JP2004210772A - Jnk inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel medicine having JNK inhibition action. <P>SOLUTION: The novel medicine having the JNK inhibition action comprises a compound represented by formula (I) (wherein the ring A is a substitutable benzene ring; R<SP>1</SP>is a substitutable cyclic hydrocarbon group or a substitutable heterocyclic group; R<SP>2</SP>is a hydrogen atom, a hydrocarbon group which may be substituted with a substitutable hydroxyl group, a cyano group, an acyl group, a carboxyl group which may be esterified, a substitutable carbamoyl group or a substitutable amino group; X is a substitutable bivalent chain hydrocarbon group; and Y is a substitutable nonaromatic hydrocarbon group, a substitutable heterocyclic group, a substitutable hydroxyl group or a substitutable amino group) or its salt. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention relates to a c-Jun N-terminal kinase (c-Jun N-terminal kinase (JNK)) inhibitor having an isoquinolinone skeleton useful as a medicament, a novel isoquinolinone derivative having a JNK inhibitory activity, and use thereof.

Mammalian cells respond to extracellular stimuli by activating a signal cascade through mitogen-activated protein kinase (MAPK) family members. There are three types of MAPKs: c-Jun N-terminal kinase (JNK) (also known as stress-activated protein kinase (SAPK)), p38 MAP kinase, extracellular signal regulated kinase (ERK), growth factors, cytokines, and ultraviolet irradiation. And is activated by various signals such as stress inducers. Since MAPK is a serine / threonine kinase, it is activated by phosphorylation of both the threonine and tyrosine of the Thr-X-Tyr sequence in the activation loop. MAPK regulates the expression of specific genes by phosphorylating and activating various transcription factors, and mediates specific responses to extracellular stimuli.
Three genes, jnk1, jnk2 and jnk3, have been identified in JNK, and at least 10 isoforms exist in mammals (see Non-Patent Document 1). JNK1 and jnk2 are expressed in many tissues, but since jnk3 is specifically expressed in the brain, JNK3 may be particularly involved in neuronal functions. The JNK signaling system of the stress-responsive MAP kinase family is activated by osmotic changes, DNA damage, anisomycin, heat shock, ultraviolet irradiation, ischemia, inflammatory cytokines, and various stress stimuli related to apoptosis induction. Therefore, it is considered to constitute a main intracellular information transmission pathway that is responsible for the stress response (see Non-Patent Document 2). Activated JNK activates various transcription factors such as c-Jun, ATF-2, Elk1, p53 and cell death domain protein (DENN), and cell death (apoptosis) signal to activate transcription activity of a specific gene. It regulates or induces apoptosis and responds to environmental changes such as various stresses (see Non-Patent Document 3). JNK activation is seen in various pathological conditions and diseases such as cancer, cell death, allergy, asthma, heart disease, autoimmune disease, ischemic disease, inflammation, and neurodegenerative disease. Has been suggested to be closely related to the onset and exacerbation of these diseases. [In the present specification, such a disease state or disease in which JNK activation is involved is referred to as “JNK-related disease state or disease”. ]
As a relationship between JNK and various JNK-related pathologies or diseases, it is known that, for example, in cardiomyocytes, JNK is activated by stretching stimulation or ischemia, and transmits a stress signal. JNK is also activated by catecholamine, angiotensin II and endothelin, and regulates the expression of factors (BNP / ANP, TNF-α, TGF-β, MMPs, etc.) involved in cardiac hypertrophy and fibrosis (Non-patented) References 4 to 6). Recently, after the onset of myocardial infarction, it has been reported that cardiac JNK activity in heart failure patients has increased and that mice overexpressing MKK7 (JNK-selective kinase) heart exhibit heart failure. Has been suggested (see Non-Patent Document 7). Also, it has been reported that JNK inhibition by dominant negative suppresses cardiac hypertrophy without affecting blood pressure in a pressure overload cardiac hypertrophy model (see Non-Patent Document 8). Furthermore, it has been reported that in an ischemia / reperfusion model, dominant negative MKK7 reduces JNK activity and suppresses cardiomyocyte death. Thus, inhibitors of JNK may be effective in treating ischemic heart disease, heart failure, prognosis of myocardial infarction and cardiac hypertrophy.
JNK plays an important role in T-cell activation by activating the IL-2 promoter. Recent experiments using knockout mice have reported that JNK also plays an important role in the differentiation of Th1 and Th2 cells. Therefore, inhibitors of JNK may be effective in treating pathological immune diseases (see Non-Patent Documents 9 to 13).
JNK is activated in synovial cells of rheumatic patients and JNK regulates the expression of MMP gene in IL-1 stimulated synovial cells, so JNK is greatly involved in joint destruction in rheumatic patients (See Non-Patent Document 14). This suggests that inhibitors of JNK may be effective in treating rheumatism.
In JNK3 knockout mice, JNK3 plays an important role in the expression of glutamate-type neurotoxicity, since it resists apoptosis of nerve cells due to the administration of a large amount of kainate (see Non-Patent Document 15). JNK3 is also activated in hypoxic or ischemic neurons to cause apoptosis. From these facts, inhibitors of JNK may be effective in treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease or ischemia and hemorrhagic stroke.
In addition, experiments using JNK1-deficient mice have reported that JNK is an important mediator related to obesity and insulin resistance (see Non-Patent Document 16).
Heretofore, compounds having JNK inhibitory activity include, for example, indolinone derivatives in Patent Documents 1, 2 and 3, uracil derivatives in Patent Document 4, isoxazole derivatives in Patent Document 5, and thiophene sulfonamide derivatives in Patent Document 6. In addition, Patent Document 9 discloses a pyrazoloanthrone derivative, and Patent Document 10 discloses a pyrimidylimidazole derivative. However, an isoquinolinone derivative having a JNK inhibitory action has been reported only in Patent Document 11 so far.
On the other hand, isoquinolinone derivatives are disclosed in Patent Documents 12 to 19 and the like.

International Publication No. 99/35906 pamphlet WO 99/35909 pamphlet International Publication No. 99/35921 pamphlet WO 00/75118 pamphlet International Publication No. 01/12621 pamphlet International Publication No. 01/23378 pamphlet International Publication No. 01/23379 pamphlet International Publication No. 01/23382 pamphlet International Publication No. 01/12609 pamphlet International Publication No. 01/91749 pamphlet International Publication No. 03/068750 pamphlet JP-A-10-298164 JP-A-2000-72675 JP 2000-72751 A JP-A-5-132463 JP-A-6-321906 JP-A-7-010844 JP-A-7-076573 WO 02/062764 pamphlet "EMBO Journal, 1996, Volume 15, p.2760-2770" "Biochemica et Biophysica Acta, 1997, Vol. 1333, p.F85-F104" "Proceedings of the National Academy of Sciences of the United States of America, 1998, Vol. 95, p.2586-2591" "Journal of Biological Chemistry, Vol. 270, p. 29710-29717" "FASEB Journal, 1996, Volume 10, p.631-636" "Circulation Research, 1997, Volume 80, pp. 139-146" `` Journal of Molecular and Cellular Cardiology, 1999, Vol. 31, p. 1429-1434 '' "Journal of Clinical Investigation, 1999, Vol. 104, p.391-398" "Journal of Immunology, 1999, Volume 162, p.3176-3187" "European Journal of Immunology, 1998, Vol. 28, p. 3867-3877" "Journal of Experimental Medicine, 1997, Volume 186, p.941-953" `` European Journal of Immunology, 1996, Volume 26, p. 989-994 '' `` Current Biology, 1999, Volume 9, p.116-125 '' "Journal of Clinical Investigation, 2001, Volume 108, p.73-81" "Nature, 1997, Vol. 389, p.865-870" "Nature, 2002, Volume 420, p.333-336"

  Compounds having the above-mentioned JNK inhibitory activity do not always have a sufficient JNK inhibitory activity and have insufficient selectivity with respect to other kinase inhibitory activities. Therefore, safety problems such as efficacy and risk of side effects remain. ing. In addition, physical properties (stability, solubility, etc.), oral absorption and transferability to target organs are not sufficient, so that it cannot be said that practically satisfactory results have been obtained as pharmaceuticals, and JNK-related disease states or There is a great need for the development of JNK inhibitors which are excellent as effective medicaments for diseases.

The present invention provides a useful and safe JNK inhibitor as a prophylactic or therapeutic agent for a JNK-related disease state or disease.
The present inventors have conducted various studies and found that a compound having an isoquinolinone skeleton or a salt thereof has unexpectedly excellent JNK-specific inhibitory activity based on its specific chemical structure, and is more stable. It also has excellent properties in terms of physical properties such as pharmacology, and has been found to be a safe and useful drug as a preventive and therapeutic drug for preventing and treating JNK-related pathologies or diseases in mammals. The present invention has been completed.

〔式中、環Ａは置換されていてもよいベンゼン環を示し、Ｒ^１は置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基を示し、Ｒ^２は水素原子、置換されていてもよいヒドロキシ基で置換されていてもよい炭化水素基、シアノ基、アシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｘは置換されていてもよい二価の鎖状の炭化水素基を示し、Ｙは置換されていてもよい非芳香族炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基または置換されていてもよいアミノ基を示す。〕で表される化合物若しくはその塩又はそのプロドラッグを含有することを特徴とするＪＮＫ阻害剤；
（２）式（Ｉ）

〔式中、環Ａは置換されていてもよいベンゼン環を示し、Ｒ^１は置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基を示し、Ｒ^２は水素原子、置換されていてもよいヒドロキシ基で置換されていてもよい炭化水素基、シアノ基、アシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｘは置換されていてもよい二価の鎖状の炭化水素基を示し、Ｙは置換されていてもよい非芳香族炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基または置換されていてもよいアミノ基を示す。〕で表される化合物（但し、2-ベンジル-6,7-ジクロロ-4-ヒドロキシ-1-オキソ-1,2-ジヒドロ-3-イソキノリンカルボン酸 エチルエステル、2-ベンジル-4-ブトキシ-6,7-ジクロロ-1-オキソ-1,2-ジヒドロ-3-イソキノリンカルボン酸 エチルエステル、2-ベンジル-4-ブトキシ-6,7-ジクロロ-1-オキソ-1,2-ジヒドロ-3-イソキノリンカルボン酸および2-ベンジル-4-ブトキシ-6,7-ジクロロ-3-ヒドロキシメチル-1(2H)-イソキノリノンを除く）又はその塩；
（３）環Ａが式

〔式中、Ｒ^３は水素原子、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいチオール基、置換スルフィニル基、置換スルホニル基、置換されていてもよいアミノ基、置換されていてもよいカルバモイル基またはエステル化されていてもよいカルボキシル基を示す。〕で表されるベンゼン環である前記（２）記載の化合物；
（４）Ｒ^３が水素原子、ハロゲン原子、置換されていてもよいアルキル基または置換されていてもよいアミノ基である前記（３）記載の化合物；
（５）Ｒ^３が水素原子、ハロゲン原子またはＣ_１−４アルキル基である前記（３）記載の化合物；
（６）Ｒ^１が置換されていてもよいフェニルである前記（２）記載の化合物；
（７）Ｘがメチレンである前記（２）記載の化合物；
（８）Ｙが置換されていてもよい非芳香族炭化水素基である前記（２）記載の化合物；
（９）Ｙが置換されていてもよい鎖状の炭化水素基である前記（２）記載の化合物；
（１０）Ｙが置換されていてもよいＣ_２−６アルケニルである前記（２）記載の化合物；
（１１）Ｙが置換されていてもよい複素環基である前記（２）記載の化合物；
（１２）Ｙが置換されていてもよい５または６員の芳香族複素環基である前記（２）記載の化合物；
（１３）Ｙが置換されていてもよいヒドロキシ基である前記（２）記載の化合物；
（１４）Ｙが置換されていてもよい炭化水素基で置換されたヒドロキシ基である前記（２）記載の化合物；
（１５）Ｙが置換されていてもよいアミノ基である前記（２）記載の化合物；
（１６）Ｙが環状アミノ基である前記（２）記載の化合物；
（１７）Ｒ^２がエステル化されていてもよいカルボキシル基または置換されていてもよいカルバモイル基である前記（２）記載の化合物；
（１８）Ｒ^２が低級アルコキシカルボニルである前記（２）記載の化合物；
（１９）Ｒ^２がアシル基、置換されていてもよいヒドロキシ基で置換されていてもよい炭化水素基または置換されていてもよいアミノ基である前記（２）記載の化合物；
（２０）6-クロロ-4-(2-ヒドロキシメチルチオフェン-3-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル、2-(4-カルボキシベンジル)-6-クロロ-4-(3-ヒドロキシメチルチオフェン-2-イル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチル エステルもしくは2-(4-メタンスルホニルベンジル)-1-オキソ-4-(ピペリジン-1-イル)-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステルまたはそれらの塩；
（２１）前記（２）記載の化合物のプロドラッグ；
（２２）前記（２）または（２１）記載の化合物を含有することを特徴とする医薬；
（２３）ＪＮＫ関連病態または疾患の予防・治療剤である前記（１）記載の剤；
（２４）ＪＮＫ関連病態または疾患が、循環器系疾患、炎症性疾患、神経変性疾患または糖尿病である前記（２３）記載の剤；
（２５）慢性もしくは急性心不全、心肥大、拡張型、肥大型もしくは拘束型心筋症、急性冠症候群、慢性虚血性心疾患、急性もしくは慢性心筋炎、左心拡張能不全、左心収縮不全、高血圧症とそれに合併した腎症・腎炎、血管内皮機能低下、動脈硬化症、血管形成術後再狭窄の予防・治療剤または心筋梗塞予後の改善剤である前記（１）記載の剤；
（２６）式（Ｉ）

〔式中、環Ａは置換されていてもよいベンゼン環を示し、Ｒ^１は置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基を示し、Ｒ^２は水素原子、置換されていてもよいヒドロキシ基で置換されていてもよい炭化水素基、シアノ基、アシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｘは置換されていてもよい二価の鎖状の炭化水素基を示し、Ｙは置換されていてもよい非芳香族炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基または置換されていてもよいアミノ基を示す。〕で表される化合物若しくはその塩又はそのプロドラッグの有効量を哺乳動物に投与することを特徴とする哺乳動物におけるＪＮＫの阻害方法；
（２７）ＪＮＫ阻害剤の製造のための式（Ｉ）

〔式中、環Ａは置換されていてもよいベンゼン環を示し、Ｒ^１は置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基を示し、Ｒ^２は水素原子、置換されていてもよいヒドロキシ基で置換されていてもよい炭化水素基、シアノ基、アシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｘは置換されていてもよい二価の鎖状の炭化水素基を示し、Ｙは置換されていてもよい非芳香族炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基または置換されていてもよいアミノ基を示す。〕で表される化合物若しくはその塩又はそのプロドラッグの使用；などに関するものである。 That is, the present invention
(1) Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. A JNK inhibitor comprising a compound represented by the formula: or a salt thereof or a prodrug thereof;
(2) Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. (However, 2-benzyl-6,7-dichloro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6 , 7-Dichloro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinoline Carboxylic acid and 2-benzyl-4-butoxy-6,7-dichloro-3-hydroxymethyl-1 (2H) -isoquinolinone) or a salt thereof;
(3) Ring A has the formula

[Wherein, R ³ represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally substituted It represents a good thiol group, substituted sulfinyl group, substituted sulfonyl group, optionally substituted amino group, optionally substituted carbamoyl group or optionally esterified carboxyl group. A compound according to the above (2), which is a benzene ring represented by the formula:
(4) The compound according to the above (3), wherein R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group or an optionally substituted amino group;
(5) The compound according to (3), wherein R ³ is a hydrogen atom, a halogen atom or a C _1-4 alkyl group;
(6) The compound according to the above (2), wherein R ¹ is an optionally substituted phenyl;
(7) The compound according to the above (2), wherein X is methylene;
(8) The compound according to the above (2), wherein Y is an optionally substituted non-aromatic hydrocarbon group;
(9) The compound according to the above (2), wherein Y is an optionally substituted chain hydrocarbon group;
(10) The compound according to the above (2), wherein Y is C _2-6 alkenyl which may be substituted;
(11) The compound according to the above (2), wherein Y is an optionally substituted heterocyclic group;
(12) The compound according to the above (2), wherein Y is an optionally substituted 5- or 6-membered aromatic heterocyclic group;
(13) The compound according to the above (2), wherein Y is an optionally substituted hydroxy group;
(14) The compound according to the above (2), wherein Y is a hydroxy group substituted with an optionally substituted hydrocarbon group;
(15) The compound according to the above (2), wherein Y is an amino group which may be substituted;
(16) The compound according to the above (2), wherein Y is a cyclic amino group;
(17) The compound according to the above (2), wherein R ² is a carboxyl group which may be esterified or a carbamoyl group which may be substituted;
(18) The compound according to the above (2), wherein R ² is lower alkoxycarbonyl;
(19) The compound according to the above (2), wherein R ² is an acyl group, a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, or an amino group which may be substituted;
(20) 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester, 2 -(4-carboxybenzyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or 2- (4-methane Sulfonylbenzyl) -1-oxo-4- (piperidin-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or a salt thereof;
(21) a prodrug of the compound according to (2);
(22) a medicament comprising the compound according to (2) or (21);
(23) the agent according to (1), which is a prophylactic / therapeutic agent for a JNK-related disease state or disease;
(24) The agent according to the above (23), wherein the JNK-related condition or disease is a circulatory disease, an inflammatory disease, a neurodegenerative disease or diabetes;
(25) Chronic or acute heart failure, cardiac hypertrophy, dilated, hypertrophic or restricted cardiomyopathy, acute coronary syndrome, chronic ischemic heart disease, acute or chronic myocarditis, left diastolic dysfunction, left heart systolic insufficiency, hypertension The agent according to the above (1), which is a preventive / therapeutic agent for postmenopausal disease and nephropathy / nephritis associated therewith, decreased vascular endothelial function, arteriosclerosis, restenosis after angioplasty or an agent for improving the prognosis of myocardial infarction;
(26) Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. A method of inhibiting JNK in a mammal, which comprises administering an effective amount of the compound represented by the formula (I) or a salt thereof or a prodrug thereof to the mammal;
(27) Formula (I) for the production of a JNK inhibitor

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. Or a salt thereof or a prodrug thereof; and the like.

In the above formula, ring A represents an optionally substituted benzene ring.
Examples of the substituent that the ring A may have include, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, an optionally substituted hydrocarbon group, and a substituted Optionally substituted heterocyclic group, optionally substituted hydroxy group, optionally substituted thiol group, substituted sulfinyl group, substituted sulfonyl group, optionally substituted amino group, acyl group, optionally substituted Examples include a good carbamoyl group and a carboxyl group which may be esterified.

Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” as a substituent that ring A may have include, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group Aralkyl group, aryl group and the like.
Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl, pentadecyl and the like. Preferably, a C _1-8 alkyl group such as “linear or branched C _1-15 alkyl group” is used, more preferably a C _1-6 alkyl group is used, and still more preferably a C _1-4 alkyl group. An alkyl group is used.
As the “cycloalkyl group”, for example, a “C _3-10 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl is used, and more preferably C _3-8 cycloalkyl An alkyl group is used, and more preferably, a C _5-7 cycloalkyl group is used.

As the “alkenyl group”, for example, a “C _2-18 alkenyl group” such as vinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl, 9-octadecenyl and the like are used, and more preferably C _2-6 alkenyl And a C _2-4 alkenyl group is more preferably used.
As the “cycloalkenyl group”, for example, a “C _3-10 cycloalkenyl group” such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like are used, and a C _3-8 cycloalkenyl group is more preferable. And more preferably a C _5-7 cycloalkenyl group.
As the “alkynyl group”, for example, a “C _2-8 alkynyl group” such as ethynyl, 1-propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and the like are used. More preferably, a C _2-6 alkynyl group is used, and further preferably, a C _2-4 alkynyl group is used.

As the “aralkyl group”, a C _7-16 aralkyl group and the like are used, and specifically, for example, a phenyl-C _1-6 alkyl group such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like, For example, a naphthyl-C _1-6 alkyl group such as (1-naphthyl) methyl, 2- (1-naphthyl) ethyl and 2- (2-naphthyl) ethyl is used.
Examples of the “aryl group” include aromatic monocyclic, bicyclic or tricyclic C _6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl and anthryl, and biphenyl groups , A tolyl group and the like, preferably a C _6-10 aryl group such as phenyl and naphthyl, more preferably phenyl.

Examples of the substituent that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent that the ring A may have may include, for example,
(i) nitro group, (ii) hydroxy group, oxo group, (iii) cyano group, (iv) carbamoyl group, (v) mono- or di- _C1-4 alkyl-carbamoyl group (for example, N-methylcarbamoyl , N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like; the alkyl group may be substituted by a halogen atom, a hydroxy group, a _C1-4 alkoxy group, etc.), mono- or Di- _C2-4 alkenyl-carbamoyl group (for example, N-allylcarbamoyl and the like; the alkenyl group may be substituted by a halogen atom, a hydroxy group, a _C1-4 alkoxy group and the like), mono- or di- Phenyl-carbamoyl, mono- or di-benzyl-carbamoyl, C _1-4 alkoxy-carbonyl-carbamoyl, C _1-4 alkyl Rusulfonyl-carbamoyl, C _1-4 alkoxy-carbamoyl, amino-carbamoyl, mono- or di-C _1-4 alkylamino-carbamoyl, mono- or di-phenylamino-carbamoyl, (vi) carboxyl A group, (vii) a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (viii) a sulfo group, (ix) a halogen atom (eg, fluorine, chlorine, bromine , Iodine, etc.), (x) an optionally halogenated C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), and a C _1-4 alkoxy group optionally substituted with a hydroxy group , which may be substituted with a carboxyl group _{a C 1-4} alkoxy _{group, C 1-4} a Kokishi - carbonyl group optionally substituted _{C 1-4} alkoxy _{group, C 1-4} alkoxy _{-C 1-4 alkoxy, C 1-4} alkoxy _{-C 1-4} alkoxy _{-C 1-4} alkoxy, (xi) phenoxy group, a phenoxy _{-C 1-4} alkyl group, a phenoxy _{-C 1-4 alkoxy, C 1-4} alkyl carbonyl - group, carbamoyloxy group, mono - or di _{-C 1-4} alkyl - carbamoyl Oxy group, (xii) phenyl group which may be halogenated, phenyl-C _1-4 alkyl group which may be halogenated, phenyl-C _2-4 alkenyl group which may be halogenated, halogenation Phenoxy group (eg, o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc.), Oxy group, C _3-10 cycloalkyl group, C _3-10 cycloalkyl-C _1-4 alkoxy group, C _3-10 cycloalkyl-C _1-4 alkyl group, (xiii) optionally halogenated C _1-4 alkyl groups (for example, methyl, ethyl, propyl, isopropyl, butyl and the like), optionally halogenated C _2-6 alkenyl groups (for example, vinyl, allyl, 2-butenyl, 3-butenyl and the like), halogenated which may be C _1-4 alkylthio group (e.g., methylthio, ethylthio, n- propylthio, isopropylthio, etc. n- butylthio) which may be substituted by a hydroxy group C _1-4 alkyl group, hydroxy A C _1-4 alkylthio group which may be substituted with a group, (xiv) a mercapto group, a thioxo group, (xv) a halogen atom, A benzyloxy group or a benzylthio group, each of which may be substituted with a substituent selected from a benzyl group and a C _1-4 alkoxy-carbonyl group, (xvi) a phenylthio group, a pyridylthio group, a phenylthio-C _1-4 alkyl group, pyridylthio-C _1-4 alkyl group, (xvii) optionally halogenated C _1-4 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl and the like), phenylsulfinyl group, phenylsulfinyl- C _1-4 alkyl group, (xviii) optionally halogenated C _1-4 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, etc.), phenylsulfonyl group, phenylsulfonyl- _C1-4 alkyl group, ( xix) amino, aminosulfonyl, mono- or di- C _1-4 alkylaminosulfonyl group (e.g., methylaminosulfonyl, ethylaminosulfonyl, N, N- dimethylamino-sulfonyl, N, etc. N- diethylamino sulfonyl; the alkyl group is a halogen atom, hydroxy _{group, C 1-4} alkoxy (Xx) C _1-10 acyl-amino group (for example, C _1-6 alkanoylamino (eg, formylamino, acetylamino, trifluoroacetylamino, propionylamino, pivaloylamino, etc.) ), Benzoylamino, C _1-6 alkylsulfonylamino (eg, methanesulfonylamino, trifluoromethanesulfonylamino, etc.), C _6-10 arylsulfonylamino (eg, benzenesulfonylamino, toluenesulfonylamino, etc.); C _1-10 Acyl Halogen atom, hydroxy group, may be substituted with a carboxyl group), benzyloxycarbonyl amino, halogenated which may be C _1-6 alkoxycarbonylamino, carbamoylamino group, mono- - or di -C _{1- 4} alkylcarbamoylamino group, (xxi) mono - or di -C _1-4 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino and the like; the alkyl group is a halogen atom, hydroxy group, C _1-4 Phenylamino, benzylamino, (xxii) 4- to 6-membered cyclic amino group (for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl and the like) ) 4- to 6-membered cyclic amino-carbonyl group (eg, For example, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 1-piperazinylcarbonyl, etc.) 4- to 6-membered cyclic amino-carbonyl-oxy group (for example, , 1-pyrrolidinylcarbonyloxy, piperidinocarbonyloxy, morpholinocarbonyloxy, thiomorpholinocarbonyloxy, 1-piperazinylcarbonyloxy, etc.) 4- to 6-membered cyclic amino-carbonyl-amino group (for example, 1- Pyrrolidinylcarbonylamino, piperidinocarbonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, 1-piperazinylcarbonylamino, etc.) 4- to 6-membered cyclic amino-sulfonyl group (for example, 1-pyrrolidinylsulfonyl) , Piperidinosulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, 1-piperazinylsulfonyl, etc.), 4- to 6-membered cyclic amino-C _1-4 alkyl group, (xxiii) halogen atom, carboxyl group and C _1-4 A C _1-6 acyl group which may be respectively substituted with a substituent selected from an alkoxy-carbonyl group (for example, a C _2-6 alkanoyl which may be halogenated such as formyl, acetyl and the like) or a benzoyl group, ( xxiv) a benzoyl group optionally substituted by a halogen atom, (xxv) a 5- to 10-membered heterocyclic group (for example, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl) , 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 1, 2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl , Indolyl and the like; the heterocyclic group may be substituted by a C _1-4 alkyl group or the like), (xxvi) a 5- to 10-membered heterocyclic-carbonyl group (for example, 2- or 3-thienylcarbonyl, 2- Or 3-furylcarbonyl, 3-, 4- or 5-pyrazolylcarbonyl, 2-, 4- or 5-thiazolylcarbonyl, 3-, 4- or 5-isothiazolylcarbonyl, 2-, 4- or 5 -Oxazolylcarbonyl, 1,2,3- or 1,2,4-triazolylcarbonyl, 1H- or 2H-tetrazolylcarbonyl, 2-, 3- or 4- Pyridylcarbonyl, 2-, 4- or 5-pyrimidylcarbonyl, 3- or 4-pyridazinylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl, indolylcarbonyl and the like; the heterocyclic group is a C _1-4 (Xxvii) hydroxyimino group, C _1-4 alkoxyimino group, aryl group (for example, 1- or 2-naphthyl) and (xxviii) halogenated A good linear or branched C _1-4 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, propylenedioxy, tetrafluoroethylenedioxy, etc.) is used. The "hydrocarbon group" may have 1 to 5 of these substituents at substitutable positions, and when having 2 or more, the substituents may be the same or different.

Examples of the “heterocyclic group” of the “optionally substituted heterocyclic group” as a substituent that the ring A may have include, for example, an oxygen atom, an atom constituting a ring system (ring atom), Aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from a sulfur atom, a nitrogen atom and the like And a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).
Examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzo Oxazolyl, 1,2-benzisoxazo Benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] Pirizi 8 to 16 members (preferably 8 to 12 members) of 1,2,4-triazolo [4,3-b] pyridazinyl, benzo [1,2,5] thiadiazolyl, benzo [1,2,5] oxadiazolyl and the like ) Aromatic heterocyclic group (preferably, one or two (preferably one) of the 5- or 6-membered aromatic monocyclic heterocyclic group described above) is one to two benzene rings (preferably one). ) Or a heterocyclic ring in which two or three (preferably two) of the same or different heterocyclic rings of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are condensed, more preferably And the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring.
Examples of the “non-aromatic heterocyclic group” include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (preferably 1-pyrrolidinyl), tetrahydrofuryl, thiolanyl, piperidinyl (preferably 1-piperidinyl or 4-piperidinyl), A 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic monocyclic heterocyclic group (aliphatic monocyclic heterocyclic group) such as tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl A non-aromatic monocyclic heterocyclic group as described above such as 2,3-dihydroindolyl, 1,3-dihydroisoindolyl, etc. A heterocyclic group fused with two (preferably one) and one or two (preferably one) of the above-mentioned non-aromatic monocyclic heterocyclic group A heterocyclic group condensed with one or two (preferably one) heterocyclic group of a 5- or 6-membered aromatic monocyclic heterocyclic group, or 1,2,3,4-tetrahydroquinolyl, 1,2 , 3,4-tetrahydroisoquinolyl and the like aromatic monocyclic heterocyclic group or a non-aromatic heterocyclic group in which a part or all of the aromatic condensed heterocyclic group has a double bond saturated, No.
As the “heterocyclic group” in the “optionally substituted heterocyclic group”, a 5- or 6-membered aromatic monocyclic heterocyclic group or the like is preferable, and the “heterocyclic group” may have As the preferable substituent, the same number of substituents as the “optionally substituted hydrocarbon group” in the “optionally substituted hydrocarbon group” as the optional substituent on the ring A may be used. Similar groups and the like are used.

