバモイルより成る群から選ばれる基で置換されていてもよいＣ_１〜Ｃ_４アルキル、および
（ｉｉｉ）Ｃ_１〜Ｃ_４アルキル置換されていてもよいカルバモイル、または
（３）複素環式基（該複素環式基は、次の（ｉ）〜（ｖｉ）より成る群から選ばれる基で置換されていてもよい）、
（ｉ）ハロゲン、アミノ、水酸基、フェニルおよびオキソから選ばれる基で置換されていてもよいアルキル、
（ｉｉ）アルキル置換されていてもよいアミノスルホニル、
（ｉｉｉ）ハロゲンで置換されていてもよいアルキルスルホニル、
（ｉｖ）アルキル置換されていてもよいカルバモイル、
（ｖ）水酸基、および
（ｖｉ）アルコキシカルボニルを表す。）
で示される化合物またはその薬理的に許容しうる塩、および薬理学的に許容される担体からなる医薬組成物。 10. Formula [Ib]

(In the formula, R ¹¹ represents a group selected from the group consisting of a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.
k represents 1 or 2, and when k is 2, two R ¹¹ may be the same or different.
R ¹² is (1) a C ₁ -C ₄ alkyl optionally substituted with a group selected from the group consisting of a hydroxyl group, alkoxy, cyano, an optionally substituted carbamoyl and amino;
₍₂₎ C 3 ~C ₄ cycloalkylmethyl,
(3) Carbamoylmethyl,
(4) cyano, halogen _atom, C 1 -C _{3 alkoxy,} C 1 -C ₃ alkyl and halogen-substituted _C 1 -C ₃ optionally substituted with a group selected from the group consisting of alkyl benzyl,
(5) represents tetrahydropyranyl, or (6) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl and optionally substituted carbamoylalkyl.
Z ⁵ represents CH or N.
R ¹³ is (1) C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with a group selected from the group consisting of the following (i) to (xii)):
(I) following a) may be substituted with a group selected from the group consisting of ~e) _C 5 ~C ₇ cycloalkyl,
a) a hydroxyl group,
_b) C 1 ~C ₄ alkyl optionally substituted amino,
_c) C 1 ~C ₄ alkanoylamino,
d) a hydroxyl group, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _e) C 1 -C ₄ alkyl-substituted An optionally substituted carbamoyl (ii) hydroxyl group, and (iii) a C ₁ -C ₄ alkyl optionally substituted carbamoyl,
(Iv) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(V) pyrrolidinyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(Vi) tetrahydropyranyl optionally substituted with a hydroxyl group,
(Vii) imidazolinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Viii) imidazolidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Ix) piperazinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(X) hexahydropyrimidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(Xi) an alkyl-substituted pyridyl, and (xii) furyl (2) C ₅ -C ₇ cycloalkyl (the C ₅ -C ₇ cycloalkyl is a group consisting of the following (i) to (iii): Optionally substituted with a group selected from:
(I) a hydroxyl group,
(Ii) hydroxyl, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _(iii) C 1 -C ₄ An optionally substituted carbamoyl, or (3) a heterocyclic group (which may be substituted with a group selected from the group consisting of the following (i) to (vi)):
(I) alkyl optionally substituted with a group selected from halogen, amino, hydroxyl group, phenyl and oxo,
(Ii) alkylsulfonyl-substituted aminosulfonyl,
(Iii) alkylsulfonyl optionally substituted with halogen,
(Iv) an optionally substituted carbamoyl,
(V) represents a hydroxyl group and (vi) alkoxycarbonyl. )
Or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

Examples of “alkyl” in the present invention, and alkyl in “alkylthio”, “alkylsulfinyl” and “alkylsulfonyl” include linear or branched C ₁ -C ₆ alkyl, specifically, methyl, ethyl Propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like. Preferred alkyl _include C 1 -C ₄ alkyl.

Examples of alkoxy in “alkoxy” and “alkoxycarbonyl” and “alkoxyoxalyl” include linear or branched C ₁ -C ₆ alkoxy, specifically methoxy, ethoxy, propoxy, isopropoxy, Examples include butoxy, isobutoxy, pentoxy, hexoxy and the like. Preferred alkoxy _include C 1 -C ₄ alkoxy.

Examples of “alkenyl” include linear or branched C ₂ -C ₇ alkenyl, and specific examples include vinyl, allyl, 3-butenyl, 2-pentenyl, 3-hexenyl and the like. With preference given to _C 2 -C ₅ alkenyl.

Examples of “alkynyl” include linear or branched C ₂ -C ₇ alkynyl, and specific examples include ethynyl, propargyl, 3-butynyl, 2-pentynyl, 3-hexynyl and the like. With preference given to _C 2 -C ₅ alkynyl.

Examples of “alkanoyl” include linear or branched C ₂ -C ₇ alkanoyl, and specific examples include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and the like. With preference given to _C 2 -C ₅ alkanoyl.

“Cycloalkyl” includes, for example, C ₃ -C ₈ cycloalkyl, preferably C ₃ -C ₆ cycloalkyl.

Examples of “cycloalkane” include C _{3 to} C ₈ cycloalkane, and preferably C _{5 to} C ₇ cycloalkane.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom and a chlorine atom.

  Examples of the “heterocyclic group” include monocyclic, dicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, bicyclic, Examples thereof include cyclic or tricyclic heterocyclic groups. Preferable examples include 5- or 6-membered monocyclic heterocyclic groups, and specific examples include furyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiapyranyl, thienyl, tetrahydrothienyl, thiazolyl, isothiazolyl, tetrahydro Isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyridyl, pyridazinyl, pyrimidinyl, hexahydropyrimidinyl, pyrazinyl, triazinyl, piperidyl, pyrazolidyl, mol Examples include triazolyl, imidazolinyl, pyrazolinyl, thiazinyl, tetrahydrothiazinyl and the like.

  Examples of the “monocyclic or bicyclic aromatic heterocycle” include a monocyclic or bicyclic aromatic heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Is mentioned. Examples of the “monocyclic aromatic heterocycle” include monocyclic aromatic heterocycles containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. A 5- or 6-membered monocyclic aromatic heterocycle may be mentioned. Specific examples of monocyclic and bicyclic aromatic heterocycles include thiophene, furan, furazane, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, Examples include triazine, quinazoline, isoquinoline, phthalazine, naphthyridine, quinazoline, quinoline, chromene, indolizine, isoindole, indole, purine, benzofuran, benzothiophene, and the like. Preferred monocyclic aromatic heterocycles include thiophene and furan.

  When the substituent on the ring B in the compound [I] or the substituent on the ring A in the compound [Ia] is “optionally substituted alkyl”, examples of the substituent on the alkyl include a halogen atom, A hydroxyl group, amino, etc. are mentioned. The alkyl may have 1 to 3 substituents, and when the number of substituents is 2 or more, the substituents may be the same or different. Specific examples of substituted alkyl include hydroxymethyl, trifluoromethyl, aminomethyl, chloroethyl and the like.

  When the substituent on the ring B or the substituent on the ring A is “optionally substituted alkoxy”, examples of the substituent on the alkoxy include a hydroxyl group and amino. The alkoxy may have 1 to 3 substituents described above, and when the number of substituents is 2 or more, each substituent may be the same or different.

When the substituent on ring B or the substituent on ring A is “optionally substituted amino”, examples of the substituent on the amino include alkyl (the alkyl consists of alkoxy, amino and carboxy). And may be substituted with 1 to 3 identical or different groups selected from the group), alkanoyl and the like. The amino may have, for example, one or two of the above substituents, and when the number of substituents is 2, each substituent may be the same or different.
When the substituent on ring B or the substituent on ring A is “optionally substituted carbamoyl”, examples of the substituent on carbamoyl include alkyl and the like. The carbamoyl may have 1 or 2 substituents described above, and when the number of substituents is 2, each substituent may be the same or different.

The substituent on ring B in compound [I] and the substituent on ring A in compound [Ia] are preferably a halogen atom, nitro, alkyl which may be substituted, alkoxy which may be substituted, substituted Examples include amino and cyano. Particularly preferred are a halogen atom, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and the like, and specific examples thereof include a fluorine atom, a chlorine atom, methyl, methoxy and the like.

When R ¹ in the compounds [I] and [Ia] is “optionally substituted alkyl”, examples of the substituent on the alkyl include alkynyl, cyano, alkoxy, hydroxyl group, amino (the amino is alkyl , May be substituted with 1 or 2 groups selected from the group consisting of alkanoyl and alkylsulfonyl), carboxy, alkoxycarbonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 alkyl), And phenyl, naphthyl and the like. The alkyl may have, for example, 1 to 3 of the above substituents, and when the number of substituents is 2 or more, each substituent may be the same or different. Preferred substituents include cyano, alkoxy, hydroxyl group, amino, carboxy, alkyl-substituted carbamoyl, phenyl and the like.

When R ¹ is “cycloalkyl which may be substituted”, examples of the substituent on the cycloalkyl include (1) hydroxyl group, (2) alkoxy (the alkoxy is substituted with 1 to 3 alkoxy groups). (3) amino [the amino may be substituted with one or two identical or different groups selected from the group consisting of the following (i) to (v): (i) alkyl , (Ii) alkanoyl, (iii) alkoxycarbonyl, (iv) carbamoyl, which may be substituted with 1 or 2 alkyls, and (v) alkylsulfonyl], (4) carboxy, (5 ) Alkyl [wherein the alkyl may be substituted with a group selected from the group consisting of a hydroxyl group, alkoxy and amino], and (6) carbamoyl optionally substituted with alkyl. The cycloalkyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

When R ¹ is “optionally substituted phenyl”, examples of the substituent on the phenyl include (1) a halogen atom, (2) nitro, (3) alkyl (the alkyl is a halogen atom, a hydroxyl group, , (4) alkenyl, (5) cyano, (6) hydroxyl group, (7) alkoxy (which may be substituted with the same or different 1 to 3 groups selected from the group consisting of amino, carboxy and phenylsulfonyl) The alkoxy may be substituted with 1 to 3 identical or different groups selected from the group consisting of a halogen atom, carboxy, alkoxycarbonyl, carbamoyl, phenyl and morpholinylcarbonyl), (8) amino [the amino May be substituted with the same or different 1 or 2 groups selected from the group consisting of the following (i) to (iv): (i) alkyl, (ii) alkano (Iii) carbamoyl (which may be substituted with one or two identical or different groups selected from the group consisting of alkyl and cycloalkyl), and (iv) alkylsulfonyl], (9) alkanoyl , (10) carboxy, (11) alkoxycarbonyl, (12) carbamoyl [the carbamoyl may be substituted with the same or different 1 or 2 groups selected from the group consisting of the following (i) and (ii): Good: (i) alkyl (the alkyl may be substituted with 1 to 3 hydroxyl groups), and (ii) cycloalkyl], (13) alkylthio, (14) alkylsulfinyl, (15) alkylsulfonyl, (16) phenyl, (17) tetrazolyl, (18) heterocyclic group-substituted carbonyl (the heterocyclic group is alkyl and alkoxycarbo Same or may be replaced with a different 1 to 3 groups) such as selected from the group consisting of Le and the like. When R ¹ is an optionally substituted phenyl, the phenyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, each substituent is the same or different. It may be. Preferred substituents include (1) a halogen atom, (2) alkyl (the alkyl is substituted with 1 to 3 identical or different groups selected from the group consisting of a halogen atom, a hydroxyl group, amino, carboxy and phenylsulfonyl. (3) cyano, (4) alkoxy (the alkoxy is the same or different 1 to 3 groups selected from the group consisting of a halogen atom, carboxy, alkoxycarbonyl, carbamoyl, phenyl and morpholinylcarbonyl) And the like may be substituted. The substitution position of the substituent may be any position that can be substituted, and a particularly preferred position is the 2-position.

When R ¹ is “phenyl substituted with a heterocyclic group-substituted carbonyl”, the heterocyclic group includes the above-mentioned heterocyclic group, and preferably includes a 5- or 6-membered monocyclic ring. Nitrogen aliphatic heterocyclic groups are mentioned. Specific examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and the like.

When R ¹ is an “optionally substituted heterocyclic group”, examples of the heterocyclic group include the above-described heterocyclic groups, and preferably a 5- or 6-membered monocyclic heterocyclic group. And cyclic groups. Specific examples include furyl, tetrahydrofuryl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, tetrahydropyranyl and the like, particularly preferably piperidyl, tetrahydropyranyl and the like. Is mentioned. Examples of the substituent on the heterocyclic group include a halogen atom, nitro, alkyl (the alkyl is substituted with a group selected from the group consisting of a hydroxyl group, an alkoxy group, an optionally substituted carbamoyl group, and a carboxy group). May be substituted), cyano, hydroxyl group, amino, alkanoyl, carboxy, alkoxycarbonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 alkyls), alkylsulfonyl, phenyl and the like. The heterocyclic group may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

As a preferable combination of n and R ¹ in the compounds [I] and [Ia], for example, (1) n is 0, and R ¹ is an optionally substituted alkyl; 1 wherein R ¹ is an optionally substituted cycloalkyl, (3) n is 1 and R ¹ is an optionally substituted phenyl, (4) n is 1 Wherein R ¹ is an optionally substituted heterocyclic group, (5) n is 0 and R ¹ is an optionally substituted cycloalkyl, and (6) Examples thereof include those in which n is 0 and R ¹ is an optionally substituted heterocyclic group. Particularly preferably, (1) n is 0 and R ¹ is an optionally substituted alkyl, and (2) n is 1 and R ¹ is an optionally substituted phenyl. (3) n is 0 and R ¹ is an optionally substituted cycloalkyl, and (4) n is 0 and R ¹ is optionally substituted heterocyclic The thing etc. which are groups are mentioned. More preferably, (1) n is 0 and R ¹ is C ₁ -C ₄ alkyl optionally substituted with a hydroxyl group, (2) n is 1 and R ¹ is phenyl Phenyl is optionally substituted with a group selected from the group consisting of cyano, fluorine, chlorine and methyl), (3) n is 0 and R ¹ is C ₃ -C ₄ cycloalkyl. And (4) n is 0 and R ¹ is tetrahydropyranyl.

When R ^{3 to} R ⁸ in the compounds [I] and [Ia] are “optionally substituted alkyl”, examples of the substituent on the alkyl include (1) hydroxyl group, (2) alkoxy, ( 3) amino (the amino may be substituted with the same or different 1 or 2 groups selected from the group consisting of alkyl, alkanoyl and alkylsulfonyl), (4) alkoxycarbonyl, (5) cycloalkyl [ The cycloalkyl is a hydroxyl group, an alkyl optionally substituted amino, an alkanoylamino, an alkylsulfonylamino, an alkyl (the alkyl is a group selected from the group consisting of a hydroxyl group, alkoxy, amino, and an optionally substituted carbamoyl Optionally substituted with carboxy and alkyl substituted May be substituted with the same or different 1 to 3 groups selected from the group consisting of moyl], (6) phenyl [the phenyl is the same selected from the group consisting of the following (i) to (vi) Or may be substituted with 1 to 3 different groups: (i) a halogen atom, (ii) alkoxy, (iii) amino (the amino is the same or different 1 selected from the group consisting of alkyl and alkoxycarbonyl) Or optionally substituted with two groups), (iv) alkoxycarbonyl, (v) carbamoyl, and (vi) morpholinylcarbonyl], (7) a heterocyclic group [the heterocyclic group May be substituted with 1 to 3 identical or different groups selected from the group consisting of the following (i) to (viii): (i) alkyl (the alkyl is substituted with 1 to 3 hydroxyl groups) (Ii) hydroxyl group, (iii) amino, (iv) alkoxy Carbonyl, (v) carbamoyl, (vi) alkanoyl, (vii) alkylsulfonyl and (viii) oxo], and (8) mercapto, and the like. When R ^{3 to} R ⁸ are optionally substituted alkyl, the alkyl may have, for example, 1 to 3 of the above substituents. When the number of substituents is 2 or more, each substituent is They may be the same or different.

When R ^{3 to} R ⁸ are “alkyl substituted with a heterocyclic group”, examples of the heterocyclic group include the above-described heterocyclic groups, and preferably a 5- or 6-membered single ring. And cyclic heterocyclic groups. Specific examples include pyridyl, pyrimidinyl, pyrazinyl, piperidyl, pyrrolidinyl, morpholinyl, thienyl, furyl, tetrahydropyranyl, imidazolinyl, imidazolidinyl, piperazinyl, hexahydropyrimidinyl and the like.

When R ^{3 to} R ⁸ are “optionally substituted amino”, examples of the substituent on the amino group include alkyl (the alkyl is selected from the group consisting of a hydroxyl group, an alkoxy group, and a heterocyclic group). And may be substituted with the same or different 1 to 3 groups), cycloalkyl (the cycloalkyl may be substituted with 1 to 3 hydroxyl groups), a heterocyclic group, and the like. The amino may have, for example, 1 or 2 of the above substituents, and when the number of substituents is 2, each substituent may be the same or different.

