JPWO2004024694A1 - 4-substituted aryl-5-hydroxyisoquinolinone derivatives - Google Patents

Abstract

Provided are a 4-substituted-5-hydroxyisoquinolinone derivative having an excellent poly (ADP-ribose) synthase inhibitory action and a pharmacologically acceptable addition salt thereof. A 4-substituted aryl-5-hydroxyisoquinolinone derivative represented by the general formula (1) and a pharmacologically acceptable addition salt thereof.

Description

  The present invention relates to 4-substituted aryl-5-hydroxyisoquinolinone derivatives and pharmacologically acceptable addition salts thereof, and poly (ADP-ribose) synthase inhibitors containing these as active ingredients.

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また、ＰＡＲＰ阻害活性を有するイソキノリノン構造を有する化合物としては、［特許文献１２］には式（Ｑ）

（式中、ＲはＯＲ^１、低級アルキル基、ＮＲ^１Ｒ^２、ハロゲン原子、トリフルオロメチル基、ＣＯＯＸ^２、ＣＮ、またはＣＯＸ^２（式中Ｒ^１は水素原子、低級アルキル基、ベンジル基、低級アルカノイル基、または（ＣＨ_２）_ｎ（ＣＨＯＨ）_ｙ（ＣＨ_２）_ｍＡ（式中ｎは１〜４の整数を表し、ｙは０、または１の整数を表し、ｍは０〜５の整数を表し、Ａは

を表す）を表し、Ｒ^２は水素原子、低級アルキル基、フェニル基、またはベンジル基を表し、Ｘ^２は低級アルキル基、アリール基、またはアラアルキル基を表す）を表し、Ｘは独立して、ＯＲ^１、Ｃ１〜４のＳ−アルキル基、またはＮＲ^４Ｒ^５（式中Ｒ^４およびＲ^５は独立して、水素原子、低級アルキル基、ベンジル基、低級アルカノイル基、または（ＣＨ_２）_ｎ（ＣＨＯＨ）_ｙ（ＣＨ_２）_ｍＱ（式中ＱはＮ（ＣＨ_３）_２、またはＮ（ＣＨ_２ＣＨ_３）_２を表す）を表す）を表し、Ｚは−ＣＨＲ^２ＣＨＲ^３−、−ＣＲ^６＝ＣＲ^３−、または−ＣＲ^３＝Ｎ−（式中Ｒ^３は水素原子、アルキル基、フェニル基、またはベンジル基を表し、Ｒ^６は水素原子、低級アルキル基、フェニル基、ベンジル基、塩素原子、臭素原子、またはＮＲ^７Ｒ^８（式中、Ｒ^７およびＲ^８は独立して、水素原子または低級アルキル基を表す）を表す）を表し、Ｚが−ＣＲ^３＝Ｎ−である場合、ＺのＮは環Ｎに結合する）で表される化合物が、［特許文献１３］には式（Ｒ）

（式中、Ｘは二重結合の酸素原子、または水酸基を表し、Ｒ^７は水素原子、または低級アルキル基を表し、Ｙは独立して、５−６員環からなる単環式、二環式または三環式の炭化水素環、または複素環である縮合環を成すのに必要な原子を表し、Ｚは−ＣＨＲ^２ＣＨＲ^３−（式中Ｒ^２およびＲ^３は独立して、水素原子、アルキル基、アリール基、またはアラアルキル基を表す）、−Ｒ^６Ｃ＝ＣＲ^３−（式中Ｒ^３およびＲ^６は独立して水素原子、低級アルキル基、アリール基、アラアルキル基、ハロゲン原子、−ＮＯ_２、−ＣＯＯＲ^７、または−ＮＲ^７Ｒ^８（式中Ｒ^８は水素原子、またはＣ_１−Ｃ_９のアルキル基を表す）を表し、Ｒ^６とＲ^３で独立して、５−６員環の芳香環を構成してもよい）、−Ｒ^２Ｃ＝Ｎ−、−ＣＲ^２（ＯＨ）−ＮＲ^７、または−Ｃ（Ｏ）−ＮＲ^７−を表す）で表される化合物が知られている。しかしながら、これら特許出願明細書中には本発明化合物の特徴である５位に水酸基を有し、かつ４位にアリール基を有するイソキノリノンは開示されておらず、さらに合成法およびＰＡＲＰ阻害活性の記載もない。また、これらにおいて開示されている化合物のＰＡＲＰ阻害活性も十分とはいえない。
また、表２に記載の式（Ｓ）

で表される化合物が知られているが、これら特許出願明細書中において開示されているイソキノリノン誘導体は５−ニトロソイソキノリノンのみであり、本発明化合物の特徴である５位に水酸基を有し、かつ４位にアリール基を有するイソキノリノン誘導体に関しては、記載が無い。
更に、ＰＡＲＰ阻害活性を有する構造類似化合物としては、［特許文献２０］には式（Ｔ）

［式中、Ｒ１は水酸基またはアミノ基によって置換されたＣ１〜４アルキル基、または−Ａ１−Ａ２−Ａ３（式中Ａ１は−ＮＲ３Ｃ（Ｏ）−、−ＮＲ４Ｃ（Ｓ）−、−ＮＲ５ＳＯ_２−等を表し、Ａ２はＣ１〜８アルキレン基、Ｃ２〜８アルケニレン基、Ｃｙｃ１等を表し、Ａ３は水素原子、−ＮＲ１７Ｒ１８、Ｃｙｃ２、−ＯＲ１９等を表す）を表す］（置換基の説明は一部を抜粋した）で表される化合物が、
［特許文献２１］には式（Ｕ）

［式中、Ｒ１は水素原子、ハロゲン原子、直鎖および分岐のＣ_１−Ｃ_６−アルキル基、水酸基、ニトロ基、ＣＦ_３、ＣＮ、ＮＲ１１Ｒ１２、ＮＨ−ＣＯ−Ｒ１３、またはＯ−Ｃ_１−Ｃ_４−アルキル基（式中Ｒ１１およびＲ１２は独立して、水素原子、またはＣ_１−Ｃ_４−アルキル基を表し、Ｒ１３は水素原子、Ｃ１−Ｃ４−アルキル基、Ｃ１−Ｃ４−アルキル−フェニル基、またはフェニル基を表す）を表し、Ａ_１は直鎖または分岐のＣ_０−Ｃ_６−アルキレンを表し、Ａ_２はＮＲ２、ＮＲ２−Ｃ_１−Ｃ_６−アルキル−、０等を表し、Ａ_３は置換基を有してもよい５−６員の単環または二環式の芳香環またはヘテロ芳香環を表す］（置換基の説明は一部を抜粋した）で表される化合物が知られているが、これらはいずれもフタラジノン誘導体であり、イソキノリノン誘導体である本発明化合物とは構造を異にする上、イソキノリノンの５位に相当する部位、すなわちフタラジノンの５位に水酸基を有している化合物は開示されていない。
また、４−置換アリール−５−ヒドロキシイソキノリノン誘導体の構造類似化合物としては、［特許文献２２］には抗アレルギー、抗炎症および異常増殖抑制作用を有する化合物として、式（Ｖ）

［式中、Ｒ１は水素原子、アルキル基、アリールメチル基等を表し、Ｒ２は水素原子、アルキル基、アリール基等を表し、Ｒ３は水素原子、アルキル基、アリールメチル基、アリール基等を表し、Ｒ４およびＲ６は独立して、水素原子、ハロゲン原子、−ＯＲ８（式中Ｒ８は独立して、水素原子、またはアルキル基を表す）等を表し、Ｒ４およびＲ６の内、少なくとも一つは−ＳＨ、−ＯＨ、−ＮＨＲ８等を表し、Ｒ５およびＲ７は独立して、水素原子、ハロゲン原子、−ＣＦ_３等を表す］（置換基の説明については一部を抜粋した）で表される化合物が知られているが、この特許出願明細書中に記載の化合物はすべてイソキノリノン環の５位と７位に同一の置換基を有しており、本発明化合物のように５位のみに水酸基を有した化合物は開示されていない上、開示されている製造法では本発明化合物のような５位のみに水酸基を有した化合物を製造することは困難である。更に４位のアリール基に関してもフェニル基のみの開示であり、置換基を有したフェニル基およびヘテロアリール基については開示されていない。また、ＰＡＲＰ阻害活性に関しても全く記載されていない。
また、表３に記載の式（Ｗ）

で表される化合物が知られているが、いずれも２位に水素原子以外の置換基を有している上、５位に水酸基を有する化合物は開示されておらず、本発明化合物とは構造を異にする。また、ＰＡＲＰ阻害活性に関しては全く記載されていない。
本発明はＰＡＲＰの過剰な活性化に起因する疾患、例えば、種々の虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）、糖尿病およびその合併症、頭部外傷等の予防および／または治療剤として開発が期待されるＰＡＲＰ阻害活性を有する新規な化合物を提供することにある。Poly (ADP-ribose) synthetase (hereinafter abbreviated as “PARP”, also known as poly (ADP-ribose) synthetase) is a protein that regulates DNA function in the nucleus and damages DNA. It is an enzyme that is activated by recognition and sequentially transfers poly (ADP-ribose) to an acceptor protein such as DNA-polymerase using NAD (nicotinamide adenine dinucleotide) as an enzyme substrate as an enzyme substrate. Therefore, it is considered that excessive activation of PARP causes a decrease in intracellular energy production ability based on depletion of NAD essential for the electron transport system, and causes cell death (). In addition, since PARP is limitedly decomposed as a substrate of caspase-3, which is one of the interleukin-1β converting enzyme-like protease family, it is also attracting attention as an apoptosis-related enzyme [Non-patent Document 1]. ].
Furthermore, in an experiment using a PARP-knockout mouse, cultured neurons collected from the brain of the knockout mouse were resistant to damage caused by excitatory amino acids such as nitric oxide and NMDA (N-methyl-D-aspartate). It has been reported that this knockout mouse suppresses infarct caused by cerebral ischemia by about 80% or more [Non-Patent Document 2]. From these facts, PARP inhibitors are considered effective for cerebral infarction and neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.). Other than this, there are also diseases caused by ischemia or ischemia-reperfusion such as diabetes, myocardial infarction and acute renal failure, cardiovascular diseases such as septic shock, inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. There is a report that it is effective [Non-Patent Document 3]. In addition, PARP inhibitors have been reported to be useful as antiretroviral agents including HIV [Non-patent document 4], sensitizers for anticancer therapy [Non-patent document 5], and [Non-patent document 6]. Yes.
Based on the above, compounds having PARP inhibitory activity are diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory) Intestinal diseases, multiple encephalopathy, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc. It is expected to be useful as
By the way, as the currently known compounds having PARP inhibitory activity, the formulas (A) to (P) shown in Table 1 are known, but they are not isoquinolinone derivatives, and have different structures from the compounds of the present invention. To do. Further, the disclosed PARP inhibitory activity is not sufficient.

In addition, as a compound having an isoquinolinone structure having PARP inhibitory activity, [Patent Document 12] has formula (Q).

(Wherein R is OR ¹ , lower alkyl group, NR ¹ R ² , halogen atom, trifluoromethyl group, COOX ² , CN, or COX ² (wherein R ¹ is hydrogen atom, lower alkyl group, benzyl group, a lower alkanoyl group or a _{(CH 2) n (CHOH)} y (CH 2) m a ( wherein n represents an integer of 1 to 4,, y represents an integer of 0 or 1,, m is 0-5 Represents an integer, A is

R ² represents a hydrogen atom, a lower alkyl group, a phenyl group, or a benzyl group, and X ² represents a lower alkyl group, an aryl group, or an araalkyl group, and X is independently oR ^1, C1 -4 of S- alkyl or ^NR 4 ^{R 5} (wherein ^{R 4} and ^{R 5} are independently hydrogen atom, a lower alkyl group, a benzyl group, a lower alkanoyl group or a _{(CH 2) n,,} (CHOH) _y (CH ₂ ) _m Q (wherein Q represents N (CH ₃ ) ₂ or N (CH ₂ CH ₃ ) ₂ )), Z represents —CHR ² CHR ³ —, — CR ⁶ = CR ³ —, or —CR ³ = N— (wherein R ³ represents a hydrogen atom, an alkyl group, a phenyl group, or a benzyl group, and R ⁶ represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group) , Chlorine atom, bromine source , Or ^NR 7 ^{R 8} (wherein, ^{R 7} and ^{R 8} independently represents a hydrogen atom or a lower alkyl group) represents a representative) and when Z is ^-CR 3 = is N-, Z of N Is bonded to ring N), [Patent Document 13] has the formula (R)

(In the formula, X represents a double-bonded oxygen atom or a hydroxyl group, R ⁷ represents a hydrogen atom or a lower alkyl group, and Y is independently a monocyclic or bicyclic ring consisting of a 5-6 membered ring. Represents an atom necessary for forming a condensed ring which is a formula or a tricyclic hydrocarbon ring or a heterocycle, and Z represents —CHR ² CHR ³ — (wherein R ² and R ³ independently represent a hydrogen atom; , Represents an alkyl group, an aryl group, or an araalkyl group), —R ⁶ C═CR ³ — (wherein R ³ and R ⁶ are independently a hydrogen atom, a lower alkyl group, an aryl group, an araalkyl group, a halogen atom, —NO ₂ , —COOR ⁷ , or —NR ⁷ R ⁸ (wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₉ alkyl group), R ⁶ and R ³ independently represent 5- may constitute an aromatic ring of 6-membered ^{ring), - R 2 C = N} -, - CR (OH) -NR ⁷ or -C (O) -NR ^7, - compounds represented by the representative of the) is known. However, these patent applications do not disclose isoquinolinones having a hydroxyl group at the 5-position and an aryl group at the 4-position, which are characteristic of the compounds of the present invention, and further describe the synthesis method and PARP inhibitory activity. Nor. Further, the PARP inhibitory activity of the compounds disclosed in these is not sufficient.
Further, the formula (S) shown in Table 2

However, the isoquinolinone derivative disclosed in these patent application specifications is only 5-nitrosoisoquinolinone and has a hydroxyl group at the 5-position, which is a feature of the compound of the present invention. In addition, there is no description regarding isoquinolinone derivatives having an aryl group at the 4-position.
Furthermore, as a structurally similar compound having PARP inhibitory activity, [Patent Document 20] has formula (T).

Wherein, R1 is C1~4 alkyl group substituted by a hydroxyl group or an amino group, or -A1-A2-A3 (wherein A1, is -NR3C (O) -, - NR4C (S) -, - NR5SO 2 - A2 represents a C1-8 alkylene group, a C2-8 alkenylene group, Cyc1, etc., and A3 represents a hydrogen atom, -NR17R18, Cyc2, -OR19, etc.] (part of explanation of substituents) The compound represented by
[Patent Document 21] includes a formula (U).

[Wherein, R1 represents a hydrogen atom, a halogen atom, linear and branched _C 1 -C ₆ - alkyl group, a hydroxyl group, a nitro _{group, CF 3, CN, NR11R12,} NH-CO-R13 or _{O-C 1,} - C ₄ - R11 and R12 in the alkyl radical (formula are independently hydrogen atom or _C 1 -C _4, - represents an alkyl group, R13 is a hydrogen atom, C1-C4- alkyl, C1-C4- alkyl - phenyl A ₁ represents a linear or branched C ₀ -C ₆ -alkylene, A ₂ represents NR ₂ , NR ₂ -C ₁ -C ₆ -alkyl-, 0 or the like, A ₃ represents a 5-6-membered monocyclic or bicyclic aromatic ring or heteroaromatic ring which may have a substituent] (the description of the substituent is partially extracted). All of these are known as lids. A compound having a structure different from that of the compound of the present invention which is a radinone derivative and is an isoquinolinone derivative and having a hydroxyl group at the 5-position of isoquinolinone, that is, the 5-position of phthalazinone is not disclosed.
In addition, as a structurally similar compound of a 4-substituted aryl-5-hydroxyisoquinolinone derivative, [Patent Document 22] discloses a compound having an antiallergic, anti-inflammatory and abnormal growth inhibitory activity, which is represented by the formula (V)

[Wherein R1 represents a hydrogen atom, an alkyl group, an arylmethyl group, etc., R2 represents a hydrogen atom, an alkyl group, an aryl group, etc., and R3 represents a hydrogen atom, an alkyl group, an arylmethyl group, an aryl group, etc. , R4 and R6 independently represent a hydrogen atom, a halogen atom, -OR8 (wherein R8 independently represents a hydrogen atom or an alkyl group) and the like, and at least one of R4 and R6 is- represents SH, -OH, a -NHR8 etc., R5 and R7 independently represent a hydrogen atom, a halogen atom, a -CF _3, etc. the compound represented by (excerpt of some description substituent) However, all the compounds described in this patent application specification have the same substituents at the 5-position and 7-position of the isoquinolinone ring, and a hydroxyl group is present only at the 5-position as in the compound of the present invention. The possessed compound is open In addition, it is difficult to produce a compound having a hydroxyl group only at the 5-position, such as the compound of the present invention, by the disclosed production method. Furthermore, regarding the aryl group at the 4-position, only the phenyl group is disclosed, and the phenyl group and heteroaryl group having a substituent are not disclosed. In addition, there is no description regarding PARP inhibitory activity.
Further, the formula (W) described in Table 3

However, none of the compounds having a substituent other than a hydrogen atom at the 2-position and a hydroxyl group at the 5-position are disclosed. Make different. Further, there is no description regarding PARP inhibitory activity.
The present invention relates to diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebral sclerosis, arthritis) Rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes and its complications, head injury, etc. It is to provide a novel compound having the above.

［式中、Ｒ^１は水素原子またはハロゲン原子を表し、
Ｒ^２は水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基またはハロゲン原子で置換されてもよい低級アルコキシ基を表し、
環Ａｒはフェニル基、ナフチル基または５員若しくは６員の複素環およびその縮合環を表し、
Ａは単結合またはＣ_１〜Ｃ_３アルキレンを表し、
Ｘは単結合、酸素原子またはＮＲ^４を表し、
Ｒ^４は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｙは酸素原子または硫黄原子を表し、
Ｒ^３は一般式（２）

（式中、Ｒ^５は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｒ^６はハロゲン原子で置換されてもよい低級アルキル基、水酸基で置換された低級アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基または置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表すか、あるいはＲ^５とＲ^６とでともに結合して置換基を有してもよい５員若しくは６員の複素環およびその縮合環を表す）、または一般式（３）

（式中、Ｑ^１は単結合またはＮＲ^８を表し、
Ｒ^８は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｑ^２はＣ_１〜Ｃ_６アルキレンを表し、
Ｒ^７は水酸基、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルコキシ基、低級アルコキシカルボニル基、カルボキシ基、置換基を有してもよい環状アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環およびその縮合環、または一般式（４）

（式中、Ｒ^９、Ｒ^１０は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基を表すか、あるいはＲ^９とＲ^１０とでともに結合して置換基を有してもよい５員若しくは６員の複素環およびその縮合環を表す）を表す）を表す］で表される４−置換アリール−５−ヒドロキシイソキノリノン誘導体とその薬理上許容される付加塩、および一般式（１ｂ）

［式中、Ｒ^１ａは水素原子を表し、
Ｒ^２ａは水素原子を表し、
Ａ^ａは単結合を表し、
Ｘ^ａは単結合、ＮＲ^４を表し、
Ｒ^４は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｙ^ａは酸素原子を表し、
Ｒ^３は一般式（２）

（式中、Ｒ^５は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｒ^６はハロゲン原子で置換されてもよい低級アルキル基、水酸基で置換された低級アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基または置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表すか、あるいはＲ^５とＲ^６とでともに結合して置換基を有してもよい５員若しくは６員の複素環およびその縮合環を表す）、または一般式（３）

（式中、Ｑ^１は単結合またはＮＲ^８を表し、
Ｒ^８は水素原子またはハロゲン原子で置換されてもよい低級アルキル基を表し、
Ｑ^２はＣ_１〜Ｃ_６アルキレンを表し、
Ｒ^７は水酸基、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルコキシ基、低級アルコキシカルボニル基、カルボキシ基、置換基を有してもよい環状アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環およびその縮合環、または一般式（４）

（式中、Ｒ^９、Ｒ^１０は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ^９とＲ^１０とでともに結合して置換基を有してもよい５員若しくは６員の複素環およびその縮合環を表す）を表す）を表す］で表される請求項１記載の４−置換アリール−５−ヒドロキシイソキノリノン誘導体とその薬理上許容される付加塩に優れたＰＡＲＰ阻害作用を見出し、本発明を完成するに至った。
本発明化合物の一般式（１）において、好ましくは、環Ａｒがフェニル基であり、Ｒ^１、Ｒ^２が水素原子である化合物が挙げられる。これら好ましい化合物としては、例えば、以下の表４〜６記載の化合物を挙げることができるが、本発明はこれら化合物またはその薬理上許容される付加塩に限定されるものではない。

上記表４〜６において、更に好ましい化合物としては、表４記載の例示番号５、７、９、１１、１３、３１、４０、４１、表５記載の例示番号１４、１８、３１、３６、４３、５４、表６記載の例示番号３１、３３〜３６、３８、３９、４２、５５、５８〜６０の化合物を挙げることができる。
本発明の一般式（１）の文中において『ハロゲン原子で置換されてもよい低級アルキル基』、『ハロゲン原子で置換されてもよい環状アルキル基』および『ハロゲン原子で置換されてもよい低級アルコキシ基』における『ハロゲン原子』とは、フッ素、塩素、臭素、ヨウ素が挙げられ、『低級アルキル基』とは、メチル、エチル、ｎ−プロピル、ｉｓｏ−プロピルなどの直鎖若しくは分岐した炭素数１〜６のものが挙げられ、『環状アルキル基』とは、シクロプロピル、シクロペンチル、シクロヘキシルなどの炭素数３〜７のものが挙げられ、『低級アルコキシ基』とは、メトキシ、エトキシ、プロポキシなどの直鎖若しくは分岐した炭素数１〜５のものが挙げられる。また文中において、『置換基を有してもよい環状アルキル基』、『置換基を有してもよい環状アルケニル基』、『置換基を有してもよいアラルキル基』、『置換基を有してもよいアラルキルオキシ基』、『置換基を有してもよいフェニル基』、『置換基を有してもよいナフチル基』および『置換基を有してもよい５員若しくは６員の複素環及びその縮合環』における『置換基』とは、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、低級アルキルチオ基、低級アルコキシカルボニル基、ニトロ基、置換基を有してもよいアミノ基、シアノ基、カルボキシル基、アルデヒド基、ヒドロキシ基で置換された低級アルキル基、カルボキシ基で置換された低級アルキル基、ハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基で置換されてもよいアミノ基で置換された低級アルキル基、置換基を有しても良い５員若しくは６員の環状アミノ基で置換された低級アルキル基、ヒドロキシ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、ハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基で置換されてもよいアミノ基で置換された低級アルコキシ基、置換基を有しても良い５員若しくは６員の環状アミノ基で置換された低級アルコキシ基、置換基を有してもよいアラルキル基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有しても良い５員若しくは６員の複素環式基などが挙げられ、『低級アルコキシカルボニル基』とは、メトキシカルボニル、エトキシカルボニルなどの直鎖若しくは分岐した炭素数１〜６のものが挙げられ、『置換基を有してもよいアミノ基』とは、アシル基、ハロゲン原子で置換されていてもよい低級アルキルスルホニル基、アリールスルホニル基、例えばアセチル、メタンスルホニル、フェニルスルホニルなどによって置換されてもよく、またハロゲン原子で置換されていてもよい低級アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいアラルキル基によって置換されていてもよいアミノ基が挙げられ、『置換基を有しても良い５員若しくは６員の環状アミノ基』における『５員若しくは６員の環状アミノ基』とは、ピロリジル、ピペリジル、ピペラジル、モルホリル、チオモルホリルなどが挙げられ、『置換基を有してもよい環状アルケニル基』における『環状アルケニル基』とはシクロペンテニル、シクロヘキセニルなどの炭素数５〜７のものが挙げられ、『置換基を有してもよいアラルキル基』および『置換基を有してもよいアラルキルオキシ基』における『アラルキル基』とは、ベンジル、ジフェニルメチル、フェネチル、フェニルプロピルなどが挙げられる。ここで言う置換基とは上記で説明した『置換基』を指す。また『５員若しくは６員の複素環及びその縮合環』における『複素環』とは、置換基を有してもよい飽和若しくは不飽和の単環式又は多環式の窒素、酸素、硫黄原子を１個以上含有し得る複素環式基であり、例えばピロリジル、ピペリジル、ピペラジル、モルホリル、チオモルホリル、テトラヒドロピリジル、フラニル、チエニル、ピラゾリル、イミダゾリル、オキサゾリル、チアゾリル、ピリジル、ピリミジル、ピリダジル、ピラチルなどが挙げられ、『その縮合環』とは、上記『複素環』のベンゼン縮合環（例えば、インドリル、テトラヒドロキノリル、ベンズオキサゾリジニル、ベンゾチアゾリジニル、ベンゾフラニル、ベンゾチエニル、ベンズイミダゾリル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、キナゾリル、キノキサリル、シンノリルなどが挙げられる）あるいは上記『複素環』より任意に選ばれた２つの環より成る縮合環（例えば、イミダゾピリジン、ピラゾロピリジン、イミダゾピリミジンなどが挙げられる）を指す。
本発明の一般式（１）で表される化合物は、必要に応じて薬理上許容される塩とすることができる。薬理上許容される塩としては、例えば、塩酸、臭化水素酸、硫酸等との無機酸塩、酢酸、フマル酸、マレイン酸、シュウ酸、クエン酸、メタンスルホン酸、トシル酸等との有機酸塩、およびナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩等の塩基との塩が挙げられる。
また本発明の一般式（１）で表される化合物とその薬理上許容される塩は、その分子内塩、それらの無水物、水和物または溶媒和物であってもよい。
本発明のＰＡＲＰ阻害活性を有する、一般式（１）で表される化合物は、公知の方法の組合せによって容易に製造することができる。例えば、以下に示す方法により製造することができる。
［製造法Ｉ］

上記式中、環Ａｒ、Ａ、Ｘ、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３は前述したものと同意義を表し、Ｒ^１１はハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基を表し、Ｒ^１２はハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよいアラルキル基あるいはアシル基を表し、Ｚはハロゲン原子を表す。
一般式（５）で表される化合物から一般式（６）で表される化合物への変換（工程Ｉ−Ａ）は、一般式（８）

（式中、環Ａｒ、Ａ、Ｘ、Ｙ、Ｒ^２、Ｒ^３は前述したものと同意義を表し、Ｒ^１３、Ｒ^１４は同一または異なって、水酸基、低級アルキル基、低級アルコキシ基を表すか、あるいはＲ^１３とＲ^１４とでともに結合して、低級アルキル基で置換されてもよい５員若しくは６員の環状ピナコールエステルを表す）で表される化合物を用い、適当な溶媒、例えば、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、ベンゼン、トルエン、１，４−ジオキサンあるいはこれらの混液等中、適当な触媒、例えば、テトラキス（トリフェニルホスフィン）パラジウム（０）、塩化ビス（トリフェニルホスフィン）パラジウム（ＩＩ）、塩化（１，１’−ビス（ジフェニルホスフィノ）フェロセン）パラジウム（ＩＩ）等の存在下、適当な塩基、例えば、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン等を加え、２０〜１６０℃で１〜４８時間反応させることにより行うことができる。
一般式（６）で表される化合物の内、Ｒ^１２がアシル基である化合物は、一般式（７）で表される化合物へ変換することができる（工程Ｉ−Ｂ）。すなわち、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化リチウム、水酸化カリウム、炭酸カリウム、炭酸水素ナトリウム等を用い、０〜８０℃で０．５〜２４時間反応させることにより行うことができる。
一般式（７）で表される化合物から一般式（１）で表される化合物への変換（工程Ｉ−Ｃ）は、無溶媒あるいは適当な溶媒、例えば水、酢酸、メタノール、ジクロロメタンあるいはこれらの混液等中、適当な酸、例えば塩酸、臭化水素酸、硫酸、トリフルオロ酢酸等を用いるか、あるいは適当な脱アルキル化剤、例えばヨウ化トリメチルシリル、三臭化ホウ素等を用いて、２０〜１００℃で１〜７２時間反応させることにより行うことができる。
また一般式（６）で表される化合物の内、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基である化合物は、直接一般式（１）で表される化合物へ変換することができる（工程Ｉ−Ｄ）。すなわち、無溶媒あるいは適当な溶媒、例えば水、酢酸、メタノール、ジクロロメタンあるいはこれらの混液等中、適当な酸、例えば塩酸、臭化水素酸、硫酸、トリフルオロ酢酸等を用いるか、あるいは適当な脱アルキル化剤、例えばヨウ化トリメチルシリル、三臭化ホウ素等を用いて、２０〜１００℃で１〜７２時間反応させることにより行うことができる。また、これら適当な酸および脱アルキル化剤を段階的に２度にわたって反応させることにより行うこともできる。
一般式（１）で表される化合物の内、Ｘが酸素原子、ＮＲ^４であり、Ｒ^３が一般式（２）、または一般式（３）において、Ｑ^１がＮＲ^８である化合物は、以下に示す方法においても合成することができる。
［製造法ＩＩ］

上記式中、環Ａｒ、Ａ、Ｒ^１、Ｒ^２、Ｒ^１１、Ｒ^１２、Ｚは前述したものと同意義を表し、Ｘ^ｄは酸素原子、ＮＲ^４を表し、Ｒ^４は前述したものと同意義を表し、Ｒ^３ｃは一般式（２）

（式中、Ｒ^５、Ｒ^６は前述したものと同意義を表す）、または一般式（３ｂ）

（式中、Ｑ^１ｂはＮＲ^８を表し、Ｑ^２、Ｒ^７、Ｒ^８は前述したものと同意義を表す）を表す。
一般式（５）で表される化合物から一般式（９）で表される化合物への変換（工程ＩＩ−Ａ）は、一般式（１２）

（式中、環Ａｒ、Ａ、Ｘ^ｄ、Ｒ^２、Ｒ^１３、Ｒ^１４は前述したものと同意義を表す）で表される化合物を用い、工程Ｉ−Ａと同様の方法により行うことができる。
一般式（９）で表される化合物から一般式（６ａ）で表される化合物への変換（工程ＩＩ−Ｂ）は、一般式（１３）

（式中、Ｒ^６、Ｙは前述したものと同意義を表す）で表される化合物、一般式（１４）

（式中、Ｒ^５、Ｒ^６は前述したものと同意義を表し、Ｚ^ａはハロゲン原子を表す）で表される化合物、または一般式（１５）

（式中、Ｒ^７、Ｒ^８、Ｚ^ｎ、Ｑ^２は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、ベンゼン、トルエン等中、無塩基あるいは適当な有機塩基、例えば、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の存在下、２０〜１２０℃で１〜２４時間反応させることにより行うことができる。
また一般式（１３）、（１４）および（１５）で表される化合物に代えて、一般式（１６）