Examples of the “optionally substituted amino group”, the “optionally substituted hydroxy group” and the “optionally substituted thiol group” as the substituents that the ring A may have are: It has a substituent such as an optionally substituted hydrocarbon group, an acyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, or an optionally substituted heterocyclic group. And an optionally substituted amino group, a hydroxy group and a thiol group. As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent and the “heterocyclic group” in the “optionally substituted heterocyclic group”, ring A is The same groups as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent that may be possessed, and the like. Is used. Further, as the “acyl group” and “optionally esterified carboxyl group” as the substituent, respectively, the “optionally esterified carboxyl group” as a substituent which ring A described below may have The same groups as the “good carboxyl group” and “acyl group” are used. As the “optionally substituted carbamoyl group”, the same groups as the “optionally substituted carbamoyl group” as a substituent which ring A described below may have, and the like are used. Further, as the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”, each of the “substituted substituents that the ring A may have” The same number of similar groups as the substituents in the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group" are used.
Among them, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloro) Methoxy, 2,2,2-trichloroethoxy, etc., optionally substituted phenyl (preferably optionally halogenated C _1-4 alkyl group, optionally halogenated C _1-4 alkoxy) And a 5- to 10-membered heterocyclic group (for example, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or -Oxazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4- Lower alkyl (eg, methyl, ethyl) which may be substituted with a substituent selected from pyridazinyl, quinolyl, isoquinolyl, indolyl and the like; the heterocyclic group may be substituted with a C _1-4 alkyl group and the like. , Propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., C _1-6 alkyl, etc., acyl (C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl etc.), benzoyl, C ₁ ) _-6 alkylsulfonyl (e.g., methanesulfonyl etc.), benzenesulfonyl, etc.), an optionally halogenated C _1- Alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, trifluoromethoxy-carbonyl, 2,2,2-trifluoroethoxy carbonyl, trichloromethoxy carbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), optionally substituted with phenyl a _{C 1-6} alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), an optionally substituted carbamoyl group (e.g., carbamoyl, N- methylcarbamoyl, N, N- dimethylcarbamoyl, lower phenylcarbamoyl, etc. _{(C 1- 6} ) a carbamoyl group which may be substituted with 1 to 2 substituents such as an alkyl group and a phenyl group), a heterocyclic group (as a substituent which the ring A may have, Group similar to "heterocyclic group" in "good heterocyclic group") "Amino group" which may have a substituent, such as "hydroxy group" and "thiol group" are preferred examples. Further, two substituents in the N, N-disubstituted amino may form a “cyclic amino group” together with the nitrogen atom, and the “cyclic amino group” includes, for example, 1-azetidinyl, -Pyrrolidinyl, piperidino, morpholino, thiomorpholino (sulfur atom may be oxidized), 1-piperazinyl and lower alkyl at position 4 (eg methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl _{C 1-6} alkyl etc.) and the like, aralkyl (e.g., benzyl, _{C 7-10} aralkyl phenethyl, etc.), aryl (e.g., phenyl, 1-naphthyl, _{C 6-10} aryl such as 2-naphthyl, etc.), etc. And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino group such as 1-piperazinyl which may have

The “substituted sulfinyl group” and the “substituted sulfonyl group” as the substituents that the ring A may have are respectively an “optionally substituted hydroxy group”, an “optionally substituted amino group”, a “ It represents a sulfinyl group or a sulfonyl group substituted with a substituent such as an "optionally substituted hydrocarbon group" or an "optionally substituted heterocyclic group". As the “hydrocarbon group” in the “optionally substituted hydrocarbon group”, the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent which ring A may have And the like. As the “heterocyclic group” in the “optionally substituted heterocyclic group”, the “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent which ring A may have And the like. Examples of the substituent which may be substituted on the hydroxy group and the amino group as the substituents of the “substituted sulfinyl group” and the “substituted sulfonyl group” include “substituents that the ring A may have” The same substituents as the `` hydroxy group '' in the `` optionally substituted hydroxy group '' and the `` amino group '' in the `` optionally substituted amino group '' may be used, and are preferably used. For example, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-4 alkenyl group, a C _6-10 aryl group, an acyl group, an amino group, a heterocyclic group (even if ring A has Examples of the preferable substituent include the same groups as the “heterocyclic group” in the “optionally substituted heterocyclic group”. Further, the "hydrocarbon group" or the "heterocyclic group" in the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group" as the substituent in the "substituted sulfinyl group" and "substituted sulfonyl group" As the substituents that the group may have, the “optionally substituted hydrocarbon groups” and the “optionally substituted heterocyclic groups” as the substituents that the ring A may have And the same groups and the like as the substituents that the “hydrocarbon group” or “heterocyclic group” may have.

The “acyl group” as a substituent which the ring A may have is, for example, a carboxylic acid such as ^RA COOH, a sulfonic acid such as ^RA SO ₃ H, a sulfinic acid such as ^RA SO ₂ H, for example. or, for example, R ^a OPO (oR B) phosphoric acid, such as ^OH (R ^a represents a hydrogen atom, optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ^B is a hydrogen atom Or an acyl group obtained by removing an OH group from a substituted or unsubstituted hydrocarbon group, and specifically, R ^A CO, R ^A SO ₂ , R ^A SO, R ^A OPO (OR ^B ) (the symbols in the formulas are as defined above) and the like.
As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^A (and R ^B ), The same as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituents that the ring A may have And the like are used. Further, as the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”, the “substituted group” which the ring A may have The same groups and the like as the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” are used.
Examples of R ^A CO include, for example, formyl; an optionally halogenated chain such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonyl, and trifluoroacetyl. Jo or cyclic _{C 2-8} alkanoyl; benzoyl, nicotinoyl, and the like isonicotinoyl, among others, acetyl, propionyl, butyryl, ^{R a} is a lower _{(C 1-4)} alkyl group such as valeryl ^R a CO ( _C2-5 alkanoyl) and the like are preferred.
The R ^A SO _2, for example, include methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, cyclopentanesulfonyl, a linear or cyclic C _1-6 alkylsulfonyl such as cyclohexane, benzenesulfonyl, etc. toluenesulfonyl Can be
Examples of ^RA SO include methanesulfinyl, ethanesulfinyl, propanesulfinyl, cyclopropanesulfinyl, cyclopentanesulfinyl, cyclohexanesulfinyl, and other chain or cyclic C _1-6 alkylsulfinyl, benzenesulfinyl, toluenesulfinyl, and the like. .
R ^A OPO (OR ^B ) includes, for example, a ring such as dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl, etc. (Mono- or di- _C1-4 alkyl) phosphono, etc.

Examples of the “carbamoyl group which may be substituted” as a substituent which ring A may have include unsubstituted carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl.
Examples of the substituent which the “carbamoyl group” in the “optionally substituted carbamoyl group” may have include a “optionally substituted amino group” as the substituent which the ring A may have And the same groups as the substituents that the "amino group" may have ("optionally substituted hydrocarbon group", "acyl group", "optionally substituted alkoxycarbonyl group", " is an optionally substituted carbamoyl group "(preferably, carbamoyl, N- methylcarbamoyl, N, N- dimethylcarbamoyl, lower (C _1-6) alkyl group phenylcarbamoyl, etc., substituents such as a phenyl group 1-2 Carbamoyl group which may be optionally substituted), `` heterocyclic group which may be substituted '', etc.), and the like having the aforementioned `` amino group which may be substituted '' A “carbamoyl group” having the aforementioned “optionally substituted hydroxy group” (ie, an “optionally substituted carbazoyl group”) (ie, an “optionally substituted N-hydroxycarbamoyl group”). "). Further, two substituents in N, N-disubstituted carbamoyl may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic aminocarbonyl include 1-azetidinylcarbonyl , 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (the sulfur atom may be oxidized), 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, methyl, ethyl, C _1-6 alkyl such as propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl), aryl (eg, phenyl, 1-naphthyl, _{2-C 6-10} aryl such as naphthyl), an acyl group (eg formyl, acetyl, benzoyl, Butoxycarbonyl, benzyloxycarbonyl, and cyclic aminocarbonyl 3-8 membered like may 1- piperazinylcarbonyl which may have a methylsulfonyl, etc.), etc. (preferably 5- to 6-membered), it is used.

Examples of the “optionally esterified carboxyl group” as a substituent which ring A may have include a group represented by the formula —COOR ^C (where R ^C is a hydrogen atom, an optionally substituted hydrocarbon group or a substituted Or a heterocyclic group which may be substituted), among which free carboxyl, lower alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heterocyclic oxycarbonyl, heterocyclic methyloxycarbonyl And the like are preferably used.
As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^C , ring A has As the optionally substituted group, the same groups as the "hydrocarbon group" in the "optionally substituted hydrocarbon group" and the "heterocyclic group" in the "optionally substituted heterocyclic group" are used. Can be Examples of the substituent which the “hydrocarbon group” and the “heterocyclic group” may substitute include “an optionally substituted hydrocarbon” as a substituent that the ring A may have. The same groups and the like as the substituents that may be possessed by the “hydrocarbon group” in the “group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” are used.
"Lower alkoxycarbonyl" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl Examples thereof include C _1-6 alkoxycarbonyl such as oxycarbonyl, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl are preferable.
The “lower alkoxycarbonyl” may have a substituent in the “lower alkyl” portion of the “lower alkoxy”, and the substituent may be “substituted” as a substituent that ring A may have. The same groups and the like as the groups exemplified as the substituents that the “hydrocarbon group” in the “hydrocarbon group which may be substituted” may have are used.
As the “aryloxycarbonyl”, for example, C _7-12 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable.
As the “aralkyloxycarbonyl”, for example, C _7-15 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable.
As the heterocyclic ring in “heterocyclic oxycarbonyl” and “heterocyclic methyloxycarbonyl”, “heterocyclic” in “optionally substituted heterocyclic group” as a substituent which ring A may have Similar ones are used, and for example, pyridyl, quinolyl, indolyl, piperidinyl, tetrahydropyranyl and the like are preferably used.
The “aryloxycarbonyl”, “aralkyloxycarbonyl” and “heterocyclicoxycarbonyl” may each have a substituent, and the substituent may be a substituent that ring A may have. In the "hydrocarbon group which may be substituted" of the above, the same groups as the groups exemplified as the substituent which the "hydrocarbon group" may have may be used in the same number.

Examples of the substituent that the ring A may have include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), A hydroxy-C _1-4 alkyl group, a C _1-4 alkoxy-C _1-4 alkyl group, a C _2-4 alkenyl group (for example, vinyl, propenyl, allyl and the like), an optionally substituted phenyl group (preferably A C _1-4 alkyl group which may be halogenated, a C _1-4 alkoxy group which may be halogenated, a phenyl which may be substituted with a substituent selected from a carboxyl group and a halogen atom), C _5-7 cycloalkyl-amino group, C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), C _{1 -4} alkylthio group (for example, methylthio, ethylthio, propylthio, isopropylthio, etc.), hydroxy group, carboxyl group, cyano group, nitro group, amino group, mono- or di- _C1-4 alkylamino group (for example, methylamino , Ethylamino, dimethylamino, diethylamino, etc.), formyl group, mercapto group, C _1-4 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl), a sulfo group _(-SO 3 _{H), C 1-4} alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, etc. propylsulfonyl), carbamoyl group and mono- - or di _{-C 1-4} Alkyl Is preferably a _C5-7 cycloalkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like) and the like. One to three of these substituents may be substituted at substitutable positions on ring A, and when two or more substituents are present, the substituents may be the same or different.

（式中、Ｒ^３は水素原子、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいチオール基、置換スルフィニル基、置換スルホニル基、置換されていてもよいアミノ基、置換されていてもよいカルバモイル基またはエステル化されていてもよいカルボキシル基を示す。）で表されるベンゼン環（すなわち、１−イソキノリノン骨格において、５位、７位および８位が無置換であり、６位に置換基Ｒ^３を有する。）が好ましく用いられる。
前記式中、Ｒ^３としては水素原子、ハロゲン原子、置換されていてもよいアルキル基（環Ａが有していてもよい置換基としての「置換されていてもよい炭化水素基」における「炭化水素基」が有していてもよい置換基と同様の基を同様な数有していてもよいＣ_１−６アルキル基など）、置換されていてもよいアミノ基などが好ましく、なかでも水素原子、ハロゲン原子、Ｃ_１−４アルキル基などがより好ましく、水素原子、ハロゲン原子、メチルなどが特に好ましく用いられる。 In the above formula, as ring A, a compound represented by the formula

(In the formula, R ³ is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, A benzene ring represented by a good thiol group, a substituted sulfinyl group, a substituted sulfonyl group, an amino group which may be substituted, a carbamoyl group which may be substituted or a carboxyl group which may be esterified. that is, 1 in isoquinolinone skeleton, 5, 7 and 8 positions is is unsubstituted. having a substituent R ³ in the 6-position) is preferably used.
In the above formula, as R ³ , a hydrogen atom, a halogen atom, an alkyl group which may be substituted (an “optionally substituted hydrocarbon group” as a substituent which ring A may have) A “hydrogen group” is preferably a C _1-6 alkyl group which may have the same number of the same substituents as the substituents which may be present), an amino group which may be substituted, and the like. An atom, a halogen atom, a _C1-4 alkyl group and the like are more preferable, and a hydrogen atom, a halogen atom, methyl and the like are particularly preferably used.

In the above formula, R ¹ represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
As the “cyclic hydrocarbon group” in the “optionally substituted cyclic hydrocarbon group” for R ¹ , the above-mentioned “optionally substituted cyclic hydrocarbon group” Among the “hydrocarbon groups” in the “good hydrocarbon group”, the same groups as the cyclic hydrocarbon groups (eg, cycloalkyl group, cycloalkenyl group, aryl group, etc.) are used.
As the “heterocyclic group” in the “optionally substituted heterocyclic group” for R ¹ , the above-mentioned “optionally substituted heterocyclic group” as a substituent that the ring A may have And the same groups as the “heterocyclic group” in the above.
The substituents in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” for R ¹ are the same as the substituents that the ring A may have, respectively. And the like. The “cyclic hydrocarbon group” and the “heterocyclic group” may each have 1 to 5 (preferably 1 to 3) of these substituents at substitutable positions, In the case of having, the substituents may be the same or different.

R ¹ is preferably an aryl group which may be substituted, a heterocyclic group which may be substituted, and the like. Among them, phenyl which may be substituted, and the like are preferable, and a meta- and / or para-substituted group is preferred. Phenyl is particularly preferred.
Examples of the substituent which the phenyl in “optionally substituted phenyl” as a preferable example of R ¹ may have include a halogen atom (for example, fluorine, chlorine, bromine, iodine and the like), C _1-4. Alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc .; C _1-4 alkyl may be substituted by a halogen atom, hydroxy group, carboxyl group, etc.), C _1-4 alkoxy-C _1-4 An alkyl group (C _1-4 alkoxy may be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc.), a C _2-4 alkenyl group (eg, vinyl, propenyl, allyl, etc .; C _2-4 alkenyl is halogen) Atom, hydroxy group, carboxyl group, etc.), phenyl group which may be substituted (preferably, Halogenated which may be C _1-4 alkyl group, optionally halogenated C _1-4 alkoxy group, such as phenyl which may be substituted with a substituent selected from a carboxyl group and a halogen atom), C _{A 5-7} cycloalkyl-amino group (C _5-7 cycloalkyl may be substituted with a halogen atom, a hydroxy group, a carboxyl group, or the like), a C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, propoxy _{etc.; C 1-4} alkoxy halogen atom, hydroxy group, may be substituted with a carboxyl _{group), C 1-4} alkylthio group (e.g., methylthio, ethylthio, propylthio, etc. _{isopropylthio; C 1-4} Alkylthio is substituted with a halogen atom, hydroxy group, carboxyl group, etc. Good), hydroxy group, carboxyl group, a cyano group, a nitro group, an amino group, a mono - or di _{-C 1-4} alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino and the _{like; C 1-4} alkyl _May be substituted with a halogen atom, a hydroxy group, a carboxyl group, or the like), a C _1-10 acyl-amino group (for example, C _1-6 alkanoylamino (eg, formylamino, acetylamino, trifluoroacetylamino, propionylamino, pivaloylamino, etc.), benzoylamino, C _1-6 alkylsulfonylamino (e.g., methanesulfonylamino, trifluoromethanesulfonylamino, etc.), C _6-10 arylsulfonylamino (e.g., benzenesulfonylamino, toluene sulfonylamino etc.) etc; _1-10 acyl halogen atom, hydroxy group, may be substituted with a carboxyl group), a formyl group, a mercapto _{group, C 1-4} alkyl - group (e.g., acetyl, propionyl, butyryl, and the _{like; C 1- 4-} alkyl may be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc., a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc .; C _1-4 alkoxy is a halogen atom , A hydroxy group, a carboxyl group or the like), a sulfo group (—SO ₃ H), a C _1-4 alkyl-sulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like; C _1-4) Alkyl is halogen atom, hydroxy group, carboxy A C _1-4 alkyl-sulfinyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, etc .; C _1-4 alkyl is substituted by a halogen atom, a hydroxy group, a carboxyl group, etc.) A carbamoyl group and a mono- or di-C _1-4 alkyl or C _5-7 cycloalkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like; _C1-4alkyl and _{C5-7cycloalkyl} may each be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc., a cyclic amino-carbonyl group (for example, 1- Pyrrolidinylcarbonyl, 1-piperidinocarboni , 4-morpholinocarbonyl and the like; cyclic amino is a halogen atom, hydroxy group, may be substituted with a carboxyl group), a sulfamoyl group and mono - or di -C _1-4 alkyl or C _5-7 cycloalkyl - sulfamoyl Groups (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, etc .; C _1-4 alkyl and C _5-7 cycloalkyl are Each of which may be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc.), a cyclic amino-sulfonyl group (eg, 1-pyrrolidinylsulfonyl, 1-piperidinosulfonyl, 4-morpholinosulfonyl, etc .; Substituted with a halogen atom, hydroxy group, carboxyl group, etc. May also be), carbazolyl (N- amino carbamoyl) group and a (mono - or di - _{(N-C 1-4} alkylamino) or _{(N-C 5-7} cycloalkylamino)) carbamoyl group (e.g., (N- Methylamino) carbamoyl, (N-ethylamino) carbamoyl, (N, N-dimethylamino) carbamoyl, (N, N-diethylamino) carbamoyl and the like; C _1-4 alkyl and C _{5-7cycloalkyl} each represent a halogen atom, A hydroxy group, a carboxyl group or the like), an N- (cyclic amino) carbamoyl group (for example, N- (1-pyrrolidinyl) carbamoyl, N- (1-piperidino) carbamoyl, N- (4-morpholino) ) Carbamoyl and the like; cyclic amino is halogen atom, hydroxy group, carboxyl group A 5- to 10-membered heterocyclic group (for example, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5 -Thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 1,2,4 -Or 1,3,4-oxadiazolyl, 5-oxo-4H-1,2,4-oxadiazolyl, 5-thioxo-4H-1,2,4-oxadiazolyl, 1,2,4- or 1,3,4 -Thiadiazolyl, 5-oxo-4H-1,2,4-thiadiazolyl, 5-thioxo-4H-1,2,4-thiadiazolyl, 2-oxo-3H-1,2,3,5-otisathidiazolyl , 2-, 3 Or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl, indolyl, and the like; the heterocyclic group may be substituted with a halogen atom, a hydroxy group, a carboxyl group, or the like. And the like. These substituents may be substituted one to three times at a substitutable position of the phenyl group. When two or more substituents are present, the substituents may be the same or different. In addition, a linear or branched C _1-4 alkylenedioxy group which may be halogenated (for example, methylenedioxy, ethylenedioxy, propylenedioxy, tetrafluoroethylenedioxy, etc.) is also phenyl. Is preferred as a substituent which may be possessed.
As a preferable example of the phenyl in the "optionally substituted phenyl" as a preferable example of R ^1, the substituent which the phenyl may have is: i) a C ₁ optionally substituted by a halogen atom, a hydroxy group or a carboxyl group. _-4 alkoxy group, ii) carboxyl group, iii) C _1-4 alkoxy-carbonyl group which may be substituted with a halogen atom, hydroxy group or carboxyl group, iv) substituted with a halogen atom, hydroxy group or carboxyl group. C _1-4 alkyl-sulfonyl group, v) carbamoyl group, vi-1) mono- or di-C _1-4 alkyl-carbamoyl group (C _1-4 alkyl is a halogen atom, a hydroxy group or a carboxyl group) may be substituted), vi-2) mono - or di -C _5-7 cycloalkyl - carbamoyl group (C _5-7 cycloalkyl May be substituted with a halogen atom, a hydroxy group or a carboxyl group), vi-3) a cyclic amino-carbonyl group (the cyclic amino may be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc.), vii ) Sulfamoyl group, viii-1) mono- or di- _C1-4 alkyl-sulfamoyl group ( _C1-4 alkyl may be substituted by halogen atom, hydroxy group or carboxyl group), viii-2) mono- -Or di- _C5-7 cycloalkyl-sulfamoyl group ( _C5-7 cycloalkyl may be substituted by a halogen atom, a hydroxy group or a carboxyl group), viii-3) a cyclic amino-sulfonyl group (cyclic amino May be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc.), ix-1) carbazoyl group, ix-2) mono- or di- ( -C _1-4 alkylamino) - carbamoyl group _{(C 1-4} alkyl may be substituted with halogen atom, hydroxy group or a carboxyl group), ix-3) mono - or di - _{(N-C 5- 7} cycloalkylamino) -carbamoyl group (C _5-7 cycloalkyl may be substituted by a halogen atom, a hydroxy group or a carboxyl group), ix-4) cyclic amino-carbamoyl group (cyclic amino is a halogen atom, hydroxy Group, a carboxyl group or the like) or x) a C _1-4 alkylenedioxy group optionally substituted with a halogen atom, a hydroxy group or a carboxyl group. Among them, carboxyl group, C _1-4 alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-4 alkyl-carbamoyl group, cyclic amino-carbonyl group, C _1-4 alkyl-sulfonyl group or C _1- Particularly preferred are _4- alkylenedioxy groups and the like.

〔式中、Ｘ^１およびＸ^２はそれぞれ独立して−Ｏ−、−Ｓ−、−Ｎ（Ｒ^’）−（Ｒ^’は水素原子または置換基を示す。）またはメチレンを示し、Ｚは置換されていてもよいアルキレンを示す。〕で表される基も好ましく用いられる。
Ｘ^１とＸ^２の組み合わせとしては、Ｘ^１およびＸ^２の両方が−Ｏ−である場合、Ｘ^１が−Ｏ−、−Ｓ−または−Ｎ（Ｒ^’）−（好ましくは−Ｏ−）あってＸ^２がメチレンである場合、Ｘ^１がメチレンであってＸ^２が−Ｏ−、−Ｓ−または−Ｎ（Ｒ^’）−（好ましくは−Ｏ−）である場合などが好ましい。
Ｒ^’で示される置換基としては、環Ａが有していてもよい置換基としての「置換されていてもよいアミノ基」においてアミノ基が有していてもよい置換基と同様の基などが用いられる。
Ｚで示される「置換されていてもよいアルキレン」におけるアルキレンとしては、例えば、Ｃ_１−４アルキレン（例、メチレン、エチレン、プロピレンなど）などが用いられる。
Ｚで示される「置換されていてもよいアルキレン」におけるアルキレンが有していてもよい置換基としては、環Ａが有していてもよい置換基としての「置換されていてもよい炭化水素基」における「炭化水素基」が有していてもよい置換基と同様の基などが同様な数用いられる。該アルキレンが有していてもよい置換基としては、ハロゲン原子、Ｃ_１−４アルキル基（例えば、メチル、エチル、プロピル、イソプロピル、ブチルなど；該Ｃ_１−４アルキルはハロゲン原子、ヒドロキシ基、カルボキシル基などで置換されていてもよい）、置換されていてもよいフェニル（好ましくは、ハロゲン化されていてもよいＣ_１−４アルキル基、ハロゲン化されていてもよいＣ_１−４アルコキシ基、カルボキシル基およびハロゲン原子から選ばれる置換基で置換されていてもよいフェニルなど）、オキソ基などが好ましい。
Ｚとしては、メチレン、エチレンなどが特に好ましい。 As a preferred example of R ¹ , “optionally substituted phenyl”,

[Wherein, X ¹ and X ² each independently represent —O—, —S—, —N (R ^′ ) — (R ^′ represents a hydrogen atom or a substituent) or methylene, and Z represents a substituent. Represents an optionally substituted alkylene. ] Is also preferably used.
Examples of the combination of X ¹ and ^{X 2,} when both of ^{X 1} and ^{X 2} are -O-, ^{X 1} is -O -, - S- or -N (R ^') - (preferably -O-) If ^{X 2} is methylene there, a ^{X 1} is methylene ^{X 2} is -O -, - S- or -N (R ^') - (preferably -O-) such as when it is are preferred.
Examples of the substituent represented by R ^′ include the same groups as the substituents that the amino group may have in the “amino group that may be substituted” as the substituent that ring A may have, and the like. Is used.
As the alkylene in the “optionally substituted alkylene” for Z, for example, C _1-4 alkylene (eg, methylene, ethylene, propylene, etc.) is used.
Examples of the substituent that the alkylene in the “optionally substituted alkylene” represented by Z may have include an “optionally substituted hydrocarbon group” as the substituent that the ring A may have And the same groups as the substituents that the “hydrocarbon group” may have, and the like. Examples of the substituent which the alkylene may have include a halogen atom, a C _1-4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl and the like; the C _1-4 alkyl is a halogen atom, a hydroxy group, Optionally substituted with a carboxyl group or the like), optionally substituted phenyl (preferably optionally substituted halogenated C _1-4 alkyl group, optionally halogenated C _1-4 alkoxy group) Phenyl which may be substituted with a substituent selected from a carboxyl group and a halogen atom), and an oxo group.
As Z, methylene, ethylene and the like are particularly preferable.

In the above formula, R ² is a hydrogen atom, a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, a cyano group, an acyl group, a carboxyl group which may be esterified, Shows a good carbamoyl group or an optionally substituted amino group.
As the “hydrocarbon group” in the “hydrocarbon group optionally substituted by an optionally substituted hydroxy group” for R ² , the term “substituent as a substituent that ring A may have” The same groups as the “hydrocarbon group” in the “hydrocarbon group which may be used” are used. Examples of the substituent in the “optionally substituted hydroxy group” that the “hydrocarbon group” may have include “optionally substituted hydroxy” as the substituent that the ring A may have. The same groups as the substituents in the "group" are used.
As the “acyl group” represented by R ² , the same groups as the “acyl group” as a substituent which ring A may have, and the like are used.
As the “optionally esterified carboxyl group” for R ² , the same group as the “optionally esterified carboxyl group” as a substituent that ring A may have, and the like are used. Can be
As the “carbamoyl group which may be substituted” represented by R ² , the same group as the “carbamoyl group which may be substituted” as a substituent which ring A may have, and the like are used.
As the “optionally substituted amino group” for R ² , the same groups as the “optionally substituted amino group” as the substituents that ring A may have, and the like are used.

As R ² , a carboxyl group which may be esterified, a carbamoyl group which may be substituted and the like are preferable. Examples of the “carboxyl group which may be esterified” represented by R ² include lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- -Butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and the like, and C _1-6 alkoxycarbonyl and the like are preferable, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is preferable. More preferred.
R ² represents a hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carbazoyl group which may be substituted or N-hydroxy which may be substituted. A carbamoyl group or an optionally substituted amino group is also preferred.
Examples of the “hydrocarbon group which may be substituted with an optionally substituted hydroxy group” for R ² include, for example, a 1-hydroxy C _1-8 alkyl group and a pyridyl-C _1-4 alkoxymethyl group ( Preferably, a pyridylmethoxymethyl group and the like are preferable.
Examples of the acyl group represented by R ^2, (indicating the R ^D is a hydrogen atom, an optionally substituted hydrocarbon group or a substituent which may be a heterocyclic group) R D ^CO is preferred. Here, the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by ^RD may be a “optionally substituted hydrocarbon” as a substituent that ring A may have. The same group as the “hydrocarbon group” in “group” is used. The “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^D is the “optionally substituted heterocyclic group” as a substituent that the ring A may have. The same group as the “heterocyclic group” is used. The substituents that the “hydrocarbon group” and the “heterocyclic group” may each have include “optionally substituted hydrocarbon” as a substituent that the ring A may have. The same groups and the like as the substituents in the “group” and the “optionally substituted heterocyclic group” are used in the same number.
R ^D CO as a preferred example of the acyl group represented by R ² includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonyl, benzoyl , nicotinoyl, isonicotinoyl, etc. trifluoroacetyl and the like, acetyl, propionyl, butyryl, ^R a CO and more preferably ^{R a} is a lower _{(C 1-4)} alkyl group such as valeryl.
As R ² , a carboxyl group which may be esterified, a carbamoyl group which may be substituted, and the like are preferable, and a lower alkoxycarbonyl and the like are particularly preferable.

In the above formula, X represents a divalent chain hydrocarbon group which may be substituted.
As the “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” for X, for example, C _1-6 alkylene (for example, methylene, ethylene, Trimethylene, tetramethylene, etc.), C _2-6 alkenylene (eg, vinylene, propylene, 1- or 2-butenylene, butadienylene, etc.) and C _2-8 alkynylene (eg, ethinylene, 1- or 2-propynylene, 1- or 2-butynylene and the like are used.
As the substituent in the “optionally substituted divalent chain hydrocarbon group” represented by X, the “optionally substituted hydrocarbon group” as a substituent that ring A may have And the same groups as the substituents that the “hydrocarbon group” may have. The “divalent chain hydrocarbon group” may have 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and when having 2 or more, the substituent is They may be the same or different.
X is preferably an optionally substituted C _1-6 alkylene, and particularly preferably methylene.

In the above formula, Y represents an optionally substituted non-aromatic hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally substituted amino group.
Examples of the “non-aromatic hydrocarbon group” in the “optionally substituted non-aromatic hydrocarbon group” for Y include, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl group And the like.
Examples of the alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group include the above-mentioned "optionally substituted hydrocarbon group" as a substituent which ring A may have. Examples of the "hydrocarbon group" in the above include the same groups as the alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group.
As the substituent that the “non-aromatic hydrocarbon group” in the “optionally substituted non-aromatic hydrocarbon group” represented by Y may have, the above-mentioned ring A may have As the substituent, the same number and the like of the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have are used.
As the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by Y, the “optionally substituted heterocyclic group” as the substituent that the ring A may have And the same groups as the “heterocyclic group” in are used.
As the substituent which the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by Y may have, the above-mentioned “substituted as the substituent that the ring A may have” The same number of similar groups as the substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” may have, and the like are used.
As the “optionally substituted hydroxy group” represented by Y, the same groups as the aforementioned “optionally substituted hydroxy group” as the substituent which the ring A may have, and the like are used. .
As the “optionally substituted amino group” for Y, the same groups as the “optionally substituted amino group” as the substituents that the ring A may have, and the like are used. .