In the case where R ^{3 to} R ⁸ are “amino substituted with a heterocyclic group-substituted alkyl” or “amino substituted with a heterocyclic group”, the heterocyclic group includes the heterocyclic group described above. Preferably, a 5- or 6-membered monocyclic heterocyclic group is used. Specific examples include pyridyl, piperidyl, pyrrolidinyl, morpholinyl and the like.

When R ^{3 to} R ⁸ are “optionally substituted alkanoyl”, examples of the substituent on the alkanoyl include a hydroxyl group, alkoxy, amino (the amino is the same selected from the group consisting of alkyl and alkanoyl). Or optionally substituted with different 1 or 2 groups), alkoxycarbonyl and the like. The alkanoyl may have, for example, 1 to 3 of the above substituents, and when the number of substituents is 2 or more, each substituent may be the same or different.

When R ^{3 to} R ⁸ are “optionally substituted carbamoyl”, examples of the substituent on the carbamoyl include alkyl, cycloalkyl, heterocyclic group and the like. The carbamoyl may have, for example, 1 or 2 of the above substituents, and when the number of substituents is 2, each substituent may be the same or different.

In the case where R ^{3 to} R ⁸ are “carbamoyl substituted with a heterocyclic group”, examples of the heterocyclic group include the above-mentioned heterocyclic groups, and preferably a 5- or 6-membered single ring. And cyclic heterocyclic groups. Specific examples include pyridyl, pyrimidinyl, piperidyl and the like.

When R ^{3 to} R ⁸ are “optionally substituted cycloalkyl”, examples of the substituent on the cycloalkyl include a halogen atom, alkyl (the alkyl is a hydroxyl group, mercapto, alkoxy, amino, and alkyl). Optionally substituted with 1 to 3 groups selected from the group consisting of optionally substituted carbamoyl), hydroxyl, alkoxy, amino (wherein the amino is alkyl, alkanoyl, carboxy, alkoxycarbonyl, alkyl-substituted) An optionally substituted carbamoyl, an optionally substituted aminosulfonyl and a halogenated optionally substituted alkylsulfonyl, which may be substituted with the same or different 1 or 2 groups), Carboxy, alkanoyloxy, alkoxycarbonyl, carbamo (Wherein the carbamoyl may be substituted with the same or different 1 or 2 groups selected from the group consisting of alkyl, cycloalkyl and heterocyclic group), alkyl-substituted carbamoyloxy and the like Can be mentioned. Preferably, alkyl (the alkyl may be substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and optionally substituted carbamoyl), a hydroxyl group, amino (wherein the amino is alkyl, alkanoyl) Alkanoyloxy and optionally substituted carbamoyl, which may be substituted with the same or different 1 or 2 groups selected from the group consisting of alkoxycarbonyl and alkylsulfonyl. When R ^{3 to} R ⁸ are an optionally substituted cycloalkyl, the cycloalkyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, The groups may be the same or different.

  Preferred substituted cycloalkyls include 4-hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-aminocyclohexyl, 4-acetylaminocyclohexyl, 4-dimethylaminocyclohexyl, 4-carbamoylmethylaminocyclohexyl, 4-acetoxycyclohexyl, 4-hydroxymethylcyclohexyl, 2-hydroxycyclopentyl, 4-carbamoylcyclohexyl, 4-methanesulfonylaminocyclohexyl, 4-methoxycarbonylaminocyclohexyl, 4-methylcarbamoylcyclohexyl, 4- (1-hydroxy-1-methylethyl) cyclohexyl, Examples include 1-hydroxymethylcyclopentyl.

When R ^{3 to} R ⁸ are “cycloalkyl substituted with a heterocyclic group-substituted carbamoyl”, examples of the heterocyclic group include the heterocyclic groups described above, preferably 5 or 6 members. And monocyclic heterocyclic groups having a ring. Specific examples include pyridyl, pyrimidinyl, piperidyl and the like.

When R ^{3 to} R ⁸ are “optionally substituted phenyl”, examples of the substituent on the phenyl include alkyl, hydroxyl group, alkoxy, halogen atom, amino (optionally substituted with a hydroxyl group) Amino may be substituted with 1 or 2 alkyls or alkylsulfonyls). The phenyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

When R ^{3 to} R ⁸ are “optionally substituted heterocyclic group”, examples of the heterocyclic group include the above-described heterocyclic groups, and preferably a 5- or 6-membered monocyclic ring Sex heterocyclic group. Specific examples include piperazinyl, piperidyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolidinyl, morpholinyl, oxazolyl, thiazolyl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyrimidinyl, tetrahydrothiapyranyl, tetrahydroisothiazolyl, tetrahydrothiazinyl and the like. Can be mentioned. Preferred heterocyclic groups include piperazinyl, piperidyl, pyridyl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyrimidinyl, tetrahydrothiapyranyl, tetrahydroisothiazolyl or tetrahydrothiazinyl. Examples of the substituent on the heterocyclic group include, for example, alkyl (wherein the alkyl is selected from the group consisting of phenyl, hydroxyl, halogen, oxo, alkoxy, amino, and optionally substituted carbamoyl). Optionally substituted with three groups), carboxy, alkoxycarbonyl, alkanoyl, alkylsulfonyl optionally substituted with halogen, carbamoyl optionally substituted with alkyl, hydroxyl, amino optionally substituted with alkyl Examples include sulfonyl and oxo. The heterocyclic group may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.
When R ^{3 to} R ⁸ are “optionally substituted cycloalkyl-substituted carbonyl”, examples of the substituent on the cycloalkyl include a hydroxyl group, alkoxy, amino (the amino is a group consisting of alkyl and alkanoyl). And may be substituted with one or two groups selected from the same or different from each other), alkoxycarbonyl and the like. The cycloalkyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

When R ^{3 to} R ⁸ are “optionally substituted phenyl-substituted carbonyl”, examples of the substituent on the phenyl include a halogen atom, a hydroxyl group, alkoxy, amino (the amino is composed of alkyl and alkanoyl). And may be substituted with the same or different 1 or 2 groups selected from the group). The phenyl may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

When R ^{3 to} R ⁸ are “optionally substituted heterocyclic group-substituted carbonyl”, examples of the heterocyclic group include the above-mentioned heterocyclic groups, and preferably a 5- or 6-membered ring. And monocyclic heterocyclic groups. Specific examples include piperidyl, pyrrolidinyl, pyridyl, pyrimidinyl, morpholinyl and the like. Examples of the substituent on the heterocyclic group include a halogen atom, alkyl, hydroxyl group, amino (the amino may be substituted with 1 or 2 alkyls), alkanoyl, oxo and the like. It is done. The heterocyclic group may have, for example, 1 to 3 substituents described above. When the number of substituents is 2 or more, the substituents may be the same or different.

R ² in the compound [Ia] is preferably —NR ³ R ⁴ and —OR ⁵ , particularly preferably —NR ³ R ⁴ , and more preferably —NHR ⁴ .

When R ² is —NHR ⁴ , R ⁴ is preferably an optionally substituted alkyl, alkenyl, an optionally substituted alkanoyl, an optionally substituted carbamoyl, or optionally substituted. Examples include cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, and optionally substituted heterocyclic group substituted carbonyl. Particularly preferably, alkyl optionally substituted, is exemplified by an heterocyclic group which may be also be cycloalkyl and substituted substituted, more preferably, C ₃ -C ₆ alkyl (said alkyl hydroxy in optionally substituted), C ₅ -C ₇ cycloalkyl (said cycloalkyl is hydroxy, methyl, hydroxymethyl, optionally substituted with a group selected from the group consisting of carbamoyl), 4-piperidinyl (wherein 4- piperidinyl _C 1 -C _{3 alkylsulfonyl,} C 1 -C ₃ optionally substituted by an alkylcarbamoyl or _C 1 -C ₃ alkoxy group selected from the group consisting of carbonyl), and 4-tetrahydropyranyl and the like Can be mentioned.

The active ingredient compounds [I], [Ia] and [Ib] of the present invention may have optical isomers based on asymmetric carbon atoms, but the present invention includes any of these optical isomers and mixtures thereof. Including. Compounds [I], [Ia] and [Ib] can be used for pharmaceutical use either in the free form or in the form of pharmacologically acceptable salts. Examples of the pharmacologically acceptable salts of the compounds [I], [Ia] and [Ib] include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, and fumaric acid. And organic acid salts such as salts, oxalates, citrates, methanesulfonates, benzenesulfonates, tosylates and maleates. In addition, when it has a substituent such as carboxy, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt) can be used.
The active ingredient compounds [I], [Ia] and [Ib] or salts thereof of the present invention include solvates such as inner salts and hydrates thereof.

（式中、Ｒはアルキルを表し、他の記号は前記と同一の意味を有する。）
本発明の化合物［Ｉａ’］は、化合物［ＩＩ］と化合物［ＩＩＩ］を反応させた後、酸で処理することにより製造することができる。本反応は、溶媒中で実施することができる（Journal of Medicinal Chemistry, 9, 858(1966)）。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、テトラヒドロフラン（ＴＨＦ）、クロロホルム、塩化メチレン、ジオキサン、酢酸エチル、エーテル、トルエン等が挙げられる。本反応は、−２０〜８０℃、とりわけ０〜３０℃で好適に進行する。また、酸処理における酸としては、例えば、塩酸、硫酸、リン酸、ｐ−トルエンスルホン酸、メタンスルホン酸等が挙げられる。また、式［ＩＩ］のＲにおけるアルキルとしては、例えば、メチル、エチル、プロピル、ブチル等が挙げられるが、このうち、メチル、エチルがとりわけ好ましい。 The active ingredient compounds [I], [Ia] and [Ib] of the present invention can be appropriately produced by a production method selected from the following [Method A] to [Method D], but are not limited thereto. . Hereinafter, the production is described using compound [Ia] (compound [Ia ′]) in which Q ¹ is hydrogen, but other compounds [I] and [Ib] can be produced in the same manner.
[Method A]

(In the formula, R represents alkyl, and other symbols have the same meaning as described above.)
Compound [Ia ′] of the present invention can be produced by reacting compound [II] with compound [III] and then treating with an acid. This reaction can be carried out in a solvent (Journal of Medicinal Chemistry, 9, 858 (1966)). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran (THF), chloroform, methylene chloride, dioxane, ethyl acetate, ether, toluene and the like. This reaction suitably proceeds at -20 to 80 ° C, particularly 0 to 30 ° C. Examples of the acid in the acid treatment include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. Examples of the alkyl in R of the formula [II] include methyl, ethyl, propyl, butyl and the like, among which methyl and ethyl are particularly preferable.

（式中、Ｙはハロゲン原子、水酸基またはジヒドロキシボラニルを表す。ｎ１は０、１、２、３または４を表し、Ｒ^１ａは、水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル、置換されていてもよいフェニルまたは置換されていてもよい複素環式基を表す（ただし、ｎ１が０であり、Ｒ^１ａが水素原子である場合を除く）。他の記号は前記と同一の意味を有する。）
化合物［Ｉａ’］において、ｎが０であり、Ｒ¹が水素原子である一般式［Ｉ−Ａ］を、化合物［ＩＶ］を反応させてアルキル化することで、本発明化合物［Ｉａ’］に含まれる化合物［Ｉ−Ｂ］を製造することができる。
式［ＩＶ］におけるＹがハロゲン原子である場合、本反応は、溶媒中、塩基の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド、１−メチルピロリドン、１，３−ジメチル−２−イミダゾリジノン等が挙げられる。塩基としては、例えば、水素化ナトリウム、水酸化ナトリウム、カリウム ｔ−ブトキシド、ブチルリチウム、リチウムジイソプロピルアミド等が挙げられる。本反応は、−２０〜１００℃、とりわけ０〜３０℃で好適に進行する。また、Ｙにおけるハロゲン原子としては、塩素、臭素、ヨウ素が挙げられるが、このうち、臭素、ヨウ素がとりわけ好ましい。
式［ＩＶ］におけるＹが水酸基である場合、本反応は、溶媒中、添加剤および活性化剤の存在下で実施することができる（Synthesis, 1 (1981)）。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、ＴＨＦ、ジオキサン、クロロホルム等が挙げられる。添加剤としては、例えば、トリフェニルホスフィン、トリブチルホスフィン、トリメチルホスフィン等が挙げられる。活性化剤としては、例えば、アゾジカルボン酸ジエチル、アゾジカルボン酸ジメチル、１，１−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）、１，１−（アゾジカルボニル）ジピペリジン等が挙げられる。本反応は、−３０〜１００℃、とりわけ０〜５０℃で好適に進行する。
式［ＩＶ］におけるＹがジヒドロキシボラニルである場合、本反応は、溶媒中、触媒および塩基の存在下で実施することができる（Tetrahedron Letters, 39, 2933(1998)）。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＤＭＦ等が挙げられる。触媒としては、例えば、酢酸銅（ＩＩ）等が挙げられる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−メチルモルホリン、ピリジン等が挙げられる。本反応は、−１０〜１００℃、とりわけ２０〜６０℃で好適に進行する。 [Method B]

(In the formula, Y represents a halogen atom, a hydroxyl group or dihydroxyboranyl. N1 represents 0, 1, 2, 3 or 4; R ^1a represents a hydrogen atom, an optionally substituted alkyl; Represents an optionally substituted cycloalkyl, an optionally substituted phenyl, or an optionally substituted heterocyclic group (except when n1 is 0 and R ^1a is a hydrogen atom). It has the same meaning as above.)
In the compound [Ia ′], the compound [Ia ′] of the present invention is obtained by alkylating the general formula [IA] in which n is 0 and R ¹ is a hydrogen atom by reacting the compound [IV]. [IB] contained in can be produced.
When Y in formula [IV] is a halogen atom, this reaction can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction. Examples thereof include dimethylformamide (DMF), dimethyl sulfoxide, 1-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like. Examples of the base include sodium hydride, sodium hydroxide, potassium t-butoxide, butyl lithium, lithium diisopropylamide and the like. This reaction suitably proceeds at -20 to 100 ° C, particularly 0 to 30 ° C. In addition, examples of the halogen atom in Y include chlorine, bromine, and iodine. Among these, bromine and iodine are particularly preferable.
When Y in formula [IV] is a hydroxyl group, this reaction can be carried out in a solvent in the presence of an additive and an activator (Synthesis, 1 (1981)). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, THF, dioxane, chloroform and the like. Examples of the additive include triphenylphosphine, tributylphosphine, trimethylphosphine, and the like. Examples of the activator include diethyl azodicarboxylate, dimethyl azodicarboxylate, 1,1-azobis (N, N-dimethylformamide), 1,1- (azodicarbonyl) dipiperidine, and the like. This reaction suitably proceeds at -30 to 100 ° C, particularly 0 to 50 ° C.
When Y in the formula [IV] is dihydroxyboranyl, this reaction can be carried out in a solvent in the presence of a catalyst and a base (Tetrahedron Letters, 39, 2933 (1998)). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, DMF and the like. Examples of the catalyst include copper (II) acetate. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine and the like. This reaction suitably proceeds at −10 to 100 ° C., particularly 20 to 60 ° C.