（式中、Ｒ^１５はＲ^６または一般式（１７）

（式中、Ｒ^７、Ｑ^２は前述したものと同意義を表す）を表し、ＤはＮＨＲ^５、ＮＨＲ^８、カルボキシ基、カルバモイル基を表し、Ｒ^５、Ｒ^８は前述したものと同意義を表す）で表される化合物を用い、公知の方法により、イソシアン（イソチオシアン）酸エステル、あるいはカルバミン酸クロリドに変換し、一般式（１３）、（１４）および（１５）で表される化合物と同様の方法により反応させても行うことができる。
例えば、一般式（１６）で表される化合物の内、ＤがＮＨＲ^５、ＮＨＲ^８である化合物は、適当な溶媒、例えば、テトラヒドロフラン、ベンゼン、トルエン等中、無塩基あるいは適当な塩基、例えば、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン等の存在下、ホスゲン（チオホスゲン）、ホスゲンダイマー（クロロ蟻酸トリクロロメチル）あるいはその同族体（クロロ蟻酸４−ニトロフェニル等）を用い、−１０〜５０℃で１〜５時間反応させることにより、イソシアン（イソチオシアン）酸エステルあるいはカルバミン酸クロリドとすることができる。
また一般式（１６）で表される化合物の内、Ｄがカルボキシ基である化合物は、カルボキシ基を公知の方法の方法により酸アジドとした後、Ｃｒｕｔｉｕｓ転移反応やＳｃｈｍｉｄｔ転移反応により、Ｄがカルバモイル基である化合物は、Ｈｏｆｍａｎｎ転移反応により、イソシアン酸エステルとすることができる。
一般式（６ａ）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｉ−Ｂと同様の方法により、一般式（７ａ）で表される化合物へ変換することができ（工程ＩＩ−Ｃ）、更に工程Ｉ−Ｃと同様の方法により、一般式（１ｆ）で表される化合物に変換することができる（工程ＩＩ−Ｄ）。
また一般式（６ａ）で表される化合物の内、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基である化合物は、工程Ｉ−Ｅと同様の方法により、直接一般式（１ｆ）で表される化合物へ変換することができる（工程ＩＩ−Ｅ）。
一般式（９）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｉ−Ｂと同様の方法により、一般式（１０）で表される化合物へ変換することができ（工程ＩＩ−Ｆ）、更に工程ＩＩ−Ｂと同様の方法により、一般式（７ａ）で表される化合物へ変換することができる（工程ＩＩ−Ｇ）。
更に一般式（１０）で表される化合物は、工程Ｉ−Ｄと同様の方法により、一般式（１１）で表される化合物へ変換（工程ＩＩ−Ｈ）した後、工程ＩＩ−Ｂと同様のほうにより、一般式（１ｆ）で表される化合物に変換することもできる（工程ＩＩ−Ｉ）。
上記製造法ＩＩにおいて、一般式（９）で表される化合物の内、ＡがＣ_１〜Ｃ_３アルキレンであり、Ｘ^ｄが酸素原子であり、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよいアラルキル基である一般式（９ａ）で表される化合物、一般式（１０）で表される化合物の内、ＡがＣ_１〜Ｃ_３アルキレンであり、Ｘ^ｄが酸素原子である一般式（１０ａ）で表される化合物、および一般式（１０）で表される化合物の内、Ｘ^ｄがＮＲ^４である一般式（１０ｂ）で表される化合物は、以下に示す方法（製造法ＩＩＩ）を用いても合成することができる。
上記製造法ＩＩにおける、一般式（１ｆ）で表される化合物、一般式（６ａ）で表される化合物および一般式（７ａ）で表される化合物の内、Ｒ^３ｃが一般式（２）であり、Ｒ^６が置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環である化合物において、その置換基を必要に応じて他の置換基に変換することも公知の方法により行うことができる。
例えば、置換基が低級アルコキシカルボニル基である化合物は、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸水素ナトリウム等を用い、２０〜１００℃で０．５〜２４時間反応させることにより、置換基がカルボキシ基である化合物に変換することができる。
また置換基がニトロ基である化合物は、適当な溶媒、例えばメタノール、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な触媒、例えばパラジウム−炭素、白金−炭素等を用い、常圧または必要に応じて加圧下、２０〜８０℃で１〜１２時間水素添加反応に付すことにより、置換基がアミノ基である化合物に変換することができる。
［製造法ＩＩＩ］

上記式中、環Ａｒ、Ａ、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^１１、Ｒ^１２、Ｚは前述したものと同意義を表し、Ａ^ｂは単結合、Ｃ_１〜Ｃ_２アルキレンを表し、Ａ^ｃはＣ_１〜Ｃ_３アルキレンを表し、Ｒ^１２ａはハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよいアラルキル基を表し、Ｒ^１２ｂはアシル基を表す。
一般式（５）で表される化合物から一般式（１８）で表される化合物への変換（工程ＩＩＩ−Ａ）は、一般式（２１）

（式中、環Ａｒ、Ａ^ｂ、Ｒ^２、Ｒ^１３、Ｒ^１４は前述したものと同意義を表す）で表される化合物を用い、工程Ｉ−Ａと同様の方法により行うことができる。
一般式（１８）で表される化合物の内、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基である化合物は、一般式（９ａ）で表される化合物へ変換することができる（工程ＩＩＩ−Ｂ）。すなわち、適当な溶媒、例えばメタノール、エタノール、イソプロパノール、テトラヒドロフランあるいはこれらの混液等中、適当な還元剤、例えば、水素化ホウ素リチウム、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム等を用い、０〜８０℃で０．５〜１２時間反応させることにより行うことができる。
また一般式（１８）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｉ−Ｂと同様の方法により、一般式（１９）で表される化合物に変換することができる（工程ＩＩＩ−Ｃ）。
一般式（１９）で表される化合物は、工程ＩＩＩ−Ｂと同様の方法により、一般式（１０ａ）で表される化合物に変換することができる（工程ＩＩＩ−Ｄ）。
一般式（１９）で表される化合物は、工程ＩＩＩ−Ｅにより、一般式（１０ｂ）で表される化合物の内、ＡがＣ_１〜Ｃ_３アルキレンである化合物に変換することができる。すなわち、一般式（２２）

（式中、Ｒ^４は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、例えばメタノール、エタノール、ジクロロメタン、クロロホルムあるいはこれらの混液等中、必要に応じて適当な酸、例えば塩酸、臭化水素酸、酢酸等、あるいは適当なルイス酸、例えば、塩化アルミニウム、塩化亜鉛等の存在下、適当な還元剤、例えば、水素化ホウ素リチウム、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム等を加え、０〜６０℃で１〜２４時間反応させることにより行うことができる。
また一般式（１０ｂ）で表される化合物の内、ＡがＣ_１〜Ｃ_３アルキレンである化合物は、一般式（１０ａ）で表される化合物から変換することもできる（工程ＩＩＩ−Ｆ）。すなわち、無溶媒あるいは適当な溶媒、例えばジクロロメタン、クロロホルム、テトラヒドロフランあるいはこれらの混液等中、適当なハロゲン化剤、例えば塩化チオニル、オキシ塩化リン、臭化チオニル等を用い、−２０〜８０℃で０．５〜６時間反応させるか、あるいは適当な溶媒、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当なスルホニル化剤、例えばメタンスルホニルクロリド、トリフルオロメタンスルホン酸無水物等を用い、−２０〜６０℃で０．５〜３時間反応させた後、一般式（２２）

（式中、Ｒ^４は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、例えばメタノール、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、必要に応じて適当なヨウ化塩、例えばヨウ化ナトリウム、ヨウ化カリウム、ヨウ化テトラブチルアンモニウム等、あるいは適当な塩基、例えばトリエチルアミン、ピリジン、Ｎ，Ｎ−ジイソプロピルエチルアミン等の存在下、０〜１２０℃で１〜１２時間反応させることにより行うことができる。
更に一般式（１０ｂ）で表される化合物の内、Ａが単結合であり、Ｒ^４が水素原子である化合物は、一般式（５ａ）で表される化合物より、誘導することができる（工程ＩＩＩ−Ｇおよび工程ＩＩＩ−Ｈ）。すなわち、一般式（５ａ）で表される化合物から一般式（２０）で表される化合物への変換（工程ＩＩＩ−Ｇ）は、一般式（２３）

（式中、環Ａｒ、Ｒ^２、Ｒ^１３、Ｒ^１４は前述したものと同意義を表す）で表される化合物を用い、工程Ｉ−Ａと同様の方法により行うことができる。更に一般式（２０）で表される化合物から一般式（１０ｂ）で表される化合物の内、Ａが単結合であり、Ｒ^４が水素原子である化合物への変換（工程ＩＩＩ−Ｈ）は、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸水素ナトリウム、アンモニア等を用い、０〜１００℃で０．５〜２４時間反応させた後、適当な溶媒、例えばメタノール、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な触媒、例えばパラジウム−炭素、白金−炭素等を用い、常圧または必要に応じて加圧下、２０〜８０℃で１〜１２時間水素添加反応に付すことにより行うことができる。またこの２段階の反応は、順序を入れ替えて行ってもよい。
一般式（１）で表される化合物の内、ＸがＮＲ^４であり、Ｒ^３が一般式（３）であり、Ｑ^１が単結合である化合物は、以下に示す方法においても合成することができる。
［製造法ＩＶ］

上記式中、環Ａｒ、Ａ、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^７、Ｒ^１１、Ｒ^１２、Ｙ、Ｑ^２は前述したものと同意義を表す。
一般式（９ｂ）で表される化合物から一般式（６ｂ）で表される化合物への変換（工程ＩＶ−Ａ）は、一般式（２４）

（式中、Ｒ^７、Ｙ、Ｑ^２は前述したものと同意義を表し、Ｚ^ｂはハロゲン原子を表す）で表される化合物を用い、適当な溶媒、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル等中、適当な塩基、例えば、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の存在下、０〜８０℃で１〜２４時間反応させるか、一般式（２５）

（式中、Ｒ^７、Ｙ、Ｑ^２は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等中、適当な縮合剤、例えば１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド、ジシクロヘキシルカルボジイミドなどの存在下、０〜８０℃で１〜３６時間反応させることにより行うことができる。
一般式（６ｂ）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｉ−Ｂと同様の方法により、一般式（７ｂ）で表される化合物へ変換することができ（工程ＩＶ−Ｃ）、更に工程Ｉ−Ｃと同様の方法により、一般式（１ｇ）で表される化合物に変換することができる（工程ＩＶ−Ｃ）。
また一般式（６ｂ）で表される化合物の内、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基である化合物は、工程Ｉ−Ｅと同様の方法により、直接一般式（１ｇ）で表される化合物へ変換することができる（工程ＩＶ−Ｄ）。
一般式（９ｂ）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｉ−Ｂと同様の方法により、一般式（１０ｂ）で表される化合物へ変換することができる（工程ＩＶ−Ｅ）。
一般式（１０ｂ）で表される化合物は、工程ＩＶ−Ａと同様の方法により、一般式（７ｂ）で表される化合物へ変換することができる（工程ＩＶ−Ｆ）。
また一般式（１０ｂ）で表される化合物は、工程Ｉ−Ｃと同様の方法により、一般式（１１ａ）で表される化合物へ変換することができ（工程ＩＶ−Ｇ）、更に、工程ＩＶ−Ａと同様の方法により、一般式（１ｇ）で表される化合物へ変換することができる（工程ＩＶ−Ｈ）。
上記製造法ＩＶにおける、一般式（１ｇ）で表される化合物、一般式（６ｂ）で表される化合物および一般式（７ｂ）で表される化合物において、Ｒ^７を必要に応じて他の置換基に変換することも公知の方法により行うことができる。
例えば、Ｒ^７が低級アルコキシカルボニル基である化合物は、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸水素ナトリウム等を用い、２０〜１００℃で０．５〜２４時間反応させることにより、Ｒ^７がカルボキシ基である化合物に変換することができる。
またＲ^７が水酸基、あるいはハロゲン原子である化合物は、Ｒ^７が一般式（４）

（式中、Ｒ^９、Ｒ^１０は前述したものと同意義を表す）で表される化合物に変換することができる。例えば、Ｒ^７が水酸基である化合物は、適当な溶媒、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な塩基、例えばトリエチルアミン、ピリジン等の存在下、適当なスルホニル化剤、例えば、メタンスルホニルクロリド、トリフルオロメタンスルホン酸無水物等を用い、０〜８０℃で１〜６時間反応させた後、一般式（２６）

（式中、Ｒ^９、Ｒ^１０は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な塩基、例えばトリエチルアミン、ピリジン等の存在下、０〜１００℃で１〜１２時間反応させることにより行うことができる。また、Ｒ^７がハロゲン原子である化合物は、一般式（２６）

（式中、Ｒ^９、Ｒ^１０は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な塩基、例えばトリエチルアミン、ピリジン等の存在下（必要に応じて適当なヨウ化塩、例えば、ヨウ化ナトリウム、ヨウ化カリウム等を加えてもよい）、０〜１００℃で１〜１２時間反応させることにより行うことができる。
一般式（１）で表される化合物の内、Ｘが単結合であり、Ｙが酸素原子であり、Ｒ^３が一般式（２）、または一般式（３）において、Ｑ^１がＮＲ^８である化合物は、以下に示す方法においても合成することができる。
［製造法Ｖ］

上記式中、環Ａｒ、Ａ、Ｒ^１、Ｒ^２、Ｒ^３ｃ、Ｒ^１１、Ｒ^１２、Ｒ^１２ａは前述したものと同意義を表し、Ｒ^１６は低級アルキル基を表す。
一般式（５）で表される化合物から一般式（２７）で表される化合物への変換（工程Ｖ−Ａ）は、一般式（３１）

（式中、環Ａｒ、Ａ、Ｒ^２、Ｒ^１３、Ｒ^１４、Ｒ^１６は前述したものと同意義を表す）で表される化合物を用い、工程Ｉ−Ａと同様の方法により行うことができる。
一般式（２７）で表される化合物の内、Ｒ^１２がハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基である化合物は、工程Ｖ−Ｂにより、一般式（２８）で表される化合物へ変換することができる。すなわち、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化リチウム、水酸化カリウム、炭酸カリウム、炭酸水素ナトリウム等を用い、０〜８０℃で０．５〜２４時間反応させることにより行うことができる。
一般式（２８）で表される化合物から一般式（６ｃ）で表される化合物への変換（工程Ｖ−Ｃ）は、一般式（３２）

（式中、Ｒ^５、Ｒ^６は前述したものと同意義を表す）で表される化合物、または一般式（３３）

（式中、Ｒ^７、Ｒ^８、Ｑ^２は前述したものと同意義を表す）で表される化合物を用い、適当な溶媒、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等中、適当な縮合剤、例えば１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド、ジシクロヘキシルカルボジイミドなどの存在下、０〜８０℃で１〜３６時間反応させることにより行うことができる。
また無溶媒あるいは適当な溶媒、例えば、ベンゼン、クロロホルム、１，２−ジクロロエタン等中、適当なハロゲン化剤、例えば、塩化チオニル、オキシ塩化リン等を用い、０〜１００℃で１〜２４時間反応させて酸ハロゲン化物とした後、適当な溶媒、例えば、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等中、一般式（３２）

（式中、Ｒ^５、Ｒ^６は前述したものと同意義を表す）で表される化合物、または一般式（３３）

（式中、Ｒ^７、Ｒ^８、Ｑ^２は前述したものと同意義を表す）で表される化合物を用いて、０〜８０℃で１〜３６時間反応させても行うことができる。
一般式（６ｃ）で表される化合物から一般式（１ｈ）で表される化合物への変換（工程Ｖ−Ｄ）は、工程Ｉ−Ｃと同様の方法により行うことができる。
また一般式（２８）で表される化合物は、工程Ｉ−Ｃと同様の方法により、一般式（２９）で表される化合物へ変換することができ（工程Ｖ−Ｅ）、更に、工程Ｖ−Ｃと同様の方法により、一般式（１ｈ）で表される化合物へ変換することができる（工程Ｖ−Ｆ）。
一般式（２７）で表される化合物の内、Ｒ^１２がアシル基である化合物は、工程Ｖ−Ｇにより、一般式（３０）で表される化合物へ変換することができる。すなわち、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化リチウム、水酸化カリウム、炭酸カリウム、炭酸水素ナトリウム等を用い、０〜８０℃で０．５〜２４時間反応させることにより行うことができる。
一般式（３０）で表される化合物から一般式（２９）で表される化合物への変換（工程Ｖ−Ｈ）は、工程Ｉ−Ｃと同様の方法により行うことができる。
また一般式（３０）で表される化合物は、工程Ｖ−Ｃと同様の方法により、一般式（７ｃ）で表される化合物へ変換することができ（工程Ｖ−Ｉ）、更に、工程Ｉ−Ｃと同様の方法により、一般式（１ｈ）で表される化合物へ変換することができる（工程Ｖ−Ｊ）。
上記製造法Ｖにおいて、一般式（３０）で表される化合物は、以下に示す方法（製造法ＶＩ）を用いても合成することができる。
［製造法ＶＩ］

上記式中、環Ａｒ、Ａ、Ｒ^１、Ｒ^２、Ｒ^１１、Ｒ^１２ｂ、Ｚは前述したものと同意義を表しＲ^１７は低級アルキル基を表す。
一般式（５ａ）で表される化合物から一般式（３４）で表される化合物への変換（工程ＶＩ−Ａ）は、一般式（３７）

（式中、環Ａｒ、Ａ、Ｒ^２、Ｒ^１３、Ｒ^１４は前述したものと同意義を表す）で表される化合物を用い、工程Ｉ−Ａと同様の方法により行うことができる。
一般式（３４）で表される化合物から一般式（３５）で表される化合物への変換（工程ＶＩ−Ｂ）は、工程Ｉ−Ｂと同様の方法により行うことができる。
一般式（３５）で表される化合物から一般式（３０）で表される化合物への変換（工程ＶＩ−Ｃ）は、公知の方法、例えば、［非特許文献７］、［非特許文献８］、［非特許文献９］、［非特許文献１０］等に記載の方法により、容易に行うことができる。
一般式（３５）で表される化合物から一般式（３６）で表される化合物への変換（工程ＶＩ−Ｄ）は、公知の方法、例えば、［非特許文献１１］、［非特許文献１２］等に記載の方法により、容易に行うことができる。
一般式（３６）で表される化合物から一般式（３０）で表される化合物へ変換（工程ＶＩ−Ｅ）は、適当な溶媒、例えば水、メタノール、エタノール、テトラヒドロフラン、１，４−ジオキサンあるいはこれらの混液等中、適当な塩基、たとえば水酸化リチウム、水酸化カリウム、炭酸カリウム、炭酸水素ナトリウム等を用い、０〜８０℃で０．５〜２４時間反応させることにより行うことができる。
製造法Ｉ〜ＩＩＩ、Ｖ、ＶＩにおいて、出発化合物である一般式（５）で表される化合物および一般式（５ａ）で表される化合物は、下記に示す方法により合成することができる。
［製造法ＶＩＩ］

上記式中、Ｒ^１、Ｒ^１１、Ｒ^１２、Ｚは前述したものと同意義を表す。
一般式（３８）で表される化合物から一般式（３９）で表される化合物への変換（工程ＶＩＩ−Ａ）は、一般式（４３）

（式中Ｒ^１２は前述したものと同意義を表し、Ｚ^ｃはハロゲン原子を表す）で表される化合物を用い、適当な溶媒、例えばトルエン、酢酸エチル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な塩基、例えば水素化ナトリウム、炭酸カリウム、トリエチルアミン等の存在下、２０〜１４０℃で２〜４８時間反応させることにより行うことができる。
一般式（３９）で表される化合物から一般式（４０）で表される化合物への変換（工程ＶＩＩ−Ｂ）は、適当な溶媒、例えばベンゼン、ジクロロメタン、酢酸エチル、メタノール等中、適当な過酸化物、例えばｍ−クロロ安息香酸、モノペルオキシフタル酸マグネシウム等を用い、０〜８０℃で４〜７２時間反応させることにより行うことができる。
一般式（４０）で表される化合物から一般式（４１）で表される化合物への変換（工程ＶＩＩ−Ｃ）は、無溶媒、または適当な溶媒、例えば酢酸、トルエン、１，４−ジオキサンあるいはこれらの混液等中、適当な酸無水物、例えば無水酢酸、無水トリフルオロ酢酸等を用い、４０〜１２０℃で１〜２４時間反応させた後、無溶媒、または適当な溶媒、例えば酢酸、メタノール、エタノール、アセトニトリルあるいはこれらの混液等中、水を用い、６０〜１２０℃で２〜４８時間反応させることにより行うことができる。
一般式（４１）で表される化合物から一般式（４２）で表される化合物への変換（工程ＶＩＩ−Ｄ）は、一般式（４４）

（式中Ｒ^１１は前述したものと同意義を表し、Ｚ^ｄはハロゲン原子を表す）で表される化合物を用い、適当な溶媒、例えばベンゼン、トルエン、酢酸エチルあるいはこれらの混液等中、適当な銀塩、例えば酸化銀、トリフルオロ酢酸銀等の存在下、６０〜１１０℃で１〜２４時間反応させるか、あるいは無溶媒あるいは適当な溶媒、例えばジクロロメタン、クロロホルム、テトラヒドロフラン等中、適当なハロゲン化剤、例えば塩化チオニル、臭化チオニル、オキシ塩化リン等を用い、０〜１００℃で０．５〜１２時間反応させた後、一般式（４５）

（式中Ｒ^１１は前述したものと同意義を表し、Ｍはナトリウムまたはカリウムを表す）で表される化合物を用い、適当な溶媒、例えばメタノール、エタノール、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、０〜１００℃で０．５〜１２時間反応させることにより行うことができる。
一般式（４２）で表される化合物から一般式（５）で表される化合物への変換（工程ＶＩＩ−Ｅ）は、適当な溶媒、例えば酢酸、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドあるいはこれらの混液等中、適当なハロゲン化剤、例えば臭素、Ｎ−ブロモスクシイミド、Ｎ−クロロスクシイミド等を用いて−２０〜１２０℃で２〜７２時間反応させて合成することができる。
また製造法Ｉ〜ＩＩＩ、Ｖ、ＶＩにおいて、一般式（８）、（１２）、（２１）、（２３）、（３１）および（３７）で表される化合物は、公知の方法、例えば、［非特許文献１３］、［非特許文献１４］、［非特許文献１５］等に記載の方法により、容易に合成することができる。
本発明の一般式（１）で表される４−置換アリール−５−ヒドロキシイソキノリノン誘導体及びその付加塩は優れたＰＡＲＰ阻害活性を示す。本発明化合物を治療又は予防剤として使用する場合には、単独あるいは適時薬理学的に許容される賦形剤、希釈剤等と混合し、錠剤、カプセル剤、顆粒剤、散剤もしくはシロップ剤等により経口的に、あるいは注射剤もしくは経皮吸収剤、座薬等により非経口的に投与することができる。
また、本発明化合物は他の薬物と組み合わせて用いることができる。この場合併用投与であっても、配合剤として用いても良い。組み合わせに用いられる薬物としては、血栓溶解剤、抗血小板薬、脳保護薬、抗浮腫薬、抗凝固薬、解熱薬、脳循環代謝改善薬又は血糖調節薬等が挙げられる。
合併症対策として組み合わされる薬物には、抗てんかん薬、抗うつ薬、抗炎症薬、ＡＣＥ阻害薬又は消炎鎮痛薬等が挙げられる。
また、本発明化合物は外科的療法、低体温療法や高圧酸素療法等の際にも併用して用いることができる。
以下に、参考例および実施例を示し、本発明をさらに詳細に説明するが、本発明の範囲は、これらに限定されるものではない。As a result of intensive research aimed at developing a compound having a novel PARP inhibitory activity, the present inventors are excellent in 4-substituted aryl-5-hydroxyisoquinolinone derivatives and pharmacologically acceptable addition salts thereof. And found to have a PARP inhibitory action.
That is, according to the present invention, the general formula (1)

[Wherein R ¹ Represents a hydrogen atom or a halogen atom,
R ² Represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom or a lower alkoxy group which may be substituted with a halogen atom;
Ring Ar represents a phenyl group, a naphthyl group, or a 5- or 6-membered heterocyclic ring and a condensed ring thereof,
A is a single bond or C ₁ ~ C ₃ Represents alkylene,
X is a single bond, oxygen atom or NR ⁴ Represents
R ⁴ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Y represents an oxygen atom or a sulfur atom,
R ³ Is the general formula (2)

(Wherein R ⁵ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ Has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. Represents a 5- or 6-membered heterocyclic ring and its condensed ring, or R ⁵ And R ⁶ And a 5- or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof, or a general formula (3)

(Where Q ¹ Is a single bond or NR ⁸ Represents
R ⁸ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² Is C ₁ ~ C ₆ Represents alkylene,
R ⁷ Is a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, a phenyl group that may have a substituent, a substituent A naphthyl group which may have a group, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ , R ¹⁰ Are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ And R ¹⁰ Represents a 5- or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))-substituted aryl-5-hydroxyisoquinolinone Derivatives and their pharmacologically acceptable addition salts, and general formula (1b)

[Wherein R ^1a Represents a hydrogen atom,
R ^2a Represents a hydrogen atom,
A ^a Represents a single bond,
X ^a Is a single bond, NR ⁴ Represents
R ⁴ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Y ^a Represents an oxygen atom,
R ³ Is the general formula (2)

(Wherein R ⁵ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ Has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. Represents a 5- or 6-membered heterocyclic ring and its condensed ring, or R ⁵ And R ⁶ And a 5- or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof), or the general formula (3)

(Where Q ¹ Is a single bond or NR ⁸ Represents
R ⁸ Represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² Is C ₁ ~ C ₆ Represents alkylene,
R ⁷ Is a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, a phenyl group that may have a substituent, a substituent A naphthyl group which may have a group, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ , R ¹⁰ Are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may have a substituent, or R ⁹ And R ¹⁰ Represents a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof)), and represents a 4-substituted aryl-5 according to claim 1. The present inventors have found an excellent PARP inhibitory action on a hydroxyisoquinolinone derivative and a pharmacologically acceptable addition salt thereof, and have completed the present invention.
In the general formula (1) of the compound of the present invention, preferably, the ring Ar is a phenyl group, and R ¹ , R ² In which is a hydrogen atom. Examples of these preferable compounds include the compounds shown in Tables 4 to 6 below, but the present invention is not limited to these compounds or pharmacologically acceptable addition salts thereof.

In Tables 4 to 6, more preferable compounds are exemplified numbers 5, 7, 9, 11, 13, 31, 40, 41 listed in Table 4, and exemplified numbers 14, 18, 31, 36, 43 listed in Table 5. , 54, and the compounds of Exemplified Nos. 31, 33 to 36, 38, 39, 42, 55, and 58 to 60 described in Table 6.
In the sentence of the general formula (1) of the present invention, “a lower alkyl group which may be substituted with a halogen atom”, “a cyclic alkyl group which may be substituted with a halogen atom” and “a lower alkoxy which may be substituted with a halogen atom” The “halogen atom” in the “group” includes fluorine, chlorine, bromine and iodine, and the “lower alkyl group” is a linear or branched carbon number such as methyl, ethyl, n-propyl, iso-propyl, etc. ˜6, and “cyclic alkyl group” includes those having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl, etc., and “lower alkoxy group” means methoxy, ethoxy, propoxy, etc. A linear or branched one having 1 to 5 carbon atoms can be mentioned. In the text, “cyclic alkyl group which may have a substituent”, “cyclic alkenyl group which may have a substituent”, “aralkyl group which may have a substituent”, “having a substituent” An aralkyloxy group that may be substituted, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, and a 5- or 6-membered group that may have a substituent. The “substituent” in “heterocycle and its condensed ring” means a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom, a lower alkylthio group, a lower alkoxy Carbonyl group, nitro group, optionally substituted amino group, cyano group, carboxyl group, aldehyde group, lower alkyl group substituted with hydroxy group, lower alkyl group substituted with carboxy group A lower alkyl group which may be substituted with a halogen atom or a lower alkyl group which is substituted with an amino group which may be substituted with an aralkyl group which may have a substituent, a 5-membered or 6-optionally substituted group A lower alkyl group substituted with a cyclic amino group, a lower alkoxy group substituted with a hydroxy group, a lower alkoxy group substituted with a carboxy group, a lower alkyl group optionally substituted with a halogen atom or a substituent A lower alkoxy group substituted with an amino group optionally substituted with an aralkyl group, a lower alkoxy group substituted with a 5-membered or 6-membered cyclic amino group optionally having a substituent, and a substituent. An aralkyl group which may have a substituent, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic group which may have a substituent. Examples of the “lower alkoxycarbonyl group” include linear or branched ones having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, etc., and “an amino group which may have a substituent” , An acyl group, a lower alkylsulfonyl group which may be substituted with a halogen atom, an arylsulfonyl group such as acetyl, methanesulfonyl, phenylsulfonyl, etc., or a lower alkyl which may be substituted with a halogen atom Group, a phenyl group which may have a substituent, an amino group which may be substituted by an aralkyl group which may have a substituent, and “an optionally substituted 5-membered or 6-membered” The term “5- or 6-membered cyclic amino group” in “cyclic amino group of” means pyrrolidyl, piperidyl, piperazyl, morpholy In the “cyclic alkenyl group which may have a substituent”, examples of the “cyclic alkenyl group” include those having 5 to 7 carbon atoms such as cyclopentenyl and cyclohexenyl. Examples of the “aralkyl group” in the “aralkyl group optionally having a substituent” and the “aralkyloxy group optionally having a substituent” include benzyl, diphenylmethyl, phenethyl, phenylpropyl and the like. The substituent mentioned here refers to the “substituent” described above. In addition, “heterocycle” in “5-membered or 6-membered heterocycle and condensed ring thereof” is a saturated or unsaturated monocyclic or polycyclic nitrogen, oxygen or sulfur atom which may have a substituent. A heterocyclic group that can contain one or more of, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, tetrahydropyridyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyratyl, etc. "The condensed ring" means a benzene condensed ring of the above "heterocycle" (for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolyl, Tetrahydroquinolyl, isoquinolyl, tetrahydroisoquino Or fused ring consisting of two rings arbitrarily selected from the above-mentioned “heterocycle” (for example, imidazopyridine, pyrazolopyridine, imidazopyrimidine, etc.) .
The compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable salt as necessary. Examples of pharmacologically acceptable salts include inorganic acid salts with hydrochloric acid, hydrobromic acid, sulfuric acid, etc., organic acids with acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, methanesulfonic acid, tosylic acid, etc. Acid salts and salts with bases such as sodium salts, potassium salts, calcium salts and ammonium salts.
Further, the compound represented by the general formula (1) of the present invention and a pharmacologically acceptable salt thereof may be an inner salt, an anhydride, a hydrate or a solvate thereof.
The compound represented by the general formula (1) having the PARP inhibitory activity of the present invention can be easily produced by a combination of known methods. For example, it can be produced by the following method.
[Production Method I]

In the above formula, rings Ar, A, X, Y, R ¹ , R ² , R ³ Represents the same meaning as described above, and R ¹¹ Represents a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, R ¹² Represents a lower alkyl group which may be substituted with a halogen atom, an aralkyl group or an acyl group which may have a substituent, and Z represents a halogen atom.
The conversion from the compound represented by the general formula (5) to the compound represented by the general formula (6) (step IA) is carried out by using the general formula (8).