As Y, a non-aromatic hydrocarbon group which may be substituted is preferable, and a chain hydrocarbon group which may be substituted (for example, alkyl group, alkenyl group, alkynyl group and the like) is more preferable. Preferably, optionally substituted C _2-6 alkenyl and the like are more preferable, and ethylene and the like are particularly preferable.

As Y, an optionally substituted heterocyclic group or the like is also preferable, and among them, an optionally substituted 5- or 6-membered aromatic heterocyclic group (2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1-pyrrolyl, 3-pyridyl, 4-pyridyl and the like) or 1-isoindolyl are particularly preferred. Examples of the substituent which the heterocyclic group may have include a carboxyl group, a C _1-4 alkoxy-carbonyl group, a halogen atom, a C _1-4 alkoxy group which may be halogenated, and a halogenated group. C _1-4 alkyl group, optionally substituted by a hydroxy group _{C 1-4} alkyl group, a mono - or such di _{-C 1-4} alkylamino group is preferred.

As Y, an optionally substituted hydroxy group and the like are also preferable, and among them, a hydroxy group substituted with an optionally substituted hydrocarbon group (for example, a halogen atom, an optionally halogenated C _1- A hydroxy group substituted by a C _1-6 alkyl optionally substituted by a _4- alkoxy group, a C _3-10 cycloalkyl group, a 5- to 10-membered heterocyclic group or a mono- or di-C _1-4 alkylamino A group substituted with a halogen atom, an optionally halogenated C _1-6 alkoxy, an optionally halogenated phenyl, a 5- to 10-membered heterocyclic group or a mono- or di-C _1-4 alkylamino. hydroxy group (preferably a phenyl _{-C 1-6} alkyl) which may _{C 7-16} aralkyl substituted by _by; substituted with _{C 3-8} cycloalkyl Hydroxy group and the like), etc. are particularly preferred.

Further, as Y, an amino group which may be substituted and the like are also preferable, and among them, C _1-6 alkyl which may be halogenated, phenyl which may be halogenated, and halogenated may be used. Particularly preferred are an amino group which may be substituted with C _2-6 alkanoyl or an optionally halogenated benzoyl, a cyclic amino group (for example, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl and the like).

  The compound represented by the formula (I) in the present invention includes 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2 -Dihydroisoquinoline-3-carboxylic acid methyl ester, 2- (4-carboxybenzyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -1-oxo-1,2-dihydroisoquinoline-3 -Carboxylic acid methyl ester or 2- (4-methanesulfonylbenzyl) -1-oxo-4- (piperidin-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester is particularly preferably used.

A prodrug of the compound represented by the above formula (I) or a salt thereof (hereinafter, sometimes referred to as compound (I)) can be converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body. A compound which is converted, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted into compound (I), or a compound which is hydrolyzed, for example, by gastric acid, to be converted into compound (I). As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolan-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.), Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Or dimethylaminomethylcarbonylated compound) or the carbohydrate of compound (I) Compounds in which the sil group is esterified or amidated (for example, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like). No. These compounds can be produced from compound (I) by a method known per se.
The prodrug of compound (I) changes into compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals," Vol. 7, Molecular Design, pp. 163 to 198. There may be.
Examples of the salt of compound (I) include pharmacologically acceptable salts and the like, for example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, Methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, acid addition salts with acids such as sulfuric acid, for example, sodium, Metal salts such as potassium, magnesium and calcium, for example, organic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine and the like can be mentioned.
If an optically active form of compound (I) is required, it can be obtained, for example, using optically active starting materials or by resolving the racemic form of the compound using methods known per se. Can be.

  Compound (I) or a salt thereof can be produced, for example, by methods A to F shown below. Each compound described in the following reaction formulas may form a salt as long as it does not inhibit the reaction, and examples of such a salt include the same as the salt of compound (I).

Method A

Method B

Method C

Method D

Method E

Method F

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＩＩ）又はその塩と式（ＩＩＩ）
Ｌ−Ｒ^４ （ＩＩＩ）
〔Ｌは脱離基（例、ハロゲン原子（例、塩素、臭素、ヨウ素など）または式 Ｒ^Ｌ−ＳＯ_２−Ｏ−（式中、Ｒ^Ｌはハロゲン原子で置換されていてもよい低級アルキル基又は置換されていてもよいフェニル基などを示す）で表される基など）、もしくは水酸基を示し、Ｒ^４は前記Ｙで示される「置換されていてもよいヒドロキシ基」におけるヒドロキシ基が有する置換基に相当する基を示す。〕で表される化合物又はその塩とを反応させることによって化合物（Ｉ）を製造することができる。 Method A
When Y of the compound (I) is a substituted hydroxy group, the compound represented by the formula (II)

[The symbols in the formula are as defined above. Or a salt thereof with a compound of the formula (III)
LR ⁴ (III)
[L is a leaving group (eg a halogen atom (e.g., chlorine, bromine, iodine) or formula R ^L -SO ₂ -O- (wherein, ^{R L} is a lower alkyl group optionally substituted by a halogen atom Or a group represented by a phenyl group which may be substituted)) or a hydroxyl group, and R ⁴ is the substitution of the hydroxy group in the “optionally substituted hydroxy group” for Y. A group corresponding to the group is shown. Compound (I) can be produced by reacting the compound represented by the formula (I) or a salt thereof.

Method A-1
When L is a hydroxyl group, compound (II) can be alkylated by a Mitsunobu reaction in a solvent that does not affect the reaction.
In this reaction, as a solvent, aromatic hydrocarbons such as toluene and benzene, carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, sulfoxides such as dimethyl sulfoxide, and acetone And ketones such as methyl ethyl ketone and methyl isobutyl ketone, and other commonly used aprotic solvents such as acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane. Among them, tetrahydrofuran is preferred.
In the Mitsunobu reaction, a combination of azodicarboxylic acids such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and bisdimethylamide azodicarboxylate and phosphines such as triphenylphosphine, tributylphosphine and trimethylphosphine is preferably used as a reagent. . Further, phosphoranes such as cyanomethylene tributylphosphorane can be used alone.
This reaction uses about 1 to 3 mol of alcohols and about 1 to 3 mol of Mitsunobu reaction reagent per 1 mol of compound (II), and is usually in tetrahydrofuran at 0 ° C to about the boiling point of the solvent for 5 to 40 hours, preferably Is carried out at about 0 ° C. to room temperature for about 1 to 20 hours.
Method A-2
When L is a leaving group, in the above formula, examples of the lower alkyl group in the “lower alkyl group optionally substituted with a halogen atom” for R ^L include methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, - include _{C 1-6} alkyl groups such as ethylbutyl, among others methyl, ethyl, propyl, isopropyl, butyl, is _{a C 1-4} alkyl group isobutyl or the like. Examples of the lower alkyl group substituted with a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) represented by ^RL include, for example, trichloromethyl, trifluoromethyl and the like.
Examples of the substituent in the “optionally substituted phenyl group” represented by ^RL include a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) and a lower alkoxy group (eg, methoxy, ethoxy, propoxy, A C _1-6 alkoxy group such as isopropoxy and butoxy), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group and the like are used.
This reaction is an alkylation reaction and can be generally performed in a solvent that does not affect the reaction in the presence of a base.
In this reaction, as a base, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, carbon atoms such as lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide Inorganic bases such as 1 to 6 metal alkoxides, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, etc., for example, triethylamine, tri (n-propyl) amine, (N-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [ 4. 3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene, 2-tert- Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorin and its resin are used.
In this reaction, an iodide such as potassium iodide or sodium iodide may be added as a reaction accelerator.
As the solvent used in this reaction, a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether. For example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and the like, for example, n-hexane, benzene, toluene and the like Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Sulfoxides, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
This reaction is carried out using about 1 to 3 mol of the alkylating agent (III) and about 1 to 3 mol of the base per 1 mol of the compound (II), usually at 0 ° C. to about the boiling point of the solvent for 5 to 40 hours, preferably. Is carried out at room temperature to about 100 ° C. for about 10 to 20 hours.

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＩＶ）又はその塩と式（Ｖ）（および（Ｖ’））
Ｌ^１−Ｒ^５ （Ｖ） （Ｌ^１−Ｒ^５’ （Ｖ’））
〔式中、Ｌ^１は脱離基を示し、Ｒ^５およびＲ^５’はそれぞれ前記「置換されていてもよいアミノ基」におけるアミノ基が有する置換基に相当する基を示す。〕、もしくは式（ＶＩ）
Ｌ^２−Ｒ^６−Ｌ^３ （ＶＩ）
〔式中、Ｌ^２及びＬ^３はそれぞれ脱離基を示し、Ｒ^６はＹで示される環状アミノ基を形成しうる２価の基を示す。〕で表されるアルキル化剤もしくはアシル化剤又はその塩とを反応させることによって化合物（Ｉ）を製造することができる。
Ｌ^１、Ｌ^２及びＬ^３で示される脱離基としては、それぞれ前記Ｌで示される脱離基と同様の基などが用いられる。
本反応はアシル化反応もしくはアルキル化反応であり、一般に反応に影響を及ぼさない溶媒中で塩基存在下で行うことが出来る。本反応では塩基として、例えば水素化カリウム、水素化ナトリウム等の水素化アルカリ金属類、例えばリチウムエトキシド、リチウム tert−ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド、カリウム tert−ブトキシド等の炭素数１ないし６の金属アルコキシド類、例えば水酸化リチウム、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等の無機塩基、例えばトリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、１,５−ジアザビシクロ［４.３.０］ノン−５−エン、１,４−ジアザビシクロ［２.２.２］オクタン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセン等の有機アミン類、2-tert-ブチルイミノ-2-ジエチルアミノ-1,3-ジメチル-ペルヒドロ-1,3,2-ジアザホスホリンならびにその樹脂等が用いられる。
本反応で用いる溶媒としては、反応を阻害しない溶媒が適宜選択される。このような溶媒としては、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
化合物（ＩＶ）に化合物（Ｖ）を反応させて化合物（Ｉ）を得る場合、反応は一段階もしくは二段階行い、二段階行う場合、一段階目と二段階目で用いる化合物（Ｖ）および（Ｖ’）、塩基及び溶媒はそれぞれ同一でも異なってもよい。
本反応は化合物（ＩＶ）もしくは化合物（Ｉａ）１モルに対して、化合物（Ｖ）もしくは化合物（Ｖ’）１〜３モル程度、塩基１〜３モル程度を用い、通常０℃〜溶媒の沸点程度で５〜40時間、好ましくは室温〜100℃程度で10〜20時間程度行うのがよい。
また、化合物（ＩＶ）に化合物（ＶＩ）を反応させて化合物（Ｉ）を得る場合、反応は、Ｌ^２及びＬ^３の置換を一段階で進行させても二段階で進行させても良く、二段階で進行させる場合、用いる塩基及び溶媒はそれぞれ同一でも異なってもよい。
本反応は化合物（ＩＶ）１モルに対して、化合物（ＶＩ）１〜３モル程度、塩基２〜４モル程度を用い、通常０℃〜溶媒の沸点程度で５〜40時間、好ましくは室温〜100℃程度で10〜20時間程度行うのがよい。また、二段階で進行させる場合、二段階目の反応は化合物（Ｉａ’）１モルに対して、塩基２〜４モル程度を用い、通常０℃〜溶媒の沸点程度で５〜40時間、好ましくは室温〜100℃程度で10〜20時間程度行うのがよい。
また、方法Ｂに類する方法として、化合物（Ｉ）でＹが置換されていてもよいピロリルである化合物は、自体公知の方法（例えば、SYNTHETIC COMMUNICATION, 1991年, 21(15-16), p.1567-1576 に示される方法）またはそれに準じた方法に従い、化合物（ＩＶ）に酸もしくは塩基存在下２，５-ジメトキシテトラヒドロフラン誘導体を作用させて製造することが出来る。
また、化合物（Ｉ）でＹが置換されていてもよいトリアゾリルである化合物は、自体公知の方法に従い、化合物（ＩＶ）に１，２−ビス[（ジメチルアミノ）メチレン]ヒドラジンなどのヒドラジン類（Journal of American Chemical Society, 1995年, 117(22), p.5951-5957 など）や[1,3,4]オキサジアゾール誘導体(Journal of Heterocyclic Chemistry, 1989年, 26(1), p. 225-230 など)を作用させて製造することが出来る。 Method B
When Y of the compound (I) is a substituted amino group (including a cyclic amino group), the compound represented by the formula (IV)

[The symbols in the formula are as defined above. And a salt thereof with a compound of the formula (V) (and (V ′))
L ¹ -R ⁵ (V) (L ¹ -R ⁵ ′ (V ′))
[In the formula, L ¹ represents a leaving group, and R ⁵ and R ⁵ ′ each represent a group corresponding to the substituent of the amino group in the “optionally substituted amino group”. Or the formula (VI)
^{L 2 -R 6 -L 3 (VI} )
[Wherein L ² and L ³ each represent a leaving group, and R ⁶ represents a divalent group capable of forming a cyclic amino group represented by Y. Compound (I) can be produced by reacting with an alkylating agent or an acylating agent represented by the formula
As the leaving groups represented by L ¹ , L ² and L ³ , the same groups as the leaving groups represented by L are used.
This reaction is an acylation reaction or an alkylation reaction, and can be generally performed in a solvent that does not affect the reaction in the presence of a base. In this reaction, as a base, for example, an alkali metal hydride such as potassium hydride or sodium hydride, for example, having 1 to 1 carbon atoms such as lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, or potassium tert-butoxide. Metal alkoxides of No. 6, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, etc .; inorganic bases such as triethylamine, tri (n-propyl) amine, tri (n) -Butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4. 3. 0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene, 2-tert-butylimino- For example, 2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine and its resin are used.
As the solvent used in this reaction, a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether. , For example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, and 1,2-dichloroethane; for example, n-hexane, benzene, and toluene Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Rusuruhokishido, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
When the compound (V) is reacted with the compound (V) to obtain the compound (I), the reaction is carried out in one or two steps. When the reaction is carried out in two steps, the compounds (V) and ( V ′), the base and the solvent may be the same or different.
This reaction uses about 1 to 3 mol of compound (V) or compound (V ') and about 1 to 3 mol of base per 1 mol of compound (IV) or compound (Ia), and is usually 0 ° C. to the boiling point of the solvent. About 5 to 40 hours, preferably at room temperature to about 100 ° C. for about 10 to 20 hours.
When the compound (VI) is reacted with the compound (VI) to obtain the compound (I), the reaction may proceed with substitution of L ² and L ³ in one step or two steps. When the reaction proceeds in two stages, the base and the solvent used may be the same or different.
This reaction uses about 1 to 3 mol of compound (VI) and about 2 to 4 mol of base per 1 mol of compound (IV), and is usually performed at 0 ° C. to about the boiling point of the solvent for 5 to 40 hours, preferably at room temperature. It is preferable to carry out at about 100 ° C for about 10 to 20 hours. When the reaction proceeds in two steps, the reaction in the second step uses about 2 to 4 mol of a base per 1 mol of compound (Ia ′), and is usually performed at 0 ° C. to about the boiling point of the solvent for 5 to 40 hours, preferably. Is carried out at room temperature to about 100 ° C. for about 10 to 20 hours.
Further, as a method similar to Method B, the compound (I) in which Y is optionally substituted pyrrolyl can be prepared by a method known per se (for example, SYNTHETIC COMMUNICATION, 1991, 21 (15-16), p. 1567-1576) or a method analogous thereto, by reacting compound (IV) with a 2,5-dimethoxytetrahydrofuran derivative in the presence of an acid or a base.
Further, the compound (I) in which Y is a triazolyl which may be substituted may be obtained by adding a hydrazine such as 1,2-bis [(dimethylamino) methylene] hydrazine to a compound (IV) according to a method known per se. Journal of American Chemical Society, 1995, 117 (22), p.5951-5957 etc.) and [1,3,4] oxadiazole derivatives (Journal of Heterocyclic Chemistry, 1989, 26 (1), p.225 -230 etc.).

〔式中、ＯＴｆはトリフルオロメタンスルホニルオキシ基を、他の記号は前記と同意義を示す。〕で表される化合物（ＶＩＩ）又はその塩と式（ＶＩＩＩ）
Ｑ-Ｙ^１ （ＶＩＩＩ）
〔式中、Ｑはクロスカップリング反応可能な原子団基（例えば、ホウ素、スズ、マグネシウム等で結合する原子団基、等）を表し、Ｙ^１は置換されていてもよい複素環基または非芳香族炭化水素基を示す。〕で表される化合物（ＶＩＩＩ）又はその塩、もしくは式（ＶＩＩＩ’）
ＮＨＲ^５Ｒ^５' （ＶＩＩＩ’）
〔式中、Ｒ^５及びＲ^５'は、前記「置換されていてもよいアミノ基」におけるアミノ基が有していてもよい置換基に相当する基を示し、Ｒ^５及びＲ^５'は窒素原子と一緒になって環状アミノ基を形成していてもよい。〕で表されるアミノ化合物（ＶＩＩＩ’）又はその塩とを反応させて、化合物（Ｉ）を製造することができる。
本法は化合物（ＶＩＩ）又はその塩と化合物（ＶＩＩＩ）又はその塩、もしくはアミノ化合物（ＶＩＩＩ’）又はその塩とを金属触媒存在下にクロスカップリング反応（鈴木カップリング反応、Ｈｅｃｋ反応、Ｓｔｉｌｌｅカップリング反応、Ｂｕｃｈｂａｌｄのアミノ化反応等）させることにより、化合物（Ｉ）を製造する。
本反応は通常塩基存在下に行い、塩基としては、例えば水素化ナトリウム、水素化カリウムなどの水素化アルカリ金属類、例えば水酸化リチウム、水酸化ナトリウム、水酸化カリウムなどの水酸化アルカリ金属類、水酸化マグネシウム、水酸化カルシウムなどの水酸化アルカリ土類金属類、炭酸ナトリウム、炭酸カリウムなどの炭酸アルカリ金属類、例えば炭酸水素ナトリウム、炭酸水素カリウムなどの炭酸水素アルカリ金属などの無機塩基類、例えばナトリウムメトキシド、ナトリウムエトキシド、ナトリウムtert-ブトキシド等の炭素数１ないし６の金属アルコキシド類、例えばトリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ピコリン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、１,５−ジアザビシクロ［４.３.０］ノン−５−エン、１,４−ジアザビシクロ［２.２.２］オクタン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセンなどの有機塩基類、メチルリチウム、ｎ−ブチロリチウム、sec−ブチロリチウム、tert−ブチロリチウムなどの有機リチウム類、リチウムジイソプロピルアミド等のリチウムアミド類等が用いられる。
本反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としては例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
本クロスカップリング反応は、一般に金属触媒を用いて反応を促進させることができる。本反応では金属触媒として、さまざまな配位子を有する金属複合体が用いられ、例えばパラジウム化合物〔例、パラジウムアセテート、テトラキス(トリフェニルホスフィン)パラジウム、塩化ビス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリエチルホスフィン)パラジウム、トリス(ジベンジリデンアセトン)ジパラジウム-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル、酢酸パラジウム(ＩＩ) と1,1'-ビス(ジフェニルホスフィノ)フェロセンの複合体など〕、ニッケル化合物〔例、テトラキス(トリフェニルホスフィン)ニッケル、塩化ビス(トリエチルホスフィン)ニッケル、塩化ビス(トリフェニルホスフィン)ニッケルなど〕、ロジウム化合物〔例、塩化トリ(トリフェニルホスフィン)ロジウムなど〕、コバルト化合物、白金化合物などが用いられるが、なかでも、パラジウムやニッケル化合物が好ましい。これらの触媒の使用量は化合物(ＶＩＩ)１モルに対して約１〜０．０００００１モル、好ましくは約０．１〜０．０００１モルである。
本反応では、化合物（ＶＩＩ）１モルに対して化合物（ＶＩＩＩ）または化合物（ＶＩＩＩ’）約０．８〜１０モル、好ましくは約０．９〜２モル、および、塩基約１〜約２０モル、好ましくは約１〜約５モルが用いられる。
反応温度は約−１０℃〜約２５０℃、好ましくは約０℃〜約１５０℃である。
反応時間は化合物（ＶＩＩ）、化合物（ＶＩＩＩ）もしくは化合物（ＶＩＩＩ’）、金属触媒、塩基又は溶媒の種類、反応温度等により異なるが、通常約１分間〜約２００時間、好ましくは約５分間〜約１００時間である。 Method C
When Y of the compound (I) is a non-aromatic hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted, the compound represented by the formula (VII)

[In the formula, OTf represents a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as described above. Or a salt thereof represented by the formula (VIII):
QY ¹ (VIII)
[In the formula, Q represents an atomic group capable of performing a cross-coupling reaction (eg, an atomic group bonded with boron, tin, magnesium, or the like), and Y ¹ represents an optionally substituted heterocyclic group or a non-substituted heterocyclic group. Shows an aromatic hydrocarbon group. Or a salt thereof, or a compound of the formula (VIII ′)
NHR ⁵ R ⁵ ′ (VIII ′)
[Wherein, R ⁵ and R ⁵ ′ represent a group corresponding to a substituent which the amino group in the “optionally substituted amino group” may have, and R ⁵ and R ^{5 ′} are nitrogen It may form a cyclic amino group together with the atom. With the amino compound (VIII ′) or a salt thereof to produce the compound (I).
In this method, compound (VII) or a salt thereof and compound (VIII) or a salt thereof, or amino compound (VIII ′) or a salt thereof are cross-coupled in the presence of a metal catalyst (Suzuki coupling reaction, Heck reaction, Stille reaction). Compound (I) is produced by a coupling reaction, an amination reaction of Buchbald, or the like.
This reaction is usually carried out in the presence of a base, for example, sodium hydride, alkali metal hydrides such as potassium hydride, for example, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, Magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, for example, sodium hydrogen carbonate, inorganic bases such as alkali metal hydrogen carbonate such as potassium hydrogen carbonate, for example C1-C6 metal alkoxides such as sodium methoxide, sodium ethoxide and sodium tert-butoxide, for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5- Diazavish Organic bases such as b [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene; Organic lithiums such as methyllithium, n-butyrolithium, sec-butyrolithium, tert-butyrolithium, and lithium amides such as lithium diisopropylamide are used.
This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether. For example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and the like, for example, n-hexane, benzene, toluene and the like Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Sulfoxides, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
This cross-coupling reaction can be generally accelerated by using a metal catalyst. In the present reaction, a metal complex having various ligands is used as a metal catalyst, for example, a palladium compound (e.g., palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, dichlorobis (triethyl (Phosphine) palladium, tris (dibenzylideneacetone) dipalladium-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, palladium (II) acetate and 1,1'-bis (diphenylphosphino) ferrocene Complex, etc.), nickel compounds (eg, tetrakis (triphenylphosphine) nickel, bis (triethylphosphine) nickel, bis (triphenylphosphine) nickel, etc.), rhodium compounds (eg, tri (triphenylphosphine) chloride Rhodium, etc.), cobalt compounds, platinum compounds, etc. Among them, palladium and nickel compounds are preferable. The amount of these catalysts to be used is about 1-0.000001 mol, preferably about 0.1-0.0001 mol, per 1 mol of compound (VII).
In this reaction, about 0.8 to 10 moles, preferably about 0.9 to 2 moles, and about 1 to about 20 moles of the compound (VIII) or the compound (VIII ') per 1 mole of the compound (VII) Preferably, about 1 to about 5 moles are used.
The reaction temperature is about -10C to about 250C, preferably about 0C to about 150C.
The reaction time varies depending on the compound (VII), the compound (VIII) or the compound (VIII ′), the type of the metal catalyst, the base or the solvent, the reaction temperature and the like, but is usually about 1 minute to about 200 hours, preferably about 5 minutes to About 100 hours.

〔式中、Ｙ^２は置換されていてもよい芳香族複素環基を示し、その他の記号は前記と同意義を示す。〕で表される化合物（ＩＸ）又はその塩を分子内環化させることによって化合物（Ｉ）のＹが置換されていてもよい芳香族複素環基である化合物（Ｉｂ）又はその塩を製造することができる。
本環化反応は化合物（ＩＸ）に塩基を作用させることにより行われる。
本反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としては、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
本反応では塩基として、例えば水素化カリウム、水素化ナトリウム等の水素化アルカリ金属類、例えばリチウムエトキシド、リチウム−tert−ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド、カリウム−tert−ブトキシド等の炭素数１ないし６の金属アルコキシド類、例えば水酸化リチウム、水酸化カリウム、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等の無機塩基、例えばトリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、１,５−ジアザビシクロ［４.３.０］ノン−５−エン、１,４−ジアザビシクロ［２.２.２］オクタン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセン等の有機アミン類、メチルリチウム、ｎ−ブチロリチウム、sec−ブチロリチウム、tert−ブチロリチウムなどの有機リチウム類、リチウムジイソプロピルアミド等のリチウムアミド類等が用いられる。
本反応では、化合物（ＩＸ）１モルに対して塩基を約０．０１ないし約１００モル、好ましくは約０．１ないし約３モル用いる。
反応温度は約−８０℃ないし約２００℃、好ましくは約−２０℃ないし約１００℃である。
反応時間は化合物（ＩＸ）、塩基触媒の種類、溶媒の種類、反応温度等により異なるが、通常約１分ないし約７２時間、好ましくは約１５分ないし約２４時間である。 Method D
When Y of the compound (I) is an optionally substituted aromatic heterocyclic group, the compound represented by the formula (IX)

[In the formula, Y ² represents an aromatic heterocyclic group which may be substituted, and other symbols have the same meanings as described above. Compound (IX) or a salt thereof is intramolecularly cyclized to produce compound (Ib) or a salt thereof, wherein Y is an aromatic heterocyclic group which may be substituted. be able to.
This cyclization reaction is carried out by reacting compound (IX) with a base.
This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether. , For example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, and 1,2-dichloroethane; for example, n-hexane, benzene, and toluene Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Rusuruhokishido, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
In this reaction, as a base, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, carbon number of lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like Inorganic bases such as 1 to 6 metal alkoxides, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., for example, triethylamine, tri (n-propyl) amine, tri (n- Butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3 .0] non- Organic amines such as -ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, methyllithium, n-butyrolithium, sec-butyrolithium; Organic lithiums such as tert-butyrolithium and the like, lithium amides such as lithium diisopropylamide and the like are used.
In this reaction, a base is used in an amount of about 0.01 to about 100 mol, preferably about 0.1 to about 3 mol, per 1 mol of compound (IX).
The reaction temperature is about -80C to about 200C, preferably about -20C to about 100C.
The reaction time varies depending on the compound (IX), the type of the base catalyst, the type of the solvent, the reaction temperature and the like, but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.

〔式中、Ｒ^２’は置換されていてもよいカルボキシル基もしくはアシル基を示し、その他の記号は前記と同意義を示す。〕で表される化合物（Ｘ）又はその塩と式（ＸＩ）
Ｈ^２Ｎ−Ｘ−Ｒ^１ （ＸＩ）
〔式中の記号は前記と同意義を示す。〕で表されるアミノ化合物（ＸＩ）又はその塩とを反応させた後、脱水させることによって、化合物（Ｉ）のＹが置換されていてもよい芳香族複素環基であり、Ｒ^２が置換されていてもよいカルボキシル基もしくはアシル基である化合物（Ｉｃ）又はその塩を製造することができる。
本反応は無溶媒または溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としては、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクロロエチレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトン、メチルエチルケトン、メチルイソブチルケトン等のケトン類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
本反応は塩基の存在下に行うのが好ましく、そのような塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、例えばトリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン等のアミン類が用いられる。
本反応では、化合物（Ｘ）１モルに対して化合物（ＸＩ）を約１ないし約２０モル、好ましくは約１ないし約５モル用いる。
反応温度は約−２０℃ないし約１５０℃、好ましくは約１０℃ないし約８０℃である。
反応時間は化合物（Ｘ）又は（ＸＩ）の種類、溶媒の種類、反応温度等により異なるが、通常約１分ないし約７２時間、好ましくは約１５分ないし約２４時間である。
また本反応の脱水工程は、条件によっては化合物（Ｘ）と化合物（ＸＩ）の反応のみで完了することもあるが、通常は酸を用いて脱水させる。かかる酸としては、例えば酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ−トルエンスルホン酸などの有機酸類、例えば塩酸、硫酸、硝酸、リン酸、臭化水素酸、過塩素酸などの鉱酸類、例えば塩化アルミニウム、塩化亜鉛、三フッ化ホウ素エーテラート、四塩化チタンなどのルイス酸類などが用いられる。
脱水工程に用いられる溶媒は反応を阻害しない溶媒が適宜選択され、このような溶媒は、化合物（Ｘ）と化合物（ＸＩ）の反応で用いる溶媒が用いられる。
反応温度は約−２０℃ないし約２００℃、好ましくは約０℃ないし約１２０℃である。
反応時間は反応条件により異なるが、通常約１分ないし約７２時間、好ましくは約１５分ないし約１５時間である。 Method E
When Y in compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is a carboxyl group or an acyl group which may be substituted, formula (X)

[Wherein, R ^{2 ′} represents a carboxyl group or an acyl group which may be substituted, and other symbols have the same meanings as described above. Or a salt thereof represented by the formula (XI)
H ² N—X—R ¹ (XI)
[The symbols in the formula are as defined above. After reacting with the amino compound (XI) or a salt thereof represented by the formula (I), Y in compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is Compound (Ic) or a salt thereof, which may be a carboxyl group or an acyl group, may be produced.
This reaction is performed without a solvent or in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether. , For example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, and 1,2-dichloroethane; for example, n-hexane, benzene, and toluene Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone Ketones, such as acetonitrile, in addition to such nitriles such as propionitrile, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
This reaction is preferably performed in the presence of a base. Examples of such a base include inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, such as triethylamine, tri (n-propyl) amine, and tri (n- Amines such as (butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used.
In this reaction, compound (XI) is used in an amount of about 1 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (X).
The reaction temperature is about -20 ° C to about 150 ° C, preferably about 10 ° C to about 80 ° C.
The reaction time varies depending on the type of compound (X) or (XI), the type of solvent, the reaction temperature and the like, but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.
In addition, the dehydration step of this reaction may be completed only by the reaction of the compound (X) and the compound (XI) depending on conditions, but is usually dehydrated using an acid. Such acids include, for example, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, for example, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, and the like. Lewis acids such as aluminum chloride, zinc chloride, boron trifluoride etherate and titanium tetrachloride are used.
As the solvent used in the dehydration step, a solvent that does not inhibit the reaction is appropriately selected, and as such a solvent, a solvent used in the reaction between compound (X) and compound (XI) is used.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about 0 ° C to about 120 ° C.
The reaction time varies depending on the reaction conditions, but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 15 hours.