（式中、Ｒ^２１は−ＮＲ^３Ｒ^４、−ＯＲ^５または−ＣＯＲ^６ａを表し、Ｒ^６ａはアルコキシを表す。他の記号は前記と同一の意味を有する。）
化合物［Ｖ］を、化合物［ＶＩ］、化合物［ＶＩＩ］または化合物［ＶＩＩＩ］と反応させることで、本発明化合物［Ｉａ’］に含まれる化合物［Ｉ−Ｃ］を製造することができる。
化合物［Ｖ］と化合物［ＶＩ］との反応は、溶媒中、触媒、塩基、および添加剤の存在下で実施することができる（Journal of Organic Chemistry, 61, 7240(1996)）。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、キシレン、ジメトキシエタン、ジオキサン等が挙げられる。触媒としては、例えば、酢酸パラジウム、ビス（ジベンジリデンアセトン）ジパラジウム等が挙げられる。塩基としては、例えば、ナトリウム ｔ−ブトキシド、カリウム ｔ−ブトキシド、リチウム ｔ−ブトキシド、トリエチルアミン等が挙げられる。添加剤としては、２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル等が挙げられる。本反応は、３０〜１５０℃、とりわけ６０〜８０℃で好適に進行する。
化合物［Ｖ］と化合物［ＶＩＩ］との反応は、溶媒中で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＴＨＦ、ジオキサン、ＤＭＦ、トルエン、メタノール、エタノール等が挙げられる。本反応は、２０〜１５０℃、とりわけ７０〜１００℃で好適に進行する。
化合物［Ｖ］と化合物［ＶＩＩＩ］との反応は、溶媒中、一酸化炭素の共存下、触媒および添加剤の存在下で実施することができる（Tetrahedron, 55, 393(1999)）。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、ジオキサン、ＤＭＦ等が挙げられる。触媒としては、例えば、酢酸パラジウム、塩化パラジウム、ビス（トリフェニルホスフィン）パラジウムジクロリド、テトラキス（トリフェニルホスフィン）パラジウム等が挙げられる。添加剤としては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、１，４−ビス（ジフェニルホスフィノ）ブタン、１，３−ビス（ジフェニルホスフィノ）プロパン、トリフェニルホスフィン等が挙げられる。本反応は、３０〜２５０℃、とりわけ８０〜１２０℃で好適に進行する。 [Method C]

(Wherein R ²¹ represents —NR ³ R ⁴ , —OR ⁵ or —COR ^6a , and R ^6a represents alkoxy. Other symbols have the same meanings as described above.)
Compound [I-C] contained in compound [Ia ′] of the present invention can be produced by reacting compound [V] with compound [VI], compound [VII] or compound [VIII].
The reaction between compound [V] and compound [VI] can be carried out in a solvent in the presence of a catalyst, a base, and an additive (Journal of Organic Chemistry, 61, 7240 (1996)). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, xylene, dimethoxyethane, dioxane and the like. Examples of the catalyst include palladium acetate and bis (dibenzylideneacetone) dipalladium. Examples of the base include sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, triethylamine and the like. Examples of the additive include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. This reaction suitably proceeds at 30 to 150 ° C, particularly 60 to 80 ° C.
The reaction of compound [V] and compound [VII] can be carried out in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include THF, dioxane, DMF, toluene, methanol, ethanol and the like. This reaction suitably proceeds at 20 to 150 ° C, particularly 70 to 100 ° C.
The reaction of compound [V] and compound [VIII] can be carried out in a solvent in the presence of carbon monoxide in the presence of a catalyst and an additive (Tetrahedron, 55, 393 (1999)). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, dioxane, DMF and the like. Examples of the catalyst include palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium and the like. Examples of the additive include 1,1′-bis (diphenylphosphino) ferrocene, 1,4-bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino) propane, and triphenylphosphine. It is done. This reaction suitably proceeds at 30 to 250 ° C, particularly 80 to 120 ° C.

（式中、ｍは１または２を表し、Ｒ^２２は−ＮＲ^３Ｒ^４または−ＯＲ^５を表す。他の記号は前記と同一の意味を有する。）
化合物［ＩＸ］を、化合物［ＶＩ］または化合物［Ｘ］と反応させることで、本発明化合物［Ｉａ’］に含まれる化合物［Ｉ−Ｄ］を製造することができる。
化合物［ＩＸ］と化合物［ＶＩ］との反応は、溶媒中で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジオキサン、ＴＨＦ、ＤＭＦ、ジメチルスルホキシド等が挙げられる。本反応は、０〜１５０℃、とりわけ５０〜１００℃で好適に進行する。
化合物［ＩＸ］と化合物［Ｘ］との反応は、溶媒中、塩基の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＴＨＦ、ジオキサン、ＤＭＦ、ジメチルスルホキシド等が挙げられる。塩基としては、例えば、水素化ナトリウム、水酸化ナトリウム、カリウム ｔ−ブトキシド、ブチルリチウム等が挙げられる。本反応は、−３０〜１００℃、とりわけ０〜３０℃で好適に進行する。 [Method D]

(In the formula, m represents 1 or 2, and R ²² represents —NR ³ R ⁴ or —OR ^{5. The} other symbols have the same meaning as described above.)
Compound [IX] contained in Compound [Ia ′] of the present invention can be produced by reacting Compound [IX] with Compound [VI] or Compound [X].
The reaction of compound [IX] and compound [VI] can be carried out in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dioxane, THF, DMF, dimethyl sulfoxide and the like. This reaction suitably proceeds at 0 to 150 ° C, particularly 50 to 100 ° C.
The reaction of compound [IX] and compound [X] can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include THF, dioxane, DMF, dimethyl sulfoxide and the like. Examples of the base include sodium hydride, sodium hydroxide, potassium t-butoxide, butyl lithium and the like. This reaction suitably proceeds at -30 to 100 ° C, particularly 0 to 30 ° C.

（式中、記号は前記と同一の意味を有する。）
化合物［Ｉ−２］とハロゲン化水素とを反応させることで、化合物［Ｉ−１］を製造することができる。ハロゲン化水素としては、フッ化水素、塩化水素、臭化水素、ヨウ化水素が挙げられるが、このうち、臭化水素がとりわけ好ましい。本反応は、０〜１５０℃、とりわけ６０〜８０℃で好適に進行する。 The compound [Ia ′] produced above can be appropriately derived into another compound [Ia ′] by converting the functional group using a generally known organic chemical reaction. What is necessary is just to select suitably the conversion method of such a substituent according to the kind of target substituent. For example, regarding the conversion of the substituent in R ² of compound [Ia ′], the conversion can be carried out as described below (Method a) to Method (g).
(Method a)

(In the formula, the symbols have the same meaning as described above.)
Compound [I-1] can be produced by reacting compound [I-2] with hydrogen halide. Examples of the hydrogen halide include hydrogen fluoride, hydrogen chloride, hydrogen bromide, and hydrogen iodide. Among these, hydrogen bromide is particularly preferable. This reaction suitably proceeds at 0 to 150 ° C, particularly 60 to 80 ° C.

（式中、Ｒ⁴¹は置換されていてもよいアルカノイル、アルキルスルホニル、置換されていてもよいシクロアルキル置換カルボニル、置換されていてもよいフェニル置換カルボニル、または置換されていてもよい複素環式基置換カルボニルを表す。Ａはハロゲン原子または水酸基を表す。他の記号は前記と同一の意味を有する。）
化合物［Ｉ−１］と化合物［ＸＩ］を反応させることで、化合物［Ｉ−３］および化合物［Ｉ−４］を製造することができる。
式［ＸＩ］におけるＡがハロゲン原子である場合、本反応は、溶媒中、塩基の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＴＨＦ、ＤＭＦ等が挙げられる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−メチルモルホリン、ピリジン等が挙げられる。本反応は、−４０〜１００℃、とりわけ−１０〜３０℃で好適に進行する。また、Ｘにおけるハロゲン原子としては、フッ素、塩素、臭素、ヨウ素が挙げられるが、このうち、塩素、臭素がとりわけ好ましい。
式［ＸＩ］におけるＡが水酸基である場合、本反応は、溶媒中、縮合剤の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＴＨＦ、ＤＭＦ等が挙げられる。縮合剤としては、例えば、１，１’−カルボニルジイミダゾール、１，３−ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド・塩酸塩等が挙げられる。本反応は、−４０〜１００℃、とりわけ−１０〜３０℃で好適に進行する。 (Method b)

Wherein R ⁴¹ is an optionally substituted alkanoyl, alkylsulfonyl, an optionally substituted cycloalkyl substituted carbonyl, an optionally substituted phenyl substituted carbonyl, or an optionally substituted heterocyclic group. Represents a substituted carbonyl, A represents a halogen atom or a hydroxyl group, and other symbols have the same meaning as described above.
Compound [I-3] and compound [I-4] can be produced by reacting compound [I-1] with compound [XI].
When A in Formula [XI] is a halogen atom, this reaction can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, THF, DMF and the like. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine and the like. This reaction suitably proceeds at −40 to 100 ° C., particularly −10 to 30 ° C. In addition, examples of the halogen atom in X include fluorine, chlorine, bromine, and iodine. Among these, chlorine and bromine are particularly preferable.
When A in formula [XI] is a hydroxyl group, this reaction can be carried out in a solvent in the presence of a condensing agent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, THF, DMF and the like. Examples of the condensing agent include 1,1′-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide / hydrochloride, and the like. This reaction suitably proceeds at −40 to 100 ° C., particularly −10 to 30 ° C.

（式中、Ｒ^９およびＲ^１０は互いに独立して水素原子またはアルキルを表す。Ｒ^１０ａはアルキルを表す。Ｘはハロゲン原子を表す。他の記号は前記と同一の意味を有する。）
化合物［Ｉ−１］を、化合物［ＸＩＩ］、トリホスゲン／化合物［ＸＩＩＩ］または化合物［ＸＩＶ］と反応させることで、化合物［Ｉ−５］を製造することができる。
化合物［Ｉ−１］と化合物［ＸＩＩ］とを、溶媒中で反応させることにより、化合物［Ｉ−５］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＴＨＦ等が挙げられる。式［ＸＩＩ］のＸにおけるハロゲン原子としては、フッ素、塩素、臭素、ヨウ素が挙げられるが、このうち、塩素がとりわけ好ましい。また、本反応は、−２０〜１００℃、とりわけ１０〜６０℃で好適に進行する。
また、化合物［Ｉ−１］とトリホスゲンとを、溶媒中、反応させた後、化合物［ＸＩＩＩ］を反応させることによって、化合物［Ｉ−５］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＴＨＦ等が挙げられる。本反応は、−２０〜１００℃、とりわけ１０〜６０℃で好適に進行する。
また、化合物［Ｉ−１］と化合物［ＸＩＶ］を溶媒中で反応させることにより、Ｒ^９が水素原子であってＲ^１０がアルキルである化合物［Ｉ−５］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＴＨＦ、塩化メチレン、クロロホルム等が挙げられる。本反応は、−２０〜１００℃、とりわけ１０〜６０℃で好適に進行する。 (Method c)

(In the formula, R ⁹ and R ¹⁰ each independently represent a hydrogen atom or alkyl. R ^10a represents an alkyl. X represents a halogen atom. Other symbols have the same meaning as described above.)
Compound [I-5] can be produced by reacting compound [I-1] with compound [XII], triphosgene / compound [XIII] or compound [XIV].
Compound [I-5] can be produced by reacting compound [I-1] with compound [XII] in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, and THF. Examples of the halogen atom in X of the formula [XII] include fluorine, chlorine, bromine and iodine. Among these, chlorine is particularly preferable. Moreover, this reaction advances suitably at -20-100 degreeC, especially 10-60 degreeC.
Alternatively, compound [I-5] can be produced by reacting compound [I-1] with triphosgene in a solvent and then reacting compound [XIII]. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, and THF. This reaction suitably proceeds at -20 to 100 ° C, particularly 10 to 60 ° C.
In addition, by reacting compound [I-1] and compound [XIV] in a solvent, compound [I-5] in which R ⁹ is a hydrogen atom and R ¹⁰ is alkyl can be produced. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include THF, methylene chloride, chloroform and the like. This reaction suitably proceeds at -20 to 100 ° C, particularly 10 to 60 ° C.

（式中、Ｒはアルキルを表し、他の記号は前記と同一の意味を有する。）
化合物［Ｉ−７］を常法により加水分解することによって、化合物［Ｉ−６］を製造することができる。 (Method d)

(In the formula, R represents alkyl, and other symbols have the same meaning as described above.)
Compound [I-6] can be produced by hydrolyzing compound [I-7] by a conventional method.

（式中、Ｒ^６１は置換されていてもよいアミノを表し、他の記号は前記と同一の意味を有する。）
化合物［Ｉ−６］と化合物［ＸＶ］とを、溶媒中、縮合剤の存在下で反応させることにより、化合物［Ｉ−８］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、アセトニトリル、ＤＭＦ、ＴＨＦ等が挙げられる。縮合剤としては、例えば、１，１’−カルボニルジイミダゾール、１，３−ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド・塩酸塩等が挙げられる。本反応は、−３０〜１００℃、とりわけ０〜７０℃で好適に進行する。 (Method e)

(Wherein R ⁶¹ represents an optionally substituted amino, and other symbols have the same meaning as described above.)
Compound [I-8] can be produced by reacting compound [I-6] with compound [XV] in the presence of a condensing agent in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, acetonitrile, DMF, and THF. Examples of the condensing agent include 1,1′-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide / hydrochloride, and the like. This reaction suitably proceeds at -30 to 100 ° C, particularly 0 to 70 ° C.

（式中、記号は前記と同一の意味を有する。）
化合物［Ｉ−６］または化合物［Ｉ−７］を、溶媒中、還元することにより、化合物［Ｉ−９］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＴＨＦ、ジエチルエーテル等が挙げられる。還元剤としては、例えば、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム等が挙げられる。本反応は、−２０〜７０℃、とりわけ０〜４０℃で好適に進行する。 (Method f)

(In the formula, the symbols have the same meaning as described above.)
Compound [I-9] can be produced by reducing compound [I-6] or compound [I-7] in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include THF, diethyl ether and the like. Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride and the like. This reaction suitably proceeds at -20 to 70 ° C, particularly 0 to 40 ° C.

（式中、Ｒ^８１は置換されていてもよいアミノを表し、他の記号は前記と同一の意味を有する。）
化合物［Ｉ−９］と化合物［ＸＶＩ］とを、溶媒中、塩基および活性化剤の存在下で反応させることにより、化合物［Ｉ−１０］を製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、ＴＨＦ、クロロホルム、トルエン等が挙げられる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等が挙げられる。活性化剤としては、例えば、メタンスルホニルクロリド、ｐ−トルエンスルホニルクロリド等が挙げられる。本反応は、−１０〜６０℃、とりわけ０〜３０℃で好適に進行する。 (G method)

(In the formula, R ⁸¹ represents an optionally substituted amino, and other symbols have the same meaning as described above.)
Compound [I-10] can be produced by reacting compound [I-9] and compound [XVI] in a solvent in the presence of a base and an activator. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, THF, chloroform, toluene and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like. Examples of the activator include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like. This reaction suitably proceeds at -10 to 60 ° C, particularly 0 to 30 ° C.

  The compound [Ia ′] of the present invention obtained according to the above [Method A] to [Method D] or (Method a) to (Method g) can be converted into a pharmaceutically acceptable salt, if desired. . Conversion to a pharmacologically acceptable salt may be performed according to methods known to those skilled in the art.

（式中、記号は前記と同一の意味を有する。）
化合物［１］とヒドロキシルアミンから化合物［２］を製造する反応は、溶媒中で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、エタノール、メタノール等が挙げられる。本反応は、０〜１５０℃、とりわけ６０〜８０℃で好適に進行する。
化合物［２］とトシルクロリドから化合物［３］を製造する反応は、溶媒中、塩基の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、塩化メチレン、クロロホルム、ＴＨＦ、トルエン等が挙げられる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等が挙げられる。本反応は、−２０〜８０℃、とりわけ０〜３０℃で好適に進行する。
化合物［３］から化合物［３ａ］を製造する反応は、溶媒中、化合物［３］とナトリウムアルコキシドとを反応させた後、酸で処理することにより実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、メタノール、エタノール、ジオキサン、ＴＨＦ、ジメトキシエタン等が挙げられる。酸としては、例えば、塩化水素等が挙げられる。本反応は、−２０〜６０℃、とりわけ０〜３０℃で好適に進行する。
化合物［３ａ］から化合物［ＩＩ］を製造する反応は、通常の還元的アルキル化反応を用いて、対応するアルデヒドを反応することで実施することができる（Journal of Organic Chemistry, 61, 3849(1996)）。 Next, the manufacturing method of the raw material compound used in the said method is demonstrated below.
The raw material compound [II] can be produced, for example, as follows.

(In the formula, the symbols have the same meaning as described above.)
The reaction for producing compound [2] from compound [1] and hydroxylamine can be carried out in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include ethanol and methanol. This reaction suitably proceeds at 0 to 150 ° C, particularly 60 to 80 ° C.
The reaction for producing compound [3] from compound [2] and tosyl chloride can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, THF, toluene and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like. This reaction suitably proceeds at -20 to 80 ° C, particularly 0 to 30 ° C.
The reaction for producing compound [3a] from compound [3] can be carried out by reacting compound [3] with sodium alkoxide in a solvent and then treating with an acid. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, ethanol, dioxane, THF, dimethoxyethane and the like. Examples of the acid include hydrogen chloride. This reaction suitably proceeds at -20 to 60 ° C, particularly at 0 to 30 ° C.
The reaction for producing the compound [II] from the compound [3a] can be carried out by reacting the corresponding aldehyde using a usual reductive alkylation reaction (Journal of Organic Chemistry, 61, 3849 (1996). )).

（式中、記号は前記と同一の意味を有する。）
化合物［４］とメチルリチウムから化合物［５］を製造する反応は、溶媒中で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＴＨＦ、ジエチルエーテル、ジメトキシエタン等が挙げられる。本反応は、−９０〜０℃、とりわけ−６０〜−４０℃で好適に進行する。
化合物［５］から化合物［６］および［７］を経て化合物［８］を製造する方法は、上述した、化合物［１］から化合物［２］および［３］を経て化合物［ＩＩ］を製造する方法と同様にして実施することができる。
化合物［８］と化合物［ＩＩＩ］から化合物［９］を製造する反応は、上記〔Ａ法〕と同様にして実施することができる。
化合物［９］と化合物［ＩＶ］から化合物［Ｖ］を製造する反応は、上記〔Ｂ法〕と同様にして実施することができる。 The raw material compound [V] can be produced, for example, as follows.