(Wherein the rings Ar, A, X, Y, R ² , R ³ Represents the same meaning as described above, and R ¹³ , R ¹⁴ Are the same or different and each represents a hydroxyl group, a lower alkyl group, a lower alkoxy group, or R ¹³ And R ¹⁴ And a suitable solvent such as tetrahydrofuran, N, N-dimethylformamide, and the like, which represents a 5- or 6-membered cyclic pinacol ester which may be substituted with a lower alkyl group. , Benzene, toluene, 1,4-dioxane or a mixture thereof, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, chloride (1, 1'-bis (diphenylphosphino) ferrocene) palladium (II) and the like in the presence of a suitable base such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, pyridine Etc. are added and reacted at 20 to 160 ° C. for 1 to 48 hours. Can be done.
Of the compounds represented by the general formula (6), R ¹² A compound in which is an acyl group can be converted to a compound represented by the general formula (7) (Step IB). That is, in an appropriate solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, an appropriate base such as lithium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc. is used. It can carry out by making it react at 0-80 degreeC for 0.5-24 hours.
Conversion from the compound represented by the general formula (7) to the compound represented by the general formula (1) (step IC) can be carried out without a solvent or an appropriate solvent such as water, acetic acid, methanol, dichloromethane, or these. In a mixed solution, an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or the like is used, or an appropriate dealkylating agent such as trimethylsilyl iodide, boron tribromide or the like is used. It can carry out by making it react at 100 degreeC for 1 to 72 hours.
Of the compounds represented by the general formula (6), R ¹² Is a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, can be directly converted to a compound represented by the general formula (1) (Step ID) ). That is, an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or the like is used in a non-solvent or an appropriate solvent such as water, acetic acid, methanol, dichloromethane or a mixture thereof, or an appropriate desorption is performed. The reaction can be performed by using an alkylating agent such as trimethylsilyl iodide, boron tribromide and the like at 20 to 100 ° C. for 1 to 72 hours. It can also be carried out by reacting these appropriate acid and dealkylating agent in a stepwise manner twice.
Of the compounds represented by the general formula (1), X is an oxygen atom, NR ⁴ And R ³ In general formula (2) or general formula (3), Q ¹ Is NR ⁸ The compound which is can also be synthesize | combined also in the method shown below.
[Production Method II]

In the above formula, rings Ar, A, R ¹ , R ² , R ¹¹ , R ¹² , Z represents the same meaning as described above, and X ^d Is an oxygen atom, NR ⁴ Represents R ⁴ Represents the same meaning as described above, and R ^3c Is the general formula (2)

(Wherein R ⁵ , R ⁶ Represents the same meaning as described above, or the general formula (3b)

(Where Q ^1b Is NR ⁸ Represents Q ² , R ⁷ , R ⁸ Represents the same meaning as described above.
The conversion from the compound represented by the general formula (5) to the compound represented by the general formula (9) (Step II-A)

(Wherein the rings Ar, A, X ^d , R ² , R ¹³ , R ¹⁴ Can be carried out by the same method as in Step IA, using the compound represented by the above).
The conversion from the compound represented by the general formula (9) to the compound represented by the general formula (6a) (step II-B)

(Wherein R ⁶ , Y represents the same meaning as described above), a compound represented by the general formula (14)

(Wherein R ⁵ , R ⁶ Represents the same meaning as described above, and Z ^a Represents a halogen atom), or a compound represented by the general formula (15)

(Wherein R ⁷ , R ⁸ , Z ⁿ , Q ² Represents the same meaning as described above), in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, benzene, toluene, etc., abasic or a suitable organic base, For example, it can be carried out by reacting at 20 to 120 ° C. for 1 to 24 hours in the presence of triethylamine, pyridine, 4-dimethylaminopyridine and the like.
Further, instead of the compounds represented by the general formulas (13), (14) and (15), the general formula (16)

(Wherein R ¹⁵ Is R ⁶ Or general formula (17)

(Wherein R ⁷ , Q ² Represents the same meaning as described above, and D represents NHR ⁵ , NHR ⁸ Represents a carboxy group or a carbamoyl group, R ⁵ , R ⁸ Is converted to isocyanic acid ester or carbamic acid chloride by a known method using a compound represented by the general formulas (13), (14) and (15). It can also be carried out by reacting in the same manner as the compound represented by
For example, among the compounds represented by the general formula (16), D is NHR. ⁵ , NHR ⁸ Is a phosgene (thiophosgene), phosgene dimer (chloroform) in a suitable solvent such as tetrahydrofuran, benzene, toluene, etc. By using trichloromethyl formate) or a homologue thereof (chloronitroformate 4-nitrophenyl, etc.) and reacting at −10 to 50 ° C. for 1 to 5 hours, it can be converted to isocyanic acid ester or carbamic acid chloride. .
Of the compounds represented by the general formula (16), a compound in which D is a carboxy group is obtained by converting D to a carbamoyl group by converting the carboxy group to an acid azide by a known method, The compound which is a group can be converted to an isocyanate by a Hofmann rearrangement reaction.
Of the compounds represented by the general formula (6a), R ¹² Can be converted to the compound represented by the general formula (7a) by the same method as in Step IB (Step II-C), and the same method as in Step IC Can be converted to a compound represented by the general formula (1f) (step II-D).
Of the compounds represented by the general formula (6a), R ¹² Is a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, to a compound represented by general formula (1f) by the same method as in Step IE. Can be converted (step II-E).
Of the compounds represented by the general formula (9), R ¹² Can be converted to a compound represented by the general formula (10) by the same method as in Step IB (Step II-F), and the same method as in Step II-B Can be converted to a compound represented by the general formula (7a) (Step II-G).
Further, the compound represented by the general formula (10) is converted into the compound represented by the general formula (11) by the same method as in the step ID (step II-H), and then the same as the step II-B. By this, it can also convert into the compound represented by general formula (1f) (process II-I).
In the production method II, A is C among the compounds represented by the general formula (9). ₁ ~ C ₃ Alkylene, X ^d Is an oxygen atom and R ¹² Of the lower alkyl group optionally substituted with a halogen atom, the compound represented by the general formula (9a) which is an aralkyl group optionally having a substituent, the compound represented by the general formula (10), A Is C ₁ ~ C ₃ Alkylene, X ^d Of the compound represented by the general formula (10a) in which is an oxygen atom, and the compound represented by the general formula (10), X ^d Is NR ⁴ The compound represented by the general formula (10b) can also be synthesized using the following method (Production Method III).
Of the compound represented by the general formula (1f), the compound represented by the general formula (6a) and the compound represented by the general formula (7a) in the production method II, R ^3c Is the general formula (2) and R ⁶ In a compound that is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent, and a condensed ring thereof, The group can be converted to other substituents as necessary by a known method.
For example, a compound in which the substituent is a lower alkoxycarbonyl group can be obtained by using an appropriate base such as sodium hydroxide, hydroxide in a suitable solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof. It can convert into the compound whose substituent is a carboxy group by making it react at 20-100 degreeC for 0.5 to 24 hours using potassium, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, etc.
In addition, a compound in which the substituent is a nitro group is usually obtained using an appropriate catalyst such as palladium-carbon, platinum-carbon, etc. in an appropriate solvent such as methanol, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. The compound can be converted to a compound in which the substituent is an amino group by subjecting it to a hydrogenation reaction at 20 to 80 ° C. for 1 to 12 hours under pressure or as required.
[Production Method III]

In the above formula, rings Ar, A, R ¹ , R ² , R ⁴ , R ¹¹ , R ¹² , Z represents the same meaning as described above, and A ^b Is a single bond, C ₁ ~ C ₂ Represents alkylene, A ^c Is C ₁ ~ C ₃ Represents alkylene, R ^12a Represents a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may have a substituent, and R ^12b Represents an acyl group.
The conversion from the compound represented by the general formula (5) to the compound represented by the general formula (18) (Step III-A) is carried out using the general formula (21).

(Wherein ring Ar, A ^b , R ² , R ¹³ , R ¹⁴ Can be carried out by the same method as in Step IA, using the compound represented by the above).
Of the compounds represented by the general formula (18), R ¹² Is a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, can be converted to a compound represented by the general formula (9a) (Step III-B) . That is, an appropriate reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride or the like is used in an appropriate solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, or a mixture thereof. It can carry out by making it react for 0.5 to 12 hours at ° C.
Of the compounds represented by the general formula (18), R ¹² A compound in which is an acyl group can be converted to a compound represented by the general formula (19) by the same method as in Step IB (Step III-C).
The compound represented by general formula (19) can be converted to the compound represented by general formula (10a) by the same method as in step III-B (step III-D).
In the compound represented by the general formula (19), A is C among the compounds represented by the general formula (10b) by Step III-E. ₁ ~ C ₃ It can be converted to a compound that is alkylene. That is, the general formula (22)

(Wherein R ⁴ Represents the same meaning as described above), and in a suitable solvent such as methanol, ethanol, dichloromethane, chloroform or a mixture thereof, a suitable acid such as hydrochloric acid, Add a suitable reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc. in the presence of hydrogen acid, acetic acid, etc., or a suitable Lewis acid such as aluminum chloride, zinc chloride, It can carry out by making it react at 0-60 degreeC for 1 to 24 hours.
Of the compounds represented by the general formula (10b), A is C ₁ ~ C ₃ The compound which is alkylene can also be converted from the compound represented by the general formula (10a) (Step III-F). That is, using a suitable halogenating agent such as thionyl chloride, phosphorus oxychloride, thionyl bromide or the like in a solvent-free or suitable solvent such as dichloromethane, chloroform, tetrahydrofuran, or a mixed solution thereof, the temperature is 0 at −20 to 80 ° C. For 5 to 6 hours, or in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof, a suitable sulfonylating agent such as methanesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. After reacting at −20 to 60 ° C. for 0.5 to 3 hours, general formula (22)

(Wherein R ⁴ Represents the same meaning as described above), and in a suitable solvent such as methanol, dichloromethane, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof, an appropriate iodide is used as necessary. The reaction is carried out at 0 to 120 ° C. for 1 to 12 hours in the presence of a salt such as sodium iodide, potassium iodide, tetrabutylammonium iodide or the like, or a suitable base such as triethylamine, pyridine, N, N-diisopropylethylamine and the like. Can be done.
Furthermore, among the compounds represented by the general formula (10b), A is a single bond, R ⁴ A compound in which is a hydrogen atom can be derived from a compound represented by the general formula (5a) (Step III-G and Step III-H). That is, the conversion (step III-G) from the compound represented by the general formula (5a) to the compound represented by the general formula (20) is performed according to the general formula (23).

(Wherein ring Ar, R ² , R ¹³ , R ¹⁴ Can be carried out by the same method as in Step IA, using the compound represented by the above). Furthermore, among the compounds represented by the general formula (20) to the compounds represented by the general formula (10b), A is a single bond, R ⁴ Is converted to a compound wherein hydrogen is a hydrogen atom (Step III-H) in a suitable solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, such as sodium hydroxide. , Potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydrogen carbonate, ammonia and the like, after reacting at 0 to 100 ° C. for 0.5 to 24 hours, an appropriate solvent such as methanol, tetrahydrofuran, N, N— A suitable catalyst such as palladium-carbon, platinum-carbon or the like is used in dimethylformamide or a mixture thereof, etc., and subjected to a hydrogenation reaction at 20 to 80 ° C. for 1 to 12 hours under normal pressure or as required under pressure. Can be performed. In addition, the two-stage reaction may be performed by changing the order.
Of the compounds represented by the general formula (1), X is NR. ⁴ And R ³ Is the general formula (3), and Q ¹ A compound in which is a single bond can also be synthesized by the method shown below.
[Production Method IV]

In the above formula, rings Ar, A, R ¹ , R ² , R ⁴ , R ⁷ , R ¹¹ , R ¹² , Y, Q ² Represents the same meaning as described above.
The conversion from the compound represented by the general formula (9b) to the compound represented by the general formula (6b) (step IV-A) is carried out using the general formula (24).

(Wherein R ⁷ , Y, Q ² Represents the same meaning as described above, and Z ^b Is a halogen atom), and in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, etc., a suitable base such as triethylamine, pyridine, 4-dimethylaminopyridine, etc. Reaction is carried out at 0-80 ° C. for 1-24 hours in the presence of

(Wherein R ⁷ , Y, Q ² Represents the same meaning as described above) in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide and the like, and a suitable condensing agent such as 1- [3- (dimethylamino). ) Propyl] -3-ethylcarbodiimide, dicyclohexylcarbodiimide and the like, and the reaction can be performed at 0 to 80 ° C. for 1 to 36 hours.
Of the compounds represented by the general formula (6b), R ¹² Can be converted to the compound represented by the general formula (7b) by the same method as in Step IB (Step IV-C), and the same method as in Step IC Can be converted to a compound represented by the general formula (1g) (step IV-C).
Of the compounds represented by the general formula (6b), R ¹² Is a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, to a compound represented by the general formula (1g) by the same method as in Step IE. Can be converted (steps IV-D).
Of the compounds represented by the general formula (9b), R ¹² A compound in which is an acyl group can be converted to a compound represented by the general formula (10b) by the same method as in Step IB (Step IV-E).
The compound represented by general formula (10b) can be converted to the compound represented by general formula (7b) by the same method as in step IV-A (step IV-F).
Further, the compound represented by the general formula (10b) can be converted to the compound represented by the general formula (11a) by the same method as in the step IC (step IV-G), and further, the step IV. It can be converted to a compound represented by the general formula (1g) by the same method as for -A (Step IV-H).
In the production method IV, in the compound represented by the general formula (1g), the compound represented by the general formula (6b), and the compound represented by the general formula (7b), R ⁷ Can be converted to other substituents as necessary by a known method.
For example, R ⁷ Is a lower alkoxycarbonyl group in a suitable solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, or a mixture thereof, such as sodium hydroxide, potassium hydroxide, hydroxide. By using lithium, potassium carbonate, sodium hydrogen carbonate or the like and reacting at 20 to 100 ° C. for 0.5 to 24 hours, R ⁷ Can be converted to a compound in which is a carboxy group.
Also R ⁷ Wherein R is a hydroxyl group or a halogen atom, R ⁷ Is the general formula (4)

(Wherein R ⁹ , R ¹⁰ Represents the same meaning as described above). For example, R ⁷ In the presence of a suitable base such as triethylamine or pyridine in a suitable solvent, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof, a compound having a hydroxyl group is a suitable sulfonylating agent such as methanesulfonyl chloride. , Using trifluoromethanesulfonic anhydride, etc., after reacting at 0 to 80 ° C. for 1 to 6 hours, general formula (26)

(Wherein R ⁹ , R ¹⁰ In the presence of a suitable base such as triethylamine, pyridine, etc. in a suitable solvent, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. It can carry out by making it react at 0-100 degreeC for 1 to 12 hours. R ⁷ The compound in which is a halogen atom has the general formula (26)

(Wherein R ⁹ , R ¹⁰ In the presence of a suitable base such as triethylamine or pyridine in a suitable solvent, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. If necessary, an appropriate iodide salt such as sodium iodide or potassium iodide may be added), and the reaction can be carried out at 0 to 100 ° C. for 1 to 12 hours.
Among the compounds represented by the general formula (1), X is a single bond, Y is an oxygen atom, R ³ In general formula (2) or general formula (3), Q ¹ Is NR ⁸ The compound which is can also be synthesize | combined also in the method shown below.
[Production Method V]

In the above formula, rings Ar, A, R ¹ , R ² , R ^3c , R ¹¹ , R ¹² , R ^12a Represents the same meaning as described above, and R ¹⁶ Represents a lower alkyl group.
The conversion from the compound represented by the general formula (5) to the compound represented by the general formula (27) (step VA) is carried out using the general formula (31).

(Wherein the rings Ar, A, R ² , R ¹³ , R ¹⁴ , R ¹⁶ Can be carried out by the same method as in Step IA, using the compound represented by the above).
Of the compounds represented by the general formula (27), R ¹² Is a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, can be converted into a compound represented by the general formula (28) by Step VB. . That is, in an appropriate solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, an appropriate base such as lithium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc. is used. It can carry out by making it react at 0-80 degreeC for 0.5-24 hours.
The conversion from the compound represented by the general formula (28) to the compound represented by the general formula (6c) (step VC) is carried out by using the general formula (32).

(Wherein R ⁵ , R ⁶ Represents the same meaning as described above, or a compound represented by the general formula (33)

(Wherein R ⁷ , R ⁸ , Q ² Represents the same meaning as described above) in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide and the like, and a suitable condensing agent such as 1- [3- (dimethylamino). ) Propyl] -3-ethylcarbodiimide, dicyclohexylcarbodiimide and the like, and the reaction can be performed at 0 to 80 ° C. for 1 to 36 hours.
The reaction is carried out at 0 to 100 ° C. for 1 to 24 hours using an appropriate halogenating agent such as thionyl chloride or phosphorus oxychloride in a solvent-free or appropriate solvent such as benzene, chloroform, 1,2-dichloroethane and the like. To give an acid halide and then in a suitable solvent such as tetrahydrofuran, N, N-dimethylformamide, etc.

(Wherein R ⁵ , R ⁶ Represents the same meaning as described above, or a compound represented by the general formula (33)

(Wherein R ⁷ , R ⁸ , Q ² Can be carried out by reacting at 0 to 80 ° C. for 1 to 36 hours using a compound represented by the same meaning as described above.
Conversion from the compound represented by the general formula (6c) to the compound represented by the general formula (1h) (step V-D) can be performed by the same method as in step IC.
Further, the compound represented by the general formula (28) can be converted to the compound represented by the general formula (29) by the same method as in the step IC (step VE), and further, the step V It can be converted to a compound represented by the general formula (1h) by the same method as for -C (step VF).
Of the compounds represented by the general formula (27), R ¹² A compound in which is an acyl group can be converted to a compound represented by the general formula (30) by Step VG. That is, in an appropriate solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, an appropriate base such as lithium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc. is used. It can carry out by making it react at 0-80 degreeC for 0.5-24 hours.
Conversion from the compound represented by the general formula (30) to the compound represented by the general formula (29) (step VH) can be performed by the same method as in step IC.
In addition, the compound represented by the general formula (30) can be converted to the compound represented by the general formula (7c) by the same method as in the step VC (step VI). It can be converted to a compound represented by the general formula (1h) by the same method as for -C (step VJ).
In the above production method V, the compound represented by the general formula (30) can also be synthesized by using the following method (production method VI).
[Production Method VI]

In the above formula, rings Ar, A, R ¹ , R ² , R ¹¹ , R ^12b , Z represents the same meaning as described above, and R ¹⁷ Represents a lower alkyl group.
The conversion from the compound represented by the general formula (5a) to the compound represented by the general formula (34) (step VI-A) is carried out according to the general formula (37).

(Wherein the rings Ar, A, R ² , R ¹³ , R ¹⁴ Can be carried out by the same method as in Step IA, using the compound represented by the above).
Conversion from the compound represented by the general formula (34) to the compound represented by the general formula (35) (step VI-B) can be performed by the same method as in step IB.
Conversion from the compound represented by the general formula (35) to the compound represented by the general formula (30) (step VI-C) can be carried out by a known method such as [Non-patent Document 7], [Non-patent Document 8]. ], [Non-patent document 9], [Non-patent document 10] and the like.
Conversion from the compound represented by the general formula (35) to the compound represented by the general formula (36) (step VI-D) can be performed by a known method such as [Non-patent Document 11], [Non-patent Document 12]. ] And the like.
Conversion from the compound represented by the general formula (36) to the compound represented by the general formula (30) (step VI-E) is carried out by using a suitable solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or The reaction can be carried out by using a suitable base such as lithium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc. in these mixed solutions and the like at 0-80 ° C. for 0.5-24 hours.
In production methods I to III, V, and VI, the compound represented by general formula (5) and the compound represented by general formula (5a), which are starting compounds, can be synthesized by the method shown below.
[Production Method VII]

In the above formula, R ¹ , R ¹¹ , R ¹² , Z represents the same meaning as described above.
The conversion from the compound represented by the general formula (38) to the compound represented by the general formula (39) (step VII-A) is carried out using the general formula (43).

(Where R ¹² Represents the same meaning as described above, and Z ^c Represents a halogen atom), and a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as toluene, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. In the presence of triethylamine, the reaction can be carried out at 20 to 140 ° C. for 2 to 48 hours.
Conversion from the compound represented by the general formula (39) to the compound represented by the general formula (40) (Step VII-B) can be carried out by using an appropriate solvent such as benzene, dichloromethane, ethyl acetate, methanol and the like. The reaction can be performed by using a peroxide such as m-chlorobenzoic acid, magnesium monoperoxyphthalate and the like at 0 to 80 ° C. for 4 to 72 hours.
Conversion from the compound represented by the general formula (40) to the compound represented by the general formula (41) (step VII-C) can be carried out without a solvent or an appropriate solvent such as acetic acid, toluene, 1,4-dioxane. Alternatively, a suitable acid anhydride such as acetic anhydride or trifluoroacetic anhydride is used in a mixture of these, and the reaction is carried out at 40 to 120 ° C. for 1 to 24 hours, and then no solvent is used or a suitable solvent such as acetic acid, The reaction can be carried out by using water in methanol, ethanol, acetonitrile or a mixed solution thereof at 60 to 120 ° C. for 2 to 48 hours.
The conversion from the compound represented by the general formula (41) to the compound represented by the general formula (42) (step VII-D) is carried out using the general formula (44).

(Where R ¹¹ Represents the same meaning as described above, and Z ^d Is a halogen atom) in a suitable solvent such as benzene, toluene, ethyl acetate or a mixture thereof, in the presence of a suitable silver salt such as silver oxide or silver trifluoroacetate, The reaction is carried out at 60 to 110 ° C. for 1 to 24 hours, or a suitable halogenating agent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, etc. is used in the absence of a solvent or in an appropriate solvent such as dichloromethane, chloroform or tetrahydrofuran. After reacting at 0 to 100 ° C. for 0.5 to 12 hours,

(Where R ¹¹ Represents the same meaning as described above, and M represents sodium or potassium), and in a suitable solvent such as methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof, It can carry out by making it react at 0-100 degreeC for 0.5 to 12 hours.
Conversion of the compound represented by the general formula (42) to the compound represented by the general formula (5) (Step VII-E) is carried out by using a suitable solvent such as acetic acid, dichloromethane, N, N-dimethylformamide, N, In N-dimethylacetamide or a mixed solution thereof, a suitable halogenating agent such as bromine, N-bromosuccinimide, N-chlorosuccinimide, etc. is used for reaction at −20 to 120 ° C. for 2 to 72 hours. Can be synthesized.
In the production methods I to III, V, and VI, the compounds represented by the general formulas (8), (12), (21), (23), (31), and (37) can be obtained by known methods, for example, It can be easily synthesized by the methods described in [Non-patent document 13], [Non-patent document 14], [Non-patent document 15] and the like.
The 4-substituted aryl-5-hydroxyisoquinolinone derivative and its addition salt represented by the general formula (1) of the present invention exhibit excellent PARP inhibitory activity. When the compound of the present invention is used as a therapeutic or prophylactic agent, it can be used alone or mixed with pharmacologically acceptable excipients, diluents, etc. in a timely manner, by tablets, capsules, granules, powders or syrups, etc. It can be administered orally or parenterally by injection, transdermal absorption agent, suppository or the like.
The compound of the present invention can be used in combination with other drugs. In this case, it may be used in combination or as a compounding agent. Examples of the drug used for the combination include a thrombolytic agent, an antiplatelet agent, a brain protective agent, an antiedema agent, an anticoagulant, an antipyretic agent, a cerebral circulation metabolism improving agent, a blood glucose regulating agent and the like.
Drugs combined as a countermeasure against complications include antiepileptic drugs, antidepressants, anti-inflammatory drugs, ACE inhibitors, anti-inflammatory analgesics, and the like.
The compound of the present invention can also be used in combination for surgical therapy, hypothermia therapy, hyperbaric oxygen therapy and the like.
Reference Examples and Examples are shown below to describe the present invention in more detail, but the scope of the present invention is not limited to these.

５−ヒドロキシイソキノリン（１５．０ｇ，１０３ｍｍｏｌ）のジクロロメタン（３００ｍＬ）溶液にトリエチルアミン（１０．９ｇ、１０８ｍｍｏｌ）を加え、０℃に冷却した。撹拌下、塩化ベンゾイル（１５．２ｇ，１０８ｍｍｏｌ）を滴下し、室温に昇温させた。室温にて６時間撹拌後、ジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液にて洗浄後、無水硫酸マグネシウムにて乾燥し、溶媒を留去することにより、淡褐色液体の表題化合物を２６．６ｇ得た。収率定量的。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：７．６８（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．７９−７．８５（３Ｈ，ｍ），８．１２−８．１６（１Ｈ，ｍ），８．２８（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），９．４５（１Ｈ，ｓ）．
＜参考例２＞ ５−ベンゾイルオキシイソキノリンＮ−オキシド

参考例１の化合物（１．９２ｇ，７．７０ｍｍｏｌ）のジクロロメタン（１００ｍＬ）溶液に３−クロロ過安息香酸（＞６５％、２．４５ｇ、９．２４ｍｍｏｌ）を加え、室温にて６時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンにて抽出し、無水硫酸マグネシウムにて乾燥後、溶媒を留去することにより、淡褐色粉末の表題化合物を２．３５ｇ得た。収率定量的。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：７．６１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６７（２Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．７５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８２（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．８６−７．８８（２Ｈ，ｍ），８．１４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．２６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．０７（１Ｈ，ｓ）．
＜参考例３＞ ５−ベンゾイルオキシ−１，２−ジヒドロ−１−オキソイソキノリン

参考例２の化合物（２９．９ｇ、１２３ｍｍｏｌ）に無水酢酸（１００ｍＬ）を加え、４時間加熱還流した。反応液を減圧濃縮後、エタノール（１００ｍＬ）、水（５０ｍＬ）を加え、３０分間加熱還流した。溶媒を留去して得られた残渣にエタノールを加え、析出晶を濾取し、エタノールにて洗浄後、風乾することにより、褐色粉末の表題化合物を１９．０ｇ得た。収率６４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．４０（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２１（１Ｈ，ｔ，Ｊ＝６．３Ｈｚ），７．５７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６４−７．７２（３Ｈ，ｍ），７．８１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．２３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），１１．４５（１Ｈ，ｂｒｓ）．
＜参考例４＞ ５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例３の化合物（２２．１ｇ、８３．３ｍｍｏｌ）のトルエン（３００ｍＬ）溶液に酸化銀（Ｉ）（５７．９ｇ、２５０ｍｍｏｌ）、ヨウ化メチル（３０ｍＬ）を加え、８時間加熱還流した。反応液をセライトを用いて濾過し、溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン：酢酸エチル（２０：１→１０：１）］にて精製することにより、無色粉末の表題化合物を９．８３ｇ得た。収率４２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１０（３Ｈ，ｓ），７．２９（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．６６−７．７３（３Ｈ，ｍ），７．７７（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．８２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２６（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ）．
＜参考例５＞ ５−ベンゾイルオキシ−４−ブロモ−１−メトキシイソキノリン

参考例４の化合物（９．８３ｇ、３５．２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２００ｍＬ）溶液を０℃に冷却し、撹拌下、Ｎ−ブロモスクシンイミド（６．３９ｇ、３５．９ｍｍｏｌ）を少量ずつ加えた。０℃にて３０分間撹拌した後、室温に昇温し、１６時間撹拌した。反応液を濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン：酢酸エチル（２０：１→１０：１）］にて精製することにより、無色粉末の表題化合物を１１．６ｇ得た。収率９２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１０（３Ｈ，ｓ），７．６６（２Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．７７−７．８２（３Ｈ，ｍ），８．２２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．２６（１Ｈ，ｓ），８．２８−８．３２（１Ｈ，ｍ）．
＜参考例６＞ ５−ベンゾイルオキシ−４−（４−ホルミルフェニル）−１−メトキシイソキノリン

参考例５の化合物（２０．０ｇ、５５．８ｍｍｏｌ）および４−ホルミルフェニルホウ酸（１２．６ｇ、８３．８ｍｍｏｌ）のトルエン（５０ｍＬ）懸濁液に、（１，１’−ビス（ジフェニルフォスフィノ）フェロセン）ジクロロパラジウム（ＩＩ）ジクロロメタン（１：１）錯体（１．２２ｇ、１．６７ｍｍｏｌ）および２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（５５．８ｍＬ，１１２ｍｍｏｌ）を加え、５時間加熱還流した。冷後、有機層を分取し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣に少量の酢酸エチルを加え、結晶を濾取し、酢酸エチルにて洗浄後、風乾することにより、黄色粉末の表題化合物を１６．６ｇ得た。収率７８％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１５（３Ｈ，ｓ），７．３０（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５１−７．５５（５Ｈ，ｍ），７．６８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．５９（１Ｈ，ｓ）．
＜参考例７＞ ４−（４−ホルミルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例６の化合物（６．６５ｇ、１７．３ｍｍｏｌ）のエタノール−水（２：１、１５０ｍＬ）懸濁液に、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１７．３ｍＬ，１７．３ｍｍｏｌ）を加え、１時間加熱還流した。冷後、反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン：酢酸エチル＝４：１］にて精製することにより、淡黄色粉末の表題化合物を２．０８ｇ得た。収率４３％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０８（３Ｈ，ｓ），７．０５（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７０（１Ｈ，ｓ），７．７４（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１０．０４（１Ｈ，ｓ），１０．０６（１Ｈ，ｓ）．
＜参考例８＞ ４−（４−カルボキシフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例７の化合物（５００ｍｇ，１．７９ｍｍｏｌ）、２−メチル−２−ブテン（１５．２ｍＬ）および２−プロパノール（１３．５ｍＬ）の混合液に、室温下、亜塩素酸ナトリウム（８０％、２．０２ｇ，１７．９ｍｍｏｌ）およびリン酸二水素ナトリウム二水和物（１．９５ｇ，１２．５ｍｍｏｌ）の水（１３．５ｍＬ）溶液を加え、室温にて４時間撹拌した。反応液に酢酸エチルを加え、有機層を分取し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル→酢酸エチル−メタノール（１０：１）］にて精製後、ヘキサンにて洗浄し、風乾することにより、黄色粉末の表題化合物を４０９ｍｇ得た。収率７７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０７（３Ｈ，ｓ），７．０４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６７（１Ｈ，ｓ），７．７３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１０．０２（１Ｈ，ｓ）．
＜参考例９＞ ４−（４−カルボキシフェニル）−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例８の化合物（４００ｍｇ，１．３５ｍｍｏｌ）の酢酸（５ｍＬ）溶液に、４７％臭化水素酸（０．５ｍＬ）および水（０．５ｍＬ）を加え、１２０℃にて２時間撹拌した。反応液を減圧濃縮して得られた残渣に氷水（２０ｍＬ）を加え、析出晶を濾取し、風乾することにより、褐色粉末の表題化合物を３４８ｍｇ得た。収率９２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．８２（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０４（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．３５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．８７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．７８（１Ｈ，ｓ），１１．３９（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
＜参考例１０＞ ４−（３−アミノフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例５の化合物（７．１８ｇ、２０．０ｍｍｏｌ）および３−ニトロフェニルホウ酸（５．００ｇ、３０．０ｍｍｏｌ）のトルエン（１００ｍＬ）懸濁液に、（１，１’−ビス（ジフェニルフォスフィノ）フェロセン）ジクロロパラジウム（ＩＩ）ジクロロメタン（１：１）錯体（１．６３ｇ、２．００ｍｍｏｌ）および２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（１５．０ｍＬ，３０．０ｍｍｏｌ）を加え、７時間加熱還流した。冷後、有機層を分取し、無水硫酸マグネシウムにて乾燥後、溶媒を留去した。得られた残渣を酢酸エチルにて洗浄し、風乾することにより、無色粉末を得た。これをメタノール（５０ｍＬ）に懸濁し、５％パラジウム−炭素（５０．０ｍｇ）のメタノール（５０ｍＬ）懸濁液を加え、水素気流（２９４ｋＰａ）下、室温にて７時間撹拌した。セライトを用いて触媒を濾去し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝２：１］にて精製することにより、淡褐色粉末の表題化合物を２．８５ｇ得た。収率３８％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１２（３Ｈ，ｓ），４．８９（２Ｈ，ｓ），５．９８−６．００（１Ｈ，ｍ），６．２９（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．４３（１Ｈ，ｓ），６．５９（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３８（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５８−７．６４（４Ｈ，ｍ），７．７１−７．７５（２Ｈ，ｍ），８．２７（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．
＜参考例１１＞ ４−（４−アミノフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例５の化合物（１．００ｇ、２．７９ｍｍｏｌ）および４−ニトロフェニルホウ酸（６９９ｍｇ、４．１９ｍｍｏｌ）を用い、参考例１０と同様の方法により、淡褐色粉末の表題化合物を２９０ｍｇ得た。収率２８％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１１（３Ｈ，ｓ），４．５０−５．２０（２Ｈ，ｂｒ），６．３０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．８６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３７−７．４１（２Ｈ，ｍ），７．５７−７．６２（４Ｈ，ｍ），７．６７（１Ｈ，ｓ），７．７１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．２６（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ）．
＜参考例１２＞ ４−（３−アミノフェニル）−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例１０の化合物（５００ｍｇ、１．３５ｍｍｏｌ）のエタノール−水（２：１、４５ｍＬ）懸濁液に、１ｍｏｌ／Ｌ水酸化カリウム水溶液（１．３６ｍＬ，１．３６ｍｍｏｌ）を加え、２時間加熱還流した。冷後、溶媒を留去して得られた残渣に水を加え、ジクロロメタンにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去することにより、褐色油状物を得た。これを酢酸（１０ｍＬ）に溶解後、４７％臭化水素酸（１ｍＬ）および水（１ｍＬ）を加え、１時間加熱還流した。冷後、溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル］にて精製することにより、暗褐色粉末の表題化合物を３０８ｍｇ得た。収率９０％
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．９４（２Ｈ，ｓ），６．４１−６．４８（３Ｈ，ｍ），６．６８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．９４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．００（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．３１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），９．４７（１Ｈ，ｓ），１１．１９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
＜参考例１３＞ ４−（４−アミノフェニル）−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例１１の化合物を用い、参考例１２と同様の方法により、淡褐色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．９５（２Ｈ，ｓ），６．５０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），６．６３（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．９１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２９（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．３４（１Ｈ，ｓ），１１．１５（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
＜参考例１４＞ ５−ベンゾイルオキシ−４−［４−（クロロメチルカルボニルアミノ）フェニル］−１−メトキシイソキノリン