〔式中の記号は前記と同意義を示す。〕で表わされる化合物（ＸＩＩ）と式（ＸＩＩＩ）
Ｌ^４−Ｘ−Ｒ^１ （ＸＩＩＩ）
〔式中、Ｌ^４は脱離基（前記Ｌと同意義を示す）を示す。〕で表される化合物（ＸＩＩＩ）を反応させることにより、化合物（Ｉ）のＹが置換されていてもよい芳香族複素環基であり、Ｒ^２が置換されていてもよいカルボキシル基もしくはアシル基である化合物（Ｉｄ）を製造することができる。
本法は化合物（ＸＩＩ）又はその塩を、化合物（ＸＩＩＩ）又はその塩を用いてアルキル化反応することにより行われる。
本反応は一般に溶媒中、塩基の存在下に行われる。本反応に用いる塩基としては、例えば水素化カリウム、水素化ナトリウム等の水素化アルカリ金属類、例えばリチウムエトキシド、リチウム tert−ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド、カリウム tert−ブトキシド等の炭素数１ないし６の金属アルコキシド類、例えば水酸化リチウム、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等の無機塩基、例えばトリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、１,５−ジアザビシクロ［４.３.０］ノン−５−エン、１,４−ジアザビシクロ［２.２.２］オクタン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセン等の有機アミン類、2-tert-ブチルイミノ-2-ジエチルアミノ-1,3-ジメチル-ペルヒドロ-1,3,2-ジアザホスホリンならびにその樹脂等が挙げられる。
またかかる溶媒としては反応を阻害しない溶媒が適宜選択される。このような溶媒としては例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
本反応では、化合物（ＸＩＩ）１モルに対して化合物（ＸＩＩＩ）約１ないし約５モル、好ましくは約１ないし約２モルを用いる。
反応温度は約−５０℃ないし約１５０℃、好ましくは約−２０℃ないし約１００℃である。
反応時間は化合物（ＸＩＩ）又は（ＸＩＩＩ）の種類、溶媒及び塩基の種類、反応温度等により異なるが、通常約１分間ないし約１００時間、好ましくは約１５分間ないし約４８時間である。 Method F
When Y in compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is a carboxyl group or an acyl group which may be substituted, formula (XII)

[The symbols in the formula are as defined above. (XII) and a compound of the formula (XIII)
^{L 4 -X-R 1 (XIII} )
[In the formula, L ⁴ represents a leaving group (having the same meaning as L above). By reacting compound (XIII) represented by the formula (I), wherein Y in compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is a carboxyl group or an acyl group which may be substituted. Compound (Id) can be produced.
This method is performed by subjecting compound (XII) or a salt thereof to an alkylation reaction using compound (XIII) or a salt thereof.
This reaction is generally performed in a solvent in the presence of a base. As the base used in this reaction, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, carbon atoms such as lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide Inorganic bases such as 1 to 6 metal alkoxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, etc., for example, triethylamine, tri (n-propyl) amine, (N-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo Organic amines such as 4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene; tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine and its resin.
A solvent that does not inhibit the reaction is appropriately selected as such a solvent. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether. For example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and the like, for example, n-hexane, benzene, toluene and the like Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Sulfoxides, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
In this reaction, about 1 to about 5 mol, preferably about 1 to about 2 mol, of compound (XIII) is used per 1 mol of compound (XII).
The reaction temperature is about -50 ° C to about 150 ° C, preferably about -20 ° C to about 100 ° C.
The reaction time varies depending on the type of compound (XII) or (XIII), the type of solvent and base, the reaction temperature and the like, but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.

〔式中の記号は前記と同意義を示す。〕で表される化合物（Ｉｅ）は、前記した方法Ｅによって、もしくは、前記した方法Ａ〜Ｄによって得られる式（Ｉｆ）

〔式中、Ｒ^７は置換されていてもよい低級（Ｃ_１−６）アルキル基（例えばメチル、エチル、プロピル、ブチル、tert-ブチル基等）を示し、その他の記号は前記と同意義を示す。〕で表される化合物（Ｉｆ）を加水分解することによって得られる。本加水分解反応は、自体公知の方法又はそれに準ずる方法を用いることができ、例えば酸による方法、塩基による方法、還元による方法、紫外光による方法、テトラブチルアンモニウムフルオリドによる方法、酢酸パラジウムによる方法等が用いられる。酸による方法は主にｔ−ブチルエステルの場合に用いられ、使用される酸の好ましい例としては、例えばギ酸、トリフルオロ酢酸、ベンゼンスルホン酸、p-トルエンスルホン酸等の有機酸；例えば塩酸、臭化水素酸、硫酸等の無機酸等が挙げられる。塩基による方法は、通常低級アルキルエステルの場合に用いられ、使用される塩基の好ましい例としては、例えば水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属、水酸化マグネシウム、水酸化カルシウム等の水酸化アルカリ土類金属、炭酸ナトリウム、炭酸カリウム等の炭酸アルカリ金属、炭酸マグネシウム、炭酸カルシウム等の炭酸アルカリ土類金属、炭酸水素ナトリウム、炭酸水素カリウム等の炭酸水素アルカリ金属、酢酸ナトリウム、酢酸カリウム等の酢酸アルカリ金属、リン酸カルシウム、リン酸マグネシウム等のリン酸アルカリ土類金属、リン酸水素二ナトリウム、リン酸水素二カリウム等のリン酸水素アルカリ金属ならびにアンモニア水等の無機塩基等が挙げられる。還元による方法は、例えばベンジルオキシメチル、ベンジル、p-ニトロベンジル、ベンズヒドリル等で保護されたカルボキシル基等の脱保護に適用される。使用される還元法の好ましい例としては、亜鉛／酢酸による還元、接触還元等が挙げられる。紫外光による方法は、例えばo-ニトロベンジルで保護されたカルボキシル基の脱保護に用いられる。テトラブチルアンモニウムフルオリドによる方法は、例えば2-トリメチルシリルエチル等のシリルエーテル型エステルならびにシリルエステル類から保護基を除去し、カルボキシル基を得る方法として用いられる。酢酸パラジウムによる方法は、例えばアリルエステルから保護基を除去してカルボキシル基を得る方法として用いられる。
反応は、一般に溶媒中で行うのが有利である。使用される溶媒は、通常水、例えばメタノール、エタノール、プロパノール等のアルコール類、例えばテトラヒドロフラン、ジメトキシエタン、ジオキサン等のエーテル類、例えばＮ,Ｎ−ジメチルホルムアミドのアミド類、例えばジメチルスルホキシド等のスルホキシド類等の非プロトン性の極性溶媒、およびこれらの混合溶媒、その他反応に悪影響を及ぼさない溶媒等が用いられる。液状の酸または塩基は溶媒としても使用できる。反応は通常−２０℃ないし１２０℃（好ましくは０℃ないし１００℃）の温度範囲で行われる。反応時間は、通常１０分間ないし４８時間、好ましくは０.５時間ないし２４時間である。
また、このようにして得た化合物（Ｉｅ）を用い、化合物（Ｉｅ）のカルボキシル基を自体公知の方法又はそれに準ずる方法を用いて修飾することで様々な誘導体を製造することができる。 Method G
Formula (Ie) wherein R ² of compound (I) is a carboxyl group

[The symbols in the formula are as defined above. The compound (Ie) represented by the formula (If) obtained by the above method E or by the above methods A to D

[Wherein, R ⁷ represents an optionally substituted lower (C _1-6 ) alkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl group, etc.), and other symbols have the same meanings as described above. Show. By hydrolyzing the compound (If) represented by the formula: The hydrolysis reaction can be performed by a method known per se or a method analogous thereto, for example, a method using an acid, a method using a base, a method using reduction, a method using ultraviolet light, a method using tetrabutylammonium fluoride, a method using palladium acetate. Are used. The acid method is mainly used in the case of t-butyl ester, and preferred examples of the acid used include organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid; And inorganic acids such as hydrobromic acid and sulfuric acid. The method using a base is generally used in the case of a lower alkyl ester. Preferred examples of the base used include, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, magnesium hydroxide, and hydroxides. Alkali earth metal hydroxides such as calcium, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium acetate , Alkali metal acetate such as potassium acetate, alkaline earth metal phosphate such as calcium phosphate and magnesium phosphate, alkali metal hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, and inorganic base such as aqueous ammonia. No. The reduction method is applied to, for example, deprotection of a carboxyl group protected by benzyloxymethyl, benzyl, p-nitrobenzyl, benzhydryl and the like. Preferred examples of the reduction method used include reduction with zinc / acetic acid, catalytic reduction and the like. A method using ultraviolet light is used, for example, for deprotection of a carboxyl group protected with o-nitrobenzyl. The method using tetrabutylammonium fluoride is used as a method for obtaining a carboxyl group by removing a protecting group from silyl ether type esters such as 2-trimethylsilylethyl and silyl esters. The method using palladium acetate is used, for example, as a method for removing a protecting group from an allyl ester to obtain a carboxyl group.
The reaction is generally advantageously carried out in a solvent. The solvent used is usually water, for example, alcohols such as methanol, ethanol and propanol, for example, ethers such as tetrahydrofuran, dimethoxyethane and dioxane, for example, amides of N, N-dimethylformamide, for example, sulfoxides such as dimethylsulfoxide. And aprotic polar solvents, such as mixed solvents, and other solvents that do not adversely affect the reaction. Liquid acids or bases can also be used as solvents. The reaction is usually performed in a temperature range of -20 ° C to 120 ° C (preferably 0 ° C to 100 ° C). The reaction time is generally 10 minutes to 48 hours, preferably 0.5 hours to 24 hours.
Various derivatives can be produced by using the compound (Ie) thus obtained and modifying the carboxyl group of the compound (Ie) by a method known per se or a method analogous thereto.

〔式中、Ｒ^８は置換基を有していてもよい炭化水素または置換基を有していてもよい複素環基を示し、その他の記号は前記と同意義を示す。〕で表される化合物（Ｉｇ）を製造することができる。
本エステル化反応は、自体公知の方法又はそれに準ずる方法を用いることができ、例えば、化合物（Ｉｅ）をＲ^８−Ｌ^５〔式中、Ｌ^５は脱離基（前記Ｌと同意義を示す）を示し、その他の記号は前記と同意義を示す。〕で表される化合物と塩基存在下に反応させる方法、化合物（Ｉｅ）をＲ^８−ＯＨで表されるアルコール類と酸触媒存在下に反応させる方法、縮合剤〔例えばカルボジイミド類（DCC、WSC、DIC等）、りん酸誘導体（例えばシアノりん酸ジエチル、アジ化りん酸ジフェニル、BOP-Cl等）等〕を用いて縮合する方法、あるいはトリフェニルホスフィンとアゾジカルボン酸ジエチル等の試薬を用いる光延反応、さらには化合物（Ｉｅ）の反応性誘導体（例えば、酸ハライド、活性エステル、酸アジド等）を塩基存在下にＲ^８−ＯＨで表されるアルコール類と反応させる方法等を用いることができる。 For example, 1) by esterifying compound (Ie), the compound of formula (Ig)

[In the formula, R ⁸ represents a hydrocarbon which may have a substituent or a heterocyclic group which may have a substituent, and other symbols have the same meanings as described above. ] (Ig) can be produced.
This esterification reaction can be carried out by a method known per se or a method analogous thereto. For example, the compound (Ie) is represented by R ⁸ -L ⁵ [wherein L ⁵ is a leaving group (having the same meaning as L above). ), And other symbols have the same meanings as described above. A method of reacting the compound (Ie) with an alcohol represented by R ⁸ —OH in the presence of an acid catalyst, a condensing agent [for example, carbodiimides (DCC, WSC DIC, etc.), phosphoric acid derivatives (eg, diethyl cyanophosphate, diphenyl azide phosphate, BOP-Cl, etc.), or Mitsunobu using reagents such as triphenylphosphine and diethyl azodicarboxylate. A reaction, or a method of reacting a reactive derivative of compound (Ie) (eg, acid halide, active ester, acid azide, etc.) with an alcohol represented by R ⁸ —OH in the presence of a base can be used. .

〔式中の記号は前記と同意義を示す。〕で表される化合物（Ｉｈ）を製造することができる。
本還元反応は、自体公知の方法又はそれに準ずる方法を用いることができ、例えば、化合物（Ｉｅ）またはその反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド、酸アジド等）を還元剤（例えば、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、ジボラン等）を用いて還元する方法等を用いることができる。 2) By reducing the compound (Ie), the compound of the formula (Ih)

[The symbols in the formula are as defined above. The compound (Ih) represented by the formula:
For the present reduction reaction, a method known per se or a method analogous thereto can be used. For example, compound (Ie) or a reactive derivative thereof (eg, acid halide, acid anhydride, active ester, ester, acid imidazolide, acid azide) Etc.) using a reducing agent (eg, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, diborane, etc.).

〔式中、Ｒ^９およびＲ^１０はそれぞれ水素原子、または前記Ｒ^２で示される「置換されていてもよいカルバモイル基」におけるカルバモイル基が有していてもよい置換基に相当する基を示す。〕で表される化合物（Ｉｉ）を製造することができる。
本アミド化反応は、自体公知の方法又はそれに準ずる方法を用いることができ、例えば、化合物（Ｉｅ）とアミンに縮合剤〔例えばカルボジイミド類（DCC、WSC、DIC等）、りん酸誘導体（例えばシアノりん酸ジエチル、DPPA、BOP-Cl等）等〕を作用させる方法、あるいは化合物（Ｉｅ）の反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド、酸アジド等）をアミンと反応させる方法等を用いることができる。 3) Compound (Ie) is amidated to give a compound of formula (Ii)

[In the formula, R ⁹ and R ¹⁰ each represent a hydrogen atom or a group corresponding to a substituent which the carbamoyl group in the “optionally substituted carbamoyl group” for R ² may have. The compound (Ii) represented by the formula [I] can be produced.
This amidation reaction can be performed by a method known per se or a method analogous thereto. For example, a compound (Ie) and an amine are condensed with a condensing agent [for example, carbodiimides (DCC, WSC, DIC, etc.), a phosphoric acid derivative (for example, cyano Diethyl phosphate, DPPA, BOP-Cl, etc.) or a reactive derivative of compound (Ie) (eg, acid halide, acid anhydride, active ester, ester, acid imidazolide, acid azide, etc.) A method of reacting with an amine or the like can be used.

〔式中の記号は前記と同意義を示す。〕で表される化合物（Ｉｊ）を製造することができる。
本変換反応は、Ｃｕｒｔｉｕｓ転位、Ｈｏｆｍａｎｎ反応、Ｓｃｈｍｉｄｔ反応などの自体公知の方法又はそれに準ずる方法を用いることができ、例えば、化合物（Ｉｅ）またはその反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド等）を酸アジド体に変換し、酸アジド体の熱転位によりイソシアネート体を生成させ、生成したイソシアネートを直接加水分解するか、又はアルコール類と反応させて生ずるアミンのカルバメート型保護基を脱保護する方法等を用いることができる。 4) By converting the carboxyl group of compound (Ie) to an amino group, the compound of formula (Ij)

[The symbols in the formula are as defined above. The compound (Ij) represented by the formula:
This conversion reaction can be performed by a method known per se such as Curtius rearrangement, Hofmann reaction, Schmidt reaction or a method analogous thereto. For example, compound (Ie) or a reactive derivative thereof (eg, acid halide, acid anhydride, Active ester, ester, acid imidazolide, etc.) to an acid azide, and the isocyanate is formed by thermal rearrangement of the acid azide, and the generated isocyanate is directly hydrolyzed or reacted with an alcohol to form an amine. A method of deprotecting a carbamate-type protecting group can be used.

Method H
In the substituents of R ¹ , R ² , R ³ , Y and ring A of compound (I), a functional group convertible to the substituent (for example, carboxyl group, amino group, hydroxy group, carbonyl group, thiol group , An ester group, a sulfo group, a halogen atom, etc.), various compounds can be produced by converting the functional group by a method known per se or a method analogous thereto.
For example, in the case of a carboxyl group, the carboxyl group can be converted by a reaction such as esterification, reduction, amidation, or conversion to an amino group which may be protected as described in the above method G. In the case of an amino group, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like. In the case of a hydroxy group, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like. In the case of a carbonyl group, it can be converted by a reaction such as reduction, oxidation, iminization (including oximation and hydrazonation), (thio) ketalization, alkylideneation, and thiocarbonylation. In the case of a thiol group, it can be converted by a reaction such as alkylation or oxidation. In the case of an ester group, it can be converted by a reaction such as reduction or hydrolysis. In the case of a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction. In the case of a halogen atom, it can be converted by various nucleophilic substitution reactions, various coupling reactions and the like.

  The starting compounds (II), (IV), (VII), (IX), (X) and (XII) used in the above-mentioned production methods A to F can be prepared by, for example, a method known per se or as shown below. It can be manufactured by a similar method.

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＩＩ）又はその塩は、例えば次に示す方法により製造できる。式（ＸＩＶ）

〔式中、Ｒ^１１は置換されていてもよい炭化水素基または置換されていてもよい複素環を、他の記号は前記と同意義を示す。〕で表わされる化合物（ＸＩＶ）またはその塩あるいはその反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド、酸アジド等）を式（ＸＶ）

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＸＶ）またはその塩と反応させることにより、式（ＸＶＩ）

〔式中の記号は前記と同意義を示す。〕で表されるアミド化合物（ＸＶＩ）またはその塩を製造することができる。
本反応はアミド化反応であり、化合物（ＸＩＶ）の反応性誘導体、反応条件、反応溶媒、反応時間等は、前記の方法Ｇ−３で説明した方法に準じて行われる。
得られた化合物（ＸＶＩ）またはその塩を、前記の方法Ｄと同様の方法により分子内環化反応を行うことにより、式（ＩＩ）

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＩＩ）又はその塩を製造することができる。
前記Ｉ法において用いられる化合物（ＸＶＩ）は、下記Ｊ法にしたがって製造することもできる。 Method I
Formula (II)

Wherein the symbols are as defined above. The compound (II) or a salt thereof can be produced, for example, by the following method. Formula (XIV)

[In the formula, R ¹¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic ring, and other symbols have the same meanings as described above. (XIV) or a salt thereof or a reactive derivative thereof (for example, acid halide, acid anhydride, active ester, ester, acid imidazolide, acid azide, etc.) by the formula (XV)

Wherein the symbols are as defined above. By reacting with the compound (XV) or a salt thereof represented by the formula (XVI)

[The symbols in the formula are as defined above. The amide compound (XVI) represented by the formula: or a salt thereof can be produced.
This reaction is an amidation reaction, and the reactive derivative of compound (XIV), reaction conditions, reaction solvent, reaction time and the like are performed according to the method described in the above-mentioned method G-3.
The obtained compound (XVI) or a salt thereof is subjected to an intramolecular cyclization reaction in the same manner as in the above method D to give a compound of the formula (II)

[The symbols in the formula are as defined above. Or a salt thereof.
Compound (XVI) used in the above-mentioned Method I can also be produced according to the following Method J.

［式中の記号は前記と同意義を示す］で表される化合物（ＸＶＩＩ）またはその塩と、式（ＸＶ）

〔式中、記号は前記と同意義を示す。〕で表わされる化合物（ＸＶ）またはその塩と反応させることにより、式（ＸＶＩＩＩ）

〔式中、記号は前記と同意義を示す。〕で表わされる化合物（ＸＶＩＩＩ）またはその塩を製造することができる。
本反応は、常法に従い、反応に悪影響をおよぼさない溶媒中で行われる。
反応に影響をおよぼさない溶媒としては、例えば、クロロホルム、ジクロロメタンなどのハロゲン化炭化水素類；ベンゼン、トルエンなどの芳香族炭化水素類；テトラヒドロフラン、ジオキサン、ジエチルエーテルなどのエーテル類、酢酸エチルなどが挙げられる。これらの溶媒は、適宜の割合で混合して用いてもよい。
化合物（ＸＶ）の使用量は、化合物（ＸＶＩＩ）に対し、約１〜約１０モル当量、好ましくは１〜３モル当量である。
反応温度は、通常、−３０℃〜１５０℃の温度範囲で行われ、好ましくは０℃〜１００℃である。反応時間は、通常、１０分間から４８時間であり、好ましくは０．５〜２０時間である。
このようにして得られる化合物（ＸＶＩＩＩ）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。
このようにして得られる化合物（ＸＶＩＩＩ）は、上記反応Ｇ−１に示す方法に従い化合物（ＸＶＩ）へと導かれる。 Method J
Formula (XVII)

A compound of the formula (XVII) or a salt thereof represented by the formula (XV)

Wherein the symbols are as defined above. By reacting with a compound (XV) or a salt thereof represented by the formula (XVIII)

Wherein the symbols are as defined above. (XVIII) or a salt thereof.
This reaction is carried out in a conventional manner in a solvent that does not adversely affect the reaction.
Examples of the solvent that does not affect the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; and ethyl acetate. Is mentioned. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XV) to be used is about 1 to about 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XVII).
The reaction temperature is usually in the range of -30C to 150C, and preferably 0C to 100C. The reaction time is generally 10 minutes to 48 hours, preferably 0.5 to 20 hours.
The compound (XVIII) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
The compound (XVIII) thus obtained is led to the compound (XVI) according to the method shown in the above Reaction G-1.

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＩＶ）又はその塩は、例えば次に示す方法により製造できる。式（ＸＩＸ）

で表わされる化合物（ＸＩＶ）またはその塩あるいはその反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド、酸アジド等）を式（ＸＶ）

〔式中、記号は前記と同意義を示す。〕で表わされる化合物（ＸＶ）またはその塩と反応させることにより、式（ＸＸ）

〔式中の記号は前記と同意義を示す。〕で表されるアミド化合物（ＸＸ）またはその塩を製造することができる。
本反応はアミド化反応であり、化合物（ＸＩＸ）の反応性誘導体、反応条件、反応溶媒、反応時間等は、前記の方法Ｇ−３で説明した方法に準じて行われる。
得られた化合物（ＸＸ）またはその塩を、前記の方法Ｄと同様の方法により分子内環化反応を行うことにより、式（ＩＶ）

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＩＶ）又はその塩を製造することができる。 Method K
Formula (IV)

Wherein the symbols are as defined above. The compound (IV) or a salt thereof can be produced, for example, by the following method. Formula (XIX)

(XIV) or a salt thereof or a reactive derivative thereof (for example, acid halide, acid anhydride, active ester, ester, acid imidazolide, acid azide, etc.) by the formula (XV)

Wherein the symbols are as defined above. By reacting with a compound (XX) represented by the formula:

[The symbols in the formula are as defined above. ] Or a salt thereof.
This reaction is an amidation reaction, and the reactive derivative of compound (XIX), reaction conditions, reaction solvent, reaction time and the like are performed according to the method described in the above-mentioned method G-3.
The obtained compound (XX) or a salt thereof is subjected to an intramolecular cyclization reaction in the same manner as in the above method D to give a compound of the formula (IV)

[The symbols in the formula are as defined above. Or a salt thereof.

〔式中の記号は前記と同意義を示す。〕で表されるイソクマリン化合物（Ｘ）又はその塩は、例えば、次に示す方法、即ち、式（ＸＸＩＩ）

（式中の記号は前記と同意義を示す。）で表わされる化合物（ＸＸＩＩ）またはその塩と式（ＸＸＩＩＩ）

〔式中、Ｚは脱離基（前記Ｌと同意義を示す。）を示し、Ｒ^１２は低級（Ｃ_１−６）アルキル基（例えばメチル、エチル、プロピル、ブチル、tert-ブチル基等）を示す。〕で表される化合物（ＸＸＩＩＩ）又はその塩とを塩基存在下に反応させ、つづいて酸性条件下にて脱水ならびに脱炭酸させてイソクマリン化合物（Ｘ）の３位がカルボキシル基の化合物を製造することができる。また、所望によりそのカルボン酸をエステル化することにより３位エステル体を製造することができる。 Method L
Formula (X)

[The symbols in the formula are as defined above. The isocoumarin compound (X) or a salt thereof represented by the formula (XXII)

(Wherein the symbols are as defined above) and a compound (XXII) or a salt thereof represented by the formula (XXIII)

[Wherein, Z represents a leaving group (having the same meaning as L above), and R ¹² represents a lower (C _1-6 ) alkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl group, etc.). Is shown. Is reacted with a compound (XXIII) or a salt thereof in the presence of a base, followed by dehydration and decarboxylation under acidic conditions to produce a compound having a carboxyl group at the 3-position of the isocoumarin compound (X). be able to. If desired, the carboxylic acid can be esterified to produce a 3-position ester.

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＸＩＩ）又はその塩は、式（Ｘ）

〔式中、記号は前記と同意義を示す。〕で表される化合物（Ｘ）又はその塩とアンモニアを反応させた後、酸性条件下で脱水させることにより製造することができる。 Method M
Formula (XII)

[The symbols in the formula are as defined above. The compound (XII) or a salt thereof represented by the formula (X)

Wherein the symbols are as defined above. After reacting the compound (X) or a salt thereof represented by the formula (1) with ammonia, followed by dehydration under acidic conditions.

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＩＸ）又はその塩は、式（ＸＸＩＩ）

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＸＸＩＩ）又はその塩あるいはその反応性誘導体（例えば、酸ハライド、酸無水物、活性エステル、エステル、酸イミダゾリド、酸アジド等）を式（ＸＶ）

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＸＶ）又はその塩と反応させることにより製造することができる。
本反応はアミド化反応であり、化合物（ＸＸＩＩ）の反応性誘導体、反応条件、反応溶媒、反応時間等は、前記の方法Ｇ−３で説明した方法に準じて行われる。 Method N
Formula (XXIV)

Wherein the symbols are as defined above. The compound (IX) or a salt thereof represented by the formula (XXII)

[The symbols in the formula are as defined above. (XXII) or a salt thereof or a reactive derivative thereof (for example, acid halide, acid anhydride, active ester, ester, acid imidazolide, acid azide, etc.) by the formula (XV)

Wherein the symbols are as defined above. ] Or a salt thereof (XV) or a salt thereof.
This reaction is an amidation reaction, and the reactive derivative of compound (XXII), reaction conditions, reaction solvent, reaction time and the like are performed according to the method described in the above-mentioned method G-3.

〔式中、記号は前記と同意義を示す。〕で表される化合物（ＶＩＩ）又はその塩は、式（ＩＩ）

〔式中の記号は前記と同意義を示す。〕で表される化合物（ＩＩ）又はその塩を塩基存在下にトリフラート化試薬（例えば、トリフルオロメタンスルホン酸無水物、ビス（トリフルオロメタンスルホニル）アニリン等）と反応させることにより製造することができる。
本反応で用いる塩基としては、例えば水素化ナトリウム、水素化カリウムなどの水素化アルカリ金属類、例えば水酸化リチウム、水酸化ナトリウム、水酸化カリウムなどの水酸化アルカリ金属類、水酸化マグネシウム、水酸化カルシウムなどの水酸化アルカリ土類金属類、炭酸ナトリウム、炭酸カリウムなどの炭酸アルカリ金属類、例えば炭酸水素ナトリウム、炭酸水素カリウムなどの炭酸水素アルカリ金属などの無機塩基類、例えばナトリウムメトキシド、ナトリウムエトキシド、ナトリウムtert-ブトキシド等の炭素数１ないし６の金属アルコキシド類、例えばトリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ピコリン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、１,５−ジアザビシクロ［４.３.０］ノン−５−エン、１,４−ジアザビシクロ［２.２.２］オクタン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセンなどの有機塩基類、メチルリチウム、ｎ−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウムなどの有機リチウム類、リチウムジイソプロピルアミド等のリチウムアミド類が好んで用いられる。
本反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としては例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等のアルコール類、例えばジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等のエーテル類、例えばギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等のエステル類、例えばジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等のハロゲン化炭化水素類、例えばｎ−ヘキサン、ベンゼン、トルエン等の炭化水素類、例えばホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えばアセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。 Method O
Formula (VII)

Wherein the symbols are as defined above. The compound (VII) or a salt thereof represented by the formula (II)

[The symbols in the formula are as defined above. Or a salt thereof with a triflating reagent (for example, trifluoromethanesulfonic anhydride, bis (trifluoromethanesulfonyl) aniline, etc.) in the presence of a base.
Examples of the base used in this reaction include alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, magnesium hydroxide, and hydroxides. Inorganic bases such as alkali earth metal hydroxides such as calcium, alkali metal carbonates such as sodium carbonate and potassium carbonate, for example, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, for example, sodium methoxide, sodium ethoxy And alkoxides having 1 to 6 carbon atoms such as sodium tert-butoxide and the like, for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3. 0] Organic bases such as -5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, methyllithium, n-butyllithium, Organic lithiums such as sec-butyllithium and tert-butyllithium, and lithium amides such as lithium diisopropylamide are preferably used.
This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether. For example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and the like, for example, n-hexane, benzene, toluene and the like Amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and nitriles such as acetonitrile and propionitrile; Sulfoxides, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.