(In the formula, the symbols have the same meaning as described above.)
The reaction for producing compound [5] from compound [4] and methyllithium can be carried out in a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include THF, diethyl ether, dimethoxyethane, and the like. This reaction suitably proceeds at -90 to 0 ° C, particularly -60 to -40 ° C.
In the method of producing compound [8] from compound [5] via compounds [6] and [7], compound [II] is produced from compound [1] via compounds [2] and [3] described above. It can be carried out in the same manner as the method.
The reaction for producing compound [9] from compound [8] and compound [III] can be carried out in the same manner as in the above [Method A].
The reaction for producing compound [V] from compound [9] and compound [IV] can be carried out in the same manner as in the above [Method B].

（式中、ｍは１または２を示し、他の記号は前記と同一の意味を有する。）
化合物［１０］と化合物［１１］から化合物［１２］を製造する反応は、溶媒中または無溶媒で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、キシレン、ジオキサン等が挙げられる。本反応は、５０〜１５０℃、とりわけ８０〜１２０℃で好適に進行する。
化合物［１２］から化合物［１３］を製造する反応は、溶媒中、化合物［１２］とチオ尿素とを塩基存在下で反応させた後、アルキル化剤を反応させることにより実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、メタノール、ＴＨＦ、ジオキサン等が挙げられる。塩基としては、例えば、ナトリウムメトキシド、水酸化ナトリウム、カリウム ｔ−ブトキシド等が挙げられる。アルキル化剤としては、例えば、ヨウ化メチル、硫酸ジメチル等が挙げられる。本反応は、０〜１００℃、とりわけ３０〜７０℃で好適に進行する。
化合物［１３］から化合物［１４］を製造する反応は、溶媒中、酸の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、水、アセトン、ＴＨＦ、ジオキサン等が挙げられる。酸としては、例えば、塩酸、硫酸、リン酸、ｐ−トルエンスルホン酸等が挙げられる。本反応は、−１０〜８０℃、とりわけ０〜３０℃で好適に進行する。
化合物［１４］は、化合物［１５］から化合物［１７］を経て製造することもできる。
化合物［１５］と化合物［１６］から化合物［１７］を製造する反応は、溶媒中、触媒の存在下で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ＤＭＦ、トルエン、キシレン等が挙げられる。触媒としては、例えば、ビス（トリフェニルホスフィン）パラジウムジクロライド、テトラキス（トリフェニルホスフィン）パラジウム等が挙げられる。本反応は、５０〜１５０℃、とりわけ７０〜９０℃で好適に進行する。
化合物［１７］から化合物［１４］を製造する反応は、上述した、化合物［１３］から化合物［１４］を製造する反応と同様にして実施することができる。
化合物［１４］から化合物［１８］および［１９］を経て化合物［２０］を製造する方法は、上述した、化合物［１］から化合物［２］および［３］を経て化合物［ＩＩ］を製造する方法と同様にして実施することができる。
化合物［２０］と化合物［ＩＩＩ］から化合物［２１］を製造する反応は、上記〔Ａ法〕と同様にして実施することができる。
化合物［２１］から化合物［２２］を製造する反応は、溶媒中、酸化剤を用いて実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、水、メタノール、ＴＨＦ、ジオキサン、クロロホルム、塩化メチレン等が挙げられる。酸化剤としては、オキソン（商品名、ＤｕＰｏｎｔ社製）、３−クロロ過安息香酸、過酸化水素等が挙げられる。本反応は、−２０〜６０℃、とりわけ−１０〜３０℃で好適に進行する。
化合物［２２］と化合物［ＩＶ］から化合物［ＩＸ］を製造する反応は、上記〔Ｂ法〕と同様にして実施することができる。
化合物［ＩＸ］は、化合物［２１］から化合物［２３］を経て製造することもできる。
化合物［２１］と化合物［ＩＶ］から化合物［２３］を製造する反応は、上記〔Ｂ法〕と同様にして実施することができる。
化合物［２３］から化合物［ＩＸ］を製造する反応は、化合物［２１］から化合物［２２］を製造する反応と同様にして実施することができる。
なお、上記の製造において、必要に応じて官能基の保護および脱保護をすることができる。その官能基の保護基としては通常の有機合成化学で使用されるものを使用することができ、その例としては例えば、“プロテクティブ グループ イン オーガニック シンセシス”（”Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991）等に記載のものが挙げられる。保護基の導入、脱保護の条件としては、例えば、同書記載の方法が挙げられる。 The raw material compound [IX] can be produced, for example, as follows.

(In the formula, m represents 1 or 2, and other symbols have the same meaning as described above.)
The reaction for producing the compound [12] from the compound [10] and the compound [11] can be carried out in a solvent or without a solvent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, xylene, dioxane and the like. This reaction suitably proceeds at 50 to 150 ° C, particularly 80 to 120 ° C.
The reaction for producing compound [13] from compound [12] can be carried out by reacting compound [12] and thiourea in a solvent in the presence of a base and then reacting with an alkylating agent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, THF, dioxane and the like. Examples of the base include sodium methoxide, sodium hydroxide, potassium t-butoxide and the like. Examples of the alkylating agent include methyl iodide and dimethyl sulfate. This reaction suitably proceeds at 0 to 100 ° C, particularly 30 to 70 ° C.
The reaction for producing compound [14] from compound [13] can be carried out in a solvent in the presence of an acid. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include water, acetone, THF, dioxane and the like. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and the like. This reaction suitably proceeds at −10 to 80 ° C., particularly 0 to 30 ° C.
Compound [14] can also be produced from compound [15] via compound [17].
The reaction for producing compound [17] from compound [15] and compound [16] can be carried out in a solvent in the presence of a catalyst. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include DMF, toluene, xylene and the like. Examples of the catalyst include bis (triphenylphosphine) palladium dichloride and tetrakis (triphenylphosphine) palladium. This reaction suitably proceeds at 50 to 150 ° C, particularly 70 to 90 ° C.
The reaction for producing compound [14] from compound [17] can be carried out in the same manner as the reaction for producing compound [14] from compound [13] described above.
In the method for producing compound [20] from compound [14] via compounds [18] and [19], compound [II] is produced from compound [1] via compounds [2] and [3] described above. It can be carried out in the same manner as the method.
The reaction for producing compound [21] from compound [20] and compound [III] can be carried out in the same manner as in the above [Method A].
The reaction for producing compound [22] from compound [21] can be carried out in a solvent using an oxidizing agent. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, methanol, THF, dioxane, chloroform, and methylene chloride. Examples of the oxidizing agent include oxone (trade name, manufactured by DuPont), 3-chloroperbenzoic acid, hydrogen peroxide, and the like. This reaction suitably proceeds at -20 to 60 ° C, particularly -10 to 30 ° C.
The reaction for producing compound [IX] from compound [22] and compound [IV] can be carried out in the same manner as in the above [Method B].
Compound [IX] can also be produced from compound [21] via compound [23].
The reaction for producing compound [23] from compound [21] and compound [IV] can be carried out in the same manner as in the above [Method B].
The reaction for producing compound [IX] from compound [23] can be carried out in the same manner as the reaction for producing compound [22] from compound [21].
In the above production, the functional group can be protected and deprotected as necessary. As the protective group for the functional group, those used in ordinary organic synthetic chemistry can be used. For example, “Protective Groups in Organic Synthesis” TW Greene, PMG Wuts, John Wiley and Sons 1991). Examples of the conditions for introducing and deprotecting a protecting group include the methods described in the same document.

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

  Since the active ingredient compounds [I], [Ia] and [Ib] of the present invention or pharmacologically acceptable salts thereof have excellent p38 MAP kinase inhibitory action, activation of p38 MAP kinase and p38 MAP kinase are involved. It is useful for the prevention or treatment of diseases involving excessive production of inflammatory mediators such as TNF-α and IL-1. Accordingly, the active ingredient compounds [I], [Ia] and [Ib] of the present invention or pharmacologically acceptable salts thereof are used for inflammatory diseases such as arthritis (rheumatoid arthritis, osteoarthritis, infectiousness). Arthritis, gouty arthritis, traumatic arthritis, synovitis, periarthritis, etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), inflammatory skin diseases (psoriasis, dermatitis (atopic dermatitis, Contact dermatitis, hives, eczema, etc.)], inflammatory respiratory diseases (asthma, bronchitis, pneumonia, pleurisy, pharyngitis, rhinitis, etc.), inflammatory eye diseases (conjunctivitis, keratitis, uveitis, etc.) ), Nephritis, hepatitis, systemic inflammatory diseases (Behcet's syndrome, systemic lupus erythematosus, etc.), shock (septic shock, endotoxin shock, etc.), cerebrovascular disorders (cerebral hemorrhage, cerebral infarction, brain edema, etc.), ischemic heart disease (Angina pectoris, myocardial infarction Congestive heart failure), osteoporosis, multiple sclerosis, diabetes, malignant tumor, cachexia, Alzheimer's disease, Parkinson's disease, acquired immune deficiency syndrome, arteriosclerosis, disseminated intravascular coagulation syndrome, rejection in organ transplantation and It is useful as a prophylactic or therapeutic agent for graft versus host disease (GvHD).

The active ingredient compound of the present invention or a pharmaceutically acceptable salt thereof is combined with one or more drugs selected from non-steroidal anti-inflammatory drugs, anti-rheumatic drugs, anti-cytokine drugs, immunosuppressive drugs and steroid drugs. Can also be used.
Non-steroidal anti-inflammatory drugs include alcofenac, aceclofenac, sulindac, tolmetine, fenoprofen, thiaprofenic acid, tenoxicam, lornoxicam, aspirin, mefenamic acid, flufenamic acid, diclofenac, loxoprofen, phenylbutazone, indomethacin, ibuprofen, ketoprofen, Naproxen, flurbiprofen, pranoprofen, piroxicam, zaltoprofen, celecoxib, rofecoxib, valdecoxib, or a salt thereof.
Examples of antirheumatic drugs include gold preparations (such as Auranofin), penicillamine, bucillamine, robenzalit, actarit, sulfasalazine, chloroquine, leflunomide and the like.
Anti-cytokine drugs include etanercept, infliximab, soluble TNF-α receptor, anti-TNF-α antibody, anti-interleukin-6 antibody, anti-interleukin-12 antibody and the like.
Examples of immunosuppressive drugs include methotrexate, cyclophosphamide, brequinar sodium, deoxyspargarine, mizoribine, mycophenolic acid 2-morpholinoethyl ester, rimexolone, cyclosporine, rapamycin, tacrolimus, gusperimus, azathioprine, and the like.
Examples of the steroid drug include dexamethasone, betamethasone, triamcinolone, fluocinonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone and the like.

The active ingredient compound of the present invention or a pharmacologically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmacologically acceptable carrier. Pharmacologically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine) ), Lubricants (magnesium stearate, talc, polyethylene glycol, silica), disintegrants (potato starch), wetting agents (sodium lauryl sulfate), and the like.
The active ingredient compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally and can be used as an appropriate pharmaceutical preparation. Examples of suitable pharmaceutical preparations for oral administration include solid preparations such as tablets, granules, capsules, powders, solution preparations, suspension preparations, and emulsion preparations. Appropriate pharmaceutical preparations for parenteral administration include suppositories, injections or infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution, or inhalants.
The dose of the active ingredient compounds [I], [Ia] and [Ib] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition. About 0.003 to 30 mg / kg per day, especially about 0.01 to 10 mg / kg is preferable.

２，２−ジエトキシ−２−ピリジン−４−イルエチルアミン（参考例２で得られる化合物）３．００ｇをＴＨＦ３０ｍｌに溶かした溶液を水冷し、４−フルオロフェニルイソシアナート１．９７ｇを滴下した。滴下後、反応液を減圧濃縮し、得られた残留物に濃塩酸３０ｍｌを加えて室温にて終夜攪拌した。氷冷した２Ｎ ＮａＯＨ水溶液１８０ｍｌに反応液を加えて中和し、析出晶を濾取後、水およびエーテルで洗浄した。６０℃にて通風乾燥し、標記化合物３．１０ｇを無色結晶として得た。融点：２６１℃（分解）。 EXAMPLES Hereinafter, although an Example, a reference example, and an experiment example demonstrate this invention further in detail, this invention is not limited to these.
In addition, the following abbreviations used in this specification represent the following meanings, respectively.
Me: Methyl Et: Ethyl THF: Tetrahydrofuran DMF: N, N-dimethylformamide t-: tert-
Example 1
1- (4-Fluorophenyl) -5- (pyridin-4-yl) -4-imidazolin-2-one

A solution prepared by dissolving 3.00 g of 2,2-diethoxy-2-pyridin-4-ylethylamine (compound obtained in Reference Example 2) in 30 ml of THF was cooled with water, and 1.97 g of 4-fluorophenyl isocyanate was added dropwise. After the addition, the reaction solution was concentrated under reduced pressure, and 30 ml of concentrated hydrochloric acid was added to the resulting residue, followed by stirring at room temperature overnight. The reaction solution was neutralized by adding 180 ml of an ice-cooled 2N NaOH aqueous solution, and the precipitated crystals were collected by filtration and washed with water and ether. By air drying at 60 ° C., 3.10 g of the title compound was obtained as colorless crystals. Melting point: 261 ° C. (decomposition).

１−（４−フルオロフェニル）−５−（ピリジン−４−イル）−４−イミダゾリン−２−オン（実施例１の化合物）１２８ｍｇ、シクロペンチルメタノール６１μｌ、トリフェニルホスフィン１９７ｍｇ、アゾジカルボン酸ジエチル２９５μｌを塩化メチレン２．５ｍｌに溶かし、室温にて２４時間攪拌した。反応液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル＝１９：１）によって精製し、得られた化合物を塩酸で処理し、標記化合物７５ｍｇを粉末として得た。 Example 2
1-cyclopentylmethyl-3- (4-fluorophenyl) -4- (pyridin-4-yl) -4-imidazolin-2-one hydrochloride

1- (4-Fluorophenyl) -5- (pyridin-4-yl) -4-imidazolin-2-one (compound of Example 1) 128 mg, cyclopentylmethanol 61 μl, triphenylphosphine 197 mg, diethyl azodicarboxylate 295 μl Dissolved in 2.5 ml of methylene chloride and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 19: 1), and the resulting compound was treated with hydrochloric acid to obtain 75 mg of the title compound as a powder.

対応原料化合物を、実施例２と同様に処理することにより、標記化合物を得た。融点：１３２−１３４℃。 Example 3
1- (oxolan-3-yl) -3- (4-fluorophenyl) -4- (pyridin-4-yl) -4-imidazolin-2-one

The corresponding starting material compound was treated in the same manner as in Example 2 to obtain the title compound. Melting point: 132-134 ° C.

４−（２−クロロピリジン−４−イル）−３−（４−フルオロフェニル）−１−（２−シアノベンジル）−４−イミダゾリン−２−オン〔参考例１(6)の化合物〕５０ｍｇ、(Ｓ)−(−)−α−メチルベンジルアミン７９μｌ、酢酸パラジウム５．５ｍｇ、２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル１５ｍｇ、ナトリウム ｔ−ブトキシド１７ｍｇをトルエン１ｍｌに懸濁し、窒素気流下、７０℃にて１８時間加熱攪拌した。反応液を酢酸エチルで希釈し、不溶物をセライトろ過で除去した。ろ液に６Ｎ塩酸水を加え、分液後、水層を重曹水でアルカリとした。クロロホルムで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２）で精製し、標記化合物３８ｍｇを無色粉末として得た。 Example 4
1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4-[(2- (1- (S) -phenylethylamino) pyridin-4-yl)]-4-imidazolin-2-one

4- (2-chloropyridin-4-yl) -3- (4-fluorophenyl) -1- (2-cyanobenzyl) -4-imidazolin-2-one [compound of Reference Example 1 (6)] 50 mg, (S)-(−)-α-methylbenzylamine 79 μl, palladium acetate 5.5 mg, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl 15 mg, sodium t-butoxide 17 mg in 1 ml toluene The suspension was suspended and stirred with heating at 70 ° C. for 18 hours under a nitrogen stream. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by Celite filtration. 6N hydrochloric acid was added to the filtrate, and after separation, the aqueous layer was made alkaline with sodium bicarbonate water. The mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 38 mg of the title compound as a colorless powder.

Example 5-12
The corresponding raw material compound was treated in the same manner as in Example 4 to obtain the compounds in Table 1.