参考例１１の化合物（１００ｍｇ，２７０μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５ｍＬ）溶液にクロロアセチルクロライド（２１．４μＬ，２７０μｍｏｌ）、４−ジメチルアミノピリジン（１．６５ｍｇ，１３．５μｍｏｌ）およびトリエチルアミン（３７．６μＬ，２７０μｍｏｌ）を加え、室温にて２時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸マグネシウムで乾燥後、溶媒を留去することにより、黄色粉末の表題化合物を１２８ｍｇ得た。収率定量的。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１３（３Ｈ，ｓ），４．１５（２Ｈ，ｓ），７．１３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２８−７．３３（４Ｈ，ｍ），７．５２−７．５８（３Ｈ，ｍ），７．６２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７４（１Ｈ，ｓ），７．７５（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），８．２９（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），９．９０（１Ｈ，ｓ）．
＜参考例１５＞ ４−［４−［（２−クロロエチル）カルボニルアミノ］フェニル］−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例１１の化合物（５０．０ｍｇ，１３５μｍｏｌ）および３−クロロプロピオニルクロライド（１３．０μＬ，１３５μｍｏｌ）を用い、参考例１４と同様の方法により、黄色粉末の表題化合物を３５．２ｍｇ得た。収率５７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．７２（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），３．８７（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），４．１３（３Ｈ，ｓ），７．１１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２９−７．３３（４Ｈ，ｍ），７．５１−７．５４（３Ｈ，ｍ），７．６２（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），７．７３−７．７７（２Ｈ，ｍ），８．２９（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），９．６８（１Ｈ，ｓ）．
＜参考例１６＞ ４−［３−（４−エトキシカルボニルフェニルアミノカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン

参考例１０の化合物（１００ｍｇ，２７０μｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、４−イソシアナート安息香酸エチル（６１．９ｍｇ，３２４μｍｏｌ）を加え、室温にて４時間撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝２：１］にて精製した。これをエタノール（１０ｍＬ）および水（５ｍＬ）混液に懸濁し、１ｍｏｌ／Ｌ水酸化カリウム水溶液（２７３μＬ，２７３μｍｏｌ）を加え、２時間加熱還流した。冷後、水を加え、６ｍｏｌ／Ｌ塩酸にて酸性とした後、酢酸エチルにて抽出し、無水硫酸マグネシウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝１：１］にて精製することにより、無色粉末の表題化合物を１０４ｍｇ得た。収率８４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．３０（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．０７（３Ｈ，ｓ），４．２７（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），６．９６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４２−７．４７（３Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．６６（１Ｈ，ｓ），７．７２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．８１（１Ｈ，ｓ），９．１０（１Ｈ，ｓ），９．９１（１Ｈ，ｓ）．
＜参考例１７〜２０＞ 参考例１６と同様の方法により、下記表７記載の化合物を得た。

《参考例１７の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．７１（３Ｈ，ｓ），４．０６（３Ｈ，ｓ），６．８５（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），６．９１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３８−７．４０（２Ｈ，ｍ），７．４５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６５（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４４（１Ｈ，ｓ），８．５７（１Ｈ，ｓ），９．８８（１Ｈ，ｓ）．
《参考例１８の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．８２（６Ｈ，ｓ），４．０６（３Ｈ，ｓ），６．６８（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２０−７．２５（３Ｈ，ｍ），７．３７−７．３９（２Ｈ，ｍ），７．４５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６４（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．２９（１Ｈ，ｓ），８．５３（１Ｈ，ｓ），９．８８（１Ｈ，ｓ）．
《参考例１９の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０５（３Ｈ，ｓ），６．９７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４１−７．４９（５Ｈ，ｍ），７．６３（１Ｈ，ｓ），７．７０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．７２（２Ｈ，ｓ）．
《参考例２０の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．３２（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ），４．０６（３Ｈ，ｓ），４．２８（２Ｈ，ｑ，Ｊ＝６．８Ｈｚ），７．０３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２−７．４６（３Ｈ，ｍ），７．６０−７．６４（３Ｈ，ｍ），７．７１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９０（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．８９（１Ｈ，ｓ），９．１９（１Ｈ，ｓ），９．８８（１Ｈ，ｓ）．
＜参考例２１＞ ４−［３−（３−カルボキシフェニルアミノカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン

参考例１０の化合物（１００ｍｇ，２７０μｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に３−イソシアナート安息香酸エチル（６１．９ｍｇ，３２４μｍｏｌ）を加え、室温にて６時間撹拌した。反応液を減圧濃縮し、エタノール（１０ｍＬ）−水（５ｍＬ）混液に懸濁後、１ｍｏｌ／Ｌ水酸化カリウム水溶液（１．０８ｍＬ，１．０８ｍｍｏｌ）を加え、２時間加熱還流した。冷後、水を加え、６ｍｏｌ／Ｌ塩酸にて酸性とした。析出晶を濾取し、水洗後、風乾することにより、無色粉末の表題化合物を４３．５ｍｇ得た。収率３８％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０７（３Ｈ，ｓ），６．９４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０３（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．２５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３６−７．４７（４Ｈ，ｍ），７．５３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６６（１Ｈ，ｓ），７．７２（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），８．１１（１Ｈ，ｓ），８．７６（１Ｈ，ｓ），８．９４（１Ｈ，ｓ），９．９１（１Ｈ，ｓ）．
＜参考例２２＞ ４−［４−（４−カルボキシフェニルアミノカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン

参考例２２の化合物（５６．５ｍｇ，１３３μｍｏｌ）のエタノール（４ｍＬ）−水（２ｍＬ）懸濁液に、１ｍｏｌ／Ｌ水酸化カリウム水溶液（２６６μＬ，２６６μｍｏｌ）を加え、２時間加熱還流した。冷後、４ｍｏｌ／Ｌ塩酸にて酸性とした後、３０分加熱還流した。冷後、析出晶を濾取し、風乾することにより、無色粉末の表題化合物を４８．７ｍｇ得た。収率８５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０６（３Ｈ，ｓ），７．０３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４３−７．４６（３Ｈ，ｍ），７．５９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．６４（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．８５（１Ｈ，ｓ），９．１２（１Ｈ，ｓ），９．８８（１Ｈ，ｓ）．
＜参考例２３＞ ４−（４−アセチルフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例５の化合物（３．８９ｇ、１０．９ｍｍｏｌ）および４−アセチルフェニルホウ酸（２．６７ｇ、１６．３ｍｍｏｌ）を用い、参考例６と同様の方法により、無色粉末の表題化合物を３．１９ｇ得た。収率７４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２６（３Ｈ，ｓ），４．１４（３Ｈ，ｓ），７．３０−７．３５（４Ｈ，ｍ），７．５２−７．５６（３Ｈ，ｍ），７．６０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６−７．８０（２Ｈ，ｍ），８．３２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
＜参考例２４＞ ５−ベンゾイルオキシ−４−［４−（ブロモアセチル）フェニル］−１−メトキシイソキノリン

参考例２３の化合物（４．２９ｇ，１０．８ｍｍｏｌ）の酢酸（５０ｍＬ）懸濁液に、４７％臭化水素酸（５ｍＬ）および三臭化テトラブチルアンモニウム（５．２１ｇ，１０．８ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応液を減圧濃縮して得られた残渣を飽和炭酸水素ナトリウム水溶液で中和後、酢酸エチルにて抽出した。有機層を無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（６：１→３：１）］にて精製することにより、無色粉末の表題化合物を２．２９ｇ得た。収率５６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１４（３Ｈ，ｓ），４．５９（２Ｈ，ｓ），７．３２（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５２（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．６７（３Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７７−７．８０（２Ｈ，ｍ），８．３１（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．
＜参考例２５＞ ４−［４−（（ジメチルアミノ）アセチル）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン

参考例２４の化合物（１００ｍｇ，２０９μｍｏｌ）のメタノール（５ｍＬ）溶液に、２ｍｏｌ／Ｌジメチルアミン−メタノール溶液（６３０μＬ，１．２６ｍｍｏｌ）を加え、８０℃にて１時間撹拌した。冷後、反応液を減圧濃縮して得られた残渣をクロマトレックスＮＨカラムクロマトグラフィ［ヘキサン−酢酸エチル（４：１→２：１）］にて精製した。これをエタノール（５ｍＬ）に溶解し、１ｍｏｌ／Ｌ水酸化カリウム水溶液（１．００ｍＬ，１．００ｍｍｏｌ）を加え４時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムで乾燥後、溶媒を留去することにより、無色アモルファスの表題化合物を２１．５ｍｇ得た。収率３２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２８（６Ｈ，ｓ），３．７６（２Ｈ，ｓ），４．０７（３Ｈ，ｓ），７．０４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．４４−７．４９（３Ｈ，ｍ），７．６８（１Ｈ，ｓ），７．７３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１０．０２（１Ｈ，ｓ）．
＜参考例２６〜２８＞ 参考例２５と同様の方法により、下記表８記載の化合物を得た。

《参考例２６の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２５（３Ｈ，ｓ），３．６７（２Ｈ，ｓ），３．９１（２Ｈ，ｓ），４．０７（３Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２５−７．３２（１Ｈ，ｍ），７．３４（４Ｈ，ｄ，Ｊ＝４．４Ｈｚ），７．４３−７．４９（３Ｈ，ｍ），７．６８（１Ｈ，ｓ），７．７３（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１０．０１（１Ｈ，ｂｒｓ）．
《参考例２７の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２２（３Ｈ，ｓ），３．６０（２Ｈ，ｓ），３．７３（３Ｈ，ｓ），３．８６（２Ｈ，ｓ），４．０７（３Ｈ，ｓ），６．９０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９８（１Ｈ，ｂｒｓ），７．２５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４３（３Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６５−７．６８（２Ｈ，ｍ），７．９２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．
《参考例２８の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．３４（３Ｈ，ｓ），２．７８−２．７９（４Ｈ，ｍ），３．９２（２Ｈ，ｓ），４．０７（３Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１６−７．３０（５Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６７（１Ｈ，ｓ），７．７３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．
＜参考例２９＞ ４−（３−アセチルフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例５の化合物（５．１３ｇ、１４．３ｍｍｏｌ）および３−アセチルフェニルホウ酸（３．５２ｇ、２１．５ｍｍｏｌ）を用い、参考例６と同様の方法により、無色粉末の表題化合物を３．９３ｇ得た。収率６９％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．３６（３Ｈ，ｓ），４．１５（３Ｈ，ｓ），７．２２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３０−７．３４（３Ｈ，ｍ），７．４６−７．５０（３Ｈ，ｍ），７．６０（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．６６（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），７．７４（１Ｈ，ｂｒｓ），７．７６−７．８０（２Ｈ，ｍ），８．３２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ）．
＜参考例３０＞ ４−［（３−ブロモアセチル）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン

参考例２９の化合物（１．７３ｇ、４．３５ｍｍｏｌ）のエタノール（２５ｍＬ）溶液に、炭酸水素ナトリウム（１．１０ｇ，１３．１ｍｍｏｌ）を加え、１８時間加熱還流した。冷後、反応液に酢酸エチルを加え、水、飽和食塩水にて順次洗浄し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン：酢酸エチル＝２：１］にて精製することにより、無色粉末の４−（３−アセチルフェニル）−５−ヒドロキシ−１−メトキシイソキノリンを得た。これを酢酸（２０ｍＬ）に懸濁液し、４７％臭化水素酸（２ｍＬ）および三臭化テトラブチルアンモニウム（２．１０ｇ，４．３５ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応液を減圧濃縮して得られた残渣に水、酢酸エチル次いで飽和炭酸水素ナトリウム水溶液を加え、３０分間撹拌した。有機層を分取し、無水硫酸ナトリウムにて乾燥後、溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝３：１］にて精製することにより、無色アモルファスの表題化合物を５５７ｍｇ得た。収率３４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０８（３Ｈ，ｓ），４．９７（２Ｈ，ｓ），７．０５（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６３−７．６６（１Ｈ，ｍ），７．７０（１Ｈ，ｓ），７．７４（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．９４−７．９８（２Ｈ，ｍ），１０．００（１Ｈ，ｓ）．
＜参考例３１＞ ５−ベンゾイルオキシ−１−メトキシ−４−（４−メチル−３−ニトロフェニル）イソキノリン

参考例５の化合物（２．５１ｇ、７．００ｍｍｏｌ）および４−メチル−３−ニトロフェニルホウ酸（１．９０ｇ、１０．５ｍｍｏｌ）を用い、参考例６と同様の方法により、無色粉末の表題化合物を２．５１ｇ得た。収率８７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．０４（３Ｈ，ｓ），４．１４（３Ｈ，ｓ），７．１４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３８（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．５７（２Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），７．６２−７．６９（２Ｈ，ｍ），７．７７−７．８１（３Ｈ，ｍ），８．３２（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ）．
＜参考例３２＞ ４−（３−アミノ−４−メチルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

工程１：参考例３１の化合物（１．３７ｇ、３．３１ｍｍｏｌ）のメタノール（２０ｍＬ）懸濁液に、１０％パラジウム−炭素（１５０ｍｇ）を加え、水素気流（２４５ｋＰａ）下、室温にて８時間撹拌した。セライトを用いて触媒を濾去し、溶媒を留去することにより、淡褐色アモルファスの４−（３−アミノ−４−メチルフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリンを１．２３ｇ得た。収率９７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．６１（３Ｈ，ｓ），４．１１（３Ｈ，ｓ），４．６４（２Ｈ，ｓ），６．２３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．４４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．４６（１Ｈ，ｓ），７．３５−７．３９（２Ｈ，ｍ），７．５６−７．６０（４Ｈ，ｍ），７．６９−７．７４（２Ｈ，ｍ），８．２６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．
工程２：４−（３−アミノ−４−メチルフェニル）−５−ベンゾイルオキシ−１−メトキシイソキノリン（１９６ｍｇ、５１０μｍｏｌ）のエタノール（３ｍＬ）溶液に、１ｍｏｌ／Ｌ水酸化カリウム水溶液（１．０２ｍＬ，１．０２ｍｍｏｌ）を加え、２時間加熱還流した。冷後、反応液に水を加え、酢酸エチルにて抽出した。これを飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝１：１］にて精製することにより、淡黄色アモルファスの表題化合物を１３４ｍｇ得た。収率９４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．０９（３Ｈ，ｓ），４．０４（３Ｈ，ｓ），４．７４（２Ｈ，ｓ），６．４２（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），６．５６（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），６．８７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．９８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５８（１Ｈ，ｓ），７．６９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），９．５９（１Ｈ，ｓ）．
＜参考例３３＞ ４−（３−アミノ−４−メチルフェニル）−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例３２の化合物（１２０ｍｇ、４２８μｍｏｌ）を用い、参考例９と同様の方法により、無色粉末の表題化合物を１１６ｍｇ得た。収率定量的。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．０６（３Ｈ，ｓ），４．７０（２Ｈ，ｓ），６．３８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．５２（１Ｈ，ｓ），６．６５（１Ｈ，ｄ，Ｊ＝３．１Ｈｚ），６．８３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．９８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．３０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．３５（１Ｈ，ｓ），１１．１６（１Ｈ，ｓ）．
＜参考例３４＞ ５−ベンゾイルオキシ−４−［３−（クロロメチルカルボニルアミノ）フェニル］−１−メトキシイソキノリン

参考例１０の化合物（２２６ｍｇ、６１０μｍｏｌ）を用い、参考例１４と同様の方法により、淡黄色アモルファスの表題化合物を２６７ｍｇ得た。収率９８％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１３（３Ｈ，ｓ），４．２２（２Ｈ，ｓ），６．８７−６．９８（３Ｈ，ｍ），７．３５（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５３−７．６５（５Ｈ，ｍ），７．７５（１Ｈ，ｓ），７．７６（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．３０（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），１０．１１（１Ｈ，ｓ）．
＜参考例３５＞ ４−［３−［（２−クロロエチル）カルボニルアミノ］フェニル］−５−ベンゾイルオキシ−１−メトキシイソキノリン

参考例１０の化合物（２００ｍｇ、５４０μｍｏｌ）を用い、参考例１５と同様の方法により、淡黄色アモルファスの表題化合物を１４９ｍｇ得た。収率６０％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．８０（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．８９（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），４．１３（３Ｈ，ｓ），６．８２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．８９（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），６．９７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．３４（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５６−７．６５（５Ｈ，ｍ），７．７４−７．７８（２Ｈ，ｍ），８．３０（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），９．８９（１Ｈ，ｓ）．
＜参考例３６＞ ４−（３−アミノフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例１０の化合物（２９５ｍｇ、７９６μｍｏｌ）を用い、参考例３２工程２と同様の方法により、淡黄色アモルファスの表題化合物を１４３ｍｇ得た。収率６７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０５（３Ｈ，ｓ），４．９７（２Ｈ，ｓ），６．４５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），６．５０−６．５２（２Ｈ，ｍ），６．９５−７．０１（２Ｈ，ｍ），７．４２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５９（１Ｈ，ｓ），７．６８−７．７０（１Ｈ，ｍ），９．７０（１Ｈ，ｓ）．
＜参考例３７＞ ４−（４−クロロメチルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

工程１：参考例７の化合物（１．７０ｇ，６．０９ｍｍｏｌ）のテトラヒドロフラン−メタノール（１：１，６０ｍＬ）溶液に、氷冷下、水素化ホウ素ナトリウム（２３０ｍｇ，６．０９ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応液を濃縮して得られた残渣を酢酸エチルに溶解後、水洗し、無水硫酸ナトリウムにて乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：１→１：２）→酢酸エチル］にて精製することにより、無色粉末の５−ヒドロキシ−４−（４−ヒドロキシメチルフェニル）−１−メトキシイソキノリンを１．９１ｇ得た。収率８８％。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δ）：１．７９（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．１６（３Ｈ，ｓ），４．８３（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），５．４３（１Ｈ，ｓ），７．１０（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．４６−７．５５（５Ｈ，ｍ），７．７１（１Ｈ，ｓ），７．９５（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
工程２：５−ヒドロキシ−４−（４−ヒドロキシメチルフェニル）−１−メトキシイソキノリン（２．０７ｇ，７．３６ｍｍｏｌ）のジクロロメタン（５０ｍｌ）溶液に、氷冷下、塩化チオニル（１．２９ｍｌ，１７．７ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応液に氷水およびジクロロメタンを加え、室温にて３０分間撹拌後、有機層を分取し、無水硫酸ナトリウムにて乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：１→１：２）］にて精製することにより、淡黄色粉末の表題化合物を２．０２ｇ得た。収率９２％。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δ）：４．１６（３Ｈ，ｓ），４．６９（２Ｈ，ｓ），５．３０（１Ｈ，ｓ），７．１０（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７２（１Ｈ，ｓ），７．９５（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
＜参考例３８＞ ４−（４−アミノメチルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例３７の化合物（１．３３ｇ，４．４４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２５ｍＬ）溶液に、フタルイミドカリウム（９８６ｍｇ，５．３２ｍｍｏｌ）を加え、８０℃にて４時間撹拌した。冷後、水を加え、酢酸エチル−メタノール（１０：１）にて抽出し、飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（２：１→１：２）］にて精製することにより、淡黄色粉末を得た。これをエタノール（４０ｍＬ）に溶解し、ヒドラジン１水和物（４３２μＬ，８．８８ｍｍｏｌ）を加え、４時間加熱還流した。冷後、不溶物を濾去し、溶媒を留去した。得られた残渣を酢酸エチルに溶解し、水次いで飽和炭酸水素ナトリウムにて洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を留去することにより、淡黄色粉末の表題化合物を４３２ｍｇ得た。収率３５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．７７（２Ｈ，ｓ），４．０６（３Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２３−７．３０（４Ｈ，ｍ），７．４４（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６１（１Ｈ，ｓ），７．６９−７．７２（１Ｈ，ｍ）．
＜参考例３９＞ ５−ベンゾイルオキシ−４−（３−ホルミルフェニル）−１−メトキシイソキノリン

参考例５の化合物（３．５８ｇ、１０．０ｍｍｏｌ）および３−ホルミルフェニルホウ酸（２．５５ｇ、１５．０ｍｍｏｌ）を用い、参考例６と同様の方法により、無色粉末の表題化合物を２．９１ｇ得た。収率７６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．１４（３Ｈ，ｓ），７．２３−７．３３（４Ｈ，ｍ），７．４６−７．４９（２Ｈ，ｍ），７．５３−７．６０（２Ｈ，ｍ），７．６７（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），７．７３−７．８０（３Ｈ，ｍ），８．３２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），９．７７（１Ｈ，ｓ）．
＜参考例４０＞ ４−（３−ホルミルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例３９の化合物（４．４６ｇ、１１．６ｍｍｏｌ）を用い、参考例７と同様の方法により、淡黄色アモルファスの表題化合物を２．４３ｇ得た。収率７５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０７（３Ｈ，ｓ），７．０４（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６６−７．７０（２Ｈ，ｍ），７．７４（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），７．８５−７．８７（２Ｈ，ｍ），１０．０６（１Ｈ，ｓ）９．８０−１０．２０（１Ｈ，ｂｒ）．
＜参考例４１＞ ５−ヒドロキシ−４−（３−ヒドロキシメチルフェニル）−１−メトキシイソキノリン

参考例４０の化合物（１．７９ｇ，６．４１ｍｍｏｌ）のメタノール−テトラヒドロフラン（２：１，３０ｍＬ）溶液に、水素化ホウ素ナトリウム（４８４ｍｇ，１２．８ｍｍｏｌ）を加え、室温にて１．５時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、溶媒を留去した。得られた残渣にイソプロピルエーテルを加えて固化し、乾燥することにより、無色粉末の表題化合物を１．５０ｇ得た。収率８３％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．０６（３Ｈ，ｓ），４．５４（２Ｈ，ｄ，Ｊ＝５．５Ｈｚ），５．１９（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１６−７．１８（１Ｈ，ｍ），７．２５−７．３１（３Ｈ，ｍ），７．４４（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６２（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．８６（１Ｈ，ｂｒｓ）．
＜参考例４２＞ Ｎ−［３−（５−メタンスルホニルオキシ−１−メトキシイソキノリン−４−イル）フェニル］メチルフタルイミド

参考例４１の化合物（４０７ｍｇ，１．４５ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液に、氷冷下、トリエチルアミン（２．０２ｍＬ，１４．５ｍｍｏｌ）、塩化メタンスルホニル（５６１μＬ，７．２５ｍｍｏｌ）を順次加え、室温にて１．５時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をＮ，Ｎ−ジメチルホルムアミド（１５ｍＬ）に溶解し、フタルイミドカリウム（３２２ｍｇ，１．７４ｍｍｏｌ）を加え、８０℃にて５時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣にイソプロピルエーテルを加えて固化し、乾燥することにより、無色粉末の表題化合物を５５５ｍｇ得た。収率７９％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．３６（３Ｈ，ｓ），４．１１（３Ｈ，ｓ），４．８５（２Ｈ，ｄ，Ｊ＝３．１Ｈｚ），７．３０−７．３６（３Ｈ，ｍ），７．４２−７．４６（１Ｈ，ｍ），７．７１−７．７６（２Ｈ，ｍ），７．８３−７．９１（５Ｈ，ｍ），８．３０−８．３３（１Ｈ，ｍ）．
＜参考例４３＞ ４−（３−アミノメチルフェニル）−５−ヒドロキシ−１−メトキシイソキノリン

参考例４２の化合物（２．０５ｇ，４．２０ｍｍｏｌ）のエタノール（４０ｍＬ）懸濁液に、１ｍｏｌ／Ｌ水酸化カリウム水溶液（４２．０ｍＬ，４２．０ｍｍｏｌ）を加え、室温にて２０時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：１）→酢酸エチル］にて精製し、黄色アモルファスを得た。これをエタノール（３０ｍＬ）に溶解後、ヒドラジン１水和物（２２２μＬ，７．１４ｍｍｏｌ）を加え、３時間加熱環流した。冷後、反応液を濃縮して得られた残渣をクロマトレックスＮＨカラムクロマトグラフィ［酢酸エチル−エタノール＝１０：１］にて精製することにより、淡黄色粉末の表題化合物を５２６ｍｇ得た。収率４５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．７４（２Ｈ，ｓ），４．０６（３Ｈ，ｓ），７．００（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１２−７．１５（１Ｈ，ｍ），７．２５（１Ｈ，ｓ），７．２６（２Ｈ，ｓ），７．４４（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６２（１Ｈ，ｓ），７．７０（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ）．
＜実施例１＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−（Ｎ−メチルカルバモイル）フェニル］−１−オキソイソキノリン

工程１：参考例８の化合物（１３６ｍｇ，４６１μｍｏｌ）に無水酢酸（５ｍＬ）を加え、１．５時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣に、ベンゼン（５ｍＬ）および塩化チオニル（０．５ｍＬ）を加え、２時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣をジクロロメタン（５ｍｌ）に溶解し、４０％メチルアミン−メタノール溶液（１０ｍＬ）に氷冷下、５分間にわたって滴下し、室温にて４時間撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル→アセトン］にて精製し、淡褐色粉末の５−ヒドロキシ−１−メトキシ−４−［４−（Ｎ−メチルカルバモイル）フェニル］イソキノリンを８７．３ｍｇ得た。収率６１％。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δ）：３．０７（３Ｈ，ｄ，Ｊ＝４．９Ｈｚ），４．１６（３Ｈ，ｓ），６．２４（１Ｈ，ｂｒｓ），７．１３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７２（１Ｈ，ｓ），７．８７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
工程２：５−ヒドロキシ−１−メトキシ−４−［４−（Ｎ−メチルカルバモイル）フェニル］イソキノリン（８２．４ｍｇ，２６７μｍｏｌ）の酢酸（５ｍｌ）溶液に、４７％臭化水素酸（０．５ｍＬ）および水（０．５ｍＬ）を加え、１２０℃にて２時間撹拌した。反応液を減圧濃縮して得られた残渣に氷水（１０ｍＬ）を加え、析出晶を濾取し、風乾した。これをシリカゲルカラムクロマトグラフィ［酢酸エチル−メタノール＝５：１］にて精製し、酢酸エチルにて洗浄後、風乾することにより、淡黄色粉末の表題化合物を４１．８ｍｇ得た。収率５２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．８０（３Ｈ，ｄ，Ｊ＝４．４Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．０３（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．３３９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３４０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），８．４１（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），９．７２（１Ｈ，ｓ），１１．３６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ_１７Ｈ_１４Ｎ_２Ｏ_３・１／２Ｈ_２Ｏ：Ｃ，６７．３２；Ｈ，４．９８；Ｎ，９．２４．
Ｆｏｕｎｄ：Ｃ，６７．４８；Ｈ，４．９４；Ｎ，９．１０．
ＨＲ−ＭＳ：２９４．０９８１（−２．４ｍｍｕ）．
＜実施例２＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−（Ｎ，Ｎ−ジプロピルカルバモイル）フェニル］−１−オキソイソキノリン

参考例８の化合物およびジプロピルアミンを用い、実施例１と同様の方法により、淡褐色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：０．７３−０．９２（６Ｈ，ｍ），１．５２−１．５９（４Ｈ，ｍ），３．２４−３．４７（４Ｈ，ｍ），６．７９（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），９．７３（１Ｈ，ｓ），１１．３４（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＭＳ：３６４．１８１３（＋２．６ｍｍｕ）．
＜実施例３＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−［Ｎ−（３−ジメチルアミノプロピル）カルバモイル］フェニル］−１−オキソイソキノリン

参考例８の化合物およびＮ，Ｎ−ジメチル−１，３−プロピレンジアミンを用い、実施例１と同様の方法により、淡褐色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．６３−１．７０（２Ｈ，ｍ），２．１３（６Ｈ，ｓ），２．２７（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．２９（２Ｈ，ｍ），６．６３（２Ｈ，ｂｒｓ），７．１５（１Ｈ，ｂｒｓ），７．２８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４７（１Ｈ，ｂｒｓ），７．７３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４７（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＭＳ：３６５．１７４３（＋０．３ｍｍｕ）．
＜実施例４＞ １，２−ジヒドロ−４−［４−［Ｎ−（４−ジメチルアミノブチル）カルバモイル］フェニル］−５−ヒドロキシ−１−オキソイソキノリン

工程１：参考例８の化合物（２００ｍｇ，６７７μｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、氷冷下、Ｎ，Ｎ−ジメチル−１，４−ブチレンジアミン（１５７ｍｇ，１．３５ｍｍｏｌ）および１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２５９ｍｇ，１．３５ｍｍｏｌ）を加え、室温にて７時間撹拌した。反応液を水洗し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル−メタノール＝１：１］にて精製し、褐色粉末の４−［４−［Ｎ−（４−ジメチルアミノブチル）カルバモイル］フェニル］−５−ヒドロキシ−１−メトキシイソキノリンを１０６ｍｇ得た。収率４０％。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δ）：１．３７−１．４２（２Ｈ，ｍ），１．５０−１．５７（２Ｈ，ｍ），２．２３（６Ｈ，ｓ），３．１４−３．２０（２Ｈ，ｍ），３．３４−３．３９（２Ｈ，ｍ），４．１５（３Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７０（１Ｈ，ｓ），７．７３（１Ｈ，ｂｒｓ），７．８４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
工程２：４−［４−［Ｎ−（４−ジメチルアミノブチル）カルバモイル］フェニル］−５−ヒドロキシ−１−メトキシイソキノリン（１０３ｍｇ，２６３μｍｏｌ）の酢酸（５ｍＬ）溶液に、４７％臭化水素酸（０．５ｍＬ）および水（０．５ｍＬ）を加え、１２０℃にて１時間撹拌した。反応液を減圧濃縮して得られた残渣に氷水（１０ｍＬ）を加え、炭酸水素ナトリウムを用いてｐＨ８とし、再度減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル−メタノール＝１：１］にて精製し、酢酸エチル、水にて順次洗浄後、風乾することにより、淡褐色粉末の表題化合物を４０．１ｍｇ得た。収率３９％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．４１−１．４８（２Ｈ，ｍ），１．５１−１．５７（２Ｈ，ｍ），２．１１（６Ｈ，ｓ），２．２１（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．０３（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），８．４５（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），９．７１（１Ｈ，ｂｒｓ），１１．３４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ_２２Ｈ_２５Ｎ_３Ｏ_３・１／２Ｈ_２Ｏ：Ｃ，６８．０２；Ｈ，６．７５；Ｎ，１０．８２．
Ｆｏｕｎｄ：Ｃ，６７．９９；Ｈ，６．４７；Ｎ，１０．６３．
ＨＲ−ＭＳ：３７９．１９０７（＋１．１ｍｍｕ）．
＜実施例５＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−［Ｎ−（２−ジメチルアミノエチル）カルバモイル］フェニル］−１−オキソイソキノリン

参考例８の化合物およびＮ，Ｎ−ジメチルエチレンジアミンを用い、実施例４と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１９（６Ｈ，ｓ），２．４１（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．３２−７．３６（３Ｈ，ｍ），７．７６−７．７９（３Ｈ，ｍ），８．３５（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），９．７５（１Ｈ，ｂｒｓ），１１．３６（１Ｈ，ｂｒｓ）．
ＨＲ−ＭＳ：３５１．１５７１（−１．２ｍｍｕ）．
＜実施例６＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−［Ｎ−［２−（ピロリジン−１−イル）エチル］カルバモイル］フェニル］−１−オキソイソキノリン

参考例８の化合物および１−（２−アミノエチル）ピロリジンを用い、実施例４と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．２４（４Ｈ，ｂｒｓ），１．６８（４Ｈ，ｂｒｓ），２．５８（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３２−７．３６（３Ｈ，ｍ），７．７６−７．７９（３Ｈ，ｍ），８．４０（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），９．７２（１Ｈ，ｂｒｓ），１１．３５（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＦＡＢ＋：３７８．１８１７（−０．１ｍｍｕ）．
＜実施例７＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−［Ｎ−（２−ヒドロキシエチル）カルバモイル］フェニル］−１−オキソイソキノリン