The starting compounds (XIV), (XV), (XVII), (XIX) and (XXII) used in the above-mentioned production methods A to O are either commercially available or produced by a method known per se or a method analogous thereto. can do.
When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also.
In addition, in each reaction of the production method of the compound (I) and each reaction of the synthesis of the starting compound, when the starting compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, these groups are generally used in peptide chemistry and the like. The protective compound may be a compound into which a protective group which is commonly used is introduced, and the target compound can be obtained by removing the protective group as necessary after the reaction.
Examples of the amino-protecting group include formyl, an optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl ( For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc., allyloxycarbonyl (Aloc), phenyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc), C _7-10 aralkyl-carbonyl (for example, benzyl Carbonyl, etc.), C _7-10 aralkyl-oxycarbonyl (eg, benzyloxycarbonyl (Z), etc.), C _7-10 aralkyl (eg, benzyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene and the like are used. Is You. Examples of these substituents include a phenyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like. The number of substituents used is about 1 to 3.
Examples of the carboxyl-protecting group include, for example, C _1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl and the like) which may have a substituent. Allyl, benzyl, phenyl, trityl or trialkylsilyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used. And the number of substituents is about 1 to 3.
Examples of the hydroxy-protecting group include, for example, C _1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl and the like) which may have a substituent. C _7-10 aralkyl (e.g., benzyl etc.), _{formyl, C 1-6} alkyl - carbonyl (e.g., acetyl, ethyl carbonyl), _{benzoyl, C 7-10} aralkyl - carbonyl (e.g., benzylcarbonyl), tetrahydropyranyl , Furanyl or silyl is used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), phenyl, C _7-10 aralkyl (eg, Benzyl, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, n-propoxy, etc.), nitro group and the like, and the number of substituents is about 1 to 4.
As a method for removing the protecting group, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride , Palladium acetate or the like.
The compound (I) thus obtained can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, preparative high-performance liquid chromatography. Isolation and purification can be performed by using means such as chromatography (HPLC) and medium pressure preparative liquid chromatography (medium pressure preparative LC).
The salt of the compound (I) can be prepared by a known method, for example, by adding an inorganic acid or an organic acid when the compound (I) is a basic compound, or by adding an inorganic acid or an organic acid when the compound (I) is an acidic compound. Can be produced by adding an organic base or an inorganic base.
When optical isomers can exist in compound (I), both of these individual optical isomers and mixtures thereof are, of course, included in the scope of the present invention. It can be optically divided according to the means, or can be manufactured individually.
Compound (I) may be a hydrate, and both a hydrate and a non-hydrate are included in the scope of the present invention. The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

  The JNK inhibitor having an isoquinolinone skeleton of the present invention selectively inhibits JNK, has low toxicity and has few side effects (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug toxicity). It is more excellent as a drug in terms of interaction, carcinogenicity, etc.) and is useful as a safe drug. The JNK inhibitor having an isoquinolinone skeleton of the present invention has an excellent JNK selective inhibitory effect on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Because of its excellent oral (oral) absorption and (metabolism) stability, JNK-related conditions or diseases such as chronic or acute heart failure, cardiac hypertrophy, dilated, hypertrophic or restricted cardiomyopathy, acute coronary syndrome ( Acute myocardial infarction, unstable angina, etc.), chronic ischemic heart disease (including exertional angina, old myocardial infarction and associated angina), acute or chronic myocarditis, left heart Diastolic dysfunction, left systolic dysfunction, ventricular, nodular or atrial arrhythmias, pulmonary hypertension, aneurysms or varices, peripheral circulatory insufficiency such as obstructive atherosclerosis, hypertension and nephropathy / nephritis associated with it ,sugar Cardiovascular diseases such as pathologic nephropathy, diabetic retinopathy, vascular endothelial dysfunction, arteriosclerosis or restenosis after coronary angioplasty; rheumatoid arthritis, osteoarthritis, gout, bronchitis, cystic fibrosis Inflammatory diseases such as inflammatory bowel disease, irritable bowel syndrome, mucinous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, multiple sclerosis, eczema, dermatitis, hepatitis, glomerulonephritis; Asthma, chronic obstructive pulmonary disease, allergic disease, obstructive pulmonary disease (COPD), obesity, diabetes, diabetic retinopathy, diabetic neuropathy, psoriasis, cancer; Alzheimer's disease, Huntington's chorea, Parkinson's disease, epilepsy, Due to prion disease such as Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, peripheral neuropathy, spinal cord injury or cerebrovascular disorder (stroke, subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, etc.) Neurodegenerative diseases such as nervous disorders; spinal cord injury, cerebrovascular disorder (stroke, subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, etc.), ischemic injury to organs selected from heart, kidney, liver and brain, ischemia reperfusion It can be used as a prophylactic or therapeutic agent for disorders, autoimmune diseases, organ failure, endotoxin shock or rejection at the time of transplantation, or an agent for improving the prognosis of myocardial infarction. Preferably, chronic or acute heart failure, cardiac hypertrophy, chronic or acute ischemic heart disease, myocarditis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, asthma, ischemic reperfusion injury, organ failure, stroke, cerebrovascular It is an agent for preventing and treating disorders and rejection after organ transplantation.

When the compound of the present invention is applied to each of the above-mentioned diseases, it can be used as appropriate in combination with drugs or therapeutic methods commonly used for those diseases. For example, in heart failure, angiotensin converting enzyme (ACE) inhibitors (eg, alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, belindopril, etc.), angiotensin II receptor antagonist Drugs (eg, losartan, candesartan cilexetil, valsartan, telmisartan, irbesartan, eprosartan, olmesartan, forasartan, etc.), β receptor antagonists (eg, propranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol, penbutrol, charte Olol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol, metoprolol, labetalo , Amosulalol, arotinolol, etc.), Ca antagonists (eg, manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amlodipine, alanidipine, etc.), diuretics (eg, bentylhydrochlorothiazide, cyclopenthiazide, ethiazide, hydrochlorothiazide, hydrochloride) Thiazide diuretics such as flumethiazide, methiclothiazide, penfluthiazide, polythiazide and trichlormethiazide; loop diuretics such as chlorthalidone, clofenamide, indapamide, mefluside, methicran, sotrazone, tribamide, quinetazone, metrazone, furosemide, mefluside; , Eplerenone, potassium-sparing diuretics such as triamterene, etc.), digitalis preparations (eg, digitoxin, digo) Syn, methyl digoxin, lanatoside C, prossilazin, etc.), endothelin antagonists (bosentan, tezosentan, etc.), vasopressin antagonists (YM-087, etc.), ANP or BNP preparations, Ca sensitivity enhancers (eg, levosimendan, pimobendan, etc.) ), Anticoagulants (eg, warfarin, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, argatroban, gabexate, ozacrel sodium, ethyl icosapentate, beraprost sodium, alprosta Jill, pentoxifylline, tisokinase, streptokinase, etc.), antiarrhythmic drugs (eg, quinidine, procainamide, disopyramide, azimaline, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propa Sodium channel blockers such as phenone, flecainide, pilsicainide, and phenytoin; potassium channel blockers such as amiodarone; calcium channel blockers such as verapamil and diltiazem; PDE inhibitors (eg, amrinone, milrinone, olprinone hydrochloride), diabetes Therapeutic agents (eg, sulfonylurea agents such as tolbutamide, chlorpropamide, glyclopyramide, acetohexamide, tolazamide, glibenclamide, and glybusol; biguanides such as metformin hydrochloride and buformin hydrochloride; α-glucosidase inhibitors such as voglibose and acarbose , Pioglitazone, troglitazone and other insulin sensitizers; insulin, glucagon, diabetic complications such as epalrestat, etc.), anti-obesity drugs, etc. A possible use, implantable artificial heart, implantable defibrillators, ventricular pacing procedure, Batista procedure is also applicable when receiving a heart transplant and cell transplantation. For example, in acute myocardial infarction or myocardial infarction prognosis, anticoagulants such as antithrombotic drugs (eg, heparin sodium, heparin calcium, warfarin, fondaparin (Alixtra), ximelagatran (exanta), factor Xa inhibitor); Thrombolytic drugs such as urokinase; antiplatelet drugs such as aspirin, sulfinpyrazone (anturane), dipyridamole (persantin), acropidine (panaldine), cilostazol (pletal), clopidogrel, aviciximab (leopro), and tirofiban (aglastat) , Angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, β receptor antagonists, antidiabetic drugs, antihyperlipidemic drugs (eg, pravastatin, fluvastatin, cerivastatin, atorvastatin HMG-CoA reductase inhibitors; fibrate drugs such as simfibrate, clofibrate aluminum, clinofibrate, and fenofibrate), cell transplantation and stem cell augmentation drugs (eg, G-CSF), stents, PTCA and CABG Can be used in combination with coronary revascularization. For example, in rheumatoid arthritis, non-steroidal anti-inflammatory drugs (eg, acetaminophen, phenacetin, etensamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin) , Ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenin, epilizol, tiaramid hydrochloride, zaltoprofen, gabexate mesilate, camostat mesylate, ulinastatin, colchicine, probenedide, sulfinpyrazone, benzbromarone , Allopurinol, sodium gold thiomalate, sodium hyaluronate, salicylic acid Thorium, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorfinol, ketoprofen, naproxen, oxymorphone or a salt thereof, an immunomodulatory or immunosuppressant (eg, methotrexate, cyclosporine, tacrolimus, gusperimus, azathioprine) , Anti-lymphocyte serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc., steroids (eg, dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinoin Lonacetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, propio Beclomethasone acid, estriol, etc., p38 MAP kinase inhibitor, anti-TNF-α drug (eg, etanercept, infliximab, D2E7, CDP-571, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF -α antibody, etc.), cyclooxygenase inhibitors (eg, salicylic acid derivatives such as celecoxib, rofecoxib, aspirin, MK-663, valdecoxib, SC-57666, thylakoxib, S-2474, diclofenac, indomethacin, loxoprofen, etc.) is there.
Furthermore, when the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in combination with a biologic (eg, antibody, vaccine preparation, etc.), and can be applied as a combination therapy in combination with gene therapy. It is also possible. As antibodies and vaccine preparations, for example, vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccine (such as DIAPEP-277 of Peptor) In addition to anti-HIV antibodies and HIV vaccine preparations, etc., antibodies or vaccine preparations for cytokines, renin-angiotensin enzymes and their products, antibodies or vaccine preparations for enzymes and proteins involved in blood lipid metabolism, blood coagulation / radiation Examples include antibodies or vaccines relating to enzymes or proteins involved in the dissolution system, and antibodies or vaccine preparations relating to proteins involved in glucose metabolism or insulin resistance. In addition, it can be used in combination with biological agents related to growth factors such as GH and IGF. Examples of gene therapy include, for example, cytokines, renin-angiotensin enzymes and their products, G proteins, G protein-coupled receptors and therapies using genes related to their kinases, and DNA such as NFκB decoy. Treatment methods using decoys, treatment methods using antisense, genes related to enzymes and proteins involved in blood lipid metabolism (for example, metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids) Therapy using genes related to enzymes and proteins (eg, growth factors such as HGF and VEGF) involved in angiogenesis therapy for peripheral vascular obstruction, etc. Treatment with genes related to proteins involved in glucose metabolism and insulin resistance, for cytokines such as TNF Antisense and the like. In addition, various organ regeneration methods such as heart regeneration, kidney regeneration, pancreatic regeneration, and blood vessel regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.), and artificial organs (artificial blood vessels and myocardium) using tissue engineering (Cell sheet).

The compound (I) or a salt thereof of the present invention can be administered orally or parenterally as it is or by mixing a pharmacologically acceptable carrier.
When the preparation of the present invention containing compound (I) or a salt thereof is administered orally, examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules) And microcapsules), syrups, emulsions, suspensions and the like. Examples of the dosage form for parenteral administration include injections, injections, drops, suppositories and the like. Can be In addition, a suitable base material (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc.) It is also effective to make a combination sustained-release preparation.
The content of compound (I) or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, but is usually 2 to 85% by weight, preferably 5 to 70% by weight based on the whole preparation.

As a method for producing the compound (I) or a salt thereof in the above-mentioned dosage form, a known production method generally used in the art can be applied. In the case of producing the above-mentioned dosage form, if necessary, an excipient, a binder, a disintegrant, a lubricant, a sweetener, an interfacial agent usually used in the field of formulation when producing the dosage form. It can be produced by appropriately containing an appropriate amount of an activator, a suspending agent, an emulsifier and the like.
For example, when compound (I) or a salt thereof is prepared into a tablet, the compound (I) or a salt thereof can be prepared by adding an excipient, a binder, a disintegrant, a lubricant, and the like, and is prepared into pills and granules. In such a case, it can be produced by including an excipient, a binder, a disintegrant and the like. In the case of powders and capsules, excipients, etc., in the case of syrups, sweeteners, etc., in the case of emulsions or suspensions, suspending agents, surfactants , An emulsifier and the like.
Examples of the excipient include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like.
Examples of the binder include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
Examples of disintegrants include starch, calcium carbonate and the like.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite and the like.
Examples of the emulsifier include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
When the compound (I) or a salt thereof is produced in the above-mentioned dosage form, if necessary, a coloring agent, a preservative, a fragrance, a flavoring agent, a stabilizer, a stabilizer, a thickener, etc., which are usually used in the field of purification, may be used. An appropriate amount can be added.

The preparation of the present invention containing compound (I) or a salt thereof is stable, has low toxicity, and can be used safely. The daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, and the like. The daily dose for an adult (body weight: about 60 kg) is about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as an active ingredient (compound (I) or a salt thereof). It can be administered in two or three divided doses.
When the compound (I) of the present invention or a salt thereof is administered parenterally, it is usually administered in the form of a liquid (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but is usually about 0.01 mg to about 100 mg, preferably about 0.01 to about 100 mg / kg body weight in the form of an injection. Conveniently 50 mg, more preferably about 0.01 to about 20 mg, is administered by intravenous injection. Injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like, and sustained-release preparations include iontophoresis transdermals. Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention or a salt thereof in a sterile aqueous or oily liquid. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents such as alcohols. (Eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50) and the like. Examples of the oily liquid include sesame oil and soybean oil, and may be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.). The prepared injection solution is usually filled in an ampoule.

  When the compound of the present invention and another drug are used in combination, the administration form of the compound of the present invention and the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. (2) Simultaneous administration of the two preparations obtained in the same administration route by the same administration route, (3) a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Separate preparation of the compound of the present invention and the concomitant drug And administration of the two preparations obtained in different times with different administration routes (for example, administration in the order of the compound of the present invention → concomitant drug or administration in the reverse order) and the like. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.

  The compound (I) or a salt thereof of the present invention has an excellent JNK-specific inhibitory activity and an excellent oral absorbability, and is therefore advantageous as a safe and effective medicament for the prevention and treatment of JNK-related conditions or diseases. Used for

The present invention is further described in the following Examples, Preparation Examples and Experimental Examples, which are merely illustrative and do not limit the present invention, and may be modified without departing from the scope of the present invention. You may let it.
Elution in the column chromatography in the examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, 60F ₂₅₄ manufactured by Merck or NH manufactured by Fuji Silysia Chemical Ltd. was used as a TLC plate, the solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. It was adopted. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh) manufactured by Merck was also used. NMR spectra were measured on a Varian Gemini 200 or Mercury 300 spectrometer using tetramethylsilane as an internal or external standard, and chemical shifts were expressed as δ values and coupling constants were expressed in Hz. The IR spectrum was measured with a Shimadzu FTIR-8200 spectrometer.
In the examples, HPLC was measured under the following conditions to determine purity and the like.
Measurement equipment: Shimadzu LC-10Avp system (unless otherwise specified) or Agilent 1100 system Column: CAPSEL PAK C18UG120 S-3 μm, 2.0 X 50mm
Solvent: solution A; water containing 0.1% trifluoroacetic acid,
Solution B: Acetonitrile gradient cycle containing 0.1% trifluoroacetic acid: (Method A): 0.00 minutes (solution A / solution B = 90/10), 2.00 minutes (solution A / solution B = 5/95), 2.75 minutes (A (Solution / B solution = 5/95), 2.76 minutes (solution A / B solution = 90/10), 3.45 minutes (solution A / solution B = 90/10), or (Method B): 0.00 minutes (solution A / B solution = 90/10), 4.00 minutes (A solution / B solution = 5/95), 5.50 minutes (A solution / B solution = 5/95), 5.51 minutes (A solution / B solution = 90/10), 8.00 minutes (A solution / B solution = 90/10)
Injection volume: 10 μl, flow rate: 0.5 ml / min, detection method: UV 220 nm
In the examples, the mass spectrum (MS) was measured under the following conditions.
Measurement equipment: Micromass Platform II, Waters ZQ, Waters ZMD, or JEOL Ltd. JMS-AX505W
Ionization method: Atmospheric Pressure Chemical Ionization (APCI), Electron Impact Ionization (Electron Spray Ionization: ESI), or Fast Atom Bombardment (FAB)
For purification of the compounds in Reference Examples and Examples, in addition to column chromatography, the following preparative HPLC apparatus or medium pressure preparative LC apparatus was used.
1) Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep ODS-A S-5 μm, 50 X 20 mm
Solvent: solution A; water containing 0.1% trifluoroacetic acid,
Solution B: Acetonitrile gradient cycle containing 0.1% trifluoroacetic acid: 0.00 minutes (solution A / solution B = 90/10), 1.20 minutes (solution A / solution B = 90/10), 4.75 minutes (solution A / solution B = 0/100), 7.30 minutes (solution A / B = 0/100), 7.40 minutes (solution A / B = 90/10), 7.50 minutes (solution A / B = 90/10)
Flow rate: 25 ml / min, detection method: UV 220nm
2) Medium pressure preparative LC equipment: Moritex high-throughput purification system (purif 8)
Column: HI-FLASH ^TM COLUMN (silica gel: 40 μm, 60 mm), 26 x 100 mm or 20 x 65 mm
Flow rate: 20 ml / min Detection method: UV 254 nm
In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. Further,% in the solution represents the number of grams in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
dd: Double doublet
m: multiplet
br: Broad
brs: Broad singlet
J: coupling constant
CDCl ₃ : heavy chloroform
DMSO-d _6: deuterated dimethyl sulfoxide
¹ H-NMR: proton nuclear magnetic resonance WSC: water-soluble carbodiimide THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethylsulfoxide Tf: trifluoromethanesulfonyl Me: methyl

4-クロロ無水フタル酸(12.1 g)のメタノール溶液(50 ml)に、ナトリウムメトキシド(3.6 g)を加え室温で12時間攪拌した。溶媒を減圧下に除去し、残留物を酢酸エチル及び1規定塩酸により分液した。有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮し、4-クロロフタル酸 1-及び2-メチルエステル混合物を得た。また、ブロモ酢酸メチル(10.1 g)、トリエチルアミン(9.7 ml)およびTHF(70 ml)の混合液に、0℃攪拌下ベンジルアミン(7.1 g)のTHF溶液(35 ml)を滴下し、1時間攪拌した。室温にて更に1時間攪拌した後、溶媒を減圧下に除去した。残留物を酢酸エチル及び水にて分液し、有機層を硫酸マグネシウムにて乾燥後、減圧下に濃縮乾固した。次いで、本品、4-クロロフタル酸 1-及び2-メチルエステル混合物(上述)及びアセトニトリル(70 ml)の混合物に、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(16.5 g)及び4-ヒドロキシベンゾトリアゾール一水和物(11.2 g)を加え、室温で12時間攪拌した。溶媒を減圧下に除去した後、残留物を酢酸エチルにて希釈し、1規定塩酸及び飽和重曹水により順次分液、乾燥後、濃縮乾固した。次いで、本品をメタノール(100 ml)に溶解し、室温攪拌下、28％ナトリウムメトキシド/メタノール溶液(26 g)を加え、室温で1時間攪拌した。反応液を濃縮し、残留物を酢酸エチル及び1規定塩酸により分液し、有機層を乾燥後濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=4/1)にて精製し、ヘキサン/酢酸エチルより再結晶することにより、黄色結晶の表題化合物(4.5 g)を得た。
¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 5.61 (2H, s), 7.00-7.10 (2H, m), 7.16-7.32 (3H, m), 7.66 (1H, dd, J = 1.8, 8.4 Hz), 8.14 (1H, d, J = 1.8 Hz), 8.44 (1H, dd, J = 0.3, 8.4 Hz), 11.02 (1H, s). Example 1
2-benzyl-6-chloro-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Sodium methoxide (3.6 g) was added to a methanol solution (50 ml) of 4-chlorophthalic anhydride (12.1 g), and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a mixture of 4-chlorophthalic acid 1- and 2-methyl esters. To a mixture of methyl bromoacetate (10.1 g), triethylamine (9.7 ml) and THF (70 ml) was added dropwise a solution of benzylamine (7.1 g) in THF (35 ml) with stirring at 0 ° C, and the mixture was stirred for 1 hour. did. After stirring at room temperature for another hour, the solvent was removed under reduced pressure. The residue was separated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.5 g) was added to a mixture of the product, a mixture of 4-chlorophthalic acid 1- and 2-methyl esters (described above) and acetonitrile (70 ml). And 4-hydroxybenzotriazole monohydrate (11.2 g) were added, and the mixture was stirred at room temperature for 12 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, liquid-separated with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried and concentrated to dryness. Next, this product was dissolved in methanol (100 ml), a 28% sodium methoxide / methanol solution (26 g) was added under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was separated with ethyl acetate and 1N hydrochloric acid, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1), and recrystallized from hexane / ethyl acetate to give the title compound as yellow crystals (4.5 g).
¹ H-NMR (CDCl ₃ ) δ: 3.81 (3H, s), 5.61 (2H, s), 7.00-7.10 (2H, m), 7.16-7.32 (3H, m), 7.66 (1H, dd, J = 1.8, 8.4 Hz), 8.14 (1H, d, J = 1.8 Hz), 8.44 (1H, dd, J = 0.3, 8.4 Hz), 11.02 (1H, s).

本化合物は実施例１に示す方法に従い、4-ブロモ無水フタル酸及びピペロニルアミンを用いて合成した。淡黄色結晶（収率29％）。
¹H NMR (CDCl₃) δ: 3.89 (3H, s), 5.27 (2H, s), 5.91 (2H, s), 6.50-6.57 (2H, m), 6.71 (1H, dd, J = 1.8, 7.8 Hz), 7.82 (1H, dd, J = 1.8, 8.4 Hz), 8.32 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 8.4 Hz), 10.96 (1H, s). MS (ESI+): 432.0 (M+H), 434.0. Example 1 (2)
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-bromophthalic anhydride and piperonylamine. Pale yellow crystals (29% yield).
¹ H NMR (CDCl ₃ ) δ: 3.89 (3H, s), 5.27 (2H, s), 5.91 (2H, s), 6.50-6.57 (2H, m), 6.71 (1H, dd, J = 1.8, 7.8) Hz), 7.82 (1H, dd, J = 1.8, 8.4 Hz), 8.32 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 8.4 Hz), 10.96 (1H, s) .MS ( ESI +): 432.0 (M + H), 434.0.

本化合物は実施例１に示す方法に従い、4-クロロ無水フタル酸及び (2,3-ジヒドロ-1-ベンゾフラン-5-イルメチル)アミンを用いて合成した。無色結晶（収率12％）。
¹H NMR (CDCl₃) δ: 3.11 (2H, t, J = 8.4 Hz), 3.89 (3H, s), 4.52 (2H, t, J = 8.4 Hz), 5.55 (2H, s), 6.67 (1H, d, J = 7.8 Hz), 6.79-6.89 (2H, m), 7.66 (1H, dd, J = 2.1, 8.1 Hz), 8.13 (1H, dd, J = 0.6, 2.1 Hz), 8.44 (1H, d, J = 8.1 Hz), 10.90 (1H, s). Example 1 (3)
6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-chlorophthalic anhydride and (2,3-dihydro-1-benzofuran-5-ylmethyl) amine. Colorless crystals (12% yield).
¹ H NMR (CDCl ₃ ) δ: 3.11 (2H, t, J = 8.4 Hz), 3.89 (3H, s), 4.52 (2H, t, J = 8.4 Hz), 5.55 (2H, s), 6.67 (1H , d, J = 7.8 Hz), 6.79-6.89 (2H, m), 7.66 (1H, dd, J = 2.1, 8.1 Hz), 8.13 (1H, dd, J = 0.6, 2.1 Hz), 8.44 (1H, d, J = 8.1 Hz), 10.90 (1H, s).

本化合物は実施例１に示す方法に従い、4-クロロ無水フタル酸及び4-(メトキシカルボニル)ベンジルアミンを用いて合成した。淡黄色結晶。
¹H NMR (CDCl₃) δ: 3.75 (3H, s), 3.89 (3H, s), 5.59 (2H, s), 7.15 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.96 (2H, d, J = 8.7 Hz), 8.17 (1H, d, J = 2.1 Hz), 8.43 (1H, d, J = 8.7 Hz), 11.9 (1H, s). Example 1 (4)
6-chloro-4-hydroxy-2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-chlorophthalic anhydride and 4- (methoxycarbonyl) benzylamine. Pale yellow crystals.
¹ H NMR (CDCl ₃ ) δ: 3.75 (3H, s), 3.89 (3H, s), 5.59 (2H, s), 7.15 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.96 (2H, d, J = 8.7 Hz), 8.17 (1H, d, J = 2.1 Hz), 8.43 (1H, d, J = 8.7 Hz), 11.9 (1H, s).

本化合物は実施例１に示す方法に従い、4-クロロ無水フタル酸及び4-(メタンスルホニル)ベンジルアミンを用いて合成した。黄色結晶。
¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.76 (3H, s), 5.55 (2H, s), 7.32 (2H, d, J = 8.7 Hz), 7.69 (1H, dd, J = 2.1, 8.7 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.19 (1H, d, J = 2.1 Hz), 8.40 (1H, d, J = 8.7 Hz), 11.29 (1H, s). Example 1 (5)
6-chloro-4-hydroxy-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-chlorophthalic anhydride and 4- (methanesulfonyl) benzylamine. Yellow crystals.
¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.76 (3H, s), 5.55 (2H, s), 7.32 (2H, d, J = 8.7 Hz), 7.69 (1H, dd, J = 2.1, 8.7 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.19 (1H, d, J = 2.1 Hz), 8.40 (1H, d, J = 8.7 Hz), 11.29 (1H, s).

2-ベンジル-6-クロロ-4-ヒドロキシ-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(4.5 g)のDMF溶液(45 ml)に、0℃攪拌下、水素化ナトリウム(630 mg)を加え、30分攪拌した。次いで、N-フェニルトリフルオロメタンスルホンイミド(5.6 g)を加え、室温にて更に3時間攪拌した後、溶媒を減圧濃縮した。残留物を酢酸エチル及び水にて分液し、有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮した。残渣を中圧分取LC（ヘキサン/酢酸エチル=4/1〜1/1）により精製し、無色結晶の表題化合物（3.0 g）を得た。
¹H-NMR (CDCl₃) δ: 3.69 (3H, s), 5.51 (2H, s), 7.14-7.19 (2H, m), 7.23-7.35 (3H, m), 7.64 (1H, dd, J = 2.1, 8.4 Hz), 7.76 (1H, d, J = 2.1 Hz), 8.46 (1H, d, J = 8.4 Hz). Example 1 (6)
2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

To a DMF solution (45 ml) of 2-benzyl-6-chloro-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (4.5 g) was added sodium hydride while stirring at 0 ° C. (630 mg) was added and stirred for 30 minutes. Next, N-phenyltrifluoromethanesulfonimide (5.6 g) was added, and the mixture was further stirred at room temperature for 3 hours, and then the solvent was concentrated under reduced pressure. The residue was separated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give the title compound (3.0 g) as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 3.69 (3H, s), 5.51 (2H, s), 7.14-7.19 (2H, m), 7.23-7.35 (3H, m), 7.64 (1H, dd, J = 2.1, 8.4 Hz), 7.76 (1H, d, J = 2.1 Hz), 8.46 (1H, d, J = 8.4 Hz).

本化合物は実施例１（６）に示す方法に従い、6-クロロ-2-(2,3-ジヒドロベンゾフラン-5-イルメチル)-4-ヒドロキシ-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステルを用いて合成した。無色結晶（収率66％）。¹H NMR (CDCl₃) δ: 3.14 (2H, t, J = 9.0 Hz), 3.78 (3H, s), 4.54 (2H, t, J = 9.0 Hz), 5.42 (2H, s), 6.69 (1H, d, J = 8.4 Hz), 6.92 (1H, dd, J = 2.1, 8.4 Hz), 7.02 (1H, s), 7.63 (1H, dd, J = 2.1, 8.7 Hz), 7.75 (1H, d, J = 2.1 Hz), 8.45 (1H, d, J = 8.7 Hz). Example 1 (7)
6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 1 (6), this compound was prepared using 6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3- It was synthesized using carboxylic acid methyl ester. Colorless crystals (66% yield). ¹ H NMR (CDCl ₃ ) δ: 3.14 (2H, t, J = 9.0 Hz), 3.78 (3H, s), 4.54 (2H, t, J = 9.0 Hz), 5.42 (2H, s), 6.69 (1H , d, J = 8.4 Hz), 6.92 (1H, dd, J = 2.1, 8.4 Hz), 7.02 (1H, s), 7.63 (1H, dd, J = 2.1, 8.7 Hz), 7.75 (1H, d, J = 2.1 Hz), 8.45 (1H, d, J = 8.7 Hz).

本化合物は実施例１（６）に示す方法に従い、6-クロロ-4-ヒドロキシ-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステルを用いて合成した。無色結晶。
¹H NMR (CDCl₃) δ: 3.71 (3H, s), 3.90 (3H, s), 5.54 (2H, s), 7.23 (2H, d, J = 8.4 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.98 (2H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz). Example 1 (8)
6-chloro-2- (4-methoxycarbonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 1 (6), the present compound was prepared by preparing 6-chloro-4-hydroxy-2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester. And synthesized. Colorless crystals.
¹ H NMR (CDCl ₃ ) δ: 3.71 (3H, s), 3.90 (3H, s), 5.54 (2H, s), 7.23 (2H, d, J = 8.4 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.98 (2H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz).

本化合物は実施例１（６）に示す方法に従い、6-クロロ-4-ヒドロキシ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステルを用いて合成した。無色結晶。
¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.79 (3H, s), 5.49 (2H, s), 7.40 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4 Hz), 7.79 (1H, d, J = 1.8 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.42 (1H, d, J = 8.4 Hz). Example 1 (9)
6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 1 (6), the present compound was prepared by treating methyl 6-chloro-4-hydroxy-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylate. And synthesized. Colorless crystals.
¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.79 (3H, s), 5.49 (2H, s), 7.40 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4 Hz), 7.79 (1H, d, J = 1.8 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.42 (1H, d, J = 8.4 Hz).