１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−［２−（４−メトキシベンジルアミノ）ピリジン−４−イル］−４−イミダゾリン−２−オン（実施例５の化合物）１．５ｇに２５％臭化水素−酢酸溶液３ｍｌを加え、７０℃にて１時間攪拌した。反応液を減圧濃縮し、残留物を重曹水でアルカリとした。酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝２０：１）で精製し、標記化合物５７２ｍｇを無色結晶として得た。融点：１８２−１８３℃。 Example 13
4- (2-Aminopyridin-4-yl) -1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4-imidazolin-2-one

1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4- [2- (4-methoxybenzylamino) pyridin-4-yl] -4-imidazolin-2-one (Compound of Example 5) ) 3 ml of a 25% hydrogen bromide-acetic acid solution was added to 1.5 g and stirred at 70 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was made alkaline with sodium bicarbonate water. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 572 mg of the title compound as colorless crystals. Melting point: 182-183 ° C.

Example 14
4- (2-N-isobutyroylaminopyridin-4-yl) -1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4-imidazolin-2-one

４−（２−アミノピリジン−４−イル）−１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−イミダゾリン−２−オン（実施例１３の化合物）５０ｍｇとイソブチロイルクロリド２０μｌの塩化メチレンの懸濁液を氷冷し、トリエチルアミン５４μｌを滴下後、室温にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：アセトン＝２０：１）により精製し、標記化合物（実施例１４）２２ｍｇを無色結晶として、標記化合物（実施例１５）１０ｍｇを無色結晶として、それぞれ得た。融点：１９６℃（実施例１４）、１８５−１８７℃（実施例１５）。 Example 15
4- (2-N, N-diisobutyroylaminopyridin-4-yl) -1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4-imidazolin-2-one

50 mg of 4- (2-aminopyridin-4-yl) -1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4-imidazolin-2-one (the compound of Example 13) and isobutyroyl A suspension of 20 μl of chloride in methylene chloride was ice-cooled, 54 μl of triethylamine was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: acetone = 20: 1) to give 22 mg of the title compound (Example 14) as colorless crystals and 10 mg of the title compound (Example 15) as colorless crystals. I got each. Melting point: 196 ° C (Example 14), 185-187 ° C (Example 15).

４−（２−クロロピリジン−４−イル）−３−（４−フルオロフェニル）−１−（２−シアノベンジル）４−イミダゾリン−２−オン〔参考例１(6)の化合物〕１ｇ、酢酸パラジウム５５ｍｇ、１，１′−ビス（ジフェニルホスフィノ）フェロセン１３７ｍｇ、酢酸ナトリウム６０８ｍｇをエタノール２０ｍｌに懸濁し、一酸化炭素雰囲気下、８０℃にて１２時間攪拌した。反応液を減圧濃縮して酢酸エチルに懸濁し、活性炭処理後、ろ過した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：２）にて精製し、標記化合物８８７ｍｇを無色結晶として得た。融点：１６４℃。 Example 16
4- (2-Ethoxycarbonylpyridin-4-yl) -1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4-imidazolin-2-one

4- (2-chloropyridin-4-yl) -3- (4-fluorophenyl) -1- (2-cyanobenzyl) -4-imidazolin-2-one [compound of Reference Example 1 (6)] 1 g, acetic acid Palladium 55 mg, 1,1′-bis (diphenylphosphino) ferrocene 137 mg, and sodium acetate 608 mg were suspended in ethanol 20 ml and stirred at 80 ° C. for 12 hours in a carbon monoxide atmosphere. The reaction solution was concentrated under reduced pressure, suspended in ethyl acetate, treated with activated carbon, and filtered. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 887 mg of the title compound as colorless crystals. Melting point: 164 ° C.

１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−（２−メチルスルフィニルピリミジン−４−イル）−４−イミダゾリン−２−オン（参考例６(２)または参考例７(２)の化合物）７０ｍｇ、３−アミノプロパノール６０．６ｍｇ、ジオキサン２ｍｌの混合物を８０℃で５時間攪拌した。反応液を濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノ−ル＝１９：１）により精製後、エーテルより結晶化して、標記化合物４４．６ｍｇを得た。融点：１６６−１６７℃。 Example 17
1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4- [2- (3-hydroxypropylamino) pyrimidin-4-yl] -4-imidazolin-2-one

1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4- (2-methylsulfinylpyrimidin-4-yl) -4-imidazolin-2-one (Reference Example 6 (2) or Reference Example 7 (2) Compound) A mixture of 70 mg, 3-aminopropanol 60.6 mg and dioxane 2 ml was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (chloroform: methanol = 19: 1), and crystallized from ether to give 44.6 mg of the title compound. Melting point: 166-167 ° C.

Examples 18-24
The corresponding starting material compound was treated in the same manner as in Example 17 to obtain the compounds in Table 2.

１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−（２−メチルスルフィニルピリミジン−４−イル）−４−イミダゾリン−２−オン（参考例６(２)または参考例７(２)の化合物）１００ｍｇをイソプロパノール５ｍｌに懸濁し、水素化ナトリウム２６．３ｍｇを加えて室温で５時間攪拌した。反応液にクエン酸水溶液、重曹水を順次加えた後、酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノ−ル＝３０：１）により精製して、標記化合物６８ｍｇを粉末として得た。 Example 25
1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4- (2-isopropoxypyrimidin-4-yl) -4-imidazolin-2-one

1- (2-Cyanobenzyl) -3- (4-fluorophenyl) -4- (2-methylsulfinylpyrimidin-4-yl) -4-imidazolin-2-one (Reference Example 6 (2) or Reference Example 7 100 mg of the compound (2)) was suspended in 5 ml of isopropanol, 26.3 mg of sodium hydride was added, and the mixture was stirred at room temperature for 5 hours. A citric acid aqueous solution and an aqueous sodium bicarbonate solution were sequentially added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed, dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 68 mg of the title compound as a powder.

Examples 26-79
By subjecting the compound of Reference Example 1 (5) and the corresponding starting material compound to N-alkylation in the same manner as in Example 2 or Reference Example 1 (6), and then amination in the same manner as in Example 4, The compounds listed in Tables 3-6 were obtained.

実施例６３の化合物１４６ｍｇに酢酸エチル０．２ｍｌ、４Ｎ塩化水素−酢酸エチル溶液１．７ｍｌを加え、室温にて３時間攪拌した。反応液を減圧濃縮し、酢酸エチルを加え粉末を濾取して、標題化合物１２８ｍｇを得た。
ＭＳ ４６２（[M+H]⁺） Example 80

To 146 mg of the compound of Example 63, 0.2 ml of ethyl acetate and 1.7 ml of 4N hydrogen chloride-ethyl acetate solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the powder was collected by filtration to give 128 mg of the title compound.
MS 462 ([M + H] ⁺ )

実施例６１の化合物１４８ｍｇをメタノール２ｍｌに溶解し濃塩酸1ｍｌを加え、室温にて終夜攪拌した。反応液を減圧濃縮後、４Ｎ ＮａＯＨ水溶液で中和し、クロロホルムで抽出した。乾燥、濃縮後、ジエチルエーテルおよびジイソプロピルエーテルを加えて粉末を濾取して、標記化合物５８ｍｇを得た。
ＭＳ ４２５（[M+H]⁺） Example 81

148 mg of the compound of Example 61 was dissolved in 2 ml of methanol, 1 ml of concentrated hydrochloric acid was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with 4N NaOH aqueous solution, and extracted with chloroform. After drying and concentration, diethyl ether and diisopropyl ether were added, and the powder was collected by filtration to obtain 58 mg of the title compound.
MS 425 ([M + H] ⁺ )

Examples 82-107
The compounds of Examples 26 to 79 or the corresponding raw material compounds obtained by the same method as above were treated in the same manner as in Example 80 or Example 81 to obtain the compounds in Tables 7 to 9.

Examples 108-126
The compound of Reference Example 8 and the corresponding isocyanate were cyclized in the same manner as in Example 1, and the corresponding amine was reacted in the same manner as in Example 4 to obtain the compounds in Table 10 and Table 11.

参考例９の化合物を実施例４と同様にしてアミノ化し、次いで実施例８０と同様にして処理することにより、標題化合物を得た。ＭＳ ４５２（[M+H]⁺） Example 127

The compound of Reference Example 9 was aminated in the same manner as in Example 4, and then treated in the same manner as in Example 80 to obtain the title compound. MS 452 ([M + H] ⁺ )

Examples 128-141
By aminating the compound of Reference Example 8 or Reference Example 10 and the corresponding starting compound in the same manner as in Example 4 and then treating with the corresponding isocyanate and cyclizing in the same manner as in Example 1, Tables 12 and 13 compounds were obtained.

Examples 142-156
The compounds of Table 14 and Table 15 were prepared by N-alkylating the compound of Reference Example 11 and the corresponding starting material compound in the same manner as in Reference Example 8, then treating with the corresponding isocyanate and cyclizing in the same manner as in Example 1. Got.

Examples 157-161
Using the compound of Example 147, the compound of Examples 157 and 158 in Table 16 was obtained by reacting with the corresponding starting material compound and acylating in the same manner as in Example 14. Moreover, the other compound of Table 16 was obtained by reacting with a corresponding raw material compound and carrying out N-alkylation similarly to the reference example 10 using the compound of Example 147. In the synthesis of the compound of Example 160, t-butyl bromoacetate was used as the corresponding raw material compound, and the ester was hydrolyzed under the same conditions as in Example 80 after the reaction.

Examples 162-168
Using the compound of Reference Example 11, the compound of Table 17 was obtained by reacting with the corresponding starting material compound in the same manner as in Reference Example 10 for N-alkylation, followed by cyclization in the same manner as in Example 1.

参考例１２の化合物２．１２ｇを実施例１と同様にして環化し、同時にｔ−ブチルエステルを加水分解することで、標題化合物１．２８ｇを得た。
ＭＳ ３８５（[M+H]⁺） Example 169

2.12 g of the compound of Reference Example 12 was cyclized in the same manner as in Example 1, and at the same time, t-butyl ester was hydrolyzed to obtain 1.28 g of the title compound.
MS 385 ([M + H] ⁺ )

（１） 実施例１６９の化合物１００ｍｇ、１−ヒドロキシベンゾトリアゾール４８ｍｇ、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩６０ｍｇ、塩化メチレン１ｍｌの混合物を室温で１時間攪拌した。反応液に２Ｎエチルアミン−ＴＨＦ溶液１ｍｌを加え室温で終夜攪拌した。反応液を水、飽和重曹水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮して得られる残渣にジエチルエーテルを加えて無色結晶を濾取した。
（２） （１）で得られた化合物をクロロホルム−メタノールの混合溶媒２ｍｌに溶かし、４Ｎ塩酸−酢酸エチル０．２ｍｌを加えた後、減圧濃縮した。残渣に酢酸エチルを加えて濾取することにより、標題化合物７５ｍｇを得た。
ＭＳ ４１２（[M+H]⁺） Example 170

(1) A mixture of 100 mg of the compound of Example 169, 48 mg of 1-hydroxybenzotriazole, 60 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1 ml of methylene chloride was stirred at room temperature for 1 hour. To the reaction solution, 1 ml of 2N ethylamine-THF solution was added and stirred at room temperature overnight. The reaction solution was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Diethyl ether was added to the residue obtained by concentration under reduced pressure, and colorless crystals were collected by filtration.
(2) The compound obtained in (1) was dissolved in 2 ml of a mixed solvent of chloroform-methanol, 0.2 ml of 4N hydrochloric acid-ethyl acetate was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and collected by filtration to obtain 75 mg of the title compound.
MS 412 ([M + H] ⁺ )

Examples 171 to 173
The compound shown in Table 18 was obtained by reacting the compound of Example 169 with the corresponding amine in the same manner as in Example 170.

Examples 174-178
The compound of Table 19 was obtained by reacting the compound of Reference Example 11 with the corresponding isocyanate in the same manner as in Example 1.

実施例５７の化合物４９０ｍｇを２５％HBｒ−酢酸溶液５ｍｌに加え、７０℃にて１５時間加熱攪拌した。反応液を冷却後、重曹水を加えて中和し、酢酸エチルで抽出、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーで精製し、無色粉末として標題化合物２３７ｍｇを得た。ＭＳ ４８２（[M+H]^＋） Example 179

490 mg of the compound of Example 57 was added to 5 ml of a 25% HBr-acetic acid solution, and the mixture was heated and stirred at 70 ° C. for 15 hours. The reaction mixture was cooled, neutralized with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 237 mg of the title compound as a colorless powder. MS 482 ([M + H] ⁺ )

実施例１７９の化合物 ２００ｍｇに２５％HBｒ−酢酸溶液２ｍｌを加え、８０℃にて３日間加熱攪拌した。反応液を冷却後、重曹水を加えてアルカリ性とし、酢酸エチルで抽出、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーで精製し、無色粉末として標題化合物７１ｍｇを得た。ＭＳ ３７６（[M+H]^＋） Example 180

2 ml of a 25% HBr-acetic acid solution was added to 200 mg of the compound of Example 179, and the mixture was heated and stirred at 80 ° C. for 3 days. The reaction mixture was cooled, basified with aqueous sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 71 mg of the title compound as a colorless powder. MS 376 ([M + H] ⁺ )

Examples 181 to 183
The compound of Example 55 was reacted in the same manner as in Example 179 and Example 180 to obtain the compound of Example 181 and Example 182 in Table 20. Further, a corresponding compound having an isobutylamino group was synthesized in the same manner as in Example 55, and subsequently reacted in the same manner as in Example 180 to obtain the compound of Example 183.

Examples 184 and 185
Using the compound of Example 70 or the compound of Example 105 and reacting under the same conditions as in Example 179 (concentrated hydrochloric acid was used instead of HBr-acetic acid), the compounds of Table 21 were obtained.

Examples 186-197
The compound of Reference Example 13 was aminated in the same manner as in Example 4, then reacted with the corresponding isocyanate in the same manner as in Example 1, and acetylated according to a conventional method as necessary to obtain the compounds in Table 22. .

参考例１３の化合物６．３０ｇを実施例４と同様にして２，４−ジメトキシベンジルアミンと反応させることで、化合物（１）を得た。次いで、化合物（１）を実施例１と同様に処理することにより、化合物（２）７４４ｍｇを得た。
ＭＳ ２７１（[M+H]^＋） Example 198

Compound (1) was obtained by reacting 6.30 g of the compound of Reference Example 13 with 2,4-dimethoxybenzylamine in the same manner as in Example 4. Next, the compound (1) was treated in the same manner as in Example 1 to obtain 744 mg of the compound (2).
MS 271 ([M + H] ⁺ )

Examples 199-221
The compounds of Example 182, Example 192, Example 189, Example 187 or Example 188 were reacted with the corresponding halides in the same manner as in Reference Example 1 (6), and alkylated to give Tables 23 and 24. To give a compound. The compound of Example 211 was synthesized by reacting with the amino group protected with t-butoxycarbonyl and deprotecting in the same manner as in Example 80. The compound of Example 214 was synthesized by removing the methoxymethyl group from Example 213 in the same manner as in Example 81.

Examples 222-225
The corresponding starting material compound obtained in the same manner as in Example 192 was reacted with the corresponding halide in the same manner as in Reference Example 1 (6) to be alkylated to obtain the compounds in Table 25.

実施例１８２の化合物を、参考例１（６）と同様にして対応ハライドと反応させてアルキル化することで化合物（１）を合成した。化合物（１）２２６ｍｇ、１Ｎ ＮａＯＨ水溶液１．１ｍｌ、エタノール１．１ｍｌの混合物を室温にて３時間攪拌した。１Ｎ塩酸で中和し、析出した結晶を濾取することにより、対応するカルボン酸１８４ｍｇを得た。このうちの１４８ｍｇを実施例１７０と同様にしてメチルアミンと反応させることにより、化合物（２）９６ｍｇを得た。ＭＳ ３８４（[M+H]^＋） Example 226

Compound (1) was synthesized by reacting the compound of Example 182 with the corresponding halide and alkylating in the same manner as in Reference Example 1 (6). A mixture of 226 mg of Compound (1), 1.1 ml of 1N NaOH aqueous solution and 1.1 ml of ethanol was stirred at room temperature for 3 hours. By neutralizing with 1N hydrochloric acid and collecting the precipitated crystals by filtration, 184 mg of the corresponding carboxylic acid was obtained. Of this, 148 mg was reacted with methylamine in the same manner as in Example 170 to obtain 96 mg of compound (2). MS 384 ([M + H] ⁺ )

実施例２２６（１）の化合物を、実施例２２６（２）と同様にしてエチルアミンと反応させることで、標題化合物を得た。ＭＳ ３９８（[M+H]^＋） Example 227

The title compound was obtained by reacting the compound of Example 226 (1) with ethylamine in the same manner as in Example 226 (2). MS 398 ([M + H] ⁺ )

Example 228, Example 229
The compound of Reference Example 1 (5) was reacted with the corresponding compound in the same manner as in Reference Example 1 (6), and then treated in the same manner as in Example 5 and Example 13, to obtain the compounds in Table 26. The compound of Example 229 was synthesized by using 2,4-dimethoxybenzyl instead of 4-methoxybenzyl and deprotecting with concentrated hydrochloric acid / THF (70 ° C.).