参考例９の化合物（１５０ｍｇ，５３３μｍｏｌ）に無水酢酸（１０ｍＬ）を加え、２時間加熱還流した。反応液を減圧濃縮して得られた残渣にベンゼン（１０ｍＬ）および塩化チオニル（１ｍＬ）を加え、２時間加熱還流した。反応液を減圧濃縮して得られた残渣をジクロロメタン（１０ｍＬ）に溶解し、２−アミノエタノール（３．２６ｇ，５３．４ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に氷冷下、５分間にわたって滴下し、室温にて５時間撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル−メタノール＝５：１］にて精製し、水洗後、風乾することにより、淡褐色粉末の表題化合物を１９．６ｍｇ得た。収率１１％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．５２（２Ｈ，ｑ，Ｊ＝５．９Ｈｚ），４．７４（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３３９８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３４０４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４０（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），９．７１（１Ｈ，ｓ），１１．３５（１Ｈ，ｄ，Ｊ＝６．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ_１８Ｈ_１６Ｎ_２Ｏ_４・４／５Ｈ_２Ｏ：Ｃ，６３．８２；Ｈ，５．２４；Ｎ，８．２７．
Ｆｏｕｎｄ：Ｃ，６３．６０；Ｈ，５．１２；Ｎ，８．２２．
ＨＲ−ＭＳ：３２４．１１１５（＋０．５ｍｍｕ）．
＜実施例８＞ １，２−ジヒドロ−５−ヒドロキシ−４−［４−［Ｎ−（１，３−ジヒドロキシプロパン−２−イル）カルバモイル］フェニル］−１−オキソイソキノリン

参考例９の化合物（１５０ｍｇ，５３３μｍｏｌ）およびセリノール（４８６ｍｇ，５．３３ｍｍｏｌ）を用い、実施例７と同様の方法により、淡褐色粉末の表題化合物を５０．１ｍｇ得た。収率２７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．５３（４Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．９６−４．０１（１Ｈ，ｍ），４．６７（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３４４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．７２（１Ｈ，ｓ），１１．３５（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ）．
ＨＲ−ＦＡＢ＋：３５５．１３２９（＋３．５ｍｍｕ）．
＜実施例９＞ １，２−ジヒドロ−４−［４−（ジメチルアミノメチルカルボニルアミノ）フェニル］−５−ヒドロキシ−１−オキソイソキノリン

工程１：参考例１４の化合物（６４．０ｍｇ，１４３μｍｏｌ）のエタノール（３ｍＬ）溶液に、２ｍｏｌ／Ｌジメチルアミン−メタノール溶液（２８７μＬ，５７３μｍｏｌ）を加え、８０℃にて４時間撹拌した。溶媒を留去して得られた残渣をクロマトレックスＮＨカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：１）→酢酸エチル］にて精製することにより、淡褐色油状物の４−［４−（ジメチルアミノメチルカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリンを２２．７ｍｇ得た。収率４５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．３０（６Ｈ，ｓ），４．０５（３Ｈ，ｓ），７．０２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６２（１Ｈ，ｓ），７．７０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．７３（１Ｈ，ｓ）．
工程２：４−［４−（ジメチルアミノメチルカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン（２２．７ｍｇ，６４．６μｍｏｌ）に酢酸（５ｍＬ）、４７％臭化水素酸（１ｍＬ）を加え、４０℃にて４８時間撹拌した。溶媒を留去して得られた残渣に水を加え、飽和炭酸水素ナトリウム水溶液を加えて塩基性とした。析出晶を濾取し、風乾することにより、無色粉末の表題化合物を８．６０ｍｇ得た。収率３９％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２９（６Ｈ，ｓ），３．０７（２Ｈ，ｓ），６．７１（１Ｈ，ｂｒｓ），７．００（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），９．６９（１Ｈ，ｓ），１１．２６（１Ｈ，ｂｒｓ）．
ＨＲ−ＭＳ：３３７．１３９５（−３．１ｍｍｕ）．
＜実施例１０＞ １，２−ジヒドロ−４−［４−［（ピロリジン−１−イル）メチルカルボニルアミノ］フェニル］−５−ヒドロキシ−１−オキソイソキノリン

参考例１４の化合物およびピロリジンを用い、実施例９と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．７６（４Ｈ，ｂｒｓ），２．６０（４Ｈ，ｂｒｓ），６．７２（１Ｈ，ｂｒｓ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），９．６８（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＭＳ：３６３．１５５０（−３．３ｍｍｕ）．
＜実施例１１＞ １，２−ジヒドロ−４−［４−［２−（ピロリジン−１−イル）エチルカルボニルアミノ］フェニル］−５−ヒドロキシ−１−オキソイソキノリン

参考例１５の化合物およびピロリジンを用い、実施例９と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．７１（４Ｈ，ｂｒｓ），６．７１（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．６２（１Ｈ，ｓ），１０．０８（１Ｈ，ｓ），１１．２６（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋：３７８．１８３２（＋１．４ｍｍｕ）．
＜実施例１２＞ ４−［３−［（３−アミノプロピル）カルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

工程１：参考例１２の化合物（１００ｍｇ，３９６μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（４ｍＬ）溶液に、４−（ｔ−ブトキシカルボニルアミノ）酪酸（９６．５ｍｇ，４７５μｍｏｌ）および１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（９１．１ｍｇ，４７５μｍｏｌ）を加え、室温にて２時間撹拌した。反応液に水を加え酢酸エチルにて抽出した。無水硫酸ナトリウムにて乾燥後、溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：３）→酢酸エチル］にて精製することにより、無色粉末の４−［３−［３−（ｔ−ブトキシカルボニルアミノ）プロピルカルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリンを５５．７ｍｇ得た。収率３２％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．３７（９Ｈ，ｓ），１．６４−１．７１（２Ｈ，ｍ），２．２８（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），２．９３−２．９７（２Ｈ，ｍ），６．７２（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．８４（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），６．９４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４８（１Ｈ，ｓ），７．５２（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．６８（１Ｈ，ｓ），９．８３（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
工程２：４−［３−［３−（ｔ−ブトキシカルボニルアミノ）プロピルカルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン（５５．７ｍｇ，１２７μｍｏｌ）のメタノール（１ｍＬ）溶液に、飽和塩化水素−メタノール溶液（２ｍＬ）を加え、室温にて１時間撹拌した。溶媒を留去して得られた残渣をクロマトレックスＮＨカラムクロマトグラフィ［酢酸エチル→酢酸エチル−メタノール（１０：１→３：１）］にて精製することにより、無色粉末の表題化合物を３．１０ｍｇ得た。収率７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．６９（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．３４（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．６３（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），６．７１（１Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４８−７．５２（２Ｈ，ｍ），７．７６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．
ＨＲ−ＦＡＢ＋：３３８．１４９７（−０．７ｍｍｕ）．
＜実施例１３＞ ４−［３−［（４−アミノブチル）カルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例１２の化合物（５０．０ｍｇ，１９８μｍｏｌ）および５−（ｔ−ブトキシカルボニルアミノ）吉草酸（６４．５ｍｇ，２９７μｍｏｌ）を用い、実施例１２と同様の方法により、無色粉末の表題化合物を４５．７ｍｇ得た。収率６６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．３３−１．４１（２Ｈ，ｍ），１．５５−１．６３（２Ｈ，ｍ），２．２８（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），６．７３（１Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４８（１Ｈ，ｓ），７．５３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．８３（１Ｈ，ｓ）．
ＨＲ−ＦＡＢ＋：３５２．１６３４（−２．７ｍｍｕ）．
＜実施例１４＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［４−（フェニルメチルカルボニルアミノ）フェニル］イソキノリン

参考例１３の化合物（３３．０ｍｇ，１３１μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）溶液にフェニル酢酸（２１．４ｍｇ，１５７μｍｏｌ）および１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（３０．１ｍｇ，１５７μｍｏｌ）を加え、室温にて５時間撹拌した。反応液に水を加え、析出晶を濾取し、風乾することにより、無色粉末の表題化合物を２９．４ｍｇを得た。収率６１％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．６５（２Ｈ，ｓ），６．７０（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２３−７．３５（６Ｈ，ｍ），７．５１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），９．６０（１Ｈ，ｓ），１０．１５（１Ｈ，ｓ），１１．２６（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋：３７１．１４２８（＋３．４ｍｍｕ）．
＜実施例１５＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［３−［（４−メトキシフェニル）アミノカルボニルアミノ］フェニル］イソキノリン

参考例１７の化合物（７３．５ｍｇ，１７７μｍｏｌ）の酢酸（２．５ｍＬ）溶液に、４７％臭化水素酸（０．２５ｍＬ）および水（０．２５ｍＬ）を加え、６０℃にて９時間撹拌した。冷後、反応液を減圧濃縮して得られた残渣に水を加え、飽和炭酸水素ナトリウム水溶液にて塩基性とした後、析出晶を濾取し、風乾した。これをシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（１：１）→酢酸エチル］にて精製することにより、無色粉末の表題化合物を２５．５ｍｇ得た。収率３６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．７１（３Ｈ，ｓ），６．７５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．８４−６．８８（３Ｈ，ｍ），７．０２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３１−７．３６（５Ｈ，ｍ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．４３（１Ｈ，ｓ），８．５３（１Ｈ，ｓ），９．６５（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋：４０２．１４５３（−０．１ｍｍｕ）．
＜実施例１６〜２０＞ 実施例１５と同様の方法により、下記表９記載の化合物を得た。

《実施例１６の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．８２（６Ｈ，ｓ），６．６８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），６．７５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．８６（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３１−７．３５（３Ｈ，ｍ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２５（１Ｈ，ｓ），８．４６（１Ｈ，ｓ），９．６５（１Ｈ，ｓ），１１．２６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）．
ＨＲ−ＦＡＢ＋：４１５．１７９９（＋２．９ｍｍｕ）．
《実施例１７の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７６（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），７．２１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３１−７．４１（４Ｈ，ｍ），７．５４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．１１（１Ｈ，ｓ），８．６５（１Ｈ，ｓ），８．８５（１Ｈ，ｓ），９．６７（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），１１．９０（１Ｈ，ｂｒｓ）．
ＨＲＭＳ（ＦＡＢ＋）：４１６．１２７６（＋２．９ｍｍｕ）．
《実施例１８の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７２（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．９７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２６−７．３４（３Ｈ，ｍ），７．３７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４７（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．６５（２Ｈ，ｄ，Ｊ＝６．８Ｈｚ），９．６２（１Ｈ，ｓ），１１．２６（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋：３７２．１３２９（−１．９ｍｍｕ）．
《実施例１９の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．３０（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．２７（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），６．７２（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．８２（１Ｈ，ｓ），９．１４（１Ｈ，ｓ），９．６３（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋：４４４．１５２５（−３．５ｍｍｕ）．
《実施例２０の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７３（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．８２（１Ｈ，ｓ），９．１０（１Ｈ，ｓ），９．６５（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
Ａｎａｌ．ｃａｌｃｄ ｆｏｒ Ｃ_２３Ｈ_１７Ｎ_３Ｏ_５・７／１０Ｈ_２Ｏ：Ｃ，６４．５４；Ｈ，４．３３；Ｎ，９．８２．
Ｆｏｕｎｄ：Ｃ，６４．４２；Ｈ，４．２３；Ｎ，９．７３．
ＨＲ−ＦＡＢ＋：４１６．１２０２（−４．４ｍｍｕ）．
＜実施例２１＞ ４−［３−（４−カルボキシフェニルアミノカルボニルアミノ）フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例１６の化合物（１０４ｍｇ，２２７μｍｏｌ）の酢酸（１０ｍＬ）溶液に、４７％臭化水素酸（１ｍＬ）および水（１ｍＬ）を加え、１時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル→酢酸エチル−メタノール（１０：１→１：１）→メタノール］にて精製した。これをエタノール（２ｍＬ）−水（１ｍＬ）混液に懸濁し、１ｍｏｌ／Ｌ水酸化カリウム水溶液（２１７μＬ，２１７μｍｏｌ）を加え、２時間加熱還流した。冷後、水を加え、６ｍｏｌ／Ｌ塩酸にて酸性とした後、析出晶を濾取し、風乾することにより、淡褐色粉末の表題化合物を５．４０ｍｇ得た。収率６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３１−７．３９（３Ｈ，ｍ），７．５５（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．８１（１Ｈ，ｓ），９．０８（１Ｈ，ｓ），９．６８（１Ｈ，ｓ），１１．２８（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），１２．５７（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋：４１６．１２５２（＋０．６ｍｍｕ）．
＜実施例２２＞ １，２−ジヒドロ−５−ヒドロキシ−４−［３−（４−ニトロフェニルアミノカルボニルアミノ）フェニル］−１−オキソイソキノリン

参考例１０の化合物（１００ｍｇ，２７０μｍｏｌ）のジクロロメタン（５ｍＬ）溶液に４−ニトロフェニルイソシアネート（５３．０ｍｇ，３２３μｍｏｌ）を加え、室温にて８時間撹拌した。析出晶を濾取し、ジクロロメタンで洗浄後、風乾した。これをエタノール（１０ｍＬ）−水（５ｍＬ）混液に懸濁し、１ｍｏｌ／Ｌ水酸化カリウム水溶液（２７３μｌ，２７３μｍｏｌ）を加え、４時間加熱還流した。冷後、水を加えて酢酸エチルにて抽出した。有機層を無水硫酸マグネシウムにて乾燥後、減圧下溶媒留去し、シリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝１：１］にて精製した。これを酢酸（５ｍｌ）に溶解し、４７％臭化水素酸（０．５ｍＬ）および水（０．５ｍＬ）を加え、６０℃にて９時間撹拌した。冷後、反応液を減圧濃縮し、水を加え、飽和炭酸水素ナトリウム水溶液にて塩基性とした。析出晶を濾取し、風乾することにより、黄色粉末の表題化合物を５１．１ｍｇ得た。収率４５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７７（１Ｈ，ｓ），６．９４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），７．２３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３８−７．４１（２Ｈ，ｍ），７．６９（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．０Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），９．０７（１Ｈ，ｓ），９．６１（１Ｈ，ｓ），９．６８（１Ｈ，ｓ），１１．２８（１Ｈ，ｓ）．
ＨＲ−ＦＡＢ＋：４１７．１２３１（＋３．２ｍｍｕ）．
＜実施例２３〜２６＞ 参考例９と同様の方法により、下記表１０記載の化合物を得た。

《実施例２３の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２９（６Ｈ，ｓ），３．７９（２Ｈ，ｂｒｓ），６．８３（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．３５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．８１（１Ｈ，ｓ），１１．４０（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＭＳ：３２２．１３０４（−１．３ｍｍｕ）．
《実施例２４の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２３（３Ｈ，ｓ），３．６６（２Ｈ，ｓ），３．８８（２Ｈ，ｓ），６．８３（１Ｈ，ｂｒｓ），７．０４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２７（１Ｈ，ｂｒｓ），７．３３−７．３７（５Ｈ，ｍ），７．３９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．８１（１Ｈ，ｂｒｓ），１１．４０（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋：３９９．１７２１（＋１．３ｍｍｕ）．
《実施例２５の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２１（３Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．７３（３Ｈ，ｓ），３．８３（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．９０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９，７９（１Ｈ，ｓ），１１．４０（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋：４２９．１８１２（−０．３ｍｍｕ）．
《実施例２６の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．３２（３Ｈ，ｓ），３．８９（２Ｈ，ｓ），６．８２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１８（１Ｈ，ｔ，Ｊ＝６．８Ｈｚ），７．２３−７．３０（４Ｈ，ｍ），７．３３−７．３７（３Ｈ，ｍ），７．７９（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．７９（１Ｈ，ｓ），１１．３９（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ）．
ＨＲ−ＦＡＢ＋：４１３．１８７８（＋１．３ｍｍｕ）．
＜実施例２７＞ ４−［３−（（Ｎ−ベンジル−Ｎ−メチルアミノ）アセチル）フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例３０の化合物（１５０ｍｇ，４０３μｍｏｌ）およびＮ−メチルベンジルアミン（３１２μＬ，２．４２ｍｍｏｌ）を用い、参考例２５次いで参考例９と同様の方法により、淡黄色粉末の表題化合物を１０．９ｍｇ得た。収率７％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２０（３Ｈ，ｓ），３．６２（２Ｈ，ｓ），３．８７（２Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０３（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．２０−７．３０（６Ｈ，ｍ），７．３５（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝１．９Ｈｚ），７．５３（１Ｈ，ｄｔ，Ｊ＝７．９，１．２Ｈｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．８３−７．８６（２Ｈ，ｍ），９．７３（１Ｈ，ｓ），１１．３８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９９．１７２９（＋２．０ｍｍｕ）．
＜実施例２８＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［４−（（２−フェニルエチル）カルボニルアミノ）フェニル］イソキノリン

参考例１３の化合物（５７．０ｍｇ，２２６μｍｏｌ）および３−フェニルプロピオン酸（４０．７ｍｇ，２７１μｍｏｌ）を用い、実施例１４と同様の方法により、無色粉末の表題化合物を４８．７ｍｇ得た。収率５６％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．６３（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），２．９３（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），６．７１（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１６−７．２１（３Ｈ，ｍ），７．２６−７．３３（５Ｈ，ｍ），７．４９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６１（１Ｈ，ｓ），９．８９（１Ｈ，ｓ），１１．２６（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３８４．１５０４（＋３．０ｍｍｕ）．
＜実施例２９＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［３−（（２−フェニルエチル）カルボニルアミノ）フェニル］イソキノリン

参考例１２の化合物（５１．０ｍｇ，２０２μｍｏｌ）を用い、実施例２８と同様の方法により、無色粉末の表題化合物を４２．３ｍｇ得た。収率５４％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．６１（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），２．９０（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），６．７２（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．９４（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１６−７．３４（７Ｈ，ｍ），７．４６（１Ｈ，ｓ），７．５３（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６７（１Ｈ，ｓ），９．８６（１Ｈ，ｓ），１１．２７（１Ｈ，ｓ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３８４．１４６２（−１．２ｍｍｕ）．
＜実施例３０＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［４−メチル−３−（フェニルメチルカルボニルアミノ）フェニル］イソキノリン

参考例３３の化合物（５５．０ｍｇ，２０７μｍｏｌ）を用い、実施例１４と同様の方法により、無色粉末の表題化合物を３５．７ｍｇ得た。収率４５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１８（３Ｈ，ｓ），３．６６（２Ｈ，ｓ），６．６８（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．９７−７．０１（２Ｈ，ｍ），７．１０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．２４（１Ｈ，ｔ，Ｊ＝６．７Ｈｚ），７．２９−７．３６（６Ｈ，ｍ），７．７６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．４６（１Ｈ，ｓ），９．６２（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８５．１５６１（＋０．９ｍｍｕ）．
＜実施例３１＞ １，２−ジヒドロ−５−ヒドロキシ−１−オキソ−４−［４−メチル−３−（（２−フェニルエチル）カルボニルアミノ）フェニル］イソキノリン

参考例３３の化合物（５５．０ｍｇ，２０７μｍｏｌ）を用い、実施例２８と同様の方法により、無色粉末の表題化合物を３３．７ｍｇ得た。収率４１％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１２（３Ｈ，ｓ），２．６５（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），２．９１（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），６．６９（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．９７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０９（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１８（１Ｈ，ｔ，Ｊ＝６．７Ｈｚ），７．２７−７．３４（６Ｈ，ｍ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．２２（１Ｈ，ｓ），９．６４（１Ｈ，ｓ），１１．２６（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９９．１７１５（＋０．６ｍｍｕ）．
＜実施例３２＞ ４−［３−［（Ｎ−ベンジル−Ｎ−メチルアミノ）メチルカルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例３４の化合物およびＮ−メチルベンジルアミンを用い、実施例９と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２６（３Ｈ，ｓ），３．１７（２Ｈ，ｓ），３．６４（２Ｈ，ｓ），６．７４（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．９７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），７．２０−７．２７（２Ｈ，ｍ），７．３１−７．４０（５Ｈ，ｍ），７．５６−７．５８（２Ｈ，ｍ），７．７８（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），９．６７（１Ｈ，ｓ），９．６８（１Ｈ，ｓ）１１．２９（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４１４．１８３５（＋１．７ｍｍｕ）．
＜実施例３３＞ ４−［３−［２−（ジメチルアミノ）エチルカルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例３５の化合物および２ｍｏｌ／Ｌジメチルアミン−メタノール溶液を用い、実施例９と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１６（６Ｈ，ｓ），２．４３（２Ｈ，ｄ，Ｊ＝６．７Ｈｚ），６．７３（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．９４（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４８（１Ｈ，ｓ），７．５２（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６７（１Ｈ，ｓ），９．９７（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５２．１６９７（＋３．６ｍｍｕ）．
＜実施例３４＞ ４−［３−［２−（Ｎ−ベンジル−Ｎ−メチルアミノ）エチルカルボニルアミノ］フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

参考例３５の化合物およびＮ−メチルベンジルアミンを用い、実施例９と同様の方法により、無色粉末の表題化合物を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１４（３Ｈ，ｓ），２．６８（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），３．５０（２Ｈ，ｓ），６．７３（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．９５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２１−７．３４（７Ｈ，ｍ），７．４５（１Ｈ，ｓ），７．５３（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６７（１Ｈ，ｓ），９．９９（１Ｈ，ｓ），１１．２８（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４２８．１９８９（＋１．５ｍｍｕ）．
＜実施例３５＞ ４−［３−（ジメチルアミノカルボニルアミノ）フェニル］−１，２−ジヒドロ−５−ヒドロキシ−１−オキソイソキノリン

工程１：参考例３６の化合物（１４１ｍｇ，５２９μｍｏｌ）のテトラヒドロフラン（３ｍｌ）溶液に、Ｎ，Ｎ−ジメチルカルバミン酸クロリド（６８．３ｍｇ，６３５μｍｏｌ）およびトリエチルアミン（８８．５μＬ，６３５μｍｏｌ）を加え、６０℃にて７時間撹拌した。冷後、酢酸エチルを加え、１ｍｏｌ／Ｌ水酸化カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水にて順次洗浄し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル（２：１→１：１）］にて精製することにより、淡褐色粉末の４−［３−（ジメチルアミノカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリンを７３．０ｍｇ得た。収率４１％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．９１（６Ｈ，ｓ），４．０６（３Ｈ，ｓ），６．８８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．００−７．０２（１Ｈ，ｍ），７．１８（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４１−７．４７（３Ｈ，ｍ），７．６２（１Ｈ，ｓ），７．７１（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．２４（１Ｈ，ｓ），９．８６（１Ｈ，ｓ）．
工程２：４−［３−（ジメチルアミノカルボニルアミノ）フェニル］−５−ヒドロキシ−１−メトキシイソキノリン（７０．０ｍｇ，２０７μｍｏｌ）を用い、実施例１５と同様の方法により、無色粉末の表題化合物を５０．５ｍｇ得た。収率７５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．９１（６Ｈ，ｓ），６．７２（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１４（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３７（１Ｈ，ｓ），７．４１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．２０（１Ｈ，ｓ），９．６４（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ_１８Ｈ_１７Ｎ_３Ｏ_３・１／５Ｈ_２Ｏ：Ｃ，６６．１２；Ｈ，５．３６；Ｎ，１２．８５．
Ｆｏｕｎｄ：Ｃ ６６．２４；Ｈ，５．３７；Ｎ，１２．６９．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３２４．１３６３（＋１．５ｍｍｕ）．
＜実施例３６〜３９＞ 参考例３２の化合物または参考例３６の化合物を用い、実施例３５と同様の方法により、下記表１１記載の化合物を得た。

《実施例３６の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．８２−１．８５（４Ｈ，ｍ），６．７２（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８３（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４１（１Ｈ，ｓ），７．４５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．０２（１Ｈ，ｓ），９．６３（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５０．１５１７（＋１．３ｍｍｕ）．
《実施例３７の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．４７−１．４８（４Ｈ，ｍ），１．５６−１．５７（２Ｈ，ｍ），３．３８−３．４１（４Ｈ，ｍ），６．７２（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．８３（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３７（１Ｈ，ｓ），７．４１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．３７（１Ｈ，ｓ），９．６４（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３６４．１６４３（−１．８ｍｍｕ）．
《実施例３８の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．１９（３Ｈ，ｓ），２．９１（６Ｈ，ｓ），６．６９（１Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１６（１Ｈ，ｓ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７２（１Ｈ，ｓ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６０（１Ｈ，ｓ），１１．２５（１Ｈ，ｓ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３３８．１４９１（−１．４ｍｍｕ）．
《実施例３９の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．８５（４Ｈ，ｓ），２．２１（３Ｈ，ｓ），６．６７（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２５（１Ｈ，ｓ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４５（１Ｈ，ｓ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．５７（１Ｈ，ｓ），１１．２４（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３６４．１６６７（＋０．６ｍｍｕ）．
＜実施例４０〜４４＞ 参考例３２の化合物または参考例３６の化合物を用い、参考例１６次いで実施例１５と同様の方法により、下記表１２記載の化合物を得た。

《実施例４０の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：０．８６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．３８−１．４７（２Ｈ，ｍ），２．９９−３．０４（２Ｈ，ｍ），６．０９（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．７２（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．８０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．２７−７．３４（３Ｈ，ｍ），７．７６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．３４（１Ｈ，ｓ），９．６３（１Ｈ，ｂｒｓ），１１．２４（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ_１９Ｈ_１９Ｎ_３Ｏ_３・１／５Ｈ_２Ｏ：Ｃ，６６．９３；Ｈ，５．７３；Ｎ，１２．３２．
Ｆｏｕｎｄ：Ｃ，６６．９９；Ｈ，５．５３；Ｎ，１２．１７．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３３８．１４９３（−１．２ｍｍｕ）．
《実施例４１の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：６．７７（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．０２−７．０５（２Ｈ，ｍ），７．１２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．２５（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３１−７．３５（３Ｈ，ｍ），７．３８（１Ｈ，ｓ），７．４４−７．４８（３Ｈ，ｍ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），９．７１（１Ｈ，ｓ），９．７３（１Ｈ，ｓ），９．８２（１Ｈ，ｓ），１１．３０（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８８．１１１１（−０．９ｍｍｕ）．
《実施例４２の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２７（３Ｈ，ｓ），６．７１（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８６（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．９４（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０９（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．２６（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７９（１Ｈ，ｓ），７．９１（１Ｈ，ｓ），９．０１（１Ｈ，ｓ），９．６０（１Ｈ，ｓ），１１．２５（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８６．１５５０（＋４．５ｍｍｕ）．
《実施例４３の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：０．８７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．３８−１．４７（２Ｈ，ｍ），２．１９（３Ｈ，ｓ），２．９９−３．０４（２Ｈ，ｍ），６．５２（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．６８（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．７８（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），６．９９−７．０３（２Ｈ，ｍ），７．３１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５６（１Ｈ，ｓ），７．７６−７．７８（２Ｈ，ｍ），９．５５（１Ｈ，ｓ），１１．２３（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５２．１６２３（−３．８ｍｍｕ）．
《実施例４４の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．２７（３Ｈ，ｓ），６．７４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０２−７．１７（４Ｈ，ｍ），７．２０（１Ｈ，ｓ），７．３０−７．３４（３Ｈ，ｍ），７．４８（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），９．３８（１Ｈ，ｓ），９．５５（１Ｈ，ｓ），９．６３（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０２．１２８７（＋１．１ｍｍｕ）．
＜実施例４５〜４９＞ 参考例３８の化合物または参考例４３の化合物を用い、参考例１６次いで実施例１５と同様の方法により、下記表１３記載の化合物を得た。

《実施例４５の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．３２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．６２（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．７１（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．２１−７．２５（６Ｈ，ｍ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．５６（１Ｈ，ｓ），９．６２（１Ｈ，ｓ），１１．２８（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８６．１４９９（−０．５ｍｍｕ）．
《実施例４６の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：０．８５（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．３７−１．４２（２Ｈ，ｍ），２．９５−３．００（２Ｈ，ｍ），４．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．９３（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．２９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．７０（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１４−７．２１（４Ｈ，ｍ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６２（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３５１．１５９９（＋１．６ｍｍｕ）．
《実施例４７の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．７７（２Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．７２（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），７．０１（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．１２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．２３−７．２８（４Ｈ，ｍ），７．３０−７．３６（３Ｈ，ｍ），７．４５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．１９（１Ｈ，ｂｒｓ），９．６４（２Ｈ，ｓ），１１．２９（１Ｈ，ｄ，Ｊ＝６．２Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０２．１３１０（＋３．４ｍｍｕ）．
《実施例４８の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：４．３１（２Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．６１（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．７１（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．８７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１３−７．２６（６Ｈ，ｍ），７．３１（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．５４（１Ｈ，ｓ），９．７０（１Ｈ，ｂｒｓ），１１．２８（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８６．１４９６（−０．９ｍｍｕ）．
《実施例４９の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：０．８１（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．３４−１．３９（２Ｈ，ｍ），２．９３−２．９８（２Ｈ，ｍ），４．２２（２Ｈ，ｄ，Ｊ＝５．５Ｈｚ），５．９０−５．９２（１Ｈ，ｍ），６．２４−６．２７（１Ｈ，ｍ），６．７０（１Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１２−７．１４（３Ｈ，ｍ），７．２３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６５（１Ｈ，ｂｒｓ），１１．２９（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５２．１６６６（＋０．５ｍｍｕ）．
＜実施例５０〜５２＞ 参考例４３の化合物を用い、実施例３５と同様の方法により、下記表１４記載の化合物を得た。

《実施例５０の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：２．８０（６Ｈ，ｓ），４．２５（２Ｈ，ｄ，Ｊ＝５．５Ｈｚ），６．７０（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８３（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．１０−７．１６（３Ｈ，ｍ），７．２１（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６３（１Ｈ，ｓ），１１．２７（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３３８．１４８５（−２．０ｍｍｕ）．
《実施例５１の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：３．１７（３Ｈ，ｓ），４．２４（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．５３（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．７０（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．０２（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），７．１０−７．１４（３Ｈ，ｍ），７．１９−７．２４（２Ｈ，ｍ），７．２６（２Ｈ，ｄｄ，Ｊ＝６．１，１．２Ｈｚ），７．３４（３Ｈ，ｑ，Ｊ＝７．９Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），９．６４（１Ｈ，ｓ），１１．２９（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４００．１６８７（＋２．６ｍｍｕ）．
《実施例５２の化合物》
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，δ）：１．４０（４Ｈ，ｂｒｓ），１．４９−１．５３（２Ｈ，ｍ），３．２７−３．３０（４Ｈ，ｍ），４．２５（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．６９（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．９７（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１２（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．１５（１Ｈ，ｓ），７．２２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），９．６３（１Ｈ，ｓ），１１．２８（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４００．１６８７（＋２．６ｍｍｕ）．
＜試験例＞ ＰＡＲＰ活性に対する阻害実験
ＰＡＲＰ（Ｔｒｅｖｉｇｅｎ ４６６７−０５０−０１）を５０ｍｍｏｌ／Ｌトリス−ＨＣｌ（ｐＨ７．８）、１００ｍｍｏｌ／Ｌ ＫＣｌおよび１ｍｍｏｌ／Ｌジチオスレイトールより成る緩衝液にて３５倍希釈して実験に用いた。
１１７．６ｍｍｏｌ／Ｌトリス−ＨＣｌ（ｐＨ８．０）、１１．８ｍｍｏｌ／Ｌ ＭｇＣｌ_２、５．９ｍｍｏｌ／Ｌジチオスレイトールおよび０．４ｍｍｏｌ／Ｌ ＮＡＤより成る緩衝液７６．５μＬ、［^１４Ｃ］ＮＡＤ（ＮＥＮ Ｌｉｆｅ Ｓｃｉｅｎｃｅ Ｐｒｏｄｕｃｔｓ，Ｉｎｃ．ＮＥＣ７４３、３７０ｋＢｑ／ｍＬ）２．５μＬ、活性化ＤＮＡ（Ｔｒｅｖｉｇｅｎ ４６６７−５０−０６）１μＬ、被験化合物または被験化合物溶剤１０μＬおよび３５倍希釈したＰＡＲＰ溶液１０μＬをプラスティック試験管に入れ、よく混合した後、水浴中にて２５℃に加温した。１０分後、氷冷２０％トリクロロ酢酸１ｍＬの添加により反応を中止し、試験管を氷上に一夜静置した。吸引濾過により、沈殿をガラス繊維フィルター上に集め、５％トリクロロ酢酸で５回洗浄した。フィルター上の放射活性を液体シンチレーションカウンターで測定した。被験化合物非存在下における酵素活性を１００％とし、これを５０％に低下させる被験化合物の濃度（ＩＣ_５０値）を算出した．