ブロモ酢酸メチル(2.47 ml)、トリエチルアミン(8.65 ml)およびTHF(46 ml)の混合液に、0℃攪拌下4-(メタンスルホニル)ベンジルアミン(4.6 g)のTHF溶液(46 ml)を滴下し、1時間攪拌した。室温にて更に3時間攪拌した後、溶媒を減圧下に除去した。残留物を酢酸エチル及び水にて分液し、有機層を硫酸マグネシウムにて乾燥後、減圧下に濃縮乾固した。次いで、本品、2-シアノ安息香酸(2.63 g)及びアセトニトリル(46 ml)の混合物に、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(5.14 g)及び4-ヒドロキシベンゾトリアゾール一水和物(3.56 g)を加え、室温で12時間攪拌した。溶媒を減圧下に除去した後、残留物を酢酸エチルにて希釈し、1規定塩酸及び飽和重曹水により順次分液、乾燥後、濃縮乾固した。次いで、本品をメタノール(41 ml)に溶解し、室温攪拌下、28％ナトリウムメトキシド/メタノール溶液(4.1 g)を加え、室温で1時間攪拌した。反応液を濃縮し、残留物を酢酸エチル及び1規定塩酸により分液し、有機層を乾燥後濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)にて精製し、ジエチルエーテル/酢酸エチルより再結晶することにより、黄色結晶の表題化合物(2.2 g)を得た。
¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.66 (3H, s), 5.43 (2H, s), 5.67 (2H, s), 7.36 (2H, d, J = 8.1 Hz), 7.68-7.88 (3H, m), 7.86 (2H, d, J = 8.1 Hz), 8.54 (1H, d, J = 8.4 Hz). MS (ESI+): 387 (M+H). Example 1 (10)
4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

To a mixture of methyl bromoacetate (2.47 ml), triethylamine (8.65 ml) and THF (46 ml) was added dropwise a THF solution (46 ml) of 4- (methanesulfonyl) benzylamine (4.6 g) while stirring at 0 ° C. And stirred for 1 hour. After stirring at room temperature for a further 3 hours, the solvent was removed under reduced pressure. The residue was separated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Then, to a mixture of the product, 2-cyanobenzoic acid (2.63 g) and acetonitrile (46 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.14 g) and 4-hydroxybenzotriazole Monohydrate (3.56 g) was added, and the mixture was stirred at room temperature for 12 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, liquid-separated with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried and concentrated to dryness. Next, this product was dissolved in methanol (41 ml), and a 28% sodium methoxide / methanol solution (4.1 g) was added under stirring at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, the residue was separated with ethyl acetate and 1N hydrochloric acid, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from diethyl ether / ethyl acetate to give the title compound (2.2 g) as yellow crystals.
¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.66 (3H, s), 5.43 (2H, s), 5.67 (2H, s), 7.36 (2H, d, J = 8.1 Hz), 7.68 -7.88 (3H, m), 7.86 (2H, d, J = 8.1 Hz), 8.54 (1H, d, J = 8.4 Hz). MS (ESI +): 387 (M + H).

2-(ベンゾ[1,3]ジオキソール-5-イルメチル)-6-ブロモ-4-ヒドロキシ-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(200 mg)、トリフェニルホスフィン（160 mg）、n-ブタノール(55 μl)のTHF溶液(4 ml)に、室温攪拌下、アゾジカルボン酸ジエチル/トルエン溶液(40％、270 μl)を加え、室温で1時間攪拌した。反応終了後、反応液を濃縮し、残渣を分取HPLCにより精製し、無色結晶の表題化合物（72 mg）を得た。¹H NMR (CDCl₃) δ: 0.99 (3H, t, J = 7.5 Hz), 1.43-1.58 (2H,m), 1.69-1.81 (2H, m), 3.80 (3H, s), 3.92 (2H, d, J = 6.3 Hz), 5.23 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.68 (1H, m), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI+) : 488.0 (M+H), 490.0. Example 1 (11)
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-butoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), triphenylphosphine ( 160 mg) and a THF solution (4 ml) of n-butanol (55 μl) were added with a diethyl azodicarboxylate / toluene solution (40%, 270 μl) under stirring at room temperature, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by preparative HPLC to obtain the title compound (72 mg) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.5 Hz), 1.43-1.58 (2H, m), 1.69-1.81 (2H, m), 3.80 (3H, s), 3.92 (2H, d, J = 6.3 Hz), 5.23 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.68 (1H, m), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI +): 488.0 (M + H), 490.0.

  The compound of Example 2-12 was prepared according to the method described in Example 1 (11) according to the procedure described in Example 1 (11). 2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-hydroxy-1-oxo-1, Synthesized using 2-dihydroisoquinoline-3-carboxylic acid methyl ester and the corresponding alcohol.

無色粉末(収率67％)。 ¹H NMR (CDCl₃) δ: 3.69 (3H, s), 4.98 (2H,s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.33-7.46 (5H, m), 7.69 (1H, dd, J = 2.1, 8.4 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.34 (1H, d, J = 8.4 Hz). MS (ESI+) : 522.1 (M+H), 524.1. Example 2
2- (benzo [1,3] dioxol-5-ylmethyl) -4-benzyloxy-6-bromo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless powder (67% yield). ¹ H NMR (CDCl ₃ ) δ: 3.69 (3H, s), 4.98 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.33-7.46 ( 5H, m), 7.69 (1H, dd, J = 2.1, 8.4 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.34 (1H, d, J = 8.4 Hz) .MS (ESI +): 522.1 ( M + H), 524.1.

ベージュ色粉末(収率42％)。¹H NMR (CDCl₃) δ: 3.67 (3H, s), 5.20 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.64-6.76 (3H, m), 7.70-7.80 (4H, m), 8.37 (1H, d, J = 8.7 Hz), 8.84 (1H, d, J = 6.6 Hz). MS (ESI+): 523.1 (M+H), 525.1. Example 3
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-1-oxo-4- (pyridin-4-ylmethoxy) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester trifluoroacetic acid salt

Beige powder (42% yield). ¹ H NMR (CDCl ₃ ) δ: 3.67 (3H, s), 5.20 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.64-6.76 (3H, m), 7.70-7.80 ( 4H, m), 8.37 (1H, d, J = 8.7 Hz), 8.84 (1H, d, J = 6.6 Hz). MS (ESI +): 523.1 (M + H), 525.1.

黄色結晶(収率41％)。¹H NMR (CDCl₃) δ: 3.73 (3H, s), 5.02 (2H, s), 5.26 (2H, s), 5.92 (2H, s), 6.67-6.77 (3H, m), 7.33-7.52 (5H, m), 7.58-7.67 (4H, m), 7.69 (1H, dd, J = 1.8, 8.4 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 8.4 Hz). MS (ESI+): 598.1 (M+H), 600.1. Example 4
2- (benzo [1,3] dioxol-5-ylmethyl) -4- (biphenyl-4-ylmethoxy) -6-bromo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (41% yield). ¹ H NMR (CDCl ₃ ) δ: 3.73 (3H, s), 5.02 (2H, s), 5.26 (2H, s), 5.92 (2H, s), 6.67-6.77 (3H, m), 7.33-7.52 ( 5H, m), 7.58-7.67 (4H, m), 7.69 (1H, dd, J = 1.8, 8.4 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 8.4 Hz ) .MS (ESI +): 598.1 (M + H), 600.1.

淡黄色油状物(収率44％)。¹H NMR (CDCl₃) δ: 1.02-1.42 (5H, m), 1.66-2.18 (6H, m), 3.71 (2H, d, J = 6.0 Hz), 3.79 (3H, s), 5.23 (2H, s), 5.92 (2H, s), 6.65-6.75 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI+): 528.1 (M+H), 530.1. Example 5
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-cyclohexylmethoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow oil (44% yield). ¹ H NMR (CDCl ₃ ) δ: 1.02-1.42 (5H, m), 1.66-2.18 (6H, m), 3.71 (2H, d, J = 6.0 Hz), 3.79 (3H, s), 5.23 (2H, s), 5.92 (2H, s), 6.65-6.75 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d , J = 8.7 Hz). MS (ESI +): 528.1 (M + H), 530.1.

淡黄色結晶(収率42％)。¹H NMR (CDCl₃) δ: 3.81 (3H, m), 4.91 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.35-6.39 (2H, m), 6.66-6.75 (3H, m), 7.47 (1H, m), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.93 (1H, d, J = 2.1 Hz), 8.32 (1H, d, J = 8.7 Hz). MS (ESI+): 512.0, (M+H), 514.0. Example 6
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- (furan-2-ylmethoxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (42% yield). ¹ H NMR (CDCl ₃ ) δ: 3.81 (3H, m), 4.91 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.35-6.39 (2H, m), 6.66-6.75 ( 3H, m), 7.47 (1H, m), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.93 (1H, d, J = 2.1 Hz), 8.32 (1H, d, J = 8.7 Hz). MS (ESI +): 512.0, (M + H), 514.0.

無色結晶(収率53％)。¹H NMR (CDCl₃) δ: 3.73 (3H, s), 3.83 (3H, s), 4.90 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 6.93 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 1.8, 8.4 Hz), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.4 Hz). MS (ESI+) : 552.0 (M+H), 554.0. Example 7
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- (4-methoxybenzyloxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless crystals (53% yield). ¹ H NMR (CDCl ₃ ) δ: 3.73 (3H, s), 3.83 (3H, s), 4.90 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 6.93 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 1.8, 8.4 Hz), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.4 Hz). MS (ESI +): 552.0 (M + H), 554.0.

淡黄色結晶(収率12％)。¹H NMR (CDCl₃) δ: 3.58 (3H, s), 4.40-4.50 (3H, m), 5.20 (2H, s), 5.91 (2H, s), 6.63-6.74 (3H, m), 7.22-7.42 (11H, m), 7.63 (1H, dd, J = 2.1, 8.7 Hz), 8.28 (1H, d, J = 8.7 Hz). MS (ESI+): 612.1 (M+H), 614.1. Example 8
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- (2,2-diphenylethoxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (12% yield). ¹ H NMR (CDCl ₃ ) δ: 3.58 (3H, s), 4.40-4.50 (3H, m), 5.20 (2H, s), 5.91 (2H, s), 6.63-6.74 (3H, m), 7.22- 7.42 (11H, m), 7.63 (1H, dd, J = 2.1, 8.7 Hz), 8.28 (1H, d, J = 8.7 Hz) .MS (ESI +): 612.1 (M + H), 614.1.

淡黄色結晶(収率44％)。¹H NMR (CDCl₃) δ: 3.47 (3H, s), 3.64-3.70 (2H, m), 3.81 (3H, s), 3.99-4.05 (2H, m), 5.24 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.32 (1H, d, J = 8.7 Hz). MS (ESI+): 490.0 (M+H), 492.0. Example 9
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- (2-methoxyethoxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (44% yield). ¹ H NMR (CDCl ₃ ) δ: 3.47 (3H, s), 3.64-3.70 (2H, m), 3.81 (3H, s), 3.99-4.05 (2H, m), 5.24 (2H, s), 5.92 ( 2H, s), 6.66-6.75 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.32 (1H, d, J = 8.7 Hz) ). MS (ESI +): 490.0 (M + H), 492.0.

無色結晶(収率53％)。¹H NMR (CDCl₃) δ: 3.06 (2H, t, J = 6.3 Hz), 3.59 (3H, s), 4.12 (2H, t, J = 6.3 Hz), 5.20 (2H, s), 5.91 (2H, s), 6.63-6.73 (3H, m), 7.23-7.39 (5H, m), 7.57 (1H, d, J = 2.1 Hz), 7.64 (1H, dd, J = 2.1, 8.4 Hz), 8.29 (1H, d, J = 8.4 Hz). MS (ESI+): 536.1 (M+H), 538.1. Example 10
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-1-oxo-4-phenethyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless crystals (53% yield). ¹ H NMR (CDCl ₃ ) δ: 3.06 (2H, t, J = 6.3 Hz), 3.59 (3H, s), 4.12 (2H, t, J = 6.3 Hz), 5.20 (2H, s), 5.91 (2H , s), 6.63-6.73 (3H, m), 7.23-7.39 (5H, m), 7.57 (1H, d, J = 2.1 Hz), 7.64 (1H, dd, J = 2.1, 8.4 Hz), 8.29 ( 1H, d, J = 8.4 Hz). MS (ESI +): 536.1 (M + H), 538.1.

茶色油状物(59％)。¹H NMR (CDCl₃) δ: 3.10 (2H, t, J = 6.0 Hz), 3.23 (6H, s), 3.68 (3H, s), 4.13 (2H, t, J = 6.0 Hz), 5.20 (2H, s), 5.92 (2H, s), 6.63-6.75 (3H, m), 7.39 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4 Hz), 8.30 (1H, d, J = 8.4 Hz). MS (ESI+): 579.1 (M+H), 581.1. Example 11
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- [2- (4-dimethylaminophenyl) ethoxy] -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid Methyl ester trifluoroacetate

Brown oil (59%). ¹ H NMR (CDCl ₃ ) δ: 3.10 (2H, t, J = 6.0 Hz), 3.23 (6H, s), 3.68 (3H, s), 4.13 (2H, t, J = 6.0 Hz), 5.20 (2H , s), 5.92 (2H, s), 6.63-6.75 (3H, m), 7.39 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4 Hz), 8.30 (1H, d, J = 8.4 Hz). MS (ESI +): 579.1 (M + H), 581.1.

淡黄色結晶(収率45％)。¹H NMR (CDCl₃) δ: 1.12-1.62 (6H, m), 1.70-1.85 (2H, m), 1.90-2.03 (2H, m), 3.77 (3H, s), 3.84 (1H, m), 5.27 (2H, s), 5.91 (2H, s), 6.62-6.74 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.95 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI+): 514.1 (M+H), 516.1. Example 12
2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-cyclohexyloxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (45% yield). ¹ H NMR (CDCl ₃ ) δ: 1.12-1.62 (6H, m), 1.70-1.85 (2H, m), 1.90-2.03 (2H, m), 3.77 (3H, s), 3.84 (1H, m), 5.27 (2H, s), 5.91 (2H, s), 6.62-6.74 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.95 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI +): 514.1 (M + H), 516.1.

  The compounds of Examples 13 to 15 were prepared according to the method described in Example 1 (11), using 2-benzyl-6-chloro-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and Synthesized using the corresponding alcohol.

黄色油状物(収率30％)。MS (ESI+): 448.1 (M+H), 450.1. Example 13
2-benzyl-6-chloro-1-oxo-4-phenethyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow oil (30% yield). MS (ESI +): 448.1 (M + H), 450.1.

黄色結晶(収率17％)。¹H NMR (CDCl₃) δ: 3.57 (3H, s), 5.01 (2H, s), 5.37 (2H, s), 7.16-7.37 (7H, m), 7.56 (1H, dd, J = 2.2, 8.8 Hz), 7.68 (1H, d, J = 2.2 Hz), 8.46 (1H, d, J = 8.8 Hz), 8.65 (2H, d, J = 6.0 Hz). MS (ESI+): 435.1 (M+H), 437.1. Example 14
2-benzyl-6-chloro-1-oxo-4- (pyridin-4-ylmethoxy) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (17% yield). ¹ H NMR (CDCl ₃ ) δ: 3.57 (3H, s), 5.01 (2H, s), 5.37 (2H, s), 7.16-7.37 (7H, m), 7.56 (1H, dd, J = 2.2, 8.8 Hz), 7.68 (1H, d, J = 2.2 Hz), 8.46 (1H, d, J = 8.8 Hz), 8.65 (2H, d, J = 6.0 Hz). MS (ESI +): 435.1 (M + H) , 437.1.

黄色結晶(収率10％)。¹H NMR (CDCl₃) δ: 3.46 (3H, s), 3.63-3.70 (2H, m), 3.72 (3H, s), 4.04-4.10 (2H, m), 5.35 (2H, m), 7.17-7.33 (5H, m), 7.53 (1H, dd, J = 2.1, 8.7 Hz), 7.97 (1H, dd, J = 0.6, 2.1 Hz), 8.41 (1H, dd, J = 0.6, 8.7 Hz). MS (ESI+): 402.1 (M+H), 404.1. Example 15
2-benzyl-6-chloro-4- (2-methoxyethoxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (10% yield). ¹ H NMR (CDCl ₃ ) δ: 3.46 (3H, s), 3.63-3.70 (2H, m), 3.72 (3H, s), 4.04-4.10 (2H, m), 5.35 (2H, m), 7.17- 7.33 (5H, m), 7.53 (1H, dd, J = 2.1, 8.7 Hz), 7.97 (1H, dd, J = 0.6, 2.1 Hz), 8.41 (1H, dd, J = 0.6, 8.7 Hz) .MS (ESI +): 402.1 (M + H), 404.1.

ジムロート付のナスフラスコに入った6-クロロ-2-(2,3-ジヒドロベンゾフラン-5-イルメチル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(175 mg)、炭酸ナトリウム(96 mg)、3-チオフェンボロン酸(52 mg)、テトラキス(トリフェニルホスフィン)パラジウム(0)(12 mg)、トルエン(2.0 ml)、水(0.4 ml)及びエタノール(0.4 ml)の混合物を、真空ラインで脱気した後アルゴンにより置換し、80℃で12時間攪拌した。反応液を冷却後、反応液を水及び酢酸エチルにより分液し、有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=６/1)にて精製し、無色粉末の表題化合物(120 mg)を得た。
¹H NMR (CDCl₃) δ: 3.14 (2H, t, J = 8.7 Hz), 3.71 (3H, s), 4.53 (2H, t, J = 8.7 Hz), 6.67 (1H, d, J = 8.1 Hz), 7.00 (1H, dd, J = 1.8, 8.1 Hz), 7.07 (1H, dd, J = 1.5, 4.8 Hz), 7.26-7.33 (4H, m), 7.28 (1H, m), 7.44 (1H, dd, J = 3.0, 4.8 Hz), 7.50 (1H, dd, J = 2.1, 8.4 Hz), 8.47 (1H, dd, J = 0.3, 8.4 Hz). MS (ESI+): 452.1 (M+H), 454.1. Example 16
6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4- (thiophen-3-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Methyl 6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylate in eggplant flask with Dimroth Ester (175 mg), sodium carbonate (96 mg), 3-thiophenboronic acid (52 mg), tetrakis (triphenylphosphine) palladium (0) (12 mg), toluene (2.0 ml), water (0.4 ml) and A mixture of ethanol (0.4 ml) was degassed by a vacuum line, replaced with argon, and stirred at 80 ° C for 12 hours. After cooling the reaction solution, the reaction solution was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give the title compound (120 mg) as a colorless powder.
¹ H NMR (CDCl ₃ ) δ: 3.14 (2H, t, J = 8.7 Hz), 3.71 (3H, s), 4.53 (2H, t, J = 8.7 Hz), 6.67 (1H, d, J = 8.1 Hz) ), 7.00 (1H, dd, J = 1.8, 8.1 Hz), 7.07 (1H, dd, J = 1.5, 4.8 Hz), 7.26-7.33 (4H, m), 7.28 (1H, m), 7.44 (1H, dd, J = 3.0, 4.8 Hz), 7.50 (1H, dd, J = 2.1, 8.4 Hz), 8.47 (1H, dd, J = 0.3, 8.4 Hz). MS (ESI +): 452.1 (M + H), 454.1.

本化合物は実施例１６に示す方法に従い、6-クロロ-2-(2,3-ジヒドロベンゾフラン-5-イルメチル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び4-ピリジルボロン酸を用いて合成した。無色結晶（収率20％）。¹H NMR (CDCl₃) δ: 3.15 (2H, t, J = 8.7 Hz), 3.30 (3H, s), 4.54 (2H, t, J = 8.7 Hz), 5.35 (2H, s), 6.68 (1H, d, J = 8.1 Hz), 6.98 (1H, dd, J = 1.8, 8.1 Hz), 7.12 (1H, d, J = 1.8 Hz), 7.14 (1H, m), 7.24 (2H, d, J = 6.0 Hz), 7.54 (1H, dd, J = 2.1, 9.0 Hz), 8.51(1H, d, J = 9.0 Hz), 8.72 (2H, d, J = 6.0 Hz). MS (ESI+): 447.1 (M+H), 449.0. Example 17
6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4- (pyridin-4-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method shown in Example 16 to give 6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3- It was synthesized using carboxylic acid methyl ester and 4-pyridylboronic acid. Colorless crystals (20% yield). ¹ H NMR (CDCl ₃ ) δ: 3.15 (2H, t, J = 8.7 Hz), 3.30 (3H, s), 4.54 (2H, t, J = 8.7 Hz), 5.35 (2H, s), 6.68 (1H , d, J = 8.1 Hz), 6.98 (1H, dd, J = 1.8, 8.1 Hz), 7.12 (1H, d, J = 1.8 Hz), 7.14 (1H, m), 7.24 (2H, d, J = 6.0 Hz), 7.54 (1H, dd, J = 2.1, 9.0 Hz), 8.51 (1H, d, J = 9.0 Hz), 8.72 (2H, d, J = 6.0 Hz) .MS (ESI +): 447.1 (M + H), 449.0.

本化合物は実施例１６に示す方法に従い、2-ベンジル-6-クロロ-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及びジエチル 3-ピリジルボランを用いて合成した。無色粉末（収率9％）。¹H NMR (CDCl₃) δ: 3.24 (3H, s), 5.44 (2H, s), 7.09 (1H, m), 7.21-7.34 (5H, m), 7.41 (1H, m), 7.54 (1H, dd, J = 2.1, 8.4 Hz), 7.64 (1H, dt, J = 2.1, 7.8 Hz), 8.51 (1H, dd, J = 0.3, 8.4 Hz), 8.55 (1H, d, J = 1.5 Hz), 8.69 (1H, dd, J = 1.5, 4.8 Hz). MS (ESI+): 405.0 (M+H), 407.0. Example 18
2-benzyl-6-chloro-1-oxo-4- (pyridin-3-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 16, the present compound was prepared by preparing 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and diethyl 3-pyridylborane. And synthesized. Colorless powder (yield 9%). ¹ H NMR (CDCl ₃ ) δ: 3.24 (3H, s), 5.44 (2H, s), 7.09 (1H, m), 7.21-7.34 (5H, m), 7.41 (1H, m), 7.54 (1H, dd, J = 2.1, 8.4 Hz), 7.64 (1H, dt, J = 2.1, 7.8 Hz), 8.51 (1H, dd, J = 0.3, 8.4 Hz), 8.55 (1H, d, J = 1.5 Hz), 8.69 (1H, dd, J = 1.5, 4.8 Hz). MS (ESI +): 405.0 (M + H), 407.0.

本化合物は実施例１６に示す方法に従い、2-ベンジル-6-クロロ-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び4-ピリジルボロン酸を用いて合成した。黄色粉末（収率23％）。¹H NMR (CDCl₃) δ: 3.22 (3H, s), 5.44 (2H, s), 7.12 (1H, d, J = 1.8 Hz), 7.20-7.34 (7H, m), 7.54 (1H, m), 8.51 (1H, d, J = 8.4 Hz), 8.72 (2H, d, J = 6.0 Hz). MS (ESI+): 405.0 (M+H), 407.0 Example 19
2-benzyl-6-chloro-1-oxo-4- (pyridin-4-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method shown in Example 16 by converting 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 4-pyridylboronic acid. And synthesized. Yellow powder (23% yield). ¹ H NMR (CDCl ₃ ) δ: 3.22 (3H, s), 5.44 (2H, s), 7.12 (1H, d, J = 1.8 Hz), 7.20-7.34 (7H, m), 7.54 (1H, m) , 8.51 (1H, d, J = 8.4 Hz), 8.72 (2H, d, J = 6.0 Hz). MS (ESI +): 405.0 (M + H), 407.0

ジムロート付のナスフラスコに入った6-クロロ-2-(4-メトキシカルボニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(180 mg)、炭酸ナトリウム(71 mg)、5-ホルミル-2-チオフェンボロン酸(63 mg)、テトラキス(トリフェニルホスフィン)パラジウム(0)(19 mg)、トルエン(2.0 ml)、水(0.4 ml)及びエタノール(0.4 ml)の混合物を、真空ラインで脱気した後アルゴンにより置換し、80℃で12時間攪拌した。反応液を冷却後、反応液を水及び酢酸エチルにより分液し、有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮した。残渣を中圧分取LC(ヘキサン/酢酸エチル=4/1〜1/1)にて精製し、黄色油状の6-クロロ-4-(5-ホルミルチオフェン-2-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(90 mg)を得た。
次いで、本品のメタノール(1.0 ml)溶液に、0℃攪拌下、水素化ホウ素ナトリウム(3.4 mg)を加え、1時間攪拌した。反応液を濃縮し、残留物を1規定塩酸及び酢酸エチルにて分液し、有機層を硫酸マグネシウムにより乾燥し、減圧濃縮した。残渣を中圧分取LC(ヘキサン/酢酸エチル=4/1〜1/1)にて精製し、無色粉末の表題化合物(50 mg)を得た。
¹H NMR (CDCl₃) δ: 2.08 (1H, t, J = 6.0 Hz), 3.73 (3H, s), 3.89 (3H, s), 4.87 (2H, d, J = 6.0 Hz), 5.41 (2H, s), 6.90 (1H, d, J = 3.3 Hz), 6.99 (1H, d, J = 3.3 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.47 (1H, d, J = 2.1 Hz), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.44 (1H, d, J = 8.7 Hz). MS (ESI+): 498 (M+H), 500. Example 20
6-chloro-4- (5-hydroxymethylthiophen-2-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-Chloro-2- (4-methoxycarbonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (180 mg) in an eggplant flask with a Dimroth , Sodium carbonate (71 mg), 5-formyl-2-thiophenboronic acid (63 mg), tetrakis (triphenylphosphine) palladium (0) (19 mg), toluene (2.0 ml), water (0.4 ml) and ethanol The mixture (0.4 ml) was degassed by a vacuum line, replaced with argon, and stirred at 80 ° C for 12 hours. After cooling the reaction solution, the reaction solution was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give 6-chloro-4- (5-formylthiophen-2-yl) -2- (4 -Methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (90 mg) was obtained.
Next, sodium borohydride (3.4 mg) was added to a methanol (1.0 ml) solution of this product while stirring at 0 ° C., and the mixture was stirred for 1 hour. The reaction solution was concentrated, the residue was separated with 1N hydrochloric acid and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give the title compound (50 mg) as a colorless powder.
¹ H NMR (CDCl ₃ ) δ: 2.08 (1H, t, J = 6.0 Hz), 3.73 (3H, s), 3.89 (3H, s), 4.87 (2H, d, J = 6.0 Hz), 5.41 (2H , s), 6.90 (1H, d, J = 3.3 Hz), 6.99 (1H, d, J = 3.3 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.47 (1H, d, J = 2.1 Hz) ), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.44 (1H, d, J = 8.7 Hz) .MS (ESI +): 498 (M + H) ), 500.

本化合物は、実施例２０に示す方法に従い、6-クロロ-2-(4-メトキシカルボニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び2-ホルミル-3-チオフェンボロン酸を用いて合成した。無色粉末（収率24％）。¹H NMR (CDCl₃) δ: 2.35 (1H, t, J = 6.3 Hz), 3.34 (3H, s), 3.90 (3H, s), 4.53 (2H, d, J = 6.3 Hz), 5.26 (1H, d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.88 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.30 (2H, d, J = 8.7 Hz), 7.40 (1H, d, J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 7.98 (2H, d, J = 8.7 Hz), 8.46 (1H, d, J = 8.4 Hz). MS (ESI+): 498 (M+H), 500. Example 21
6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method described in Example 20 by methyl 6-chloro-2- (4-methoxycarbonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylate. And 2-formyl-3-thiophenboronic acid. Colorless powder (24% yield). ¹ H NMR (CDCl ₃ ) δ: 2.35 (1H, t, J = 6.3 Hz), 3.34 (3H, s), 3.90 (3H, s), 4.53 (2H, d, J = 6.3 Hz), 5.26 (1H , d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.88 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.30 (2H, d , J = 8.7 Hz), 7.40 (1H, d, J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 7.98 (2H, d, J = 8.7 Hz), 8.46 (1H, d , J = 8.4 Hz). MS (ESI +): 498 (M + H), 500.

6-クロロ-4-(5-ヒドロキシメチルチオフェン-2-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(50 mg)のメタノール(4.0 ml)溶液に、1規定水酸化ナトリウム(250 μl)を加え、室温にて1時間攪拌した。反応液を1規定塩酸によりpH3に調整した後、減圧下に濃縮した。残留物を水及び酢酸エチルで分液した後、有機層を硫酸マグネシウムで乾燥し、減圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/メタノール=10/1）により精製し、黄色結晶の表題化合物（44 mg）を得た。
¹H NMR (CDCl₃) δ: 3.40 (3H, s), 4.88 (2H, s), 5.41 (2H, s), 6.92 (1H, d, J = 3.3 Hz), 7.00 (1H, dt, J = 0.6, 3.3 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.47-7.56 (2H, m), 8.04 (2H, d, J = 8.7 Hz), 8.45 (1H, dd, J = 0.6, 8.4 Hz). MS (ESI+): 484 (M+H), 486. Example 22
2- (4-carboxybenzyl) -6-chloro-4- (5-hydroxymethylthiophen-2-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-chloro-4- (5-hydroxymethylthiophen-2-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (50 mg) 1N sodium hydroxide (250 μl) was added to a methanol (4.0 ml) solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid, and then concentrated under reduced pressure. After partitioning the residue with water and ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (44 mg) as yellow crystals.
¹ H NMR (CDCl ₃ ) δ: 3.40 (3H, s), 4.88 (2H, s), 5.41 (2H, s), 6.92 (1H, d, J = 3.3 Hz), 7.00 (1H, dt, J = 0.6, 3.3 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.47-7.56 (2H, m), 8.04 (2H, d, J = 8.7 Hz), 8.45 (1H, dd, J = 0.6, 8.4) Hz). MS (ESI +): 484 (M + H), 486.