参考例９の化合物１．５ｇを、実施例２２９と同様に２，４−ジメトキシベンジルアミンと反応し、脱保護することで、化合物（１）７０７ｍｇを得た。この化合物（１）７０７ｍｇをＴＨＦ７ｍｌに溶かし、Ｂｏｃ_２Ｏ４１０ｍｇを加えて室温で３０分間攪拌した。減圧濃縮後、ジエチルエーテルを加えて濾取することにより、化合物（２）７７０ｍｇを無色結晶として得た。
ＭＳ ４５４（[M+H]^＋） Example 230

In the same manner as in Example 229, 1.5 g of the compound of Reference Example 9 was reacted with 2,4-dimethoxybenzylamine and deprotected to obtain 707 mg of Compound (1). 707 mg of this compound (1) was dissolved in 7 ml of THF, 410 mg of Boc ₂ O was added, and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, diethyl ether was added and collected by filtration to obtain 770 mg of Compound (2) as colorless crystals.
MS 454 ([M + H] ⁺ )

Examples 231 to 242
Using the compounds of Example 13 and Examples 228 to 230, the reaction with acid halide was performed in the same manner as in Example 14, and t-butoxycarbonyl was eliminated as in Example 80 as necessary. A compound was obtained.

Cis−４−（メトキシメトキシ）シクロヘキサンカルボン酸４．５ｇをアセトニトリル４５ｍｌに溶かし、１，１’−カルボニルジイミダゾール３．７３ｇを加え、室温にて１時間攪拌した。実施例２２９の化合物４．０７ｇおよびアセトニトリル４５ｍｌを加え、４日間加熱還流した。反応液に水および重曹水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物にメタノール５０ｍｌを加えて３０分間攪拌した。反応液を減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィーで精製しアミド体を得た。本化合物を実施例８１と同様に処理することにより、標記化合物５．２６ｇを得た。ＭＳ ４３９（[M+H]^＋） Example 243

Cis-4- (methoxymethoxy) cyclohexanecarboxylic acid (4.5 g) was dissolved in acetonitrile (45 ml), 1,1′-carbonyldiimidazole (3.73 g) was added, and the mixture was stirred at room temperature for 1 hour. 4.07 g of the compound of Example 229 and 45 ml of acetonitrile were added, and the mixture was heated to reflux for 4 days. Water and aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 50 ml of methanol was added to the residue and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an amide form. This compound was treated in the same manner as in Example 81 to obtain 5.26 g of the title compound. MS 439 ([M + H] ⁺ )

Examples 244-263
Using the compounds of Examples 228 to 230, reacting with the corresponding carboxylic acid in the same manner as in Example 243, and removing t-butoxycarbonyl as necessary in the same manner as in Example 80, the compounds in Table 28 and Table 29 were used. A compound was obtained.

Examples 264-267
Using the compounds of Reference Example 14 and Reference Example 15 and reacting with the corresponding isocyanate in the same manner as in Example 1, followed by reacting with the corresponding carboxylic acid in the same manner as in Example 243, the compounds in Table 30 were obtained. Obtained.

Cis-4-(t-ブトキシカルボニルアミノ)シクロヘキサンカルボン酸５４０ｍｇおよび1，1’−カルボニルジイミダゾール３９６ｍｇをアセトニトリル５ｍｌに溶かし、室温にて１時間攪拌した。ついでこの反応液に実施例１９８の化合物２００ｍｇおよびアセトニトリル５ｍｌを加え、２日間加熱還流した。反応液に重曹水を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をメタノール５ｍｌに溶かし、炭酸カリウム１０２ｍｇを加えた。クロロホルムで希釈し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーで精製し、無色粉末として化合物（１）２５５ｍｇを得た。ＭＳ ４９６（[M＋H]^＋）
化合物（１）５０ｍｇをメタノールとクロロホルムの混合溶媒に溶かし、４N塩酸−酢酸エチル溶液０．５ｍｌを加え室温にて終夜攪拌した。反応液を減圧濃縮し、黄色粉末として化合物（２）４６ｍｇを得た。ＭＳ ３９６（[M＋H]^＋） Example 268

Cis-4- (t-butoxycarbonylamino) cyclohexanecarboxylic acid (540 mg) and 1,1′-carbonyldiimidazole (396 mg) were dissolved in acetonitrile (5 ml), and the mixture was stirred at room temperature for 1 hour. Next, 200 mg of the compound of Example 198 and 5 ml of acetonitrile were added to the reaction solution, and the mixture was heated to reflux for 2 days. Sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 5 ml of methanol, and 102 mg of potassium carbonate was added. The mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 255 mg of compound (1) as a colorless powder. MS 496 ([M + H] ⁺ )
50 mg of compound (1) was dissolved in a mixed solvent of methanol and chloroform, 0.5 ml of 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain 46 mg of Compound (2) as a yellow powder. MS 396 ([M + H] ⁺ )

実施例２６８の化合物（１）１００ｍｇを塩化メチレン５ｍｌに溶かし、これにジエチルアゾジカルボキシレート（４０％トルエン溶液）１３２ｍｇ、トリフェニルホスフィン７９ｍｇおよび（４−ヒドロキシメチルシクロヘキシル）カルバミン酸t−ブチル５５ｍｇを加え、室温にて２１時間攪拌した。反応液を減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィーで精製した後、メタノール１ｍｌに溶かし、４N塩酸−ジオキサン１ｍｌを加え、室温にて１時間攪拌した。反応液を濃縮し、黄色粉末として標記化合物１１８ｍｇを得た。ＭＳ ５０７（[M＋H]^＋） Example 269

100 mg of the compound (1) of Example 268 was dissolved in 5 ml of methylene chloride, and 132 mg of diethyl azodicarboxylate (40% toluene solution), 79 mg of triphenylphosphine and 55 mg of t-butyl (4-hydroxymethylcyclohexyl) carbamate were added thereto. In addition, the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, dissolved in 1 ml of methanol, added with 1 ml of 4N hydrochloric acid-dioxane, and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 118 mg of the title compound as a yellow powder. MS 507 ([M + H] ⁺ )

参考例７（１）の化合物を、実施例１７と同様にしてベンジルアミンと反応させることで、標題化合物を得た。ＭＳ ３６２（[M+H]^＋） Example 270

The title compound was obtained by reacting the compound of Reference Example 7 (1) with benzylamine in the same manner as in Example 17. MS 362 ([M + H] ⁺ )

Examples 271 to 336
The compound of Reference Example 5 (4) is reacted in the same manner as in Example 2 or Reference Example 1 (6) and oxidized with 3-chloroperbenzoic acid in the same manner as in Reference Example 6 (2). The compounds shown in Tables 31 to 35 were obtained by reacting with the corresponding amine in the same manner as in Example 17, and then removing t-butoxycarbonyl or methoxymethyl as necessary in the same manner as in Example 80 or Example 81. .

Examples 337-343
The compound of Reference Example 16 was reacted with the corresponding isocyanate in the same manner as in Example 1, oxidized with 3-chloroperbenzoic acid in the same manner as in Reference Example 6 (2), and subsequently in the same manner as in Example 17. Reaction with the corresponding amine gave the compounds in Table 36.

Examples 344-349
The compound shown in Table 37 was obtained by reacting the compound of Reference Example 17 (3) with the corresponding isocyanate in the same manner as in Example 1.

（１） 参考例５（３）の化合物５２．０ｇのジエチルエーテル３００ｍｌ溶液に４−フルオロフェニルイソシアネート３０．２ｇのジエチルエーテル１００ｍｌ溶液を氷冷下滴下し、室温にて３０分間攪拌した。減圧濃縮後、ジイソプロピルエーテルを加えて濾取し、化合物（１）７５．０ｇを無色結晶として得た。
（２） 化合物（１）３０．０ｇをクロロホルムに溶解し、氷冷下、3−クロロ過安息香酸４６．４ｇを加え室温にて２時間攪拌した。減圧濃縮後、ジエチルエーテルを加えて濾取し、化合物（２）３０．８ｇを無色結晶として得た。
（３） 化合物（２）２０．０ｇと対応原料化合物を実施例１７と同様に処理することにより得られた化合物に濃塩酸１００ｍｌを加え、室温にて終夜攪拌した。２Ｎ水酸化ナトリウム水溶液を加えて中和し、酢酸エチルを加えて攪拌した後、析出晶を濾取し、標記化合物１２．４ｇを無色結晶として得た。
ＭＳ ３１４（[M+H]^＋） Example 350

(1) To a solution of 52.0 g of the compound of Reference Example 5 (3) in 300 ml of diethyl ether was added dropwise a solution of 30.2 g of 4-fluorophenyl isocyanate in 100 ml of diethyl ether under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, diisopropyl ether was added and the mixture was collected by filtration to obtain 75.0 g of Compound (1) as colorless crystals.
(2) 30.0 g of compound (1) was dissolved in chloroform, and 46.4 g of 3-chloroperbenzoic acid was added under ice cooling, followed by stirring at room temperature for 2 hours. After concentration under reduced pressure, diethyl ether was added and collected by filtration to obtain 30.8 g of Compound (2) as colorless crystals.
(3) 100 ml of concentrated hydrochloric acid was added to the compound obtained by treating 20.0 g of compound (2) and the corresponding starting compound in the same manner as in Example 17, and the mixture was stirred overnight at room temperature. The mixture was neutralized with 2N aqueous sodium hydroxide solution, and ethyl acetate was added and stirred. The precipitated crystals were collected by filtration to give 12.4 g of the title compound as colorless crystals.
MS 314 ([M + H] ⁺ )

Examples 351-354
The compound of Table 38 was obtained by treating the compound of Reference Example 5 (3) and the corresponding starting material compound in the same manner as in Example 350.

Examples 355-367
By treating in the same manner as in Reference Example 1 (6) using the compound of Example 350, Example 353 or Example 354, or the compound produced in the same manner as in Example 350, the compound in Table 39 was obtained. It was.

Examples 368-382
The compound of Reference Example 5 (4) is reacted in the same manner as in Example 2 or Reference Example 1 (6) and oxidized with 3-chloroperbenzoic acid in the same manner as in Reference Example 6 (2). The compounds of Table 40 and Table 41 were obtained by reacting with the corresponding amine in the same manner as in Example 17, and removing t-butoxycarbonyl as necessary in the same manner as in Example 80.

Examples 383-386
The compound shown in Table 42 was obtained by methanesulfonylating and methoxycarbonylating the compound of Example 303 or 304 by a conventional method.

実施例１の化合物１００ｍｇ、４−アセチルフェニルボロン酸１２９ｍｇ、酢酸銅（II）７２ｍｇ、トリエチルアミン２２０μｌを塩化メチレン１０ｍｌに懸濁し、室温にて２４時間攪拌した。反応液に２８％アンモニア水を加え、クロロホルムで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残渣にエーテルを加え析出する結晶を濾取することにより標記化合物９２ｍｇを得た。融点２０６℃（分解） Example 387

100 mg of the compound of Example 1, 129 mg of 4-acetylphenylboronic acid, 72 mg of copper (II) acetate and 220 μl of triethylamine were suspended in 10 ml of methylene chloride and stirred at room temperature for 24 hours. To the reaction solution was added 28% aqueous ammonia, extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, ether was added to the residue and the precipitated crystals were collected by filtration to obtain 92 mg of the title compound. Melting point 206 ° C (decomposition)

Examples 388-389
The compound shown in Table 43 was obtained by reacting the compound of Example 1 and the corresponding starting material compound in the same manner as in Example 387.

実施例１３の化合物５０ｍｇのＴＨＦ溶液にイソシアン酸エチル１２μｌを加え、室温にて６時間攪拌した。反応液を減圧濃縮し、シリカゲルカラムクロマトグラフィーにて精製し、標記化合物１９ｍｇを無色結晶として得た。
融点２０９−２１０℃ Example 390

To a solution of the compound of Example 13 in 50 mg of THF, 12 μl of ethyl isocyanate was added and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 19 mg of the title compound as colorless crystals.
Melting point 209-210 ° C

Examples 391-394
The compounds prepared in the same manner as in Example 16 and Example 16 were hydrolyzed by a conventional method and then amidated, or reduced by a conventional method, then mesylated, and then dimethylaminated to give a table 44 To give a compound.

Examples 395-398
The corresponding raw material compounds were reacted in the same manner as in Example 368 to give the compounds in Table 45.

Examples 399-416
The compound of Reference Example 5 (4) and the corresponding starting compound are reacted in the same manner as in Reference Example 1 (6), oxidized with 3-chloroperbenzoic acid in the same manner as in Reference Example 6 (2), and then Example The compounds shown in Tables 46 and 47 were obtained by reacting with the corresponding amine in the same manner as in Example 17, and removing t-butoxycarbonyl as necessary in the same manner as in Example 80.

Examples 417-433
The compound of Reference Example 5 (4) is reacted in the same manner as in Example 2 or Reference Example 1 (6), and if necessary, reacted with methylmagnesium bromide, followed by the same procedure as in Reference Example 6 (2). The compounds of Tables 48 and 49 were obtained by oxidation with chloroperbenzoic acid and further reaction with the corresponding amine in the same manner as in Example 17.

Examples 434-460
The compound of Reference Example 5 (3) and the corresponding starting material compound are reacted in the same manner as in Reference Example 9, oxidized with 3-chloroperbenzoic acid in the same manner as in Reference Example 6 (2), and subsequently in the same manner as in Example 17. By reacting with the corresponding amines, the compounds listed in Tables 50-52 were obtained.

Examples 461-476
The compounds shown in Tables 53 and 54 were obtained by alkylsulfonylating and acylating the compound of Example 378 or Example 416 by a conventional method or reacting with isocyanate.

Examples 477, 478
The compound shown in Table 55 was obtained by alkylsulfonylating the compound of Example 147 by a conventional method.

  The following compounds were obtained in the same manner as in the above examples.

  In the same manner as in the above examples, the following compounds can be obtained.

  In accordance with the above examples, the production methods described in the present specification, and the synthesis methods usually used in the field of synthetic organic chemistry, each compound obtained by combining each substituent described in the following table can be produced.