上記結果から、本発明の新規な４−置換アリール−５−ヒドロキシイソキノリノンは、優れたＰＡＲＰ阻害活性を有することが確認された。
産業上利用可能性
以上のことから本発明の新規な４−置換アリール−５−ヒドロキシイソキノリノンは優れたＰＡＲＰ阻害活性を示す。
ＰＡＲＰ阻害活性を有する化合物は、ＰＡＲＰの過剰な活性化に起因する疾患、例えば、種々の虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）、糖尿病、敗血症性ショック、頭部外傷等の予防および／または治療剤として有用である。Reference Example 1 5-Benzoyloxyisoquinoline

Triethylamine (10.9 g, 108 mmol) was added to a solution of 5-hydroxyisoquinoline (15.0 g, 103 mmol) in dichloromethane (300 mL) and cooled to 0 ° C. Under stirring, benzoyl chloride (15.2 g, 108 mmol) was added dropwise, and the temperature was raised to room temperature. After stirring at room temperature for 6 hours, dichloromethane was added, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 26.6 g of the title compound as a light brown liquid. . Yield quantitative.
¹ H-NMR (DMSO-d ₆ , Δ): 7.68 (2H, t, J = 7.3 Hz), 7.75 (1H, d, J = 5.9 Hz), 7.79-7.85 (3H, m), 8.12 −8.16 (1H, m), 8.28 (2H, d, J = 7.3 Hz), 8.55 (1H, d, J = 5.9 Hz), 9.45 (1H, s).
Reference Example 2 5-Benzoyloxyisoquinoline N-oxide

To a solution of the compound of Reference Example 1 (1.92 g, 7.70 mmol) in dichloromethane (100 mL) was added 3-chloroperbenzoic acid (> 65%, 2.45 g, 9.24 mmol), and the mixture was stirred at room temperature for 6 hours. . Saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 2.35 g of the title compound as a light brown powder. Yield quantitative.
¹ H-NMR (DMSO-d ₆ , Δ): 7.61 (1H, d, J = 7.8 Hz), 7.67 (2H, t, J = 8.3 Hz), 7.75 (1H, t, J = 7.8 Hz), 7 .82 (1H, t, J = 8.3 Hz), 7.86-7.88 (2H, m), 8.14 (1H, d, J = 7.3 Hz), 8.26 (2H, d, J = 8.3 Hz), 9.07 (1H, s).
Reference Example 3 5-Benzoyloxy-1,2-dihydro-1-oxoisoquinoline

Acetic anhydride (100 mL) was added to the compound of Reference Example 2 (29.9 g, 123 mmol), and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, ethanol (100 mL) and water (50 mL) were added, and the mixture was heated to reflux for 30 min. Ethanol was added to the residue obtained by distilling off the solvent, and the precipitated crystals were collected by filtration, washed with ethanol, and then air-dried to obtain 19.0 g of the title compound as a brown powder. Yield 64%.
¹ H-NMR (DMSO-d ₆ , Δ): 6.40 (1H, d, J = 7.3 Hz), 7.21 (1H, t, J = 6.3 Hz), 7.57 (1H, t, J = 7.8 Hz), 7 .64-7.72 (3H, m), 7.81 (1H, t, J = 7.3 Hz), 8.16 (1H, d, J = 7.3 Hz), 8.23 (2H, d, J = 7.8 Hz), 11.45 (1H, brs).
Reference Example 4 5-Benzoyloxy-1-methoxyisoquinoline

Silver (I) oxide (57.9 g, 250 mmol) and methyl iodide (30 mL) were added to a toluene (300 mL) solution of the compound of Reference Example 3 (22.1 g, 83.3 mmol), and the mixture was heated to reflux for 8 hours. The reaction solution was filtered using celite, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [hexane: ethyl acetate (20: 1 → 10: 1)] to give the title as a colorless powder. 9.83 g of compound was obtained. Yield 42%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.10 (3H, s), 7.29 (1H, d, J = 5.8 Hz), 7.66-7.73 (3H, m), 7.77 (1H, dd, J = 7.8, 1.0 Hz), 7.82 (1H, t, J = 7.3 Hz), 8.05 (1H, d, J = 5.8 Hz), 8.16 (1H, d, J = 7.8 Hz), 8.26 (2H, d, J = 7.3 Hz).
Reference Example 5 5-Benzoyloxy-4-bromo-1-methoxyisoquinoline

A solution of the compound of Reference Example 4 (9.83 g, 35.2 mmol) in N, N-dimethylformamide (200 mL) was cooled to 0 ° C., and a little N-bromosuccinimide (6.39 g, 35.9 mmol) was added with stirring. Added one by one. After stirring at 0 ° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 16 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography [hexane: ethyl acetate (20: 1 → 10: 1)] to obtain 11.6 g of the title compound as a colorless powder. Yield 92%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.10 (3H, s), 7.66 (2H, t, J = 8.3 Hz), 7.77-7.82 (3H, m), 8.22 (2H, d, J = 8.3 Hz), 8.26 (1 H, s), 8.28-8.32 (1 H, m).
Reference Example 6 5-Benzoyloxy-4- (4-formylphenyl) -1-methoxyisoquinoline

To a suspension of the compound of Reference Example 5 (20.0 g, 55.8 mmol) and 4-formylphenylboric acid (12.6 g, 83.8 mmol) in toluene (50 mL) was added (1,1′-bis (diphenylphosphine). Fino) ferrocene) dichloropalladium (II) dichloromethane (1: 1) complex (1.22 g, 1.67 mmol) and 2 mol / L aqueous sodium carbonate solution (55.8 mL, 112 mmol) were added, and the mixture was heated to reflux for 5 hours. After cooling, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off. A small amount of ethyl acetate was added to the resulting residue, and the crystals were collected by filtration, washed with ethyl acetate, and then air-dried to obtain 16.6 g of the title compound as a yellow powder. Yield 78%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.15 (3H, s), 7.30 (2H, t, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.51-7.55 (5H, m), 7.68 (1H, d, J = 7.3 Hz), 7.78 (1H, d, J = 7.8 Hz), 8.32 (1H, d, J = 8.3 Hz) , 9.59 (1H, s).
Reference Example 7 4- (4-Formylphenyl) -5-hydroxy-1-methoxyisoquinoline

To a suspension of the compound of Reference Example 6 (6.65 g, 17.3 mmol) in ethanol-water (2: 1, 150 mL) was added 1 mol / L aqueous sodium hydroxide solution (17.3 mL, 17.3 mmol). Heated to reflux for hours. After cooling, water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane: ethyl acetate = 4: 1] to obtain 2.08 g of the title compound as a pale yellow powder. Yield 43%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.08 (3H, s), 7.05 (1H, dd, J = 7.8, 1.0 Hz), 7.48 (1H, t, J = 7.8 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.70 (1H, s), 7.74 (1H, dd, J = 8.3, 1.0 Hz), 7.89 (2H, d, J = 8.3 Hz), 10.04 (1H, s), 10.06 (1H, s).
Reference Example 8 4- (4-Carboxyphenyl) -5-hydroxy-1-methoxyisoquinoline

A mixture of the compound of Reference Example 7 (500 mg, 1.79 mmol), 2-methyl-2-butene (15.2 mL) and 2-propanol (13.5 mL) was added sodium chlorite (80%, 2.02 g, 17.9 mmol) and sodium dihydrogen phosphate dihydrate (1.95 g, 12.5 mmol) in water (13.5 mL) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [ethyl acetate → ethyl acetate-methanol (10: 1)], washed with hexane, and air-dried to obtain 409 mg of the title compound as a yellow powder. Yield 77%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.07 (3H, s), 7.04 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.47 (1H, t , J = 7.8 Hz), 7.67 (1H, s), 7.73 (1H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz), 10.02. (1H, s).
Reference Example 9 4- (4-Carboxyphenyl) -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

47% hydrobromic acid (0.5 mL) and water (0.5 mL) were added to a solution of the compound of Reference Example 8 (400 mg, 1.35 mmol) in acetic acid (5 mL), and the mixture was stirred at 120 ° C. for 2 hours. Ice water (20 mL) was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the precipitated crystals were collected by filtration and air-dried to obtain 348 mg of the title compound as a brown powder. Yield 92%.
¹ H-NMR (DMSO-d ₆ , Δ): 6.82 (1H, d, J = 5.9 Hz), 7.04 (1H, dd, J = 7.8, 1.0 Hz), 7.35 (1H, t, J = 7. 8 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.78 (1H, dd, J = 7.8, 1.0 Hz), 7.87 (2H, d, J = 8.3 Hz) ), 9.78 (1H, s), 11.39 (1H, d, J = 5.9 Hz).
Reference Example 10 4- (3-Aminophenyl) -5-benzoyloxy-1-methoxyisoquinoline

To a suspension of the compound of Reference Example 5 (7.18 g, 20.0 mmol) and 3-nitrophenylboric acid (5.00 g, 30.0 mmol) in toluene (100 mL) was added (1,1′-bis (diphenylphosphine). Fino) ferrocene) dichloropalladium (II) dichloromethane (1: 1) complex (1.63 g, 2.00 mmol) and 2 mol / L aqueous sodium carbonate solution (15.0 mL, 30.0 mmol) were added, and the mixture was heated to reflux for 7 hours. After cooling, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was washed with ethyl acetate and air-dried to obtain a colorless powder. This was suspended in methanol (50 mL), a 5% palladium-carbon (50.0 mg) suspension in methanol (50 mL) was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen stream (294 kPa). The catalyst was removed by filtration using Celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1] to obtain 2.85 g of the title compound as a light brown powder. Yield 38%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.12 (3H, s), 4.89 (2H, s), 5.98-6.00 (1H, m), 6.29 (1H, d, J = 7.3 Hz), 6.43 (1H, s), 6.59 (2H, t, J = 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.58-7.64 (4H, m ), 7.71-7.75 (2H, m), 8.27 (1H, d, J = 8.6 Hz).
Reference Example 11 4- (4-Aminophenyl) -5-benzoyloxy-1-methoxyisoquinoline

Using the compound of Reference Example 5 (1.00 g, 2.79 mmol) and 4-nitrophenylboric acid (699 mg, 4.19 mmol), 290 mg of the title compound as a light brown powder was obtained in the same manner as in Reference Example 10. . Yield 28%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.11 (3H, s), 4.50-5.20 (2H, br), 6.30 (2H, d, J = 8.3 Hz), 6.86 (2H, d, J = 8.3 Hz), 7.37-7.41 (2H, m), 7.57-7.62 (4H, m), 7.67 (1H, s), 7.71 (1H, t, J = 7.8 Hz), 8.26 (1H, dd, J = 8.3, 1.0 Hz).
Reference Example 12 4- (3-Aminophenyl) -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

To a suspension of the compound of Reference Example 10 (500 mg, 1.35 mmol) in ethanol-water (2: 1, 45 mL), 1 mol / L aqueous potassium hydroxide solution (1.36 mL, 1.36 mmol) was added and heated for 2 hours. Refluxed. After cooling, water was added to the residue obtained by evaporating the solvent, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and evaporating the solvent to obtain a brown oil. This was dissolved in acetic acid (10 mL), 47% hydrobromic acid (1 mL) and water (1 mL) were added, and the mixture was heated to reflux for 1 hr. After cooling, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography [ethyl acetate] to obtain 308 mg of the title compound as a dark brown powder. Yield 90%
¹ H-NMR (DMSO-d ₆ , Δ): 4.94 (2H, s), 6.41-6.48 (3H, m), 6.68 (1H, d, J = 5.9 Hz), 6.94 (1H, t, J = 7.8 Hz), 7.00 (1H, dd, J = 7.8, 1.0 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.76 (1H, dd, J = 7.8, 1.0 Hz), 9.47 (1 H, s), 11.19 (1 H, d, J = 3.9 Hz).
Reference Example 13 4- (4-Aminophenyl) -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 11, the title compound as a light brown powder was obtained in the same manner as in Reference Example 12.
¹ H-NMR (DMSO-d ₆ , Δ): 4.95 (2H, s), 6.50 (2H, d, J = 8.6 Hz), 6.63 (1H, d, J = 5.5 Hz), 6.91 (2H, d) , J = 8.6 Hz), 7.00 (1H, d, J = 6.8 Hz), 7.29 (1H, t, J = 7.9 Hz), 7.76 (1H, d, J = 7. 9 Hz), 9.34 (1 H, s), 11.15 (1 H, d, J = 5.5 Hz).
Reference Example 14 5-Benzoyloxy-4- [4- (chloromethylcarbonylamino) phenyl] -1-methoxyisoquinoline

To a solution of the compound of Reference Example 11 (100 mg, 270 μmol) in N, N-dimethylformamide (5 mL), chloroacetyl chloride (21.4 μL, 270 μmol), 4-dimethylaminopyridine (1.65 mg, 13.5 μmol) and triethylamine ( (37.6 μL, 270 μmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 128 mg of the title compound as a yellow powder. Yield quantitative.
¹ H-NMR (DMSO-d ₆ , Δ): 4.13 (3H, s), 4.15 (2H, s), 7.13 (2H, d, J = 8.3 Hz), 7.28-7.33 (4H, m), 7.52-7.58 (3H, m), 7.62 (1H, d, J = 7.8 Hz), 7.74 (1H, s), 7.75 (1H, t, J = 8.3 Hz) ), 8.29 (1H, dd, J = 8.3, 1.0 Hz), 9.90 (1H, s).
Reference Example 15 4- [4-[(2-Chloroethyl) carbonylamino] phenyl] -5-benzoyloxy-1-methoxyisoquinoline

Using the compound of Reference Example 11 (50.0 mg, 135 μmol) and 3-chloropropionyl chloride (13.0 μL, 135 μmol), 35.2 mg of the title compound as a yellow powder was obtained in the same manner as in Reference Example 14. Yield 57%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.72 (2H, t, J = 6.3 Hz), 3.87 (2H, t, J = 6.3 Hz), 4.13 (3H, s), 7.11 (2H, d) , J = 8.2 Hz), 7.29-7.33 (4H, m), 7.51-7.54 (3H, m), 7.62 (1H, dd, J = 7.8,1. 5 Hz), 7.73-7.77 (2 H, m), 8.29 (1 H, dd, J = 8.3, 1.5 Hz), 9.68 (1 H, s).
Reference Example 16 4- [3- (4-Ethoxycarbonylphenylaminocarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline

To a solution of the compound of Reference Example 10 (100 mg, 270 μmol) in dichloromethane (5 mL) was added ethyl 4-isocyanate benzoate (61.9 mg, 324 μmol), and the mixture was stirred at room temperature for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1]. This was suspended in a mixed solution of ethanol (10 mL) and water (5 mL), 1 mol / L aqueous potassium hydroxide solution (273 μL, 273 μmol) was added, and the mixture was heated to reflux for 2 hours. After cooling, water was added and the mixture was acidified with 6 mol / L hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 1: 1] to obtain 104 mg of the title compound as a colorless powder. Yield 84%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.30 (3H, t, J = 7.3 Hz), 4.07 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 6.96 (1H, d) , J = 7.8 Hz), 7.03 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.42-7.47 (3H, m) 7.57 (2H, d, J = 8.8 Hz), 7.66 (1 H, s), 7.72 (1 H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.81 (1H, s), 9.10 (1H, s), 9.91 (1H, s).
Reference Examples 17 to 20 By the same method as Reference Example 16, the compounds shown in Table 7 below were obtained.

<< Compound of Reference Example 17 >>
¹ H-NMR (DMSO-d ₆ , Δ): 3.71 (3H, s), 4.06 (3H, s), 6.85 (2H, d, J = 9.3 Hz), 6.91 (1H, d, J = 7.8 Hz) ), 7.02 (1H, d, J = 7.8 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.38 −7.40 (2H, m), 7.45 (1H, t, J = 7.8 Hz), 7.65 (1H, s), 7.71 (1H, d, J = 8.3 Hz), 8 .44 (1H, s), 8.57 (1H, s), 9.88 (1H, s).
<< Compound of Reference Example 18 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.82 (6H, s), 4.06 (3H, s), 6.68 (2H, d, J = 9.3 Hz), 6.89 (1H, d, J = 7.8 Hz) ), 7.02 (1H, d, J = 6.8 Hz), 7.20-7.25 (3H, m), 7.37-7.39 (2H, m), 7.45 (1H, t , J = 7.8 Hz), 7.64 (1H, s), 7.71 (1H, d, J = 8.3 Hz), 8.29 (1H, s), 8.53 (1H, s), 9.88 (1H, s).
<< Compound of Reference Example 19 >>
¹ H-NMR (DMSO-d ₆ , Δ): 4.05 (3H, s), 6.97 (1H, t, J = 7.3 Hz), 7.02 (1H, d, J = 6.8 Hz), 7.22 (2H, d) , J = 8.3 Hz), 7.29 (2H, t, J = 7.8 Hz), 7.41-7.49 (5H, m), 7.63 (1H, s), 7.70 (1H) , D, J = 7.8 Hz), 8.72 (2H, s).
<< Compound of Reference Example 20 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.32 (3H, t, J = 6.8 Hz), 4.06 (3H, s), 4.28 (2H, q, J = 6.8 Hz), 7.03 (1H, d) , J = 7.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.42-7.46 (3H, m), 7.60-7.64 (3H, m), 7 .71 (1H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.8 Hz), 8.89 (1H, s), 9.19 (1H, s), 9.88 (1H, s).
Reference Example 21 4- [3- (3-Carboxyphenylaminocarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline

To a solution of the compound of Reference Example 10 (100 mg, 270 μmol) in dichloromethane (10 mL) was added ethyl 3-isocyanate benzoate (61.9 mg, 324 μmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, suspended in a mixture of ethanol (10 mL) -water (5 mL), 1 mol / L aqueous potassium hydroxide solution (1.08 mL, 1.08 mmol) was added, and the mixture was heated to reflux for 2 hours. After cooling, water was added and acidified with 6 mol / L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 43.5 mg of the title compound as a colorless powder. Yield 38%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.07 (3H, s), 6.94 (1H, d, J = 7.3 Hz), 7.03 (1H, dd, J = 7.8, 1.0 Hz), 7.25 (1H, t, J = 7.8 Hz), 7.36-7.47 (4H, m), 7.53 (1H, d, J = 7.8 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.66 (1 H, s), 7.72 (1 H, dd, J = 8.3, 1.0 Hz), 8.11 (1 H, s), 8.76 (1 H, s) , 8.94 (1H, s), 9.91 (1H, s).
Reference Example 22 4- [4- (4-Carboxyphenylaminocarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline

A 1 mol / L aqueous potassium hydroxide solution (266 μL, 266 μmol) was added to a suspension of the compound of Reference Example 22 (56.5 mg, 133 μmol) in ethanol (4 mL) -water (2 mL), and the mixture was heated to reflux for 2 hours. After cooling, the solution was acidified with 4 mol / L hydrochloric acid and then heated to reflux for 30 minutes. After cooling, the precipitated crystals were collected by filtration and air-dried to obtain 48.7 mg of the title compound as a colorless powder. Yield 85%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.06 (3H, s), 7.03 (1H, d, J = 7.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.43-7.46. (3H, m), 7.59 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.71 (1H, d, J = 8.3 Hz), 7.88 (2H , D, J = 8.8 Hz), 8.85 (1H, s), 9.12 (1H, s), 9.88 (1H, s).
Reference Example 23 4- (4-acetylphenyl) -5-benzoyloxy-1-methoxyisoquinoline

Using the compound of Reference Example 5 (3.89 g, 10.9 mmol) and 4-acetylphenylboric acid (2.67 g, 16.3 mmol), the title compound as a colorless powder was obtained in the same manner as in Reference Example 6. 19 g was obtained. Yield 74%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.26 (3H, s), 4.14 (3H, s), 7.30-7.35 (4H, m), 7.52-7.56 (3H, m), 7. 60 (2H, d, J = 7.8 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.76-7.80 (2H, m), 8.32 (1H, dd, J = 8.3, 1.5 Hz).
Reference Example 24 5-Benzoyloxy-4- [4- (bromoacetyl) phenyl] -1-methoxyisoquinoline

To a suspension of the compound of Reference Example 23 (4.29 g, 10.8 mmol) in acetic acid (50 mL), 47% hydrobromic acid (5 mL) and tetrabutylammonium tribromide (5.21 g, 10.8 mmol) were added. The mixture was further stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction solution under reduced pressure was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (6: 1 → 3: 1)] to obtain 2.29 g of the title compound as a colorless powder. Yield 56%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.14 (3H, s), 4.59 (2H, s), 7.32 (2H, t, J = 6.8 Hz), 7.38 (2H, d, J = 7.8 Hz) ), 7.52 (3H, d, J = 6.8 Hz), 7.67 (3H, d, J = 7.8 Hz), 7.77-7.80 (2H, m), 8.31 (1H) , D, J = 8.8 Hz).
Reference Example 25 4- [4-((Dimethylamino) acetyl) phenyl] -5-hydroxy-1-methoxyisoquinoline

To a methanol (5 mL) solution of the compound of Reference Example 24 (100 mg, 209 μmol) was added 2 mol / L dimethylamine-methanol solution (630 μL, 1.26 mmol), and the mixture was stirred at 80 ° C. for 1 hour. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was purified by Chromatrex NH column chromatography [hexane-ethyl acetate (4: 1 → 2: 1)]. This was dissolved in ethanol (5 mL), 1 mol / L aqueous potassium hydroxide solution (1.00 mL, 1.00 mmol) was added, and the mixture was heated to reflux for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 21.5 mg of the colorless amorphous title compound. Obtained. Yield 32%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.28 (6H, s), 3.76 (2H, s), 4.07 (3H, s), 7.04 (1H, d, J = 7.3 Hz), 7.44− 7.49 (3H, m), 7.68 (1H, s), 7.73 (1H, d, J = 8.3 Hz), 7.97 (2H, d, J = 8.3 Hz), 10. 02 (1H, s).
<Reference Examples 26 to 28> By the same method as Reference Example 25, the compounds shown in Table 8 below were obtained.

<< Compound of Reference Example 26 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.25 (3H, s), 3.67 (2H, s), 3.91 (2H, s), 4.07 (3H, s), 7.05 (1H, d, J = 6.8 Hz), 7.25-7.32 (1 H, m), 7.34 (4 H, d, J = 4.4 Hz), 7.43-7.49 (3 H, m), 7.68 ( 1H, s), 7.73 (1H, dd, J = 8.3, 1.0 Hz), 7.94 (2H, d, J = 8.3 Hz), 10.01 (1H, brs).
<< Compound of Reference Example 27 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.22 (3H, s), 3.60 (2H, s), 3.73 (3H, s), 3.86 (2H, s), 4.07 (3H, s), 6 .90 (2H, d, J = 8.3 Hz), 6.98 (1H, brs), 7.25 (2H, d, J = 8.3 Hz), 7.43 (3H, d, J = 8. 3 Hz), 7.65-7.68 (2H, m), 7.92 (2H, d, J = 7.8 Hz).
<< Compound of Reference Example 28 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.34 (3H, s), 2.78-2.79 (4H, m), 3.92 (2H, s), 4.07 (3H, s), 7.05 (1H, d, J = 7.3 Hz), 7.16-7.30 (5H, m), 7.41 (2H, d, J = 8.3 Hz), 7.47 (1H, t, J = 7.8 Hz) ), 7.67 (1H, s), 7.73 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz).
Reference Example 29 4- (3-Acetylphenyl) -5-benzoyloxy-1-methoxyisoquinoline

Using the compound of Reference Example 5 (5.13 g, 14.3 mmol) and 3-acetylphenylboric acid (3.52 g, 21.5 mmol), the title compound as a colorless powder was obtained in the same manner as in Reference Example 6 using 3. 93 g was obtained. Yield 69%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.36 (3H, s), 4.15 (3H, s), 7.22 (1H, t, J = 7.3 Hz), 7.30-7.34 (3H, m), 7.46-7.50 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 7.66 (1H, d, J = 6.7 Hz), 7.74 (1H, brs) ), 7.76-7.80 (2H, m), 8.32 (1H, d, J = 7.3 Hz).
Reference Example 30 4-[(3-Bromoacetyl) phenyl] -5-hydroxy-1-methoxyisoquinoline

Sodium bicarbonate (1.10 g, 13.1 mmol) was added to a solution of the compound of Reference Example 29 (1.73 g, 4.35 mmol) in ethanol (25 mL), and the mixture was heated to reflux for 18 hours. After cooling, ethyl acetate was added to the reaction solution, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1] to obtain 4- (3-acetylphenyl) -5-hydroxy-1-methoxyisoquinoline as a colorless powder. This was suspended in acetic acid (20 mL), 47% hydrobromic acid (2 mL) and tetrabutylammonium tribromide (2.10 g, 4.35 mmol) were added, and the mixture was stirred at room temperature for 1 hr. Water, ethyl acetate and then saturated aqueous sodium hydrogen carbonate solution were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was stirred for 30 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [hexane-ethyl acetate = 3: 1] to give a colorless amorphous title. 557 mg of compound was obtained. Yield 34%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.08 (3H, s), 4.97 (2H, s), 7.05 (1H, dd, J = 7.9, 1.2 Hz), 7.47 (1H, t, J = 7.9 Hz), 7.53 (1 H, t, J = 7.9 Hz), 7.63-7.66 (1 H, m), 7.70 (1 H, s), 7.74 (1 H, dd) , J = 7.9, 1.2 Hz), 7.94-7.98 (2H, m), 10.00 (1H, s).
Reference Example 31 5-Benzoyloxy-1-methoxy-4- (4-methyl-3-nitrophenyl) isoquinoline

Using the compound of Reference Example 5 (2.51 g, 7.00 mmol) and 4-methyl-3-nitrophenylboric acid (1.90 g, 10.5 mmol), the title of colorless powder was obtained in the same manner as in Reference Example 6. 2.51 g of compound was obtained. Yield 87%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.04 (3H, s), 4.14 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.38 (2H, t, J = 7.3 Hz) ), 7.46 (1H, dd, J = 7.8, 2.0 Hz), 7.57 (2H, dd, J = 8.3, 1.0 Hz), 7.62-7.69 (2H, m), 7.77-7.81 (3H, m), 8.32 (1H, dd, J = 8.3, 1.0 Hz).
Reference Example 32 4- (3-Amino-4-methylphenyl) -5-hydroxy-1-methoxyisoquinoline

Process 1 : 10% palladium-carbon (150 mg) was added to a suspension of the compound of Reference Example 31 (1.37 g, 3.31 mmol) in methanol (20 mL), and the mixture was stirred at room temperature for 8 hours under a hydrogen stream (245 kPa). . The catalyst was removed by filtration using Celite, and the solvent was distilled off to obtain 1.23 g of light brown amorphous 4- (3-amino-4-methylphenyl) -5-benzoyloxy-1-methoxyisoquinoline. . Yield 97%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.61 (3H, s), 4.11 (3H, s), 4.64 (2H, s), 6.23 (1H, d, J = 7.3 Hz), 6.44 ( 1H, d, J = 7.3 Hz), 6.46 (1H, s), 7.35-7.39 (2H, m), 7.56-7.60 (4H, m), 7.69- 7.74 (2H, m), 8.26 (1 H, d, J = 7.9 Hz).
Step 2: To a solution of 4- (3-amino-4-methylphenyl) -5-benzoyloxy-1-methoxyisoquinoline (196 mg, 510 μmol) in ethanol (3 mL) was added a 1 mol / L aqueous potassium hydroxide solution (1.02 mL, 1.02 mmol). ) And heated to reflux for 2 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 1: 1] to obtain 134 mg of a pale yellow amorphous title compound. Yield 94%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.09 (3H, s), 4.04 (3H, s), 4.74 (2H, s), 6.42 (1H, dd, J = 7.3, 1.8 Hz), 6.56 (1H, d, J = 1.2 Hz), 6.87 (1H, d, J = 7.3 Hz), 6.98 (1H, d, J = 7.9 Hz), 7.42 (1H , T, J = 7.9 Hz), 7.58 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 9.59 (1H, s).
Reference Example 33 4- (3-Amino-4-methylphenyl) -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 32 (120 mg, 428 μmol), 116 mg of the title compound as a colorless powder was obtained in the same manner as in Reference Example 9. Yield quantitative.
¹ H-NMR (DMSO-d ₆ , Δ): 2.06 (3H, s), 4.70 (2H, s), 6.38 (1H, d, J = 7.3 Hz), 6.52 (1H, s), 6.65 ( 1H, d, J = 3.1 Hz), 6.83 (1H, d, J = 7.3 Hz), 6.98 (1H, d, J = 7.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.75 (1H, d, J = 7.9 Hz), 9.35 (1H, s), 11.16 (1H, s).
Reference Example 34 5-Benzoyloxy-4- [3- (chloromethylcarbonylamino) phenyl] -1-methoxyisoquinoline

Using the compound of Reference Example 10 (226 mg, 610 μmol), 267 mg of a pale yellow amorphous title compound was obtained in the same manner as in Reference Example 14. Yield 98%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.13 (3H, s), 4.22 (2H, s), 6.87-6.98 (3H, m), 7.35 (2H, t, J = 7.9 Hz), 7.53-7.65 (5H, m), 7.75 (1H, s), 7.76 (1H, t, J = 7.9 Hz), 8.30 (1H, dd, J = 8.6) , 1.2 Hz), 10.11 (1 H, s).
Reference Example 35 4- [3-[(2-Chloroethyl) carbonylamino] phenyl] -5-benzoyloxy-1-methoxyisoquinoline

Using the compound of Reference Example 10 (200 mg, 540 μmol), 149 mg of pale yellow amorphous title compound was obtained by the same method as Reference Example 15. Yield 60%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.80 (2H, t, J = 6.1 Hz), 3.89 (2H, t, J = 6.1 Hz), 4.13 (3H, s), 6.82 (1H, d) , J = 7.3 Hz), 6.89 (1H, t, J = 7.9 Hz), 6.97 (1H, d, J = 7.9 Hz), 7.34 (2H, t, J = 7. 9 Hz), 7.56-7.65 (5 H, m), 7.74-7.78 (2 H, m), 8.30 (1 H, dd, J = 7.9, 1.2 Hz), 9. 89 (1H, s).
Reference Example 36 4- (3-Aminophenyl) -5-hydroxy-1-methoxyisoquinoline

Using the compound of Reference Example 10 (295 mg, 796 μmol), 143 mg of a pale yellow amorphous title compound was obtained in the same manner as in Reference Example 32, Step 2. Yield 67%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.05 (3H, s), 4.97 (2H, s), 6.45 (1H, d, J = 7.9 Hz), 6.50-6.52 (2H, m), 6.95-7.01 (2H, m), 7.42 (1 H, t, J = 7.9 Hz), 7.59 (1 H, s), 7.68-7.70 (1 H, m), 9.70 (1H, s).
Reference Example 37 4- (4-Chloromethylphenyl) -5-hydroxy-1-methoxyisoquinoline

Process 1 : Sodium borohydride (230 mg, 6.09 mmol) was added to a tetrahydrofuran-methanol (1: 1, 60 mL) solution of the compound of Reference Example 7 (1.70 g, 6.09 mmol) under ice cooling, and at room temperature. Stir for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1 → 1: 2) → ethyl acetate] to give colorless powder of 5-hydroxy-4- (4-hydroxymethylphenyl)- 1.91 g of 1-methoxyisoquinoline was obtained. Yield 88%.
¹ H-NMR (CDCl ₃ , Δ): 1.79 (1H, t, J = 5.9 Hz), 4.16 (3H, s), 4.83 (2H, d, J = 5.9 Hz), 5.43 (1H, s) ), 7.10 (1H, dd, J = 7.8, 1.0 Hz), 7.46-7.55 (5H, m), 7.71 (1H, s), 7.95 (1H, dd) , J = 8.3, 1.5 Hz).
Process 2 : To a solution of 5-hydroxy-4- (4-hydroxymethylphenyl) -1-methoxyisoquinoline (2.07 g, 7.36 mmol) in dichloromethane (50 ml) under ice cooling, thionyl chloride (1.29 ml, 17.7 mmol). ) And stirred at room temperature for 3 hours. Ice water and dichloromethane were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1 → 1: 2)] to obtain 2.02 g of the title compound as a pale yellow powder. Yield 92%.
¹ H-NMR (CDCl ₃ , Δ): 4.16 (3H, s), 4.69 (2H, s), 5.30 (1H, s), 7.10 (1H, dd, J = 7.8, 1.5 Hz), 7.48 (1H, t, J = 7.8 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.72 (1H , S), 7.95 (1H, dd, J = 8.3, 1.5 Hz).
Reference Example 38 4- (4-Aminomethylphenyl) -5-hydroxy-1-methoxyisoquinoline