本化合物は、実施例２２に示す方法に従い、6-クロロ-4-(2-ヒドロキシメチルチオフェン-3-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステルを用いて合成した。淡黄色粉末（収率100％）。¹H NMR (CDCl₃) δ: 3.36 (3H, s), 4.55 (2H, s), 5.26 (1H, d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.41 (1H, d, J = 5.1 Hz), 7.54 (1H, dd, J = 1.8, 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.47 (1H, d, J = 8.4 Hz). MS (ESI+): 484 (M+H), 486. Example 23
2- (4-carboxybenzyl) -6-chloro-4- (2-hydroxymethylthiophen-3-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method described in Example 22 by using 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline It was synthesized using methyl 3-carboxylate. Light yellow powder (100% yield). ¹ H NMR (CDCl ₃ ) δ: 3.36 (3H, s), 4.55 (2H, s), 5.26 (1H, d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.89 (1H , d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.41 (1H, d, J = 5.1 Hz), 7.54 (1H, dd , J = 1.8, 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.47 (1H, d, J = 8.4 Hz). MS (ESI +): 484 (M + H), 486.

ジムロート付のナスフラスコに入った6-クロロ-2-(4-メトキシカルボニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(180 mg)、炭酸ナトリウム(71 mg)、3-ホルミル-2-チオフェンボロン酸(63 mg)、テトラキス(トリフェニルホスフィン)パラジウム(0)(19 mg)、トルエン(2.0 ml)、水(0.4 ml)及びエタノール(0.4 ml)の混合物を、真空ラインで脱気した後アルゴンにより置換し、80℃で12時間攪拌した。反応液を冷却後、反応液を水及び酢酸エチルにより分液し、有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮した。残渣を中圧分取LC(ヘキサン/酢酸エチル=4/1〜1/1)にて精製し、黄色油状の6-クロロ-4-(3-ホルミルチオフェン-2-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(40 mg)を得た。
本品のメタノール(1.0 ml)溶液に、0℃攪拌下、水素化ホウ素ナトリウム(3 mg)を加え、1時間攪拌した。反応液を濃縮し、残留物を1規定塩酸及び酢酸エチルにて分液し、有機層を硫酸マグネシウムにより乾燥した後濃縮した。残渣を中圧分取LC(ヘキサン/酢酸エチル=4/1〜1/1)にて精製し、無色粉末の6-クロロ-4-(3-ヒドロキシメチルチオフェン-2-イル)-2-(4-メトキシカルボニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(22 mg)を得た。次いで、本品のメタノール(2.0 ml)溶液に、1規定水酸化ナトリウム(110 μl)を加え、室温にて1時間攪拌した。反応液を1規定塩酸によりpH3に調整した後、減圧下に濃縮した。残留物を水及び酢酸エチルで分液した後、有機層を硫酸マグネシウムで乾燥し、減圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/メタノール=10/1）により精製し、淡黄色結晶の表題化合物（17 mg）を得た。
¹H NMR (CDCl₃) δ: 3.42 (3H, s), 4.35 (1H, d, J = 12.6 Hz), 4.43 (1H, d, J = 12.6 Hz), 5.30 (1H, d, J = 16.2 Hz), 5.46 (1H, d, J = 16.2 Hz), 7.18 (1H, m), 7.24 (1H, d, J = 5.1 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz). MS (ESI+): 484 (M+H), 486. Example 24
2- (4-carboxybenzyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-Chloro-2- (4-methoxycarbonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (180 mg) in an eggplant flask with a Dimroth , Sodium carbonate (71 mg), 3-formyl-2-thiophenboronic acid (63 mg), tetrakis (triphenylphosphine) palladium (0) (19 mg), toluene (2.0 ml), water (0.4 ml) and ethanol The mixture (0.4 ml) was degassed by a vacuum line, replaced with argon, and stirred at 80 ° C for 12 hours. After cooling the reaction solution, the reaction solution was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give 6-chloro-4- (3-formylthiophen-2-yl) -2- (4 -Methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (40 mg) was obtained.
Sodium borohydride (3 mg) was added to a methanol (1.0 ml) solution of this product while stirring at 0 ° C., and the mixture was stirred for 1 hour. The reaction solution was concentrated, the residue was separated with 1N hydrochloric acid and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give 6-chloro-4- (3-hydroxymethylthiophen-2-yl) -2- (a colorless powder. 4-Methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (22 mg) was obtained. Next, 1N sodium hydroxide (110 μl) was added to a methanol (2.0 ml) solution of this product, and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid, and then concentrated under reduced pressure. After partitioning the residue with water and ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to obtain the title compound (17 mg) as pale yellow crystals.
¹ H NMR (CDCl ₃ ) δ: 3.42 (3H, s), 4.35 (1H, d, J = 12.6 Hz), 4.43 (1H, d, J = 12.6 Hz), 5.30 (1H, d, J = 16.2 Hz) ), 5.46 (1H, d, J = 16.2 Hz), 7.18 (1H, m), 7.24 (1H, d, J = 5.1 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.47 (1H, d , J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz) .MS (ESI +): 484 (M + H), 486.

ジムロート付のナスフラスコに入った6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(2.0 g)、炭酸ナトリウム(765 mg)、3-ホルミル-2-チオフェンボロン酸(675 mg)、テトラキス(トリフェニルホスフィン)パラジウム(0)(208 mg)、トルエン(20 ml)、水(4 ml)及びエタノール(4 ml)の混合物を、真空ラインで脱気した後アルゴンにより置換し、80℃で12時間攪拌した。反応液を冷却後、反応液を水及び酢酸エチルにより分液し、有機層を硫酸マグネシウムにより乾燥した後、減圧濃縮した。残渣を中圧分取LC(ヘキサン/酢酸エチル=4/1〜1/1)にて精製し、淡黄色粉末の6-クロロ-4-(3-ホルミルチオフェン-2-イル)-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(140 mg)を得た。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.42 (3H, s), 5.35 (1H, d, J = 15.6 Hz), 5.42 (1H, d, J = 15.6 Hz), 7.18 (1H, d, J = 2.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.50-7.62 (3H, m), 7.90 (2H, d, J = 8.1 Hz), 8.44 (1H, dd, J = 0.6, 8.7 Hz), 9.62 (1H, s).
本品（62 mg）のTHF溶液(2 ml)に、メチルマグネシウムブロミドのTHF溶液(1mol/l, 240μl)を室温で加え、1時間攪拌した。反応終了後、反応液に1規定塩酸を加え、酢酸エチルにて分液抽出し、有機層を硫酸マグネシウムにて乾燥後、減圧下で濃縮した。残留物を中圧分取LC(ヘキサン/酢酸エチル=1/1〜1/4)にて精製し、淡黄色粉末の表題化合物(22 mg)を得た。
¹H NMR (CDCl₃) δ: 1.40 (3H, d, J = 6.6 Hz), 2.52 (1H, s), 3.03 (3H, s), 3.49 (3H, s), 4.59 (1H, m), 5.20 (1H, d, J = 16.2 Hz), 5.44 (1H, d, J = 16.2 Hz), 7.15 (1H, d, J = 2.1 Hz), 7.27 (1H, d, J = 5.4 Hz), 7.40-7.50 (3H, m), 7.53 (1H, dd, J = 2.1, 8.7 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.41 (1H, d, J = 8.7 Hz). MS (ESI+): 514 (M-H₂O), 516. Example 25
6-chloro-4- [3- (1-hydroxyethyl) thiophen-2-yl] -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-Chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (2.0 g) in an eggplant flask with a Dimroth , Sodium carbonate (765 mg), 3-formyl-2-thiophenboronic acid (675 mg), tetrakis (triphenylphosphine) palladium (0) (208 mg), toluene (20 ml), water (4 ml) and ethanol The mixture (4 ml) was degassed with a vacuum line, replaced with argon, and stirred at 80 ° C for 12 hours. After cooling the reaction solution, the reaction solution was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give 6-chloro-4- (3-formylthiophen-2-yl) -2- ( 4-Methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (140 mg) was obtained. ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.42 (3H, s), 5.35 (1H, d, J = 15.6 Hz), 5.42 (1H, d, J = 15.6 Hz), 7.18 (1H , d, J = 2.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.50-7.62 (3H, m), 7.90 (2H, d, J = 8.1 Hz), 8.44 (1H, dd, J = 0.6, 8.7 Hz), 9.62 (1H, s).
To a THF solution (2 ml) of this product (62 mg) was added a THF solution of methylmagnesium bromide (1 mol / l, 240 μl) at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (22 mg) as a pale-yellow powder.
¹ H NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 6.6 Hz), 2.52 (1H, s), 3.03 (3H, s), 3.49 (3H, s), 4.59 (1H, m), 5.20 (1H, d, J = 16.2 Hz), 5.44 (1H, d, J = 16.2 Hz), 7.15 (1H, d, J = 2.1 Hz), 7.27 (1H, d, J = 5.4 Hz), 7.40-7.50 (3H, m), 7.53 (1H, dd, J = 2.1, 8.7 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.41 (1H, d, J = 8.7 Hz) .MS (ESI +): 514 (MH ₂ O), 516.

本化合物は、実施例２５に示す方法に従い、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及びフェニルマグネシウムブロミドを用いて合成した。淡黄色粉末(収率45％)。
¹H NMR (CDCl₃) δ: 2.91 (1H, d, J = 2.6 Hz), 3.04 (3H, s), 3.55 (3H, s), 5.25 (1H, d, J = 16.0 Hz), 5.48 (1H, d, J = 16.0 Hz), 5.56 (1H, d, J = 2.6 Hz), 7.05-7.11 (2H, m), 7.12-7.27 (5H, m), 7.42 (1H, d, J = 5.8 Hz), 7.46-7.56 (3H, m), 7.93 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 8.8 Hz). MS (ESI+): 576 (M+H), 578. Example 26
6-chloro-4- [3- [hydroxy (phenyl) methyl] thiophen-2-yl] -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 25, the present compound was prepared as follows: 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester And phenylmagnesium bromide. Pale yellow powder (yield 45%).
¹ H NMR (CDCl ₃ ) δ: 2.91 (1H, d, J = 2.6 Hz), 3.04 (3H, s), 3.55 (3H, s), 5.25 (1H, d, J = 16.0 Hz), 5.48 (1H , d, J = 16.0 Hz), 5.56 (1H, d, J = 2.6 Hz), 7.05-7.11 (2H, m), 7.12-7.27 (5H, m), 7.42 (1H, d, J = 5.8 Hz) , 7.46-7.56 (3H, m), 7.93 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 8.8 Hz). MS (ESI +): 576 (M + H), 578.

本化合物は実施例16に示す方法により、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び5-ホルミル-2-チオフェンボロン酸を用いて合成した。茶色粉末(収率68％)。
¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.44 (3H, s), 5.39 (2H, s), 7.17 (1H, d, J = 3.6 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.80 (1H, d, J = 2.1 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8.7 Hz), 9.95 (1H, s). MS (ESI+): 516 (M+H), 518. Example 27
6-chloro-4- (5-formylthiophen-2-yl) -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method shown in Example 16 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and It was synthesized using 5-formyl-2-thiophenboronic acid. Brown powder (68% yield).
¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.44 (3H, s), 5.39 (2H, s), 7.17 (1H, d, J = 3.6 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.80 (1H, d, J = 2.1 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8.7 Hz), 9.95 (1H, s). MS (ESI +): 516 (M + H), 518.

6-クロロ-4-(5-ホルミルチオフェン-2-イル)-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（90 mg）のTHF溶液(3.6 ml)に、メチルマグネシウムブロミドのTHF溶液(1mol/l, 348μl)を室温で加え、1時間攪拌した。反応終了後、反応液に1規定塩酸を加え、酢酸エチルにて分液抽出し、有機層を硫酸マグネシウムにて乾燥後、減圧下で濃縮した。残留物を中圧分取LC(ヘキサン/酢酸エチル=1/1〜1/4)にて精製し、無色結晶の表題化合物(59 mg)を得た。¹H NMR (CDCl₃) δ: 1.65 (3H, d, J = 6.3 Hz), 2.05 (1H, d, J = 4.5 Hz), 3.02 (3H, s), 3.44 (3H, s), 5.16 (1H, m), 5.37 (2H, s), 6.93 (1H, d, J = 3.6 Hz), 6.96 (1H, d, J = 3.6 Hz), 7.44-7.56 (4H, m), 7.88 (2H, d, J = 8.7 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESI+): 532 (M+H), 534. Example 28
6-chloro-4- [5- (1-hydroxyethyl) thiophen-2-yl] -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-Chloro-4- (5-formylthiophen-2-yl) -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (90 mg) in THF To the solution (3.6 ml), a THF solution of methylmagnesium bromide (1 mol / l, 348 μl) was added at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (59 mg) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ: 1.65 (3H, d, J = 6.3 Hz), 2.05 (1H, d, J = 4.5 Hz), 3.02 (3H, s), 3.44 (3H, s), 5.16 (1H , m), 5.37 (2H, s), 6.93 (1H, d, J = 3.6 Hz), 6.96 (1H, d, J = 3.6 Hz), 7.44-7.56 (4H, m), 7.88 (2H, d, J = 8.7 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESI +): 532 (M + H), 534.

6-クロロ-4-(5-ホルミルチオフェン-2-イル)-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル(90 mg)、リン酸二水素ナトリウム(21 mg)、2-メチル-2-ブテン(83 μl)、THF(2.0 ml)、ブタノール(1.0 ml)及び水(2.0 ml)の混合物に、0℃攪拌下、亜塩素酸ナトリウム(59 mg)を加え、1時間攪拌した。溶媒を減圧下に除去し、残留物を1規定塩酸及び酢酸エチルにて分液した後、有機層を硫酸マグネシウムにより乾燥し、濃縮した。残留物を酢酸エチルにて洗浄、乾燥し、淡黄色粉末の表題化合物(53 mg)を得た。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.46 (3H, s), 5.39 (2H, s), 7.09 (1H, d, J = 3.6 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.47 (2H, d, J = 9.0 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.86-7.94 (3H, m), 8.44 (1H, d, J = 8.1 Hz). MS (ESI+): 532 (M+H), 534. Example 29
4- (5-carboxythiophen-2-yl) -6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-chloro-4- (5-formylthiophen-2-yl) -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (90 mg), phosphorus A mixture of sodium dihydrogen oxide (21 mg), 2-methyl-2-butene (83 μl), THF (2.0 ml), butanol (1.0 ml) and water (2.0 ml) was added to a mixture of Sodium (59 mg) was added, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was separated with 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was washed with ethyl acetate and dried to give the title compound (53 mg) as a pale yellow powder. ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.46 (3H, s), 5.39 (2H, s), 7.09 (1H, d, J = 3.6 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.47 (2H, d, J = 9.0 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.86-7.94 (3H, m), 8.44 (1H, d, J = 8.1 Hz) MS (ESI +): 532 (M + H), 534.

本化合物は、実施例16に示す方法により、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び2-チオフェンボロン酸を用いて合成した。ベージュ粉末(収率32％)。¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.41 (3H, s), 5.38 (2H, s), 7.03-7.15 (2H, m), 7.42-7.55 (5H, m), 7.89 (2H, d, J = 8.1 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESI+): 488 (M+H), 490. Example 30
6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4- (thiophen-2-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared by the method described in Example 16 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester And 2-thiophenboronic acid. Beige powder (32% yield). ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.41 (3H, s), 5.38 (2H, s), 7.03-7.15 (2H, m), 7.42-7.55 (5H, m), 7.89 ( 2H, d, J = 8.1 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESI +): 488 (M + H), 490.

本化合物は、実施例16に示す方法により、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び3-チオフェンボロン酸を用いて合成した。無色結晶(収率78％)。¹H NMR (CDCl₃) δ: 3.07 (3H, s), 3.70 (3H, s), 5.39 (2H, br), 7.09 (1H, dd, J = 1.2, 4.8 Hz), 7.29 (1H, dd, J = 1.2, 3.0 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.44-7.50 (3H, m), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.88 (2H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.7 Hz). MS (ESI+): 488 (M+H), 490. Example 31
6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4- (thiophen-3-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared by the method described in Example 16 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester And 3-thiophenboronic acid. Colorless crystals (78% yield). ¹ H NMR (CDCl ₃ ) δ: 3.07 (3H, s), 3.70 (3H, s), 5.39 (2H, br), 7.09 (1H, dd, J = 1.2, 4.8 Hz), 7.29 (1H, dd, J = 1.2, 3.0 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.44-7.50 (3H, m), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.88 (2H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.7 Hz). MS (ESI +): 488 (M + H), 490.

6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル (100 mg)、塩化リチウム（23 mg）、ビス(トリフェニルホスフィン)パラジウム(II)クロリド（3 mg）、2,6-ジ-tert-ブチル-4-メチルフェノール（4 mg）、ビニルトリブチル錫（55 μl）をDMF（4.9 ml）に溶解し、窒素雰囲気下90℃にて2時間撹拌した。反応液を冷却後、系内に水を加え、酢酸エチルにて抽出し、有機層を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（ヘキサン/酢酸エチル=1/1）にて精製し、淡黄粉末の表題化合物（5 mg）を得た。 ¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.66 (3H, s), 5.36 (2H, s), 5.48 (1H, dd, J = 1.5, 17.4 Hz), 5.60 (1H, dd, J = 1.5, 11.1 Hz), 6.69 (1H, dd, J = 11.1, 17.4 Hz), 7.44 (2H, d, J = 8.7 Hz), 7.53 (1H, dd, J = 2.1, 8.4 Hz), 7.68 (1H, d, J = 2.1 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.40 (1H, d, J = 8.4 Hz). MS (ESI+): 432 (M+H), 434. Example 32
6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-vinyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg), lithium chloride (23 mg), Dissolve bis (triphenylphosphine) palladium (II) chloride (3 mg), 2,6-di-tert-butyl-4-methylphenol (4 mg), and vinyltributyltin (55 μl) in DMF (4.9 ml) Then, the mixture was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. After cooling the reaction solution, water was added to the system, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give the title compound (5 mg) as a pale yellow powder. ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.66 (3H, s), 5.36 (2H, s), 5.48 (1H, dd, J = 1.5, 17.4 Hz), 5.60 (1H, dd, J = 1.5, 11.1 Hz), 6.69 (1H, dd, J = 11.1, 17.4 Hz), 7.44 (2H, d, J = 8.7 Hz), 7.53 (1H, dd, J = 2.1, 8.4 Hz), 7.68 ( 1H, d, J = 2.1 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.40 (1H, d, J = 8.4 Hz). MS (ESI +): 432 (M + H), 434.

本化合物は、実施例３２の反応において副生成物として得た。無色粉末(収率33％)。¹H NMR (CDCl₃) δ: 3.02 (3H, s), 5.29 (2H, s), 5.37 (1H, dd, J = 1.2, 10.8 Hz), 5.53 (1H, dd, J = 0.6, 17.1 Hz), 6.84 (1H, dd, J = 10.8, 17.1 Hz), 7.21 (1H, s), 7.46-7.54 (3H, m), 7.69 (1H, d, J = 2.1 Hz), 7.91 (2H, d, J = 8.1 Hz), 8.39 (1H, d, J = 8.7 Hz). MS (ESI+): 374 (M+H), 376. Example 33
6-chloro-2- (4-methanesulfonylbenzyl) -4-vinyl-2H-isoquinolin-1-one

This compound was obtained as a by-product in the reaction of Example 32. Colorless powder (33% yield). ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 5.29 (2H, s), 5.37 (1H, dd, J = 1.2, 10.8 Hz), 5.53 (1H, dd, J = 0.6, 17.1 Hz) , 6.84 (1H, dd, J = 10.8, 17.1 Hz), 7.21 (1H, s), 7.46-7.54 (3H, m), 7.69 (1H, d, J = 2.1 Hz), 7.91 (2H, d, J = 8.1 Hz), 8.39 (1H, d, J = 8.7 Hz). MS (ESI +): 374 (M + H), 376.

本化合物は、実施例３２に示す方法により、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び2-トリブチル錫フランを用いて合成した。黄色粉末(収率47％)。¹H NMR (CDCl₃) δ: 3.02 (3H, s), 5.31 (2H, s), 6.54 (2H, s), 7.38 (1H, s), 7.48-7.58 (4H, m), 7.88-7.96 (3H, m), 8.43 (1H, d, J = 8.4 Hz). MS (ESI+): 414 (M+H), 416. Example 34
6-chloro-4- (furan-2-yl) -2- (4-methanesulfonylbenzyl) -2H-isoquinolin-1-one

This compound was prepared by the method described in Example 32 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester And 2-tributyltinfuran. Yellow powder (47% yield). ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 5.31 (2H, s), 6.54 (2H, s), 7.38 (1H, s), 7.48-7.58 (4H, m), 7.88-7.96 ( 3H, m), 8.43 (1H, d, J = 8.4 Hz). MS (ESI +): 414 (M + H), 416.

本化合物は、実施例３２に示す方法により、6-クロロ-2-(4-メタンスルホニルベンジル)-1-オキソ-4-トリフルオロメタンスルホニルオキシ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル及び2-トリブチル錫チオフェンを用いて合成した。無色粉末(収率31％)。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 5.29 (2H, s), 7.11-7.18 (2H, m), 7.24 (1H, s), 7.41 (1H, dd, J = 1.5, 5.1 Hz), 7.50 (1H, m), 7.53 (2H, d, J = 8.4 Hz), 7.74 (1H, d, J = 1.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.7 Hz). MS (ESI+): 430 (M+H), 432. Example 35
6-chloro-2- (4-methanesulfonylbenzyl) -4- (thiophen-2-yl) -2H-isoquinolin-1-one

This compound was prepared by the method described in Example 32 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester And 2-tributyltin thiophene. Colorless powder (31% yield). ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 5.29 (2H, s), 7.11-7.18 (2H, m), 7.24 (1H, s), 7.41 (1H, dd, J = 1.5, 5.1 Hz), 7.50 (1H, m), 7.53 (2H, d, J = 8.4 Hz), 7.74 (1H, d, J = 1.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.7 Hz). MS (ESI +): 430 (M + H), 432.

実施例１−（１０）で得た4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.12 g）、2,5-ジメトキシテトラヒドロフラン（40 μl）及び酢酸（1.2 ml）の混合物を1.5時間加熱還流した。反応液を冷却後、溶媒を減圧下に留去し、残留物を酢酸エチルにて希釈し、飽和重曹水にて洗浄した。有機層を硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣を中圧分取LC（ヘキサン/酢酸エチル=2/1〜1/2）により精製し、無色結晶の表題化合物（0.11 g）を得た。¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.45 (3H, s), 5.42 (2H, s), 6.31 (2H, t, J = 2.1 Hz), 6.75 (2H, t, J = 2.1 Hz), 7.13 (1H, dd, J = 1.2, 8.1 Hz), 7.49 (2H, d, J = 8.1 Hz), 7.58-7.72 (2H, m), 7.89 (2H, d, J = 8.1 Hz), 8.48 (1H, m). MS (ESI+): 437 (M+H). Example 36
2- (4-methanesulfonylbenzyl) -1-oxo-4- (pyrrol-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester obtained in Example 1- (10) (0.12 g), 2,5- A mixture of dimethoxytetrahydrofuran (40 μl) and acetic acid (1.2 ml) was heated under reflux for 1.5 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 2/1 to 1/2) to give the title compound (0.11 g) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.45 (3H, s), 5.42 (2H, s), 6.31 (2H, t, J = 2.1 Hz), 6.75 (2H, t, J = 2.1 Hz), 7.13 (1H, dd, J = 1.2, 8.1 Hz), 7.49 (2H, d, J = 8.1 Hz), 7.58-7.72 (2H, m), 7.89 (2H, d, J = 8.1 Hz) , 8.48 (1H, m). MS (ESI +): 437 (M + H).

実施例１−（１０）で得た4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.10 g）、1,5-ジブロモペンタン（44μl）及びDMF（2.0ml）の混合物に水素化ナトリウム（33mg）を加え、室温で1時間撹拌した。反応終了後、反応液を酢酸エチルにて希釈し、5%硫酸水素カリウム水溶液にて洗浄した。有機層を硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣を中圧分取LC（ヘキサン/酢酸エチル=2/1〜1/1）により精製し、黄色粉末の表題化合物（37 mg）を得た。¹H NMR (CDCl₃) δ: 1.44-1.80 (6H, m), 2.88-2.99 (2H, m), 3.01 (3H, s), 3.22-3.34 (2H, m), 3.77 (3H, s), 5.25 (2H, s), 7.46 (2H, d, J = 8.1 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.83-7.93 (3H, m), 8.46 (1H, dd, J = 0.6, 8.1 Hz). Example 37
2- (4-methanesulfonylbenzyl) -1-oxo-4- (piperidin-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester obtained in Example 1- (10) (0.10 g), 1,5- Sodium hydride (33 mg) was added to a mixture of dibromopentane (44 μl) and DMF (2.0 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with ethyl acetate, and washed with a 5% aqueous potassium hydrogen sulfate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (37 mg) as a yellow powder. ¹ H NMR (CDCl ₃ ) δ: 1.44-1.80 (6H, m), 2.88-2.99 (2H, m), 3.01 (3H, s), 3.22-3.34 (2H, m), 3.77 (3H, s), 5.25 (2H, s), 7.46 (2H, d, J = 8.1 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.83-7.93 (3H, m), 8.46 (1H, dd, J = 0.6, 8.1 Hz).

  Examples 38-41 were synthesized according to a method similar to that shown in Example 37.

黄色粉末(収率15％)。¹H NMR (CDCl₃) δ: 1.94-2.12 (4H, m), 3.02 (3H, s), 3.18-3.28 (4H, m), 3.73 (3H, s), 5.24 (2H, s), 7.49 (2H, d, J = 8.7 Hz), 7.50-7.63 (2H, m), 7.70 (1H, m), 7.87 (2H, d, J = 8.7 Hz), 8.49 (1H, dd, J = 0.9, 8.1 Hz). Example 38
2- (4-methanesulfonylbenzyl) -1-oxo-4- (pyrrolidin-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow powder (15% yield). ¹ H NMR (CDCl ₃ ) δ: 1.94-2.12 (4H, m), 3.02 (3H, s), 3.18-3.28 (4H, m), 3.73 (3H, s), 5.24 (2H, s), 7.49 ( 2H, d, J = 8.7 Hz), 7.50-7.63 (2H, m), 7.70 (1H, m), 7.87 (2H, d, J = 8.7 Hz), 8.49 (1H, dd, J = 0.9, 8.1 Hz ).

黄色結晶(収率15％)。¹H NMR (CDCl₃) δ: 2.84-2.94 (2H, m), 3.02 (3H, s), 3.44-3.68 (4H, m), 3.79 (3H, s), 3.89 (2H, dt, J = 3.6, 10.8 Hz), 5.25 (2H, s), 7.46 (2H, d, J = 9.0 Hz), 7.57 (1H, m), 7.74 (1H, m), 7.84-7.96 (3H, m), 8.48 (1H, dd, J = 1.5, 8.1 Hz). Example 39
2- (4-methanesulfonylbenzyl) -4- (morpholin-4-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (15% yield). ¹ H NMR (CDCl ₃ ) δ: 2.84-2.94 (2H, m), 3.02 (3H, s), 3.44-3.68 (4H, m), 3.79 (3H, s), 3.89 (2H, dt, J = 3.6 , 10.8 Hz), 5.25 (2H, s), 7.46 (2H, d, J = 9.0 Hz), 7.57 (1H, m), 7.74 (1H, m), 7.84-7.96 (3H, m), 8.48 (1H , dd, J = 1.5, 8.1 Hz).

無色結晶(収率23％)。¹H NMR (CDCl₃) δ: 2.88 (6H, s), 3.01 (3H, s), 3.75 (3H, s), 5.26 (2H, s), 7.46 (2H, d, J = 8.4 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.78-7.90 (3H, m), 8.47 (1H, m). Example 40
4-dimethylamino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless crystals (23% yield). ¹ H NMR (CDCl ₃ ) δ: 2.88 (6H, s), 3.01 (3H, s), 3.75 (3H, s), 5.26 (2H, s), 7.46 (2H, d, J = 8.4 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.78-7.90 (3H, m), 8.47 (1H, m).

淡黄色粉末(収率21％)。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.68 (3H, s), 4.64 (4H, s), 5.28 (2H, s), 7.23-7.36 (5H, m), 7.52 (2H, d, J = 8.4 Hz), 7.48-7.65 (2H, m), 7.89 (2H, d, J = 8.4 Hz), 8.51 (1H, m). Example 41
4- (1,3-dihydroisoindol-2-yl) -2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow powder (21% yield). ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.68 (3H, s), 4.64 (4H, s), 5.28 (2H, s), 7.23-7.36 (5H, m), 7.52 (2H, d, J = 8.4 Hz), 7.48-7.65 (2H, m), 7.89 (2H, d, J = 8.4 Hz), 8.51 (1H, m).

実施例１（１０）で得た4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.15g）、1,2-ビス[(ジメチルアミノ)メチレン]ヒドラジン二塩酸塩（0.11g）及びピリジン（3ml）の混合物を48時間加熱還流した。反応液を冷却後、溶媒を減圧下に留去した。残渣を中圧分取LC（酢酸エチル〜酢酸エチル/メタノール=4/1）により精製し、茶色粉末の表題化合物（23mg）を得た。¹H NMR (CDCl₃) δ: 3.04 (3H, s), 5.33 (2H, s), 7.04 (1H, d, J = 7.8 Hz), 7.36 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.67 (1H, m), 7.75 (1H, dt, J = 1.5, 14.4 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.33 (2H, s), 8.54 (1H, d, J = 0.9, 7.8 Hz). Example 42
2- (4-methanesulfonylbenzyl) -4-([1,2,4] triazol-4-yl) -2H-isoquinolin-1-one

4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.15 g) obtained in Example 1 (10), 1,2-bis A mixture of [(dimethylamino) methylene] hydrazine dihydrochloride (0.11 g) and pyridine (3 ml) was heated under reflux for 48 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure preparative LC (ethyl acetate-ethyl acetate / methanol = 4/1) to give the title compound (23 mg) as a brown powder. ¹ H NMR (CDCl ₃ ) δ: 3.04 (3H, s), 5.33 (2H, s), 7.04 (1H, d, J = 7.8 Hz), 7.36 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.67 (1H, m), 7.75 (1H, dt, J = 1.5, 14.4 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.33 (2H, s), 8.54 (1H, d, J = 0.9, 7.8 Hz).