（１） ２−クロロイソニコチン酸２２ｇをＴＨＦ４４０ｍｌに懸濁し、窒素気流下、−７０℃以下に冷却し、１．１４Ｍメチルリチウム−エーテル溶液２４５ｍｌを滴下した。同温にて１時間攪拌後、１時間かけて０℃まで昇温し、さらに同温にて１時間攪拌した。反応液に水５００ｍｌを加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。活性炭を加え、ろ過後、減圧濃縮し、４−アセチル−２−クロロピリジン１９．５ｇを無色結晶として得た。融点：３６℃。
（２） （１）で得られた化合物５５．１ｇ、ヒドロキシルアミン塩酸塩４９．２ｇ、酢酸ナトリウム５８．１ｇをエタノール５５０ｍｌに懸濁し、１時間加熱還流した。室温まで放冷後、エタノールを減圧留去し、析出晶を濾取して水で洗浄した。６０℃にて一晩通風乾燥し、１−（２−クロロピリジン−４−イル）エタノン オキシム５５ｇを無色結晶として得た。融点：１４３℃。
（３） （２）で得られた化合物１０５ｇとトシルクロリド１２３ｇを塩化メチレンに懸濁し、氷冷下にてトリエチルアミン９４ｍｌを滴下後、室温に昇温して４時間攪拌した。反応液に水５００ｍｌを加え、塩化メチレンで抽出し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。ろ過後、減圧濃縮し、得られた結晶を濾取してイソプロピルエーテルで洗浄し、１−（２−クロロピリジン−４−イル）エタノン オキシム トシレート１９２ｇを無色結晶として得た。融点：１５３℃。
（４） 窒素気流下、室温にて無水エタノール２２０ｍｌに金属ナトリウム３．１１ｇを加え、攪拌溶解した。これを氷冷し、（３）で得られた化合物４０ｇを加え、室温で１時間攪拌した。反応液に無水エーテル２２０ｍｌを加え、不溶物を除去した。ろ液に水冷下にて４Ｎ塩酸/ジオキサン溶液６２ｍｌを加えて１５分間攪拌した。反応液を減圧濃縮後、残留物を水に溶かし、炭酸カリウムを加えアルカリとした。これを酢酸エチルで数回抽出し、抽出液を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧濃縮後、残留物にヘキサン１００ｍｌを加え、赤色不溶物をろ過で除去した。ろ液を減圧濃縮し、再びヘキサンを加え、不溶物をセライトろ過で除去した。減圧濃縮し、真空ポンプで乾燥後、２−（２−クロロピリジン−４−イル）−２，２−ジエトキシエチルアミン２６．９ｇを赤色油状物として得た。
（５） （４）で得られた化合物２０ｇをＴＨＦ５０ｍｌに溶かした溶液を水冷し、４−フルオロフェニルイソシアナート１１．２ｇを滴下した。滴下後、反応液を減圧濃縮し、得られる残留物に濃塩酸３０ｍｌを加えて室温にて終夜攪拌した。氷冷した２Ｎ ＮａＯＨ水溶液１８０ｍｌに反応液を加えて中和し、析出晶を濾取後、水およびエーテルで洗浄した。６０℃にて通風乾燥し、５−（２−クロロピリジン−４−イル）−１−（４−フルオロフェニル）−４−イミダゾリン−２−オン２２．３ｇを無色結晶として得た。融点：２７０℃。
（６） （５）で得られた化合物１０ｇをＤＭＦ５０ｍｌに懸濁し、氷冷下、６３％水素化ナトリウム１．４６ｇを加えた後、室温にて３０分間攪拌した。反応液を再び氷冷し、２−シアノベンジルブロミド７．４４ｇを加えた後、室温にて３時間攪拌した。反応液を氷冷水２５０ｍｌに注ぎ、酢酸エチルで抽出し、抽出液を水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、シリカゲルカラムクロマトグラフィーにて精製し、４−（２−クロロピリジン−４−イル）−３−（４−フルオロフェニル）−１−（２−シアノベンジル）−４−イミダゾリン−２−オン１１．４ｇを無色結晶として得た。融点：１０９℃。 Reference example 1

(1) 22 g of 2-chloroisonicotinic acid was suspended in 440 ml of THF, cooled to −70 ° C. or lower under a nitrogen stream, and 245 ml of a 1.14 M methyl lithium-ether solution was added dropwise. After stirring at the same temperature for 1 hour, the temperature was raised to 0 ° C. over 1 hour, and further stirred at the same temperature for 1 hour. To the reaction solution was added 500 ml of water, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. Activated carbon was added, filtered, and concentrated under reduced pressure to obtain 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals. Melting point: 36 ° C.
(2) 55.1 g of the compound obtained in (1), 49.2 g of hydroxylamine hydrochloride and 58.1 g of sodium acetate were suspended in 550 ml of ethanol and heated to reflux for 1 hour. After cooling to room temperature, ethanol was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with water. By air-drying at 60 ° C. overnight, 55 g of 1- (2-chloropyridin-4-yl) ethanone oxime was obtained as colorless crystals. Melting point: 143 ° C.
(3) 105 g of the compound obtained in (2) and 123 g of tosyl chloride were suspended in methylene chloride, 94 ml of triethylamine was added dropwise under ice cooling, and the mixture was warmed to room temperature and stirred for 4 hours. To the reaction solution was added 500 ml of water, extracted with methylene chloride, washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with isopropyl ether to obtain 192 g of 1- (2-chloropyridin-4-yl) ethanone oxime tosylate as colorless crystals. Melting point: 153 ° C.
(4) Under a nitrogen stream, 3.11 g of metallic sodium was added to 220 ml of absolute ethanol at room temperature and dissolved by stirring. This was ice-cooled, 40 g of the compound obtained in (3) was added, and the mixture was stirred at room temperature for 1 hour. 220 ml of anhydrous ether was added to the reaction solution to remove insoluble matters. Under cooling with water, 62 ml of 4N hydrochloric acid / dioxane solution was added to the filtrate and stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and potassium carbonate was added to make it alkaline. This was extracted several times with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 100 ml of hexane was added to the residue, and red insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, hexane was added again, and insoluble matters were removed by Celite filtration. After concentration under reduced pressure and drying with a vacuum pump, 26.9 g of 2- (2-chloropyridin-4-yl) -2,2-diethoxyethylamine was obtained as a red oil.
(5) A solution of 20 g of the compound obtained in (4) in 50 ml of THF was cooled with water, and 11.2 g of 4-fluorophenyl isocyanate was added dropwise. After the addition, the reaction solution was concentrated under reduced pressure, 30 ml of concentrated hydrochloric acid was added to the resulting residue, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized by adding 180 ml of an ice-cooled 2N NaOH aqueous solution, and the precipitated crystals were collected by filtration and washed with water and ether. By air-drying at 60 ° C., 22.3 g of 5- (2-chloropyridin-4-yl) -1- (4-fluorophenyl) -4-imidazolin-2-one was obtained as colorless crystals. Melting point: 270 ° C.
(6) 10 g of the compound obtained in (5) was suspended in 50 ml of DMF, and 1.46 g of 63% sodium hydride was added under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was ice-cooled again, and 7.44 g of 2-cyanobenzyl bromide was added, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into 250 ml of ice-cold water and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 4- (2-chloropyridin-4-yl) -3- (4-fluorophenyl) -1- (2-cyanobenzyl) -4-imidazoline-2- 11.4 g of ON was obtained as colorless crystals. Melting point: 109 ° C.

４−アセチルピリジン（市販品）を原料化合物として、参考例１（２）〜（４）と同様の処理を行うことにより、２，２−ジエトキシ−２−ピリジン−４−イルエチルアミンを褐色油状物として得た。 Reference example 2

By using 4-acetylpyridine (commercial product) as a raw material compound, the same treatment as in Reference Examples 1 (2) to (4) was carried out to convert 2,2-diethoxy-2-pyridin-4-ylethylamine into a brown oily substance. Got as.

（１） ３，３−ジメトキシ−２−ブタノン１００ｇ、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール９９．２ｇの混合物を、１００℃で、４２時間撹拌した。反応液を冷却後、減圧濃縮して１−ジメチルアミノ−４，４−ジメトキシ−１−ペンテン−３−オン１４１ｇを得た。
（２） （１）で得られた化合物１４１ｇをメタノール８００ｍｌに溶解し、チオ尿素１１４ｇ、２８％ナトリウムメトキシド−メタノール２９２ｇを加えた後、７０℃で３時間撹拌した。反応液を氷冷し、よう化メチル２１５ｇを滴下した後、室温で１時間撹拌した。反応液を濃縮後、水を加え、酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮して４−（１，１−ジメトキシエチル）−２−メチルスルファニルピリミジン１４２ｇを得た。
（３） （２）で得られた化合物１４２ｇをアセトン５７０ｍｌに溶解し、 氷冷下、６Ｍ塩酸１１４ｍｌを加え、室温で３時間攪拌した。水４５０ｍｌを加えた後、溶媒を留去し、酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮して１−（２−メチルスルファニルピリミジン−４−イル）エタノン１０７ｇを得た。 Reference example 3

(1) A mixture of 100 g of 3,3-dimethoxy-2-butanone and 99.2 g of N, N-dimethylformamide dimethyl acetal was stirred at 100 ° C. for 42 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain 141 g of 1-dimethylamino-4,4-dimethoxy-1-penten-3-one.
(2) 141 g of the compound obtained in (1) was dissolved in 800 ml of methanol, and 114 g of thiourea and 292 g of 28% sodium methoxide-methanol were added, followed by stirring at 70 ° C. for 3 hours. The reaction solution was ice-cooled, 215 g of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated to obtain 142 g of 4- (1,1-dimethoxyethyl) -2-methylsulfanylpyrimidine.
(3) 142 g of the compound obtained in (2) was dissolved in 570 ml of acetone, 114 ml of 6M hydrochloric acid was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After adding 450 ml of water, the solvent was distilled off and extracted with ethyl acetate. The organic layer was washed, dried and concentrated to obtain 107 g of 1- (2-methylsulfanylpyrimidin-4-yl) ethanone.

（１） ４−クロロ−２−メチルスルファニルピリミジン１６．４ｇ、トリブチル（１−エトキシビニル）スズ３８ｇ、ビス（トリフェニルホスフィン）パラジウム（II）ジクロリド１．４３ｇ、ＤＭＦ１００ｍｌの混合物を８０℃で３時間攪拌した。反応液を冷却後、酢酸エチル３００ｍｌ、フッ化カリウム１７．８ｇを加え、室温で終夜攪拌した。セライトろ過した後、洗浄、乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１）により精製して、４−（１−エトキシビニル）−２−メチルスルファニルピリミジン１８．９ｇを得た。
（２） （１）で得られた化合物１８．９ｇをアセトン２００ｍｌに溶解し、４Ｍ塩酸６０ｍｌを加え、室温で１時間攪拌した。反応液を飽和重曹水に加え、酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮して、１−（２−メチルスルファニルピリミジン−４−イル）エタノン１５．９ｇを得た。 Reference example 4

(1) A mixture of 16.4 g of 4-chloro-2-methylsulfanylpyrimidine, 38 g of tributyl (1-ethoxyvinyl) tin, 1.43 g of bis (triphenylphosphine) palladium (II) dichloride and 100 ml of DMF at 80 ° C. for 3 hours. Stir. After cooling the reaction solution, 300 ml of ethyl acetate and 17.8 g of potassium fluoride were added and stirred at room temperature overnight. After filtration through celite, washing, drying and concentration were performed. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain 18.9 g of 4- (1-ethoxyvinyl) -2-methylsulfanylpyrimidine.
(2) 18.9 g of the compound obtained in (1) was dissolved in 200 ml of acetone, 60 ml of 4M hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed, dried and concentrated to obtain 15.9 g of 1- (2-methylsulfanylpyrimidin-4-yl) ethanone.

（１） 参考例３(３)または参考例４(２)で得られた化合物１７．６ｇをメタノール１８０ｍｌに溶解し、ヒドロキシルアミン塩酸塩１４．５ｇ、酢酸ナトリウム１７．２ｇを加え、３０分間加熱還流した。反応液を冷却後、溶媒を留去し、水を加えて酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮後、残渣にヘキサンを加え、析出する結晶をろ取し、１−（２−メチルスルファニルピリミジン−４−イル）エタノン オキシム１８．３ｇを得た。
融点：１５０−１５２℃。
（２） （１）で得られた化合物８９ｇを塩化メチレン１２００ｍｌに懸濁し、トリエチルアミン８１．２ｍｌ、トシルクロリド１０２ｇを加えて室温で終夜撹拌した。反応液を洗浄、乾燥、濃縮し、残渣にジエチルエーテルを加え、析出する結晶をろ取して１−（２−メチルスルファニルピリミジン−４−イル）エタノン オキシム トシレート１５９ｇを得た。融点：１４１−１４２℃。
（３） ２８％ナトリウムメトキシド−メタノール１２．９ｇのメタノール３０ｍｌ溶液に、氷冷下、（２）で得られた化合物１５ｇのＴＨＦ１２０ｍｌ溶液を滴下し、室温で終夜攪拌した。氷冷下、４Ｍ塩酸―ジオキサン溶液１００ｍｌを加えて、室温で４時間攪拌した後、反応液を濃縮し、残渣を炭酸カリウム水溶液に加えてクロロホルムで抽出した。有機層を乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノ−ル＝１５：１）により精製して２，２−ジメトキシ−２−（２−メチルスルファニルピリミジン−４−イル）エチルアミン８．１４ｇを得た。
（４） （３）で得られた化合物８ｇのＴＨＦ１２０ｍｌ溶液に、氷冷下、４−フルオロフェニルイソシアネート４．７８ｇのＴＨＦ３０ｍｌ溶液を滴下し、室温で３０分間攪拌した。氷冷下、濃塩酸１２０ｍｌを加えた後、室温で終夜攪拌した。析出する結晶をろ取し、水、エーテルで洗浄後、乾燥して、１−（４−フルオロフェニル）−５−（２−メチルスルファニルピリミジン−４−イル）−４−イミダゾリン−２−オン７．３５ｇを得た。融点：２６０−２６１℃。 Reference Example 5

(1) Dissolve 17.6 g of the compound obtained in Reference Example 3 (3) or Reference Example 4 (2) in 180 ml of methanol, add 14.5 g of hydroxylamine hydrochloride and 17.2 g of sodium acetate, and heat for 30 minutes. Refluxed. After cooling the reaction solution, the solvent was distilled off, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated, hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 18.3 g of 1- (2-methylsulfanylpyrimidin-4-yl) ethanone oxime.
Melting point: 150-152 ° C.
(2) 89 g of the compound obtained in (1) was suspended in 1200 ml of methylene chloride, 81.2 ml of triethylamine and 102 g of tosyl chloride were added, and the mixture was stirred overnight at room temperature. The reaction solution was washed, dried and concentrated, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 159 g of 1- (2-methylsulfanylpyrimidin-4-yl) ethanone oxime tosylate. Melting point: 141-142 ° C.
(3) To a 30 ml methanol solution of 12.9 g of 28% sodium methoxide-methanol, a 120 ml THF solution of 15 g of the compound obtained in (2) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. Under ice-cooling, 4 ml of 4M hydrochloric acid-dioxane solution was added and stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was added to an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give 2,2-dimethoxy-2- (2-methylsulfanylpyrimidin-4-yl) ethylamine 8 .14 g was obtained.
(4) To a 120 ml THF solution of 8 g of the compound obtained in (3) was added dropwise a 30 ml THF solution of 4.78 g of 4-fluorophenyl isocyanate under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 120 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature overnight. The precipitated crystals are collected by filtration, washed with water and ether, and dried to give 1- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) -4-imidazolin-2-one 7 .35 g was obtained. Melting point: 260-261 [deg.] C.

（１） 参考例５(４)で得られた化合物２．６ｇのＤＭＦ４０ｍｌ溶液に、室温で、水素化ナトリウム３２７ｍｇを加え、室温で３０分間攪拌した。２−シアノベンジルブロミド１．７７ｇを加え、室温で３０分間攪拌した後、水素化ナトリウム３３ｍｇ、２−シアノベンジルブロミド８５ｍｇを加え、室温で１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を洗浄、乾燥、濃縮し、ジエチルエーテルより結晶化して１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−（２−メチルスルファニルピリミジン−４−イル）−４−イミダゾリン−２−オン３．２８ｇを得た。
融点：１４１−１４２℃。
（２） （１）で得られた化合物３．２７ｇのクロロホルム溶液に、室温でメタクロロ過安息香酸２．０３ｇを加え、室温で１時間攪拌した。反応液に水酸化カルシウム１．１６ｇを加えて室温で２時間攪拌した後、セライトろ過し、濾液を濃縮した。残渣を酢酸エチルより結晶化して、１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−（２−メチルスルフィニルピリミジン−４−イル）−４−イミダゾリン−２−オン２．３９ｇを得た。
融点：１３３−１３６℃。 Reference Example 6

(1) To a solution of 2.6 g of the compound obtained in Reference Example 5 (4) in 40 ml of DMF, 327 mg of sodium hydride was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After adding 1.77 g of 2-cyanobenzyl bromide and stirring at room temperature for 30 minutes, 33 mg of sodium hydride and 85 mg of 2-cyanobenzyl bromide were added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried, concentrated and crystallized from diethyl ether to give 1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4- (2-methylsulfanylpyrimidin-4-yl) -4- 3.28 g of imidazolin-2-one was obtained.
Melting point: 141-142 ° C.
(2) To a chloroform solution of the compound 3.27 g obtained in (1) was added 2.03 g of metachloroperbenzoic acid at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1.16 g of calcium hydroxide, and the mixture was stirred at room temperature for 2 hours, filtered through celite, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give 1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4- (2-methylsulfinylpyrimidin-4-yl) -4-imidazolin-2-one. 39 g was obtained.
Melting point: 133-136 ° C.

（１） 参考例５(４)で得られた化合物１．４７ｇのメタノール１５０ｍｌ溶液に、室温下、オキソン１．７９ｇの水１０ｍｌ溶液を滴下した。３０分後及び２時間後にオキソン２９９ｍｇの水２ｍｌ溶液を滴下し、室温で２時間攪拌した。不溶物をろ過した後、濃縮し、重曹水を加えクロロホルムで抽出した。有機層を洗浄、乾燥、濃縮し、析出する結晶を酢酸エチル−エーテル（１：１）の混合溶媒でろ取して、１−（４−フルオロフェニル）−５−（２−メチルスルフィニルピリミジン−４−イル）−４−イミダゾリン−２−オン１．０３ｇを得た。融点：２０８−２１１℃（分解）。
（２） （１）で得られた化合物９３０ｍｇを、前記参考例６(1)と同様に処理することにより、１−（２−シアノベンジル）−３−（４−フルオロフェニル）−４−（２−メチルスルフィニルピリミジン−４−イル）−４−イミダゾリン−２−オン５４１ｍｇを得た。 Reference Example 7

(1) A solution of 1.47 g of the compound obtained in Reference Example 5 (4) in 150 ml of methanol was added dropwise at room temperature with 1.79 g of oxone in 10 ml of water. After 30 minutes and 2 hours, a solution of oxone 299 mg in 2 ml of water was added dropwise and stirred at room temperature for 2 hours. The insoluble material was filtered off, concentrated, aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform. The organic layer was washed, dried and concentrated, and the precipitated crystals were collected by filtration with a mixed solvent of ethyl acetate-ether (1: 1) to give 1- (4-fluorophenyl) -5- (2-methylsulfinylpyrimidine-4. -Ill) -4-imidazolin-2-one 1.03 g was obtained. Melting point: 208-211 ° C (decomposition).
(2) By treating 930 mg of the compound obtained in (1) in the same manner as in Reference Example 6 (1), 1- (2-cyanobenzyl) -3- (4-fluorophenyl) -4- ( 541 mg of 2-methylsulfinylpyrimidin-4-yl) -4-imidazolin-2-one was obtained.