To a solution of the compound of Reference Example 37 (1.33 g, 4.44 mmol) in N, N-dimethylformamide (25 mL) was added potassium phthalimide (986 mg, 5.32 mmol), and the mixture was stirred at 80 ° C. for 4 hours. After cooling, water was added, the mixture was extracted with ethyl acetate-methanol (10: 1), washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [hexane-ethyl acetate (2: 1 → 1: 2)] to obtain a light yellow powder. This was dissolved in ethanol (40 mL), hydrazine monohydrate (432 μL, 8.88 mmol) was added, and the mixture was heated to reflux for 4 hours. After cooling, the insoluble material was removed by filtration, and the solvent was distilled off. The obtained residue was dissolved in ethyl acetate, washed with water and then saturated sodium bicarbonate, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 432 mg of the title compound as a pale yellow powder. Yield 35%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.77 (2H, s), 4.06 (3H, s), 7.01 (1H, d, J = 7.3 Hz), 7.23-7.30 (4H, m), 7.44 (1H, t, J = 7.9 Hz), 7.61 (1H, s), 7.69-7.72 (1H, m).
Reference Example 39 5-Benzoyloxy-4- (3-formylphenyl) -1-methoxyisoquinoline

Using the compound of Reference Example 5 (3.58 g, 10.0 mmol) and 3-formylphenylboric acid (2.55 g, 15.0 mmol) in the same manner as in Reference Example 6, the title compound as a colorless powder was obtained in the form of 2. 91 g was obtained. Yield 76%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.14 (3H, s), 7.23-7.33 (4H, m), 7.46-7.49 (2H, m), 7.53-7.60 (2H, m) ), 7.67 (1H, dd, J = 7.8, 1.5 Hz), 7.73-7.80 (3H, m), 8.32 (1H, dd, J = 8.3, 1. 5 Hz), 9.77 (1 H, s).
Reference Example 40 4- (3-Formylphenyl) -5-hydroxy-1-methoxyisoquinoline

Using the compound of Reference Example 39 (4.46 g, 11.6 mmol), 2.43 g of a pale yellow amorphous title compound was obtained in the same manner as in Reference Example 7. Yield 75%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.07 (3H, s), 7.04 (1H, dd, J = 7.8, 1.0 Hz), 7.47 (1H, t, J = 7.8 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.66-7.70 (2H, m), 7.74 (1H, dd, J = 8.3, 1.0 Hz), 7.85-7. 87 (2H, m), 10.06 (1H, s) 9.80-10.20 (1H, br).
Reference Example 41 5-hydroxy-4- (3-hydroxymethylphenyl) -1-methoxyisoquinoline

Sodium borohydride (484 mg, 12.8 mmol) was added to a methanol-tetrahydrofuran (2: 1, 30 mL) solution of the compound of Reference Example 40 (1.79 g, 6.41 mmol) and stirred at room temperature for 1.5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was solidified by adding isopropyl ether and dried to obtain 1.50 g of the title compound as a colorless powder. Yield 83%.
¹ H-NMR (DMSO-d ₆ , Δ): 4.06 (3H, s), 4.54 (2H, d, J = 5.5 Hz), 5.19 (1H, t, J = 5.5 Hz), 7.01 (1H, d) , J = 7.9 Hz), 7.16-7.18 (1H, m), 7.25-7.31 (3H, m), 7.44 (1 H, t, J = 7.9 Hz), 7 .62 (1H, s), 7.71 (1H, d, J = 7.9 Hz), 9.86 (1H, brs).
Reference Example 42 N- [3- (5-Methanesulfonyloxy-1-methoxyisoquinolin-4-yl) phenyl] methylphthalimide

Triethylamine (2.02 mL, 14.5 mmol) and methanesulfonyl chloride (561 μL, 7.25 mmol) were sequentially added to a tetrahydrofuran (15 mL) solution of the compound of Reference Example 41 (407 mg, 1.45 mmol) under ice-cooling. For 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was dissolved in N, N-dimethylformamide (15 mL), potassium phthalimide (322 mg, 1.74 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was solidified by adding isopropyl ether and dried to obtain 555 mg of the title compound as a colorless powder. Yield 79%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.36 (3H, s), 4.11 (3H, s), 4.85 (2H, d, J = 3.1 Hz), 7.30-7.36 (3H, m), 7.42-7.46 (1H, m), 7.71-7.76 (2H, m), 7.83-7.91 (5H, m), 8.30-8.33 (1H, m) ).
Reference Example 43 4- (3-Aminomethylphenyl) -5-hydroxy-1-methoxyisoquinoline

To a suspension of the compound of Reference Example 42 (2.05 g, 4.20 mmol) in ethanol (40 mL) was added 1 mol / L potassium hydroxide aqueous solution (42.0 mL, 42.0 mmol), and the mixture was stirred at room temperature for 20 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1) → ethyl acetate] to obtain a yellow amorphous. This was dissolved in ethanol (30 mL), hydrazine monohydrate (222 μL, 7.14 mmol) was added, and the mixture was heated to reflux for 3 hours. After cooling, the residue obtained by concentrating the reaction solution was purified by Chromatrex NH column chromatography [ethyl acetate-ethanol = 10: 1] to obtain 526 mg of the title compound as a pale yellow powder. Yield 45%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.74 (2H, s), 4.06 (3H, s), 7.00 (1H, d, J = 7.9 Hz), 7.12-7.15 (1H, m), 7.25 (1H, s), 7.26 (2H, s), 7.44 (1H, t, J = 7.9 Hz), 7.62 (1H, s), 7.70 (1H, dd, J = 7.9, 1.2 Hz).
Example 1 1,2-Dihydro-5-hydroxy-4- [4- (N-methylcarbamoyl) phenyl] -1-oxoisoquinoline

Process 1 : Acetic anhydride (5 mL) was added to the compound of Reference Example 8 (136 mg, 461 μmol), and the mixture was heated to reflux for 1.5 hours. After cooling, benzene (5 mL) and thionyl chloride (0.5 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was heated to reflux for 2 hours. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was dissolved in dichloromethane (5 ml), added dropwise to a 40% methylamine-methanol solution (10 mL) over 5 minutes under ice cooling, and stirred at room temperature for 4 hours. did. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography [ethyl acetate → acetone] to give 5-hydroxy-1-methoxy-4- [4- (N-methylcarbamoyl) phenyl as a light brown powder. ] 87.3 mg of isoquinoline was obtained. Yield 61%.
¹ H-NMR (CDCl ₃ , Δ): 3.07 (3H, d, J = 4.9 Hz), 4.16 (3H, s), 6.24 (1H, brs), 7.13 (1H, d, J = 7.8 Hz) ), 7.48 (1H, t, J = 7.8 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.72 (1H, s), 7.87 (2H, d, J = 8.3 Hz), 7.96 (1H, d, J = 8.3 Hz).
Process 2 To a solution of 5-hydroxy-1-methoxy-4- [4- (N-methylcarbamoyl) phenyl] isoquinoline (82.4 mg, 267 μmol) in acetic acid (5 ml), 47% hydrobromic acid (0.5 mL) and Water (0.5 mL) was added and stirred at 120 ° C. for 2 hours. Ice water (10 mL) was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the precipitated crystals were collected by filtration and air-dried. This was purified by silica gel column chromatography [ethyl acetate-methanol = 5: 1], washed with ethyl acetate, and then air-dried to obtain 41.8 mg of the title compound as a pale yellow powder. Yield 52%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.80 (3H, d, J = 4.4 Hz), 6.79 (1H, d, J = 5.4 Hz), 7.03 (1H, d, J = 6.8 Hz), 7 .339 (1H, t, J = 7.8 Hz), 7.340 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.3 Hz), 7.78 (1H, dd, J = 7.8, 1.0 Hz), 8.41 (1H, d, J = 4.9 Hz), 9.72 (1H, s), 11.36 (1H, d, J = 5.4 Hz) ).
Anal. Calcd for C ₁₇ H ₁₄ N ₂ O ₃ ・ 1 / 2H ₂ O: C, 67.32; H, 4.98; N, 9.24.
Found: C, 67.48; H, 4.94; N, 9.10.
HR-MS: 294.0981 (-2.4 mmu).
Example 2 1,2-Dihydro-5-hydroxy-4- [4- (N, N-dipropylcarbamoyl) phenyl] -1-oxoisoquinoline

Using the compound of Reference Example 8 and dipropylamine, the title compound was obtained as a light brown powder in the same manner as in Example 1.
¹ H-NMR (DMSO-d ₆ , Δ): 0.73-0.92 (6H, m), 1.52-1.59 (4H, m), 3.24-3.47 (4H, m), 6.79 (1H, d) , J = 5.9 Hz), 7.04 (1H, d, J = 6.8 Hz), 7.23 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 7. 8 Hz), 7.33 (1 H, t, J = 7.8 Hz), 7.78 (1 H, d, J = 6.8 Hz), 9.73 (1 H, s), 11.34 (1 H, d, J = 5.9 Hz).
HR-MS: 364.1813 (+2.6 mmu).
Example 3 1,2-Dihydro-5-hydroxy-4- [4- [N- (3-dimethylaminopropyl) carbamoyl] phenyl] -1-oxoisoquinoline

Using the compound of Reference Example 8 and N, N-dimethyl-1,3-propylenediamine, the title compound as a light brown powder was obtained in the same manner as in Example 1.
¹ H-NMR (DMSO-d ₆ , Δ): 1.63-1.70 (2H, m), 2.13 (6H, s), 2.27 (2H, t, J = 6.8 Hz), 3.29 (2H, m), 6.63 (2H, brs), 7.15 (1H, brs), 7.28 (2H, d, J = 8.3 Hz), 7.47 (1H, brs), 7.73 (2H, d, J = 8.3 Hz), 8.47 (1H, t, J = 5.9 Hz).
HR-MS: 365.1433 (+0.3 mmu).
Example 4 1,2-Dihydro-4- [4- [N- (4-dimethylaminobutyl) carbamoyl] phenyl] -5-hydroxy-1-oxoisoquinoline

Process 1 : N, N-dimethyl-1,4-butylenediamine (157 mg, 1.35 mmol) and 1- (3-dimethylamino) were added to a solution of the compound of Reference Example 8 (200 mg, 677 μmol) in dichloromethane (10 mL) under ice cooling. Propyl) -3-ethylcarbodiimide (259 mg, 1.35 mmol) was added and stirred at room temperature for 7 hours. The reaction solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [ethyl acetate-methanol = 1: 1] to give 4- [4- [N- (4-dimethylaminobutyl) carbamoyl] phenyl] -5-hydroxy- brown powder. 106 mg of 1-methoxyisoquinoline was obtained. Yield 40%.
¹ H-NMR (CDCl ₃ , Δ): 1.37-1.42 (2H, m), 1.50-1.57 (2H, m), 2.23 (6H, s), 3.14-3.20 (2H, m ), 3.34-3.39 (2H, m), 4.15 (3H, s), 6.87 (1H, d, J = 7.3 Hz), 7.40 (1H, t, J = 7) .8 Hz), 7.48 (2 H, d, J = 8.3 Hz), 7.70 (1 H, s), 7.73 (1 H, brs), 7.84 (1 H, d, J = 8.3 Hz) ), 7.84 (2H, d, J = 8.3 Hz).
Process 2 : 4- [4- [N- (4-dimethylaminobutyl) carbamoyl] phenyl] -5-hydroxy-1-methoxyisoquinoline (103 mg, 263 μmol) in acetic acid (5 mL) was dissolved in 47% hydrobromic acid (0 0.5 mL) and water (0.5 mL) were added, and the mixture was stirred at 120 ° C. for 1 hour. Ice water (10 mL) was added to the residue obtained by concentrating the reaction solution under reduced pressure, the pH was adjusted to 8 using sodium bicarbonate, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate-methanol = 1: 1], washed successively with ethyl acetate and water, and then air-dried to obtain 40.1 mg of the title compound as a light brown powder. . Yield 39%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.41-1.48 (2H, m), 1.51-1.57 (2H, m), 2.11 (6H, s), 2.21 (2H, t, J = 6) .8 Hz), 6.78 (1H, d, J = 5.4 Hz), 7.03 (1H, dd, J = 7.8, 1.0 Hz), 7.33 (2H, d, J = 8. 3 Hz), 7.34 (1 H, t, J = 7.8 Hz), 7.77 (2 H, d, J = 8.3 Hz), 7.78 (1 H, dd, J = 7.8, 1.0 Hz) ), 8.45 (1H, t, J = 5.4 Hz), 9.71 (1H, brs), 11.34 (1H, d, J = 5.4 Hz).
Anal. Calcd for C ₂₂ H ₂₅ N ₃ O ₃ ・ 1 / 2H ₂ O: C, 68.02; H, 6.75; N, 10.82.
Found: C, 67.99; H, 6.47; N, 10.63.
HR-MS: 379.1907 (+1.1 mmu).
Example 5 1,2-Dihydro-5-hydroxy-4- [4- [N- (2-dimethylaminoethyl) carbamoyl] phenyl] -1-oxoisoquinoline

Using the compound of Reference Example 8 and N, N-dimethylethylenediamine, the title compound as a colorless powder was obtained in the same manner as in Example 4.
¹ H-NMR (DMSO-d ₆ , Δ): 2.19 (6H, s), 2.41 (2H, t, J = 6.8 Hz), 6.79 (1H, d, J = 4.4 Hz), 7.04 (1H, d , J = 6.8 Hz), 7.32-7.36 (3H, m), 7.76-7.79 (3H, m), 8.35 (1H, t, J = 5.9 Hz), 9 .75 (1H, brs), 11.36 (1H, brs).
HR-MS: 351.1571 (-1.2 mmu).
Example 6 1,2-Dihydro-5-hydroxy-4- [4- [N- [2- (pyrrolidin-1-yl) ethyl] carbamoyl] phenyl] -1-oxoisoquinoline

Using the compound of Reference Example 8 and 1- (2-aminoethyl) pyrrolidine, the title compound as a colorless powder was obtained in the same manner as in Example 4.
¹ H-NMR (DMSO-d ₆ , Δ): 1.24 (4H, brs), 1.68 (4H, brs), 2.58 (2H, t, J = 6.8 Hz), 6.79 (1H, d, J = 4.9 Hz). ), 7.03 (1H, d, J = 7.8 Hz), 7.32-7.36 (3H, m), 7.76-7.79 (3H, m), 8.40 (1H, t , J = 5.9 Hz), 9.72 (1H, brs), 11.35 (1H, d, J = 5.5 Hz).
HR-FAB +: 378.1817 (-0.1 mmu).
Example 7 1,2-Dihydro-5-hydroxy-4- [4- [N- (2-hydroxyethyl) carbamoyl] phenyl] -1-oxoisoquinoline

Acetic anhydride (10 mL) was added to the compound of Reference Example 9 (150 mg, 533 μmol), and the mixture was heated to reflux for 2 hours. Benzene (10 mL) and thionyl chloride (1 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was heated to reflux for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in dichloromethane (10 mL) and added dropwise to a solution of 2-aminoethanol (3.26 g, 53.4 mmol) in dichloromethane (10 mL) over 5 minutes under ice-cooling. Stir at room temperature for 5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography [ethyl acetate-methanol = 5: 1], washed with water, and then air-dried to obtain 19.6 mg of the title compound as a light brown powder. . Yield 11%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.52 (2H, q, J = 5.9 Hz), 4.74 (1H, t, J = 5.9 Hz), 6.78 (1H, d, J = 5.9 Hz), 7 .04 (1H, d, J = 7.8 Hz), 7.3398 (2H, d, J = 8.3 Hz), 7.3404 (1H, t, J = 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.79 (2H, d, J = 8.3 Hz), 8.40 (1H, t, J = 5.9 Hz), 9.71 (1H, s), 11. 35 (1H, d, J = 6.3 Hz).
Anal. Calcd for C ₁₈ H ₁₆ N ₂ O ₄ ・ 4 / 5H ₂ O: C, 63.82; H, 5.24; N, 8.27.
Found: C, 63.60; H, 5.12; N, 8.22.
HR-MS: 324.1115 (+0.5 mmu).
Example 8 1,2-Dihydro-5-hydroxy-4- [4- [N- (1,3-dihydroxypropan-2-yl) carbamoyl] phenyl] -1-oxoisoquinoline

By using the compound of Reference Example 9 (150 mg, 533 μmol) and serinol (486 mg, 5.33 mmol) in the same manner as in Example 7, 50.1 mg of the title compound as a light brown powder was obtained. Yield 27%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.53 (4H, t, J = 5.9 Hz), 3.96-4.01 (1H, m), 4.67 (2H, t, J = 5.9 Hz), 6.78. (1H, d, J = 5.9 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.342 (2H, d, J = 8.3 Hz), 7.344 (1H, t, J = 7.8 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz), 7.91 (1H, d, J = 7.8 Hz) ), 9.72 (1H, s), 11.35 (1H, d, J = 6.8 Hz).
HR-FAB +: 3555.1329 (+3.5 mmu).
Example 9 1,2-Dihydro-4- [4- (dimethylaminomethylcarbonylamino) phenyl] -5-hydroxy-1-oxoisoquinoline

Process 1 : 2 mol / L dimethylamine-methanol solution (287 μL, 573 μmol) was added to a solution of the compound of Reference Example 14 (64.0 mg, 143 μmol) in ethanol (3 mL), and the mixture was stirred at 80 ° C. for 4 hours. The residue obtained by distilling off the solvent was purified by chromatolex NH column chromatography [hexane-ethyl acetate (1: 1) → ethyl acetate] to give 4- [4- (dimethylamino) as a pale brown oil. 22.7 mg of methylcarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline was obtained. Yield 45%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.30 (6H, s), 4.05 (3H, s), 7.02 (1H, d, J = 7.8 Hz), 7.23 (2H, d, J = 8.3 Hz) ), 7.44 (1H, t, J = 7.8 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.62 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 9.73 (1H, s).
Process 2 : Acetic acid (5 mL) and 47% hydrobromic acid (1 mL) were added to 4- [4- (dimethylaminomethylcarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline (22.7 mg, 64.6 μmol). , And stirred at 40 ° C. for 48 hours. Water was added to the residue obtained by distilling off the solvent, and the mixture was made basic by adding a saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration and air-dried to obtain 8.60 mg of the title compound as a colorless powder. Yield 39%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.29 (6H, s), 3.07 (2H, s), 6.71 (1H, brs), 7.00 (1H, d, J = 7.3 Hz), 7.18 ( 2H, d, J = 8.8 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.76 (1H, d, J = 6.8 Hz), 9.69 (1H, s), 11.26 (1H, brs).
HR-MS: 337.1395 (-3.1 mmu).
Example 10 1,2-Dihydro-4- [4-[(pyrrolidin-1-yl) methylcarbonylamino] phenyl] -5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 14 and pyrrolidine, the title compound as a colorless powder was obtained in the same manner as in Example 9.
¹ H-NMR (DMSO-d ₆ , Δ): 1.76 (4H, brs), 2.60 (4H, brs), 6.72 (1H, brs), 7.01 (1H, d, J = 7.3 Hz), 7.18 ( 2H, d, J = 8.8 Hz), 7.32 (1H, t, J = 8.3 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7.3 Hz), 9.68 (1 H, s), 11.27 (1 H, d, J = 5.9 Hz).
HR-MS: 363.1550 (-3.3 mmu).
Example 11 1,2-Dihydro-4- [4- [2- (pyrrolidin-1-yl) ethylcarbonylamino] phenyl] -5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 15 and pyrrolidine, the title compound as a colorless powder was obtained in the same manner as in Example 9.
¹ H-NMR (DMSO-d ₆ , Δ): 1.71 (4H, brs), 6.71 (1H, d, J = 5.9 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.18 (2H, d) , J = 8.8 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7. 8Hz), 9.62 (1H, s), 10.08 (1H, s), 11.26 (1H, brs).
HR-FAB +: 378.1832 (+1.4 mmu).
Example 12 4- [3-[(3-Aminopropyl) carbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Process 1 : To a solution of the compound of Reference Example 12 (100 mg, 396 μmol) in N, N-dimethylformamide (4 mL), 4- (t-butoxycarbonylamino) butyric acid (96.5 mg, 475 μmol) and 1- (3-dimethylaminopropyl) ) -3-Ethylcarbodiimide (91.1 mg, 475 μmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 3) → ethyl acetate] to give 4- [3 55.7 mg of-[3- (t-butoxycarbonylamino) propylcarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline was obtained. Yield 32%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.37 (9H, s), 1.64-1.71 (2H, m), 2.28 (2H, t, J = 7.8 Hz), 2.92-2.97 (2H) M), 6.72 (1H, d, J = 5.9 Hz), 6.84 (1H, t, J = 5.4 Hz), 6.94 (1H, d, J = 7.8 Hz), 7 .01 (1H, d, J = 7.8 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.48 (1H, s), 7.52 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 7.8 Hz), 9.68 (1H, s), 9.83 (1H, s) , 11.27 (1H, d, J = 5.9 Hz).
Process 2 : 4- [3- [3- (t-butoxycarbonylamino) propylcarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline (55.7 mg, 127 μmol) in methanol (1 mL) To the mixture, a saturated hydrogen chloride-methanol solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by distilling off the solvent was purified by Chromatrex NH column chromatography [ethyl acetate → ethyl acetate-methanol (10: 1 → 3: 1)] to give 3.10 mg of the title compound as a colorless powder. Obtained. Yield 7%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.69 (2H, t, J = 7.3 Hz), 2.34 (2H, t, J = 7.3 Hz), 2.63 (2H, t, J = 7.3 Hz), 6 .71 (1H, s), 6.93 (1H, d, J = 7.8 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.19 (1H, t, J = 7. 8 Hz), 7.31 (1 H, t, J = 7.8 Hz), 7.48-7.52 (2 H, m), 7.76 (1 H, d, J = 7.8 Hz).
HR-FAB +: 338.1497 (-0.7 mmu).
Example 13 4- [3-[(4-Aminobutyl) carbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 12 (50.0 mg, 198 μmol) and 5- (t-butoxycarbonylamino) valeric acid (64.5 mg, 297 μmol), the title compound as a colorless powder was converted into 45 by the same method as in Example 12. .7 mg was obtained. Yield 66%.
¹ H-NMR (DMSO-d ₆ , Δ): 1.33-1.41 (2H, m), 1.55-1.63 (2H, m), 2.28 (2H, t, J = 7.3 Hz), 6.73 (1H , S), 6.93 (1H, d, J = 7.3 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.20 (1H, t, J = 7.8 Hz), 7 .32 (1H, t, J = 7.8 Hz), 7.48 (1H, s), 7.53 (1H, d, J = 7.8 Hz), 7.76 (1H, d, J = 7. 8 Hz), 9.83 (1 H, s).
HR-FAB +: 352.1634 (-2.7 mmu).
Example 14 1,2-Dihydro-5-hydroxy-1-oxo-4- [4- (phenylmethylcarbonylamino) phenyl] isoquinoline

A solution of the compound of Reference Example 13 (33.0 mg, 131 μmol) in N, N-dimethylformamide (3 mL) was added to phenylacetic acid (21.4 mg, 157 μmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (30 .1 mg, 157 μmol) was added and stirred at room temperature for 5 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and air-dried to obtain 29.4 mg of the title compound as a colorless powder. Yield 61%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.65 (2H, s), 6.70 (1H, d, J = 5.9 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.18 (2H, d) , J = 8.3 Hz), 7.23-7.35 (6H, m), 7.51 (2H, d, J = 8.3 Hz), 7.77 (1H, d, J = 6.8 Hz) , 9.60 (1H, s), 10.15 (1H, s), 11.26 (1H, d, J = 5.9 Hz).
HR-FAB +: 371.1428 (+3.4 mmu).
Example 15 1,2-Dihydro-5-hydroxy-1-oxo-4- [3-[(4-methoxyphenyl) aminocarbonylamino] phenyl] isoquinoline

47% hydrobromic acid (0.25 mL) and water (0.25 mL) were added to a solution of the compound of Reference Example 17 (73.5 mg, 177 μmol) in acetic acid (2.5 mL), and the mixture was stirred at 60 ° C. for 9 hours. did. After cooling, water was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration and air-dried. This was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1) → ethyl acetate] to obtain 25.5 mg of the title compound as a colorless powder. Yield 36%.
¹ H-NMR (DMSO-d ₆ , Δ): 3.71 (3H, s), 6.75 (1H, d, J = 5.9 Hz), 6.84-6.88 (3H, m), 7.02 (1H, d, J = 7.8 Hz), 7.18 (1 H, t, J = 7.8 Hz), 7.31-7.36 (5 H, m), 7.78 (1 H, d, J = 7.8 Hz), 8 .43 (1H, s), 8.53 (1H, s), 9.65 (1H, s), 11.27 (1H, d, J = 5.9 Hz).
HR-FAB +: 402.453 (-0.1 mmu).
<Examples 16 to 20> By the same method as in Example 15, the compounds shown in Table 9 below were obtained.

<< Compound of Example 16 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.82 (6H, s), 6.68 (2H, d, J = 8.8 Hz), 6.75 (1H, d, J = 5.9 Hz), 6.86 (1H, d) , J = 7.3 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.18 (1H, t, J = 7.8 Hz), 7.24 (2H, d, J = 8. 8 Hz), 7.31-7.35 (3 H, m), 7.78 (1 H, d, J = 7.8 Hz), 8.25 (1 H, s), 8.46 (1 H, s), 9 .65 (1H, s), 11.26 (1H, d, J = 5.4 Hz).
HR-FAB +: 415.1799 (+2.9 mmu).
<< Compound of Example 17 >>
¹ H-NMR (DMSO-d ₆ , Δ): 6.76 (1H, d, J = 5.9 Hz), 6.90 (1H, d, J = 7.3 Hz), 7.02 (1H, dd, J = 7.8, 1.). 5 Hz), 7.21 (1 H, t, J = 7.8 Hz), 7.31-7.41 (4 H, m), 7.54 (1 H, d, J = 7.8 Hz), 7.62 ( 1H, d, J = 8.3 Hz), 7.78 (1H, dd, J = 7.8, 1.5 Hz), 8.11 (1H, s), 8.65 (1H, s), 8. 85 (1H, s), 9.67 (1H, s), 11.27 (1H, d, J = 5.9 Hz), 11.90 (1H, brs).
HRMS (FAB +): 416.1276 (+2.9 mmu).
<< Compound of Example 18 >>
¹ H-NMR (DMSO-d ₆ , Δ): 6.72 (1H, d, J = 5.9 Hz), 6.97 (1H, t, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 7 .17 (2H, d, J = 8.3 Hz), 7.26-7.34 (3H, m), 7.37 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 7.3 Hz), 7.77 (1H, d, J = 7.8 Hz), 8.65 (2H, d, J = 6.8 Hz), 9.62 (1H, s), 11.26 ( 1H, d, J = 5.9 Hz).
HR-FAB +: 372.1329 (-1.9 mmu).
<< Compound of Example 19 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.30 (3H, t, J = 7.3 Hz), 4.27 (2H, q, J = 7.3 Hz), 6.72 (1H, d, J = 5.4 Hz), 7 .01 (1H, d, J = 7.3 Hz), 7.18 (2H, d, J = 8.3 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.38 (2H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.76 (1H, d, J = 7.8 Hz), 7.88 (2H, d, J = 8) .8 Hz), 8.82 (1 H, s), 9.14 (1 H, s), 9.63 (1 H, s), 11.25 (1 H, d, J = 5.9 Hz).
HR-FAB +: 444.1525 (-3.5 mmu).
<< Compound of Example 20 >>
¹ H-NMR (DMSO-d ₆ , Δ): 6.73 (1H, d, J = 5.9 Hz), 7.02 (1H, d, J = 7.8 Hz), 7.19 (2H, d, J = 8.3 Hz), 7 .32 (1H, t, J = 7.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.87 (2H, d, J = 8.8 Hz), 8.82 (1 H, s), 9.10 (1 H, s), 9.65 (1 H, s) , 11.27 (1H, d, J = 5.9 Hz).
Anal. calcd for C ₂₃ H ₁₇ N ₃ O ₅ ・ 7 / 10H ₂ O: C, 64.54; H, 4.33; N, 9.82.
Found: C, 64.42; H, 4.23; N, 9.73.
HR-FAB +: 416.1202 (-4.4 mmu).
Example 21 4- [3- (4-Carboxyphenylaminocarbonylamino) phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

47% hydrobromic acid (1 mL) and water (1 mL) were added to a solution of the compound of Reference Example 16 (104 mg, 227 μmol) in acetic acid (10 mL), and the mixture was heated to reflux for 1 hour. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography [ethyl acetate → ethyl acetate-methanol (10: 1 → 1: 1) → methanol]. This was suspended in a mixed solution of ethanol (2 mL) -water (1 mL), 1 mol / L aqueous potassium hydroxide solution (217 μL, 217 μmol) was added, and the mixture was heated to reflux for 2 hours. After cooling, water was added and the mixture was acidified with 6 mol / L hydrochloric acid. The precipitated crystals were collected by filtration and air-dried to obtain 5.40 mg of the title compound as a light brown powder. Yield 6%.
¹ H-NMR (DMSO-d ₆ , Δ): 6.76 (1H, d, J = 5.4 Hz), 6.92 (1H, d, J = 7.3 Hz), 7.02 (1H, d, J = 7.3 Hz), 7 .22 (1H, t, J = 7.8 Hz), 7.31-7.39 (3H, m), 7.55 (2H, d, J = 8.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.85 (2H, d, J = 8.3 Hz), 8.81 (1H, s), 9.08 (1H, s), 9.68 (1H, s), 11 .28 (1H, d, J = 5.4 Hz), 12.57 (1H, brs).
HR-FAB +: 416.1252 (+0.6 mmu).
Example 22 1,2-Dihydro-5-hydroxy-4- [3- (4-nitrophenylaminocarbonylamino) phenyl] -1-oxoisoquinoline

4-Nitrophenyl isocyanate (53.0 mg, 323 μmol) was added to a solution of the compound of Reference Example 10 (100 mg, 270 μmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 8 hours. Precipitated crystals were collected by filtration, washed with dichloromethane and air-dried. This was suspended in a mixed solution of ethanol (10 mL) -water (5 mL), 1 mol / L potassium hydroxide aqueous solution (273 μl, 273 μmol) was added, and the mixture was heated to reflux for 4 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane-ethyl acetate = 1: 1]. This was dissolved in acetic acid (5 ml), 47% hydrobromic acid (0.5 mL) and water (0.5 mL) were added, and the mixture was stirred at 60 ° C. for 9 hr. After cooling, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was made basic with saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration and air-dried to obtain 51.1 mg of the title compound as a yellow powder. Yield 45%.
¹ H-NMR (DMSO-d ₆ , Δ): 6.77 (1H, s), 6.94 (1H, d, J = 7.3 Hz), 7.02 (1H, dd, J = 7.8, 1.0 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.38-7.41 (2H, m), 7.69 (2H, d, J = 9.3 Hz), 7.78 (1H, dd, J = 7.8, 1.0 Hz), 8.18 (2H, d, J = 9.3 Hz), 9.07 (1H, s), 9. 61 (1H, s), 9.68 (1H, s), 11.28 (1H, s).
HR-FAB +: 417.1231 (+3.2 mmu).
<Examples 23 to 26> The compounds shown in Table 10 below were obtained in the same manner as in Reference Example 9.