実施例１（１０）で得た4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.47 g）、ベンジルオキシカルボニルクロリド（260μl）、炭酸カリウム(252mg)及びTHF（5.0ml）の混合物を10時間加熱還流した。反応終了後、反応液をジクロロメタンにて希釈し、1規定塩酸にて洗浄した。有機層を硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣を中圧分取LC（ヘキサン/酢酸エチル=1/1〜1/10）により精製し、無色粉末の表題化合物（600 mg）を得た。¹H NMR (CDCl₃) δ: 3.02 (3H, s), 3.61 (3H, s), 5.18 (2H, br), 5.39 (2H, s), 7.26-7.48 (5H, m), 7.43 (2H, d, J = 8.4 Hz), 7.59-7.70 (2H, m), 7.76 (1H, m), 7.87 (2H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 0.6, 8.7 Hz). Example 43
4-benzyloxycarbonylamino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.47 g) obtained in Example 1 (10), benzyloxycarbonyl chloride ( 260 μl), a mixture of potassium carbonate (252 mg) and THF (5.0 ml) was heated under reflux for 10 hours. After the completion of the reaction, the reaction solution was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/10) to give the title compound (600 mg) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ: 3.02 (3H, s), 3.61 (3H, s), 5.18 (2H, br), 5.39 (2H, s), 7.26-7.48 (5H, m), 7.43 (2H, d, J = 8.4 Hz), 7.59-7.70 (2H, m), 7.76 (1H, m), 7.87 (2H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 0.6, 8.7 Hz).

実施例４３で得た4-ベンジルオキシカルボニルアミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.59 g）、水酸化リチウム一水和物(238mg)、 1,4-ジオキサン（6ml）及び水（2.0ml）の混合物を室温にて2時間撹拌した。反応終了後、反応液をジクロロメタンにて希釈し、1規定塩酸にて洗浄した。有機層を硫酸マグネシウムにて乾燥後、減圧濃縮し、淡黄色粉末の表題化合物（480 mg）を得た。¹H NMR (DMSO-d₆) δ: 3.18 (3H, s), 5.13 (2H, s), 5.34 (2H, s), 7.06-7.50 (7H, m), 7.56-7.70 (2H, m), 7.78-7.92 (3H, m), 8.27 (1H, d, J = 8.1 Hz), 9.18 (1H, s). Example 44
4-benzyloxycarbonylamino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid

4-benzyloxycarbonylamino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.59 g) obtained in Example 43, lithium hydroxide monohydrate A mixture of the hydrate (238 mg), 1,4-dioxane (6 ml) and water (2.0 ml) was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound (480 mg) as a pale yellow powder. ¹ H NMR (DMSO-d ₆ ) δ: 3.18 (3H, s), 5.13 (2H, s), 5.34 (2H, s), 7.06-7.50 (7H, m), 7.56-7.70 (2H, m), 7.78-7.92 (3H, m), 8.27 (1H, d, J = 8.1 Hz), 9.18 (1H, s).

実施例１（１０）で得た4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボン酸 メチルエステル（0.25 g）、二酢酸トリフェニルビスマス（0.43 g）、ビス(2,2-ジメチルプロパン酸)銅(II)（0.25 g）及びジクロロメタン(12ml)の混合物を、窒素雰囲気下で24時間攪拌した。反応終了後、反応液を1規定塩酸及び飽和食塩水にて洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣を中圧分取LC（ヘキサン/酢酸エチル=1/1〜1/4）にて精製し、無色結晶の表題化合物（260 mg）を得た。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 3.62 (3H, s), 5.40 (2H, s), 5.64 (1H, s), 6.60 (2H, d, J = 8.1 Hz), 6.82 (1H, t, J = 7.2 Hz), 7.15 (2H, t, J = 7.8 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.54-7.72 (3H, m), 7.89 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 2.1, 7.5 Hz). Example 45
2- (4-methanesulfonylbenzyl) -1-oxo-4-phenylamino-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.25 g) obtained in Example 1 (10), triphenylbismuth diacetate (0.43 g), a mixture of bis (2,2-dimethylpropanoic acid) copper (II) (0.25 g) and dichloromethane (12 ml) was stirred under a nitrogen atmosphere for 24 hours. After completion of the reaction, the reaction solution was washed with 1N hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (260 mg) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.62 (3H, s), 5.40 (2H, s), 5.64 (1H, s), 6.60 (2H, d, J = 8.1 Hz), 6.82 (1H, t, J = 7.2 Hz), 7.15 (2H, t, J = 7.8 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.54-7.72 (3H, m), 7.89 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 2.1, 7.5 Hz).

4-(メタンスルホニル)ベンジルアミン塩酸塩(10.3 g)、炭酸カリウム(16.1 g)およびDMF(100 ml)の混合液に、0℃攪拌下ブロモアセトニトリル(3.4 ml)を滴下し、室温にて1時間攪拌した。不溶物を濾過して除き、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル〜酢酸エチル/メタノール=10/1)にて精製し、無色結晶の(4-メタンスルホニルベンジルアミノ)アセトニトリル(5.6 g)を得た。
本品、2-シアノ安息香酸（3.86 g）及びアセトニトリル(56 ml)の混合物に、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(7.2 g)及び4-ヒドロキシベンゾトリアゾール一水和物(5.0 g)を加え、室温で12時間攪拌した。溶媒を減圧下に除去し、残留物を酢酸エチルで希釈し、5%硫酸水素カリウム水溶液、飽和重曹水及び飽和食塩水にて順次洗浄、乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=1/1〜酢酸エチル)にて精製し、無色油状の2-シアノ-N-シアノメチル-N-(4-メタンスルホニルベンジル)ベンズアミド(3.9 g)を得た。
次いで、本品をメタノール(78 ml)に溶解し、室温攪拌下、28％ナトリウムメトキシド/メタノール溶液(4.3 g)を加え、室温で1時間攪拌した。反応液を濃縮し、残留物を酢酸エチル及び1規定塩酸により分液し、有機層を乾燥後濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=１/4)にて精製し、淡黄色結晶の表題化合物(3.0 g)を得た。¹H NMR (CDCl₃) δ: 3.03 (3H, s), 4.46 (2H, s), 5.45 (2H, s), 7.62 (2H, d, J = 8.7 Hz), 7.65-7.88 (3H, m), 7.90 (2H, d, J = 8.7 Hz), 8.58 (1H, dd, J = 1.5, 8.1 Hz). Example 46
4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carbonitrile

Bromoacetonitrile (3.4 ml) was added dropwise to a mixture of 4- (methanesulfonyl) benzylamine hydrochloride (10.3 g), potassium carbonate (16.1 g) and DMF (100 ml) with stirring at 0 ° C. Stirred for hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 10/1) to obtain colorless crystals of (4-methanesulfonylbenzylamino). Acetonitrile (5.6 g) was obtained.
To a mixture of this product, 2-cyanobenzoic acid (3.86 g) and acetonitrile (56 ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (7.2 g) and 4-hydroxybenzotriazole monohydrate The hydrate (5.0 g) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed sequentially with a 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate) to give 2-cyano-N-cyanomethyl-N- (4-methanesulfonylbenzyl) benzamide (3.9 g) as a colorless oil. Obtained.
Next, this product was dissolved in methanol (78 ml), and a 28% sodium methoxide / methanol solution (4.3 g) was added under stirring at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, the residue was separated with ethyl acetate and 1N hydrochloric acid, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give the title compound (3.0 g) as pale yellow crystals. ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 4.46 (2H, s), 5.45 (2H, s), 7.62 (2H, d, J = 8.7 Hz), 7.65-7.88 (3H, m) , 7.90 (2H, d, J = 8.7 Hz), 8.58 (1H, dd, J = 1.5, 8.1 Hz).

本化合物は実施例３７に示す方法に従い、4-アミノ-2-(4-メタンスルホニルベンジル)-1-オキソ-1,2-ジヒドロイソキノリン-3-カルボニトリル及び1,5-ジブロモペンタンを用いて合成した。淡黄色結晶(収率35％)。¹H NMR (CDCl₃) δ: 1.70-1.86 (6H, m), 3.03 (3H, s), 3.10-3.34 (4H, m), 5.50 (2H, s), 7.60 (2H, d, J = 8.1 Hz), 7.69 (1H, m), 7.79 (1H, m), 7.90 (2H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.49 (1H, dd, J = 0.6, 8.1 Hz). Example 47
2- (4-methanesulfonylbenzyl) -1-oxo- (4-piperidin-1-yl) -1,2-dihydroisoquinoline-3-carbonitrile

This compound was prepared using 4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carbonitrile and 1,5-dibromopentane according to the method described in Example 37. Synthesized. Pale yellow crystals (35% yield). ¹ H NMR (CDCl ₃ ) δ: 1.70-1.86 (6H, m), 3.03 (3H, s), 3.10-3.34 (4H, m), 5.50 (2H, s), 7.60 (2H, d, J = 8.1 Hz), 7.69 (1H, m), 7.79 (1H, m), 7.90 (2H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.49 (1H, dd, J = 0.6 , 8.1 Hz).

Formulation Example 1
JNK inhibitors containing a compound represented by the formula (I) or a salt thereof according to the present invention as an active ingredient (eg, chronic or acute heart failure, cardiac hypertrophy, prognosis of myocardial infarction, myocarditis, rheumatoid arthritis, osteoarthritis, Inflammatory bowel disease, asthma, ischemia / reperfusion injury, organ failure, stroke, cerebrovascular disorder, etc.) can be produced, for example, by the following formulation.
In addition, in the following prescription, as components (additives) other than the active ingredient, products listed in the Japanese Pharmacopoeia, non-Japanese Pharmacopoeia drug standards or drug excipient standards can be used.
1. Capsule (1) 40 mg of compound obtained in Example 21
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) 1 mg of magnesium stearate
120mg per capsule
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.
2. Capsule (1) 40 mg of compound obtained in Example 24
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) 1 mg of magnesium stearate
120mg per capsule
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.
3. Capsule (1) 40 mg of compound obtained in Example 37
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) 1 mg of magnesium stearate
120mg per capsule
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.
4. Tablet (1) 40 mg of the compound obtained in Example 21
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
5. Tablet (1) 40 mg of the compound obtained in Example 24
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
6. Tablet (1) 40 mg of the compound obtained in Example 37
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation Example 2
1. After 50 mg of the compound obtained in Example 21 is dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection, the Japanese Pharmacopoeia distilled water for injection is added to make 100 ml. The solution is filtered under sterile conditions, then 1 ml each of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.
2. After dissolving 50 mg of the compound obtained in Example 24 in 50 ml of distilled water for injection in Japan, add distilled water for injection to make 100 ml. The solution is filtered under sterile conditions, then 1 ml each of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.
3. After dissolving 50 mg of the compound obtained in Example 37 in 50 ml of distilled water for injection in Japan, add distilled water for injection to make 100 ml. The solution is filtered under sterile conditions, then 1 ml each of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.

Experimental example 1
The genetic manipulation method described in the following experimental examples was in accordance with the method described in a compendium (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or the protocol described in the protocol attached to the reagent. .
(1) Cloning of Human JNK1 Gene and Preparation of Recombinant Baculovirus The cloning of the human JNK1 gene was reported by Derijard, B. et al. Using kidney cDNA (Toyobo, QUICK-Clone cDNA) as a template (Cell, 76, 1025- 1037 (1994)), a primer set prepared based on the base sequence of the JNK1 gene
JNK1-U:
^5'- ACAACTCGAGATAACATATGGCTCATCATCATCATCATCATAGCAGAAGCAAGCGTGACAAC -3 ^'
(SEQ ID NO: 1)
JNK1-L:
5 ^' -TCCCGGGTACCTCACTGCTGCACCTGTGCTAA -3 ^'
(SEQ ID NO: 2)
Was performed by the PCR method.
The PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo). As the lower layer mixture, 2 μl of 10 × LA PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution, ₂ μl of 25 mM MgCl ₂ solution, and 8 μl of sterile distilled water were mixed. As the upper layer mixture, 1 μl of human kidney cDNA (1 ng / ml) as a template, 3 μl of 10 × LA PCR Buffer, 5 μl of 2.5 mM dNTP solution, 3 μl of 25 mM MgCl ₂ solution, TaKaRa LA Taq DNA po1ymerase (Takara Shuzo) 0.5 μl and sterile distilled water 17.5 μl were mixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer) and treated at 95 ° C. for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes. The resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.2 kb DNA fragment containing the JNK1 gene was recovered from the gel, digested with the restriction enzymes KpnI and XhoI, and 4.8 kb XhoI of the plasmid pFASTBAC1 (GIBCO BRL). The plasmid pFBJNK1 inserted into the -KpnI fragment was prepared. Using the plasmid pFBJNK1 and the BAC-TO-BAC Baculovirus Expression System (GIBCO BRL), a virus stock BAC-HJNK1 of a recombinant baculovirus was prepared.

(2) Cloning of Human MKK7 Gene and Preparation of Recombinant Baculovirus The cloning of the human MKK7 gene was reported by Foltz, IN et al. Using pancreatic cDNA (Toyobo, QUICK-Clone cDNA) as a template (J. Biol. Chem., 273 (15), 9344-9351 (1998)), a primer set prepared with reference to the nucleotide sequence of the MKK7 gene
MKK7-U:
5 ^' -ACCAGAATTCATAACATATGGCTCATCATCATCATCATCATGCGGCGTCCTCCCTGGAACAG-3 ^'
(SEQ ID NO: 3)
MKK7-L:
5 ^' -ACCCTCTAGACAAGCAGCTACCTGAAGAAGG -3 ^'
(SEQ ID NO: 4)
Was performed by the PCR method.
The PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo). As the lower layer mixture, 2 μl of 10 × LA PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution, ₂ μl of 25 mM MgCl ₂ solution, and 8 μl of sterile distilled water were mixed. As the upper layer mixture, 1 μl of human pancreatic cDNA (1 ng / ml) as a template, 3 μl of 10 × LA PCR Buffer, 5 μl of 2.5 mM dNTP solution, 3 μl of 25 mM MgCl ₂ solution, TaKaRa LA Taq DNA po1ymerase (Takara Shuzo) 0.5 μl and 17.5 μl of sterile distilled water were mixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer) and treated at 95 ° C. for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes. The obtained PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.3 kb DNA fragment containing the MKK7 gene was recovered from the gel, and inserted into a pT7Blue-T vector (Novagen) to obtain a plasmid pHMKK7.
The constitutively active form of MKK7 reported by Wang, Y. et al. (J. Biol. Chem., 273 (10), 5423-5426, 1998) (Asp for Ser at position 271 and Asp for position 275) was used. Primer set to make
CAM7-U:
5 ^' -GGCCGCCTGGTGGACGACAAAGCCAAGGACCGGAGCGCCGGCTG-3 ^'
(SEQ ID NO: 5)
CAM7-L:
5 ^' -CAGCCGGCGCTCCGGTCCTTGGCTTTGTCGTCCACCAGGCGGCC -3 ^'
(SEQ ID NO: 6)
Was used to introduce a mutation with the QuikChange Site-Directed Mutagenesis Kit (Stratagene) to obtain pcaMKK7.
The 4.8 kb EcoRI-XbaI fragment of plasmid pFASTBAC1 (GIBCO BRL) and the 1.3 kb EcoRI-XbaI fragment of plasmid pcaMKK7 were ligated to prepare plasmid pFBcaMKK7.
Using the plasmid pFBcaMKK7 and the BAC-TO-BAC Baculovirus Expression System (GIBCO BRL), a virus stock BAC-caMKK7 of a recombinant baculovirus was prepared.

(3) Cloning of the human cJUN gene The cloning of the human cJUN gene was reported by Hattori, K., et al. (Proc. Natl. Acad. Sci. USA, 85, using skeletal muscle cDNA (Toyobo, QUICK-Clone cDNA) as a template. 23), 9148-9152 (1988)), a primer set prepared with reference to the nucleotide sequence of the cJUN gene
cJUN-U:
5 ^' -AAAAGAATTCATGACTGCAAAGATGGAAACGACC-3 ^'
(SEQ ID NO: 7)
cJUN-L:
5 ^' -AAAAGCGGCCGCTCACAGGCGCTCCAGCTCGGGCGACGC -3 ^'
(SEQ ID NO: 8)
The gene encoding the N-terminal 79 amino acids of cJUN was amplified by PCR using PCR.
The PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo). As the lower layer mixture, 2 μl of 10 × Pyrobest PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution, and 10 μl of sterile distilled water were mixed. As the upper layer mixture, 1 μl of human skeletal muscle cDNA (1 ng / ml) as a template, 3 μl of 10 × Pyrobest PCR Buffer, 2 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa Pyrobest DNA po1ymerase (Takara Shuzo), 24.5 of sterilized distilled water μl was mixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer) and treated at 95 ° C. for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 30 seconds was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes. The resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 240 bp DNA fragment containing the cJUN gene was recovered from the gel, digested with restriction enzymes EcoRI and NotI, and plasmid pGEX6P-1 (Amersham Pharmacia) was digested. A plasmid pGEJUN inserted into the 4.9 kb EcoRI-NotI fragment was prepared.

(4) Preparation of activated JNK1
After inoculating Sf-21 cells at 1 × 10 ⁶ cells / ml in 100 ml Sf-900 II SFM medium (GIBCOBRL) containing 10% fetal bovine serum, the cells were cultured at 27 ° C. for 24 hours. After adding 0.2 ml of each of the recombinant baculovirus virus stocks BAC-HJNK1 and BAC-caMKK7, the cells were further cultured for 60 hours. After the cells were separated from the culture solution by centrifugation (3000 rpm, 10 min), the cells were washed twice with PBS. After suspending the cells in 10 ml Lysis buffer (25 mM HEPES (pH 7.5), 1% TritonX, 130 mM NaCl, 1 mM EDTA, 1 mM DTT, 25 mM β-glycerophosphate, 20 μM leupeptin, 1 mM APMSF, 1 mM Sodium orthovanadate), homogenizer (POLYTRON) ), The cells were disrupted by performing the treatment four times at 20,000 rpm for 30 seconds. Active JNK1 was purified from the supernatant obtained by centrifugation (40000 rpm, 45 minutes) using Anti-FLAG M2 Affinity Gel (Sigma).

(5) Preparation of Recombinant cJUN The plasmid pGEJUN was transformed into Escherichia coli JM109 (Toyobo) to obtain an ampicillin-resistant strain pGEJUN / JM109. The pGEJUN / JM109 strain was cultured overnight at 200 rpm and 37 ° C. in 150 ml of LB medium (10 g / l tryptone, 5 g / l yeast extract, 10 g / l sodium chloride) containing 50 μg / ml ampicillin. 15 ml of the culture was added to 150 ml of fresh LB medium, cultured at 200 rpm at 37 ° C. for 2 hours, and further cultured for 1 hour with 1 mM IPTG (Wako Pure Chemical Industries). The culture was centrifuged at 8000 rpm for 10 minutes to collect the cells, washed with PBS, and frozen at -80 ° C. After suspending in 20 ml of Lysis buffer (B-PER bacterial protein extraction reagent (Pierce), Proteinase inhibitor Complete (Boehringer)), it was shaken at room temperature for 10 minutes. Centrifugation (14000 rpm, 15 minutes, 4 ° C.) was performed, and the GST-cJUN fusion protein was purified from the supernatant using Redipack GST Purification Module (Amersham Pharmacia).

(6) Measurement of JNK inhibitory activity
2.5 μl of a test compound dissolved in DMSO was added to a 37.5 μl reaction solution (25 mM HEPES (pH 7.5), 10 mM magnesium acetate) containing 50 ng active JNK1 and 1 μg cJUN, and the mixture was kept at 30 ° C. for 5 minutes. The reaction was started by adding 10 μl of an ATP solution (2.5 μM ATP, 0.01 μCi [γ- ³² P] ATP). After reacting at 30 ° C. for 60 minutes, the reaction was stopped by adding 50 μl of a 20% TCA solution. After leaving the reaction solution at 0 ° C. for 20 minutes, the acid-insoluble fraction was transferred to a GF / C filter (Packard Japan) using a cell harvester (Packard Japan), and washed with 250 mM phosphoric acid. After drying at 45 ° C. for 60 minutes, 40 μl of Microscint 0 (Packard Japan) was added, and the radioactivity was measured by Top Count (Packard Japan). The concentration (IC ₅₀ value) of the test compound required to inhibit the incorporation of ³² P into the acid-insoluble fraction by 50% was calculated using PRISM 2.01 (Graph Pad Software).

Experimental example 2
Measurement of TNFα production inhibitory activity
THP-1 cells cultured in RPMI1640 medium (GIBCO BRL) containing 1% inactivated fetal bovine serum and 10 mM HEPES (pH 7.5) were seeded at 1 × 10 ⁵ cells / well in a 96-well plate, and then added to DMSO. 1 μl of the dissolved test compound was added.
After culturing in a carbon dioxide gas incubator at 37 ° C. for 1 hour, LPS (Wako Pure Chemical Industries) was added to a final concentration of 5 μg / ml. After culturing at 37 ° C. for 4 hours in a carbon dioxide gas incubator, a supernatant was obtained by centrifugation. The TNFα concentration in the supernatant was measured using an ELISA kit (Diacron). The concentration (IC ₅₀ value) of the test compound required to inhibit TNFα production by 50% was calculated using PRISM 2.01 (GraphPad Software).

Experimental example 3
TNFα measurement after LPS administration (rat)
(1) Oral administration:
9-10 week old male Jcl: Wistar rats were used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 mg / kg. Compounds were suspended in 0.5% methylcellulose and performed 60 minutes before LPS administration. The control group similarly received only 0.5% methylcellulose. 90 minutes after LPS administration, blood was collected from the abdominal aorta with a syringe containing aprotinin / EDTA under pentobarbital (50 mg / kg, intraperitoneal administration) anesthesia, and plasma was obtained by centrifugation at 3000 rpm, 4 ° C for 10 minutes. . TNFα in plasma was measured using an ELISA Kit (GENZYME).
(2) Intravenous administration:
9-10 week old male Jcl: Wistar rats were used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 mg / kg. Compounds were dissolved in DMAA / PEG400 (1: 1) and performed 10 minutes before LPS administration. The control group similarly received only DMAA / PEG400 (1: 1). Ninety minutes after LPS administration, blood was collected from the abdominal aorta using a syringe containing aprotinin / EDTA under pentobarbital (50 mg / kg, intraperitoneal administration) anesthesia, and plasma was obtained by centrifugation at 3000 rpm, 4 ° C for 10 minutes. . TNFα in plasma was measured using an ELISA Kit (GENZYME).

Experimental example 4
Measurement of cardiac phosphorylated c-Jun after LPS administration (rat)
9-10 week old male Jcl: Wistar rats were used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 mg / kg. The compound was orally or intravenously administered by the method described in (1-1) or (1-2). Ninety minutes after LPS administration, the heart was excised, the heartbeat was stopped in ice-cooled TBS buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl), and the left ventricle was collected. Left ventricle in 5.0 ml of ice-cold Lysis buffer (20 mM Tris-HCl pH 7.4, 1% NP40, 0.1% SDS, 150 mM NaCl, 1 mM EDTA 0.1 mg / ml PMSF, 0.3 TIU aprotinin, 1 mM sodium orthovanadate) After homogenizing and centrifuging at 12000 rpm (15800 g) at 4 ° C. for 30 minutes, the supernatant was collected and used as a tissue extract. The protein amount was measured using the Bradford method (BIORAD: Protein assay). 8 μg of anti-c-Jun rabbit polyclonal antibody (H79: SANTA CRUZ) and 20 μl of Protein A-Agarose (SANTA CRUZ) were added to the tissue extract containing 10 mg of protein, and the mixture was stirred at 4 ° C. overnight. Centrifuge at 2500rpm, 4 ° C for 5 minutes, remove supernatant, wash 3 times with TBS buffer (50mM Tris-HCl pH7.4, 150mM NaCl, 0.1mg / ml PMSF, 0.3TIU aprotinin, 1mM sodium orthovanadate), 60μl Was dissolved in a Laemmli sample buffer (BIORAD). 10 μl of the sample was loaded on a 10% separation gel (BIORAD) and electrophoresed at 150 V for 60 minutes. The protein on the gel was transferred to a methanol-treated PVDF membrane (BIORAD) at 100 V for 1 hour using a wet blotting method. After washing the membrane with TBS-T (0.05% Tween20), the membrane was blocked with 5% skim milk / TBS-T (blocking buffer) for 1 hour at room temperature. Thereafter, the mixture was reacted with an anti-phosphorylated c-Jun (ser63) mouse monoclonal antibody (KM-1: SANTA CRUZ; diluted 1: 250 with a blocking buffer) at room temperature for 1.5 hours. After washing the membrane with TBS-T (5 minutes, twice), the membrane was reacted with an HRP-labeled anti-mouse IgG secondary antibody (Amersham) diluted 2000-fold with a blocking buffer for 1 hour at room temperature, followed by TBS-T ( 3 times for 5 minutes) and washed with TBS. The membrane was reacted with 2 ml of ECL reaction solution (ECL Plus: Amersham) for 5 minutes, exposed to X-ray film for 1 minute, immersed in developer for 90 seconds, washed with water, and immersed in fixer to remove the film. Developed. The developed X-ray film was captured by DeskscanII and automatically corrected, and then automatically corrected by Photoshop to reverse the color tone. The density of the band observed at the target molecular weight was quantified using a histogram of Photoshop.

これより、本発明の化合物（Ｉ）またはその塩は優れたＪＮＫ特異的阻害活性を有することがわかる。 Experimental Results Table 1 shows the inhibitory effects of human JNK1, p38α and ERK1.

This indicates that the compound (I) of the present invention or a salt thereof has excellent JNK-specific inhibitory activity.

  The compound (I) or a salt thereof of the present invention has an excellent JNK-specific inhibitory activity and an excellent oral absorbability, and is therefore advantageous as a safe and effective medicament for the prevention and treatment of JNK-related conditions or diseases. Used for

The sequence numbers in the sequence listing in the present specification indicate the following sequences.
[SEQ ID NO: 1]
2 shows the nucleotide sequence of primer JNK1-U.
[SEQ ID NO: 2]
2 shows the nucleotide sequence of primer JNK1-L.
[SEQ ID NO: 3]
3 shows the nucleotide sequence of primer MKK7-U.
[SEQ ID NO: 4]
2 shows the nucleotide sequence of primer MKK7-L.
[SEQ ID NO: 5]
2 shows the nucleotide sequence of primer CAM7-U.
[SEQ ID NO: 6]
2 shows the nucleotide sequence of primer CAM7-L.
[SEQ ID NO: 7]
2 shows the nucleotide sequence of primer cJUN-U.
[SEQ ID NO: 8]
2 shows the nucleotide sequence of primer cJUN-L.

Claims (27)

Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. ] Or a salt thereof or a prodrug thereof. Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. (However, 2-benzyl-6,7-dichloro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6 , 7-Dichloro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinoline Carboxylic acid and 2-benzyl-4-butoxy-6,7-dichloro-3-hydroxymethyl-1 (2H) -isoquinolinone) or a salt thereof. Ring A has the formula

[Wherein, R ³ represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally substituted It represents a good thiol group, substituted sulfinyl group, substituted sulfonyl group, optionally substituted amino group, optionally substituted carbamoyl group or optionally esterified carboxyl group. The compound according to claim 2, which is a benzene ring represented by the formula: 4. The compound according to claim ³ , wherein R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group or an optionally substituted amino group. The compound according to claim ³ , wherein R3 is a hydrogen atom, a halogen atom or a _C1-4 alkyl group. The compound according to claim 2, wherein R ¹ is phenyl which may be substituted. 3. The compound according to claim 2, wherein X is methylene. The compound according to claim 2, wherein Y is an optionally substituted non-aromatic hydrocarbon group. 3. The compound according to claim 2, wherein Y is a chain hydrocarbon group which may be substituted. The compound according to claim 2, wherein Y is an optionally substituted _C2-6 alkenyl. 3. The compound according to claim 2, wherein Y is an optionally substituted heterocyclic group. The compound according to claim 2, wherein Y is an optionally substituted 5- or 6-membered aromatic heterocyclic group. 3. The compound according to claim 2, wherein Y is an optionally substituted hydroxy group. The compound according to claim 2, wherein Y is a hydroxy group substituted with an optionally substituted hydrocarbon group. 3. The compound according to claim 2, wherein Y is an amino group which may be substituted. 3. The compound according to claim 2, wherein Y is a cyclic amino group. The compound according to claim 2, wherein R ² is a carboxyl group which may be esterified or a carbamoyl group which may be substituted. ^3. The compound according to claim 2, wherein R2 is lower alkoxycarbonyl. The compound according to claim 2, wherein R ² is an acyl group, a hydrocarbon group optionally substituted with an optionally substituted hydroxy group, or an amino group optionally substituted. 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester, 2- (4 -Carboxybenzyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or 2- (4-methanesulfonylbenzyl) 1-oxo-4- (piperidin-1-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or a salt thereof. A prodrug of the compound of claim 2. A medicament comprising the compound according to claim 2 or 21. The agent according to claim 1, which is an agent for preventing or treating a JNK-related disease state or disease. 24. The agent according to claim 23, wherein the JNK-related condition or disease is a circulatory disease, an inflammatory disease, a neurodegenerative disease or diabetes. Chronic or acute heart failure, hypertrophy, dilated, hypertrophic or restricted cardiomyopathy, acute coronary syndrome, chronic ischemic heart disease, acute or chronic myocarditis, left diastolic dysfunction, left heart systolic insufficiency, hypertension and it The agent according to claim 1, which is a preventive or therapeutic agent for combined nephropathy / nephritis, decreased vascular endothelial function, arteriosclerosis, restenosis after angioplasty, or an agent for improving the prognosis of myocardial infarction. Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. Or a salt thereof or a prodrug thereof is administered to the mammal in an effective amount. Formula (I) for the production of JNK inhibitors

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents a hydrogen atom. A hydrocarbon group which may be substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted or A good amino group, X represents an optionally substituted divalent chain hydrocarbon group, and Y represents an optionally substituted non-aromatic hydrocarbon group or an optionally substituted heterocyclic group. And a hydroxy group which may be substituted or an amino group which may be substituted. Or a salt thereof or a prodrug thereof.