参考例１（４）で得られた化合物１．０ｇをメタノール１０ｍｌに溶かし、２−フルオロベンズアルデヒド０．５１ｇを加え、室温にて３０分間攪拌した。水素化ホウ素ナトリウム１５５ｍｇを加え、さらに室温にて１時間攪拌した。減圧濃縮後、残留物に水を加えて酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）により精製し、標記化合物１．４５ｇを油状物として得た。 Reference Example 8

1.0 g of the compound obtained in Reference Example 1 (4) was dissolved in 10 ml of methanol, 0.51 g of 2-fluorobenzaldehyde was added, and the mixture was stirred at room temperature for 30 minutes. 155 mg of sodium borohydride was added, and further stirred at room temperature for 1 hour. After concentration under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1.45 g of the title compound as an oil.

参考例１（４）で得られた化合物５ｇと対応原料化合物を参考例８と同様に処理することにより、化合物（１）８．４７ｇを得た。化合物（１）３ｇを実施例１と同様に処理して環化し、続いてＴＨＦ２０ｍｌに溶解し、Ｂｏｃ_２Ｏ １．１ｇを加えて室温にて３０分間攪拌した後、減圧濃縮し、ジイソプロピルエーテルを加えて濾取することにより、化合物（２）２．５３ｇを得た。 Reference Example 9

The compound 5g obtained in Reference Example 1 (4) and the corresponding starting material compound were treated in the same manner as in Reference Example 8 to obtain 8.47 g of Compound (1). The compound (1) 3 g was treated and cyclized in the same manner as in Example 1, and then dissolved in 20 ml of THF, 1.1 g of Boc ₂ O was added and stirred at room temperature for 30 minutes, and then concentrated under reduced pressure, and diisopropyl ether was added. In addition, 2.53 g of compound (2) was obtained by filtration.

参考例１（４）で得られた化合物３．８ｇ、ヨウ化エチル１．７ｍｌ、トリエチルアミン３．０ｍｌの混合物を５０℃にて終夜攪拌した。２Ｎ ＮａＯＨ水溶液で中和した後クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。ＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）により精製し、標記化合物１．９ｇを油状物として得た。 Reference Example 10

A mixture of 3.8 g of the compound obtained in Reference Example 1 (4), 1.7 ml of ethyl iodide, and 3.0 ml of triethylamine was stirred at 50 ° C. overnight. The mixture was neutralized with 2N NaOH aqueous solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. Purification by NH silica gel column chromatography (hexane: ethyl acetate = 4: 1) gave 1.9 g of the title compound as an oil.

参考例１（４）で得られた化合物５．０ｇ、イソプロピルアミン３５ｍｌ、酢酸パラジウム４５８ｍｇ、２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル１．２８ｇ、ナトリウム ｔ−ブトキシド３．０ｇをトルエン７５ｍｌに懸濁し、窒素気流下、７０℃にて８時間加熱攪拌した。減圧濃縮後、残留物に水を加え、クロロホルムで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）により精製し、標記化合物４．３ｇを油状物として得た。 Reference Example 11

5.0 g of the compound obtained in Reference Example 1 (4), 35 ml of isopropylamine, 458 mg of palladium acetate, 1.28 g of 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, sodium t-butoxide 3 0.0 g was suspended in 75 ml of toluene and heated and stirred at 70 ° C. for 8 hours under a nitrogen stream. After concentration under reduced pressure, water was added to the residue, extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 4.3 g of the title compound as an oil.

参考例１（４）で得られた化合物２．０ｇ、アクリル酸ｔ−ブチル０．８２ｍｌ、ＴＨＦ１０ｍｌの混合物を加熱還流下、４日間攪拌した。反応液を減圧濃縮することにより化合物（１）３．１ｇを油状物として得た。次いで化合物（１）と対応原料化合物を実施例４と同様に処理することにより化合物（２）２．１２ｇを油状物として得た。 Reference Example 12

A mixture of 2.0 g of the compound obtained in Reference Example 1 (4), 0.82 ml of t-butyl acrylate, and 10 ml of THF was stirred for 4 days while heating under reflux. The reaction solution was concentrated under reduced pressure to obtain 3.1 g of Compound (1) as an oil. Then, compound (1) and the corresponding starting material compound were treated in the same manner as in Example 4 to obtain 2.12 g of compound (2) as an oil.

参考例１（４）で得られた化合物５．０ｇを参考例８と同様にして２，４−ジメトキシベンズアルデヒドと反応させることにより、標記化合物６．４ｇを得た。 Reference Example 13

By reacting 5.0 g of the compound obtained in Reference Example 1 (4) with 2,4-dimethoxybenzaldehyde in the same manner as in Reference Example 8, 6.4 g of the title compound was obtained.

参考例１０の化合物１．３９ｇを参考例１１と同様にして２，４−ジメトキシベンジルアミンと反応させることで、標記化合物１．５８ｇを得た。 Reference Example 14

In the same manner as in Reference Example 11, 1.39 g of the compound of Reference Example 10 was reacted with 2,4-dimethoxybenzylamine to obtain 1.58 g of the title compound.

参考例１（４）の化合物１０．０ｇを参考例８と同様にして対応原料化合物と反応させ、次いで参考例１１と同様にして２，４−ジメトキシベンジルアミンと反応させることで、標記化合物９．７５ｇを得た。 Reference Example 15

By reacting 10.0 g of the compound of Reference Example 1 (4) with the corresponding starting material compound in the same manner as in Reference Example 8, and then reacting with 2,4-dimethoxybenzylamine in the same manner as in Reference Example 11, the title compound 9 .75 g was obtained.

参考例５（３）の化合物２６．８ｇと対応原料化合物を参考例８と同様に処理することにより標記化合物３０．８ｇを得た。 Reference Example 16

By treating 26.8 g of the compound of Reference Example 5 (3) and the corresponding starting material compound in the same manner as in Reference Example 8, 30.8 g of the title compound was obtained.

（１） 参考例５（３）の化合物３．０ｇを塩化メチレン３０ｍｌに溶解し、トリエチルアミン３．６５ｍｌを加え、氷冷下、ベンジルオキシカルボニルクロリド３．３５ｇを滴下し、室温にて終夜攪拌した。反応液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーにて精製し、化合物（１）２．２３ｇを無色結晶として得た。ＭＳ ３６４（[M＋H]^＋）
（２） 化合物（１）４．２ｇをDMF１７ｍｌに溶解し、氷冷下、水素化ナトリウム５２８ｍｇを加えた後、室温にて１時間攪拌した。再び反応液を氷冷し、ヨウ化エチル１．３９ｍｌを加え、室温にて３０分間攪拌した。反応液に水を加え、酢酸エチルで抽出し、抽出液を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をクロロホルム５０ｍｌに溶かし、室温にてｍ−クロロ過安息香酸６．２６ｇを加え、同温にて３０分間攪拌した。反応液に水酸化カルシウム２．５８ｇを加えて攪拌後、不溶物をろ過で除去した。ろ液を減圧濃縮後、シリカゲルカラムクロマトグラフィーにて精製し、化合物（２）４．５５ｇを無色油状物として得た。ＭＳ ４２３（[M＋H]^＋）
（３） 化合物（２）２．１９ｇをジオキサン３０ｍｌに溶かし、トランス−４−（メトキシメトキシ）シクロヘキシルアミン１．６５ｇとN,N'−ジイソプロピルエチルアミン１．０８ｍｌを加え、１００℃にて１４時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーにて精製し、褐色油状物２．０ｇを得た。これをメタノール４０ｍｌに溶かし、１０％パラジウム−炭素１ｇを加え、水素気圧下（２.７気圧）、２時間接触還元を行った。パラジウムをろ過で除去し、減圧濃縮後、残留物をNHシリカゲルカラムクロマトグラフィーで精製し、化合物（３）１．０４ｇを褐色油状物として得た。ＭＳ ３６９（[M＋H]^＋） Reference Example 17

(1) 3.0 g of the compound of Reference Example 5 (3) was dissolved in 30 ml of methylene chloride, 3.65 ml of triethylamine was added, 3.35 g of benzyloxycarbonyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. . The reaction solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 2.23 g of compound (1) as colorless crystals. MS 364 ([M + H] ⁺ )
(2) 4.2 g of compound (1) was dissolved in 17 ml of DMF, and 528 mg of sodium hydride was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled again, 1.39 ml of ethyl iodide was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 50 ml of chloroform, 6.26 g of m-chloroperbenzoic acid was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution, 2.58 g of calcium hydroxide was added and stirred, and then insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 4.55 g of compound (2) as a colorless oil. MS 423 ([M + H] ⁺ )
(3) Dissolve 2.19 g of compound (2) in 30 ml of dioxane, add 1.65 g of trans-4- (methoxymethoxy) cyclohexylamine and 1.08 ml of N, N′-diisopropylethylamine, and stir at 100 ° C. for 14 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 2.0 g of a brown oil. This was dissolved in 40 ml of methanol, 1 g of 10% palladium-carbon was added, and catalytic reduction was performed under hydrogen pressure (2.7 atm) for 2 hours. Palladium was removed by filtration and after concentration under reduced pressure, the residue was purified by NH silica gel column chromatography to obtain 1.04 g of compound (3) as a brown oil. MS 369 ([M + H] ⁺ )

Experimental Example 1: Inhibition test of lipopolysaccharide (LPS) -stimulated TNF-α production in mice (In vivo)
This test is a method for experimentally measuring the inhibitory effect of the compound of the present invention on TNF-α production after LPS stimulation in mice.
Test compounds dissolved in Balb / cAnNCrj mice (6-8 weeks old, female, obtained from Charles River, Japan) with 0.5% methylcellulose and 0.2% PEG-60 hydrogenated castor oil (HCO60, purchased from Nikko Chemicals) 10 mg / kg, po), 30 minutes later, LPS (obtained from E. coli 0111: B4, Difco, adjusted to a final concentration of 1 mg / kg with phosphate buffered saline, 0.4 ml / head, ip ) Was administered. After 90 minutes, the mice were bled from the abdominal vein under diethyl ether anesthesia. The collected blood was centrifuged at 3000 g and serum was collected. Serum TNF-α was measured with DuoSet mouse TNF-α ELISA kit (genzymeTECHNE).
As a result, as shown in Table 80, the following Example compounds of the present invention significantly suppressed the production of TNF-α.

Since the active ingredient compound of the present invention has an excellent p38 MAP kinase inhibitory action, it can provide a preventive or therapeutic agent for diseases involving p38 MAP kinase.

Claims (7)

Formula [I]:

[Wherein G ¹ represents the formula :

(In the formula, ring B represents a benzene ring or a thiophene ring , and the benzene ring and the thiophene ring are a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, a substituted And optionally substituted with 1 to 3 identical or different groups selected from the group consisting of optionally substituted carbamoyl, optionally substituted carbamoyl, hydroxyl and cyano, W is a single bond or 1 or 2 alkyls in substituted represents an _C 1 -C ₄ alkylene.)
Represents a group represented by
Q ¹ and Q ² may be the same or different and each represents a hydrogen atom, a halogen atom or alkyl.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and each represents CH or N, provided that three or more of Z ¹ , Z ² , Z ³ and Z ⁴ are N. Never become.
G ² represents —NR ³ R ⁴ , —OR ⁵ , —COR ⁶ , —CHR ⁷ R ⁸ or a heterocyclic group.
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. ]
Or a pharmacologically acceptable salt thereof. Formula [Ia]:

(In the formula, ring A represents a benzene ring or a thiophene ring , and the benzene ring and the thiophene ring are a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, a substituted It may be substituted with 1 to 3 identical or different groups selected from the group consisting of amino, optionally substituted carbamoyl, hydroxyl and cyano.
Q ¹ represents a hydrogen atom, a halogen atom or alkyl.
W represents a single bond or C ₁ -C ₄ alkylene which may be substituted with 1 or 2 alkyls.
n represents 0, 1, 2, 3 or 4.
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group.
Z represents CH or N.
R ² represents a hydrogen atom, —NR ³ R ⁴ , —OR ⁵ , —COR ⁶ or —CHR ⁷ R ⁸ .
R ^{3 to} R ⁸ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, hydroxyl group, alkoxy, optionally substituted amino, optionally substituted alkanoyl, or substituted. Optionally substituted carbamoyl, alkoxyoxalyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted cycloalkyl substituted carbonyl, Represents an optionally substituted phenyl-substituted carbonyl or an optionally substituted heterocyclic group-substituted carbonyl. )
Or a pharmacologically acceptable salt thereof. Formula [Ib]

(In the formula, R ¹¹ represents a group selected from the group consisting of a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.
k represents 1 or 2, and when k is 2, two R ¹¹ may be the same or different.
R ¹² is (1) a C ₁ -C ₄ alkyl optionally substituted with a group selected from the group consisting of a hydroxyl group, alkoxy, cyano, an optionally substituted carbamoyl and amino;
₍₂₎ C 3 ~C ₄ cycloalkylmethyl,
(3) Carbamoylmethyl,
(4) cyano, halogen _atom, C 1 -C _{3 alkoxy,} C 1 -C ₃ alkyl and halogen-substituted _C 1 -C ₃ optionally substituted with a group selected from the group consisting of alkyl benzyl,
(5) represents tetrahydropyranyl, or (6) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl and optionally substituted carbamoylalkyl.
Z ⁵ represents CH or N.
R ¹³ is (1) C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with a group selected from the group consisting of the following (i) to (xii)):
(I) following a) may be substituted with a group selected from the group consisting of ~e) _C 5 ~C ₇ cycloalkyl,
a) a hydroxyl group,
_b) C 1 ~C ₄ alkyl optionally substituted amino,
_c) C 1 ~C ₄ alkanoylamino,
d) a hydroxyl group, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _e) C 1 -C ₄ alkyl-substituted which may be carbamoyl (ii) hydroxyl, and _(iii) C 1 ~C ₄ alkyl optionally substituted carbamoyl,
(Iv) piperidyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(V) pyrrolidinyl optionally substituted with a group selected from the group consisting of alkyl, alkanoyl, alkylsulfonyl and oxo,
(Vi) tetrahydropyranyl optionally substituted with a hydroxyl group,
(Vii) imidazolinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Viii) imidazolidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo;
(Ix) piperazinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(X) hexahydropyrimidinyl optionally substituted with a group selected from the group consisting of alkyl and oxo,
(Xi) alkyl optionally substituted pyridyl, and (xii) furyl ₍₂₎ C 5 ~C ₇ cycloalkyl (said _C 5 -C ₇ cycloalkyl, the group consisting of the following (i) ~ (iii) Optionally substituted with a group selected from:
(I) a hydroxyl group,
(Ii) hydroxyl, amino and _C 1 -C ₄ alkyl-substituted _C 1 may be substituted with a group which is also selected from the group consisting of a carbamoyl optionally -C ₄ alkyl, and _(iii) C 1 -C ₄ An optionally substituted carbamoyl, or (3) a heterocyclic group (which may be substituted with a group selected from the group consisting of the following (i) to (vi)):
(I) alkyl optionally substituted with a group selected from halogen, amino, hydroxyl group, phenyl and oxo,
(Ii) alkylsulfonyl-substituted aminosulfonyl,
(Iii) alkylsulfonyl optionally substituted with halogen,
(Iv) an optionally substituted carbamoyl,
(V) represents a hydroxyl group, and (vi) represents alkoxycarbonyl. )
Or a pharmacologically acceptable salt thereof. The compound of any of Compound Nos. 1 to 80 or a pharmaceutically acceptable salt thereof.

The pharmaceutical which consists of a compound in any one of the compound numbers 1-80 described in Claim 4, or its pharmacologically acceptable salt. The medicament according to any one of claims 1 to 3 and 5, which is a prophylactic or therapeutic agent for inflammatory diseases. The medicament according to any one of claims 1 to 3 and 5, which is a prophylactic or therapeutic agent for arthritis.