<< Compound of Example 23 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.29 (6H, s), 3.79 (2H, brs), 6.83 (1H, d, J = 5.9 Hz), 7.04 (1H, d, J = 6.8 Hz). ), 7.35 (1H, t, J = 7.8 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.92 (2H, d, J = 8.3 Hz), 9.81 (1H, s), 11.40 (1H, d, J = 5.9 Hz).
HR-MS: 322.1304 (-1.3 mmu).
<< Compound of Example 24 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.23 (3H, s), 3.66 (2H, s), 3.88 (2H, s), 6.83 (1H, brs), 7.04 (1H, d, J = 7.8 Hz), 7.27 (1 H, brs), 7.33-7.37 (5 H, m), 7.39 (2 H, d, J = 8.3 Hz), 7.79 (1 H, d, J = 8.3 Hz), 7.89 (2H, d, J = 7.8 Hz), 9.81 (1H, brs), 11.40 (1H, brs).
HR-FAB +: 399.1721 (+1.3 mmu).
<< Compound of Example 25 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.21 (3H, s), 3.58 (2H, s), 3.73 (3H, s), 3.83 (2H, s), 6.83 (1H, d, J = 5.9 Hz), 6.90 (2H, d, J = 8.3 Hz), 7.04 (1H, d, J = 6.8 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.35 (1H, t, J = 7.8 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.79 (1H, d, J = 6.8 Hz), 7.89 (2H) , D, J = 8.3 Hz), 9, 79 (1H, s), 11.40 (1H, d, J = 5.9 Hz).
HR-FAB +: 429.1812 (-0.3 mmu).
<< Compound of Example 26 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.32 (3H, s), 3.89 (2H, s), 6.82 (1H, d, J = 4.9 Hz), 7.04 (1H, d, J = 7.8 Hz) ), 7.18 (1H, t, J = 6.8 Hz), 7.23-7.30 (4H, m), 7.33-7.37 (3H, m), 7.79 (1H, d) , J = 8.8 Hz), 7.89 (2H, d, J = 7.8 Hz), 9.79 (1 H, s), 11.39 (1 H, d, J = 6.8 Hz).
HR-FAB +: 413.1878 (+1.3 mmu).
Example 27 4- [3-((N-Benzyl-N-methylamino) acetyl) phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 30 (150 mg, 403 μmol) and N-methylbenzylamine (312 μL, 2.42 mmol), 10.9 mg of the title compound as a pale yellow powder was obtained in the same manner as Reference Example 25 and then Reference Example 9. It was. Yield 7%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.20 (3H, s), 3.62 (2H, s), 3.87 (2H, s), 6.81 (1H, d, J = 4.9 Hz), 7.03 ( 1H, dd, J = 7.9, 1.2 Hz), 7.20-7.30 (6H, m), 7.35 (1H, t, J = 7.3 Hz), 7.43 (1H, t , J = 1.9 Hz), 7.53 (1H, dt, J = 7.9, 1.2 Hz), 7.80 (1H, dd, J = 7.9, 1.2 Hz), 7.83− 7.86 (2H, m), 9.73 (1H, s), 11.38 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 399.1729 (+2.0 mmu).
Example 28 1,2-Dihydro-5-hydroxy-1-oxo-4- [4-((2-phenylethyl) carbonylamino) phenyl] isoquinoline

Using the compound of Reference Example 13 (57.0 mg, 226 μmol) and 3-phenylpropionic acid (40.7 mg, 271 μmol), 48.7 mg of the title compound as a colorless powder was obtained in the same manner as in Example 14. Yield 56%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.63 (2H, t, J = 7.9 Hz), 2.93 (2H, t, J = 7.9 Hz), 6.71 (1H, d, J = 5.5 Hz), 7 .01 (1H, d, J = 7.3 Hz), 7.16-7.21 (3H, m), 7.26-7.33 (5H, m), 7.49 (2H, d, J = 8.6 Hz), 7.77 (1H, d, J = 7.9 Hz), 9.61 (1H, s), 9.89 (1H, s), 11.26 (1H, d, J = 5. 5 Hz).
HR-MS (m / z): 384.1504 (+3.0 mmu).
Example 29 1,2-Dihydro-5-hydroxy-1-oxo-4- [3-((2-phenylethyl) carbonylamino) phenyl] isoquinoline

Using the compound of Reference Example 12 (51.0 mg, 202 μmol), 42.3 mg of the title compound as a colorless powder was obtained in the same manner as in Example 28. Yield 54%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.61 (2H, t, J = 7.9 Hz), 2.90 (2H, t, J = 7.9 Hz), 6.72 (1H, d, J = 4.3 Hz), 6 .94 (1H, d, J = 7.9 Hz), 7.00 (1H, d, J = 7.3 Hz), 7.16-7.34 (7H, m), 7.46 (1H, s) 7.53 (1H, d, J = 7.9 Hz), 7.77 (1H, d, J = 7.9 Hz), 9.67 (1H, s), 9.86 (1H, s), 11 .27 (1H, s).
HR-MS (m / z): 384.1462 (-1.2 mmu).
Example 30 1,2-Dihydro-5-hydroxy-1-oxo-4- [4-methyl-3- (phenylmethylcarbonylamino) phenyl] isoquinoline

Using the compound of Reference Example 33 (55.0 mg, 207 μmol), 35.7 mg of the title compound as a colorless powder was obtained in the same manner as in Example 14. Yield 45%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.18 (3H, s), 3.66 (2H, s), 6.68 (1H, d, J = 5.5 Hz), 6.97-7.01 (2H, m), 7.10 (1H, d, J = 7.9 Hz), 7.24 (1 H, t, J = 6.7 Hz), 7.29-7.36 (6H, m), 7.76 (1H, d , J = 7.9 Hz), 9.46 (1H, s), 9.62 (1H, s), 11.25 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 385.1561 (+0.9 mmu).
Example 31 1,2-Dihydro-5-hydroxy-1-oxo-4- [4-methyl-3-((2-phenylethyl) carbonylamino) phenyl] isoquinoline

Using the compound of Reference Example 33 (55.0 mg, 207 μmol), 33.7 mg of the title compound as a colorless powder was obtained in the same manner as in Example 28. Yield 41%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.12 (3H, s), 2.65 (2H, t, J = 7.9 Hz), 2.91 (2H, t, J = 7.9 Hz), 6.69 (1H, d) , J = 4.3 Hz), 6.97 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.09 (1H, d, J = 7. 9 Hz), 7.18 (1 H, t, J = 6.7 Hz), 7.27-7.34 (6 H, m), 7.77 (1 H, d, J = 7.9 Hz), 9.22 ( 1H, s), 9.64 (1H, s), 11.26 (1H, d, J = 4.3 Hz).
HR-FAB + (m / z): 399.1715 (+0.6 mmu).
Example 32 4- [3-[(N-Benzyl-N-methylamino) methylcarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 34 and N-methylbenzylamine, the title compound as a colorless powder was obtained in the same manner as in Example 9.
¹ H-NMR (DMSO-d ₆ , Δ): 2.26 (3H, s), 3.17 (2H, s), 3.64 (2H, s), 6.74 (1H, d, J = 6.1 Hz), 6.97 ( 1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 6.7 Hz), 7.20-7.27 (2H, m), 7.31-7.40 (5H, m ), 7.56-7.58 (2H, m), 7.78 (1H, d, J = 6.7 Hz), 9.67 (1H, s), 9.68 (1H, s) 11.29. (1H, d, J = 6.1 Hz).
HR-FAB + (m / z): 414.1835 (+1.7 mmu).
Example 33 4- [3- [2- (Dimethylamino) ethylcarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 35 and a 2 mol / L dimethylamine-methanol solution, a colorless powder of the title compound was obtained in the same manner as in Example 9.
¹ H-NMR (DMSO-d ₆ , Δ): 2.16 (6H, s), 2.43 (2H, d, J = 6.7 Hz), 6.73 (1H, d, J = 5.5 Hz), 6.94 (1H, d , J = 6.7 Hz), 7.01 (1H, d, J = 7.3 Hz), 7.20 (1H, t, J = 7.9 Hz), 7.32 (1H, t, J = 7. 9 Hz), 7.48 (1 H, s), 7.52 (1 H, d, J = 7.9 Hz), 7.77 (1 H, d, J = 7.9 Hz), 9.67 (1 H, s) 9.97 (1H, s), 11.27 (1H, d, J = 6.1 Hz).
HR-FAB + (m / z): 352.1697 (+3.6 mmu).
Example 34 4- [3- [2- (N-Benzyl-N-methylamino) ethylcarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Using the compound of Reference Example 35 and N-methylbenzylamine, the title compound as a colorless powder was obtained in the same manner as in Example 9.
¹ H-NMR (DMSO-d ₆ , Δ): 2.14 (3H, s), 2.68 (2H, t, J = 6.7 Hz), 3.50 (2H, s), 6.73 (1H, d, J = 4.3 Hz). ), 6.95 (1H, d, J = 7.3 Hz), 7.01 (1H, d, J = 7.3 Hz), 7.21-7.34 (7H, m), 7.45 (1H) , S), 7.53 (1H, d, J = 7.9 Hz), 7.77 (1H, d, J = 7.9 Hz), 9.67 (1H, s), 9.99 (1H, s) ), 11.28 (1H, d, J = 4.3 Hz).
HR-FAB + (m / z): 428.1989 (+1.5 mmu).
Example 35 4- [3- (Dimethylaminocarbonylamino) phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline

Process 1 : N, N-dimethylcarbamic acid chloride (68.3 mg, 635 μmol) and triethylamine (88.5 μL, 635 μmol) were added to a solution of the compound of Reference Example 36 (141 mg, 529 μmol) in tetrahydrofuran (3 ml) at 60 ° C. Stir for 7 hours. After cooling, ethyl acetate was added, and the mixture was washed successively with 1 mol / L aqueous potassium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (2: 1 → 1: 1)] to give 4- [3- (dimethylaminocarbonylamino) phenyl] -5- pale brown powder. 73.0 mg of hydroxy-1-methoxyisoquinoline was obtained. Yield 41%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.91 (6H, s), 4.06 (3H, s), 6.88 (1H, d, J = 7.3 Hz), 7.00-7.02 (1H, m), 7.18 (1H, t, J = 7.9 Hz), 7.41-7.47 (3H, m), 7.62 (1H, s), 7.71 (1H, dd, J = 7.9) , 1.2 Hz), 8.24 (1H, s), 9.86 (1H, s).
Process 2 : 4- [3- (dimethylaminocarbonylamino) phenyl] -5-hydroxy-1-methoxyisoquinoline (70.0 mg, 207 μmol) was used in the same manner as in Example 15 to obtain 50. 5 mg was obtained. Yield 75%.
¹ H-NMR (DMSO-d ₆ , Δ): 2.91 (6H, s), 6.72 (1H, d, J = 6.1 Hz), 6.84 (1H, d, J = 7.3 Hz), 7.01 (1H, d) , J = 7.9 Hz), 7.14 (1H, t, J = 7.9 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.37 (1H, s), 7.41 (1H, d, J = 7.9 Hz), 7.77 (1H, d, J = 7.9 Hz), 8.20 (1 H, s), 9.64 (1 H, s), 11.25 (1 H , D, J = 4.9 Hz).
Anal. Calcd for C ₁₈ H ₁₇ N ₃ O ₃ ・ 1 / 5H ₂ O: C, 66.12; H, 5.36; N, 12.85.
Found: C 66.24; H, 5.37; N, 12.69.
HR-FAB + (m / z): 324.1363 (+1.5 mmu).
<Examples 36 to 39> Using the compound of Reference Example 32 or the compound of Reference Example 36, the compounds described in Table 11 below were obtained in the same manner as in Example 35.

<< Compound of Example 36 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.82-1.85 (4H, m), 6.72 (1H, d, J = 6.1 Hz), 6.83 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.13 (1H, t, J = 7.9 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.41 (1H, s) , 7.45 (1H, d, J = 7.9 Hz), 7.77 (1H, dd, J = 7.9, 1.2 Hz), 8.02 (1H, s), 9.63 (1H, s), 11.25 (1H, d, J = 6.1 Hz).
HR-FAB + (m / z): 350.1517 (+1.3 mmu).
<< Compound of Example 37 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.47-1.48 (4H, m), 1.56-1.57 (2H, m), 3.38-3.41 (4H, m), 6.72 (1H, d) , J = 5.5 Hz), 6.83 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 6.7 Hz), 7.13 (1H, t, J = 7. 9 Hz), 7.32 (1 H, t, J = 7.9 Hz), 7.37 (1 H, s), 7.41 (1 H, d, J = 7.9 Hz), 7.77 (1 H, d, J = 7.3 Hz), 8.37 (1 H, s), 9.64 (1 H, s), 11.25 (1 H, d, J = 6.1 Hz).
HR-FAB + (m / z): 364.1643 (-1.8 mmu).
<< Compound of Example 38 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.19 (3H, s), 2.91 (6H, s), 6.69 (1H, s), 6.93 (1H, d, J = 7.3 Hz), 7.02 ( 1H, d, J = 7.3 Hz), 7.07 (1H, d, J = 7.9 Hz), 7.16 (1H, s), 7.32 (1H, t, J = 7.9 Hz), 7.72 (1H, s), 7.77 (1H, d, J = 7.9 Hz), 9.60 (1H, s), 11.25 (1H, s).
HR-FAB + (m / z): 338.1491 (-1.4 mmu).
<< Compound of Example 39 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.85 (4H, s), 2.21 (3H, s), 6.67 (1H, d, J = 6.1 Hz), 6.92 (1H, d, J = 7.3 Hz). ), 7.02 (1H, d, J = 7.9 Hz), 7.07 (1H, d, J = 7.3 Hz), 7.25 (1H, s), 7.32 (1H, t, J = 7.9 Hz), 7.45 (1H, s), 7.77 (1H, d, J = 7.9 Hz), 9.57 (1H, s), 11.24 (1H, d, J = 6) .1 Hz).
HR-FAB + (m / z): 364.1667 (+0.6 mmu).
<Examples 40 to 44> Using the compound of Reference Example 32 or the compound of Reference Example 36, the compounds shown in Table 12 below were obtained in the same manner as Reference Example 16 and then Example 15.

<< Compound of Example 40 >>
¹ H-NMR (DMSO-d ₆ , Δ): 0.86 (3H, t, J = 7.3 Hz), 1.38-1.47 (2H, m), 2.99-3.04 (2H, m), 6.09 (1H , T, J = 5.5 Hz), 6.72 (1H, d, J = 4.3 Hz), 6.80 (1H, d, J = 7.9 Hz), 7.00 (1H, d, J = 7.9 Hz), 7.13 (1 H, t, J = 7.9 Hz), 7.27-7.34 (3 H, m), 7.76 (1 H, d, J = 7.9 Hz), 8. 34 (1H, s), 9.63 (1H, brs), 11.24 (1H, d, J = 4.3 Hz).
Anal. Calcd for C ₁₉ H ₁₉ N ₃ O ₃ ・ 1 / 5H ₂ O: C, 66.93; H, 5.73; N, 12.32.
Found: C, 66.99; H, 5.53; N, 12.17.
HR-FAB + (m / z): 338.1493 (-1.2 mmu).
<< Compound of Example 41 >>
¹ H-NMR (DMSO-d ₆ , Δ): 6.77 (1H, d, J = 6.1 Hz), 7.02-7.05 (2H, m), 7.12 (1H, t, J = 7.3 Hz), 7.25 (1H, t, J = 7.3 Hz), 7.31-7.35 (3H, m), 7.38 (1H, s), 7.44-7.48 (3H, m), 7.78 (1H, dd, J = 7.9, 1.2 Hz), 9.71 (1H, s), 9.73 (1H, s), 9.82 (1H, s), 11.30 (1H, d , J = 6.1 Hz).
HR-FAB + (m / z): 388.111 (-0.9 mmu).
<< Compound of Example 42 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.27 (3H, s), 6.71 (1H, d, J = 6.1 Hz), 6.86 (1H, d, J = 7.3 Hz), 6.94 (1H, t , J = 7.9 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.09 (1H, d, J = 7.9 Hz), 7.26 (2H, t, J = 7. 9 Hz), 7.32 (1 H, t, J = 7.9 Hz), 7.43 (2 H, d, J = 7.9 Hz), 7.78 (1 H, d, J = 7.9 Hz), 7. 79 (1H, s), 7.91 (1H, s), 9.01 (1H, s), 9.60 (1H, s), 11.25 (1H, d, J = 5.5 Hz).
HR-FAB + (m / z): 386.1550 (+4.5 mmu).
<< Compound of Example 43 >>
¹ H-NMR (DMSO-d ₆ , Δ): 0.87 (3H, t, J = 7.3 Hz), 1.38-1.47 (2H, m), 2.19 (3H, s), 2.99-3.04 (2H) M), 6.52 (1H, t, J = 5.5 Hz), 6.68 (1H, d, J = 5.5 Hz), 6.78 (1H, dd, J = 7.3, 1.. 2Hz), 6.99-7.03 (2H, m), 7.31 (1H, t, J = 7.3 Hz), 7.56 (1H, s), 7.76-7.78 (2H, m), 9.55 (1H, s), 11.23 (1H, d, J = 6.1 Hz).
HR-FAB + (m / z): 352.1623 (-3.8 mmu).
<< Compound of Example 44 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.27 (3H, s), 6.74 (1H, d, J = 4.9 Hz), 7.02-7.17 (4H, m), 7.20 (1H, s), 7.30-7.34 (3H, m), 7.48 (2H, d, J = 7.9 Hz), 7.78 (1H, d, J = 7.2 Hz), 9.38 (1H, s ), 9.55 (1H, s), 9.63 (1H, s), 11.27 (1H, d, J = 5.5 Hz).
HR-FAB + (m / z): 402.287 (+1.1 mmu).
<Examples 45 to 49> Using the compound of Reference Example 38 or the compound of Reference Example 43, the compounds shown in Table 13 below were obtained in the same manner as in Reference Example 16 and then Example 15.

<< Compound of Example 45 >>
¹ H-NMR (DMSO-d ₆ , Δ): 4.32 (2H, d, J = 6.1 Hz), 6.62 (1H, t, J = 6.1 Hz), 6.71 (1H, d, J = 6.1 Hz), 6 .89 (1H, t, J = 7.3 Hz), 7.00 (1H, d, J = 7.3 Hz), 7.21-7.25 (6H, m), 7.32 (1H, t, J = 7.9 Hz), 7.41 (2H, d, J = 7.9 Hz), 7.77 (1H, dd, J = 7.9, 1.2 Hz), 8.56 (1H, s), 9.62 (1H, s), 11.28 (1H, d, J = 6.1 Hz).
HR-FAB + (m / z): 386.1499 (-0.5 mmu).
<< Compound of Example 46 >>
¹ H-NMR (DMSO-d ₆ , Δ): 0.85 (3H, t, J = 7.3 Hz), 1.37-1.42 (2H, m), 2.95-3.00 (2H, m), 4.22 (2H) , D, J = 6.1 Hz), 5.93 (1H, t, J = 6.1 Hz), 6.29 (1H, t, J = 6.1 Hz), 6.70 (1H, d, J = 5.5 Hz), 7.00 (1 H, d, J = 7.9 Hz), 7.14-7.21 (4 H, m), 7.32 (1 H, t, J = 7.9 Hz), 7. 77 (1H, d, J = 7.9 Hz), 9.62 (1H, s), 11.27 (1H, d, J = 5.5 Hz).
HR-MS (m / z): 351.1599 (+1.6 mmu).
<< Compound of Example 47 >>
¹ H-NMR (DMSO-d ₆ , Δ): 4.77 (2H, d, J = 5.5 Hz), 6.72 (1H, d, J = 5.5 Hz), 7.01 (1H, dd, J = 7.9, 1.). 2 Hz), 7.12 (1H, t, J = 7.3 Hz), 7.23-7.28 (4H, m), 7.30-7.36 (3H, m), 7.45 (1H, d, J = 7.9 Hz), 7.78 (1H, dd, J = 7.9, 1.2 Hz), 8.19 (1H, brs), 9.64 (2H, s), 11.29 ( 1H, d, J = 6.2 Hz).
HR-FAB + (m / z): 402.1310 (+3.4 mmu).
<< Compound of Example 48 >>
¹ H-NMR (DMSO-d ₆ , Δ): 4.31 (2H, d, J = 5.5 Hz), 6.61 (1H, t, J = 5.5 Hz), 6.71 (1H, d, J = 4.3 Hz), 6 .87 (1H, t, J = 7.3 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.13-7.26 (6H, m), 7.31 (1H, t, J = 7.9 Hz), 7.37 (2H, d, J = 8.5 Hz), 7.76 (1H, d, J = 7.9 Hz), 8.54 (1 H, s), 9.70 ( 1H, brs), 11.28 (1H, brs).
HR-FAB + (m / z): 386.1497 (-0.9 mmu).
<< Compound of Example 49 >>
¹ H-NMR (DMSO-d ₆ , Δ): 0.81 (3H, t, J = 7.3 Hz), 1.34-1.39 (2H, m), 2.93-2.98 (2H, m), 4.22 (2H , D, J = 5.5 Hz), 5.90-5.92 (1H, m), 6.24-6.27 (1H, m), 6.70 (1H, s), 7.01 (1H) , D, J = 7.3 Hz), 7.12-7.14 (3H, m), 7.23 (1H, t, J = 7.9 Hz), 7.32 (1H, t, J = 7. 9 Hz), 7.77 (1 H, d, J = 7.9 Hz), 9.65 (1 H, brs), 11.29 (1 H, brs).
HR-FAB + (m / z): 352.1666 (+0.5 mmu).
<Examples 50 to 52> The compounds shown in Table 14 below were obtained in the same manner as in Example 35 using the compound of Reference Example 43.

<< Compound of Example 50 >>
¹ H-NMR (DMSO-d ₆ , Δ): 2.80 (6H, s), 4.25 (2H, d, J = 5.5 Hz), 6.70 (1H, d, J = 6.1 Hz), 6.83 (1H, t , J = 5.5 Hz), 7.02 (1H, d, J = 7.3 Hz), 7.10-7.16 (3H, m), 7.21 (1H, t, J = 7.9 Hz) , 7.33 (1H, t, J = 7.9 Hz), 7.78 (1H, d, J = 7.9 Hz), 9.63 (1H, s), 11.27 (1H, d, J = 5.5 Hz).
HR-FAB + (m / z): 338.1485 (-2.0 mmu).
<< Compound of Example 51 >>
¹ H-NMR (DMSO-d ₆ , Δ): 3.17 (3H, s), 4.24 (2H, d, J = 6.1 Hz), 6.53 (1H, t, J = 6.1 Hz), 6.70 (1H, d) , J = 6.1 Hz), 7.02 (1H, dd, J = 7.9, 1.2 Hz), 7.10-7.14 (3H, m), 7.19-7.24 (2H, m), 7.26 (2H, dd, J = 6.1, 1.2 Hz), 7.34 (3H, q, J = 7.9 Hz), 7.78 (1H, dd, J = 7.9). , 1.2 Hz), 9.64 (1 H, s), 11.29 (1 H, d, J = 6.1 Hz).
HR-FAB + (m / z): 400.1687 (+2.6 mmu).
<< Compound of Example 52 >>
¹ H-NMR (DMSO-d ₆ , Δ): 1.40 (4H, brs), 1.49-1.53 (2H, m), 3.27-3.30 (4H, m), 4.25 (2H, d, J = 6) .1 Hz), 6.69 (1 H, t, J = 5.5 Hz), 6.97 (1 H, t, J = 5.5 Hz), 7.01 (1 H, d, J = 7.9 Hz), 7 .12 (2H, t, J = 7.3 Hz), 7.15 (1H, s), 7.22 (1H, t, J = 7.3 Hz), 7.32 (1H, t, J = 7. 9 Hz), 7.77 (1 H, d, J = 7.9 Hz), 9.63 (1 H, s), 11.28 (1 H, d, J = 5.5 Hz).
HR-FAB + (m / z): 400.1687 (+2.6 mmu).
<Test Example> Inhibition experiment on PARP activity
PARP (Trevigen 4667-050-01) was diluted 35-fold with a buffer consisting of 50 mmol / L Tris-HCl (pH 7.8), 100 mmol / L KCl and 1 mmol / L dithiothreitol and used in the experiment.
117.6 mmol / L Tris-HCl (pH 8.0), 11.8 mmol / L MgCl ₂ 76.5 μL of a buffer consisting of 5.9 mmol / L dithiothreitol and 0.4 mmol / L NAD, [ ¹⁴ C] 2.5 μL of NAD (NEN Life Science Products, Inc. NEC743, 370 kBq / mL), 1 μL of activated DNA (Trevigen 4667-50-06), 10 μL of test compound or test compound solvent and 10 μL of 35-fold diluted PARP solution After putting in a plastic test tube and mixing well, it was heated to 25 ° C. in a water bath. After 10 minutes, the reaction was stopped by adding 1 mL of ice-cold 20% trichloroacetic acid, and the test tube was left on ice overnight. The precipitate was collected on a glass fiber filter by suction filtration and washed 5 times with 5% trichloroacetic acid. Radioactivity on the filter was measured with a liquid scintillation counter. The concentration of the test compound that reduces the enzyme activity in the absence of the test compound to 100% and reduces it to 50% (IC ₅₀ Value).

From the above results, it was confirmed that the novel 4-substituted aryl-5-hydroxyisoquinolinone of the present invention has excellent PARP inhibitory activity.
Industrial applicability
From the above, the novel 4-substituted aryl-5-hydroxyisoquinolinone of the present invention exhibits excellent PARP inhibitory activity.
A compound having PARP inhibitory activity is a disease caused by excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple diseases) It is useful as a preventive and / or therapeutic agent for encephalopathy, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma and the like.

Claims (14)

General formula (1)

[Wherein R ¹ represents a hydrogen atom or a halogen atom,
R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, or a lower alkoxy group that may be substituted with a halogen atom;
Ring Ar represents a phenyl group, a naphthyl group, or a 5- or 6-membered heterocyclic ring and a condensed ring thereof,
A represents a single bond or a _C 1 -C ₃ alkylene,
X represents a single bond, an oxygen atom or NR ⁴ ;
R ⁴ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Y represents an oxygen atom or a sulfur atom,
R ³ represents the general formula (2)

(Wherein R ⁵ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ has a lower alkyl group which may be substituted with a halogen atom, a lower alkyl group substituted with a hydroxyl group, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or a substituent. A 5-membered or 6-membered heterocyclic ring or a condensed ring thereof, or a 5-membered or 6-membered heterocyclic ring which may be bonded to each other by R ⁵ and R ⁶ and a substituent thereof Represents a condensed ring) or represented by the general formula (3)

(Wherein Q ¹ represents a single bond or NR ⁸ ;
R ⁸ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² represents C ₁ -C ₆ alkylene,
R ⁷ represents a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, or a phenyl group that may have a substituent. A naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ and R ^10. Represents a 5-membered or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))
A 4-substituted aryl-5-hydroxyisoquinolinone derivative represented by the formula: and a pharmacologically acceptable addition salt thereof. General formula (1a)

[Wherein R ¹ represents a hydrogen atom or a halogen atom,
R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, or a lower alkoxy group that may be substituted with a halogen atom;
A represents a single bond or a _C 1 -C ₃ alkylene,
X represents a single bond, an oxygen atom or NR ⁴ ;
R ⁴ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Y represents an oxygen atom or a sulfur atom,
R ³ represents the general formula (2)

(Wherein R ⁵ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. A 5-membered or 6-membered heterocyclic ring and a condensed ring thereof, or a 5-membered or 6-membered heterocyclic ring which may be bonded together by R ⁵ and R ⁶ and a substituent thereof; Represents a condensed ring) or represented by the general formula (3)

(Wherein Q ¹ represents a single bond or NR ⁸ ;
R ⁸ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² represents C ₁ -C ₆ alkylene,
R ⁷ represents a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, or a phenyl group that may have a substituent. A naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ and R ^10. Represents a 5-membered or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))
The 4-substituted aryl-5-hydroxyisoquinolinone derivative of Claim 1 represented by these, and its pharmacologically acceptable addition salt. General formula (1b)

[Wherein R ^1a represents a hydrogen atom,
R ^2a represents a hydrogen atom,
A ^a represents ^a single bond,
X ^a represents a single bond or NR ⁴ ,
R ⁴ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Y ^a represents an oxygen atom,
R ³ represents the general formula (2)

(Wherein R ⁵ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. A 5-membered or 6-membered heterocyclic ring and a condensed ring thereof, or a 5-membered or 6-membered heterocyclic ring which may be bonded together by R ⁵ and R ⁶ and a substituent thereof; Represents a condensed ring) or represented by the general formula (3)

(Wherein Q ¹ represents a single bond or NR ⁸ ;
R ⁸ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² represents C ₁ -C ₆ alkylene,
R ⁷ represents a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, or a phenyl group that may have a substituent. A naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ and R ^10. Represents a 5-membered or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))
The 4-substituted aryl-5-hydroxyisoquinolinone derivative of Claim 1 represented by these, and its pharmacologically acceptable addition salt. General formula (1c)

[Wherein R ^1a represents a hydrogen atom,
R ^2a represents a hydrogen atom,
A ^a represents ^a single bond,
X ^b represents NR ^4a ,
R ^4a represents a hydrogen atom,
Y ^a represents an oxygen atom,
R ^3a is represented by the general formula (2)

(Wherein R ⁵ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. A 5-membered or 6-membered heterocyclic ring and a condensed ring thereof, or a 5-membered or 6-membered heterocyclic ring which may be bonded together by R ⁵ and R ⁶ and a substituent thereof; Represents a condensed ring)]
The 4-substituted aryl-5-hydroxyisoquinolinone derivative of Claim 1 represented by these, and its pharmacologically acceptable addition salt. General formula (1d)

[Wherein R ^1a represents a hydrogen atom,
R ^2a represents a hydrogen atom,
A ^a represents ^a single bond,
X ^b represents NR ^4a ,
R ^4a represents a hydrogen atom,
Y ^a represents an oxygen atom,
R ^3b represents the general formula (3a)

( ^Wherein Q ^1a represents a single bond,
Q ² represents C ₁ -C ₆ alkylene,
R ⁷ represents a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, or a phenyl group that may have a substituent. A naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ and R ^10. Represents a 5-membered or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))
The 4-substituted aryl-5-hydroxyisoquinolinone derivative of Claim 1 represented by these, and its pharmacologically acceptable addition salt. General formula (1e)

[Wherein R ^1a represents a hydrogen atom,
R ^2a represents a hydrogen atom,
A ^a represents ^a single bond,
X ^c represents a single bond,
Y ^a represents an oxygen atom,
R ^3c represents the general formula (2)

(Wherein R ⁵ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
R ⁶ has a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxyl group, a phenyl group that may have a substituent, a naphthyl group that may have a substituent, or a substituent. A 5-membered or 6-membered heterocyclic ring and a condensed ring thereof, or a 5-membered or 6-membered heterocyclic ring which may be bonded together by R ⁵ and R ⁶ and a substituent thereof; Represents a condensed ring) or represented by the general formula (3b)

(Wherein Q ^1b represents NR ⁸ ;
R ⁸ represents a lower alkyl group which may be substituted with a hydrogen atom or a halogen atom,
Q ² represents C ₁ -C ₆ alkylene,
R ⁷ represents a hydroxyl group, a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkoxycarbonyl group, a carboxy group, a cyclic alkyl group that may have a substituent, or a phenyl group that may have a substituent. A naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, or the general formula (4)

(Wherein R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or an aralkyl group which may have a substituent, or R ⁹ and R ^10. Represents a 5-membered or 6-membered heterocyclic ring optionally having a substituent and a condensed ring thereof))
The 4-substituted aryl-5-hydroxyisoquinolinone derivative of Claim 1 represented by these, and its pharmacologically acceptable addition salt. The compound represented by the general formula (1) is 1,2-dihydro-5-hydroxy-4- [4- (N-methylcarbamoyl) phenyl] -1-oxoisoquinoline, 1,2-dihydro-4- [4. -[2- (Pyrrolidin-1-yl) ethylcarbonylamino] phenyl] -5-hydroxy-1-oxoisoquinoline, 1,2-dihydro-5-hydroxy-1-oxo-4- [4- (phenylaminocarbonyl) The compound according to claim 1, which is amino) phenyl] isoquinoline or 4- [4-[(4-carboxyphenyl) aminocarbonylamino] phenyl] -1,2-dihydro-5-hydroxy-1-oxoisoquinoline. A poly (characteristic) comprising one or more 4-substituted aryl-5-hydroxyisoquinolinone derivatives according to any one of claims 1 to 7 and pharmacologically acceptable addition salts thereof as active ingredients. (ADP-ribose) synthase inhibitor. A pharmaceutical comprising one or more of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. It contains at least one of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. A prophylactic and / or therapeutic agent for blood diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.). An inflammation comprising at least one of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. Preventive and / or therapeutic agents for sexual diseases (inflammatory bowel disease, multiple encephalopathy, arthritis, rheumatoid arthritis, etc.). A nerve comprising one or more of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. A preventive and / or therapeutic agent for degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.). Diabetes comprising at least one of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. And a preventive and / or therapeutic agent for its complications. A head comprising at least one of the 4-substituted aryl-5-hydroxyisoquinolinone derivative according to any one of claims 1 to 7 and a pharmacologically acceptable addition salt thereof as an active ingredient. A treatment for trauma.