JPWO2006137465A1 - Nitrogen-containing heterocyclic derivatives - Google Patents

Abstract

It has been found that the nitrogen-containing heterocyclic derivative represented by the formula (I) specifically binds to the NR1 / NR2B receptor and is used as an analgesic (pain treatment). (In the formula, A1 has at least one hydroxy and / or amino, and may be further substituted with another group, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group, or Is a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group, which may contain other ring-constituting atoms, and A2 has a substituent. An aromatic hydrocarbon cyclic group or the like, wherein R1 and R2 are each hydrogen or hydroxy, m is 0 or 1, and X is an optionally substituted lower alkylene or lower alkenylene. , -CO (CR3R4) n-, -CONR5 (CR3R4) n-, -NR5CO (CR3R4) n-, -A3- (CR3R4) n-, etc., wherein R3 and R4 are each hydrogen or lower alkyl , N and r are each independently 0 to 4, A3 is phenylene, pyridinylene, etc., Y is a single bond, lower alkylene, —O—, —S— or —NR15—, etc., and R3 to R15 Are each independently hydrogen or optionally substituted lower alkyl) or a pharmaceutically acceptable salt thereof or a solvate thereof.

Description

   The present invention shows a specific antagonistic action on a central nerve cell glutamate receptor, particularly NR1 / NR2B receptor, which is one of NMDA receptors, preferably motor function (eg, sensory abnormality), psychiatric symptoms The present invention relates to a nitrogen-containing heterocyclic derivative useful as a medicament such as an analgesic agent having few side effects on (eg schizophrenia).

Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activation as neurotransmitters in the central nervous system. However, the extracellular accumulation of these excitatory amino acids can cause various neurological disorders such as Parkinson's disease, senile dementia, Huntington's chorea, epilepsy, as well as oxygen deficiency, ischemia, hypoglycemia It is thought to cause a loss of mental and motor function, such as that seen during conditions, head or spinal cord injury.
It is known that the activity of the excitatory amino acids against central nerve cells acts via glutamate receptors present on the nerve cells, and glutamate receptor antagonists are therapeutic agents for the above diseases and symptoms, for example, It is considered useful as an antiepileptic drug, an ischemic brain injury preventive drug, and an antiparkinsonian drug.
The NMDA receptor, which is one of the glutamate receptors, is composed of two subunits, NR1 and NR2, and there are four additional families (NR2A, 2B, 2C, 2D) in the NR2 subunit. To do. The NR1 / NR2A receptor is exclusively involved in memory formation and learning acquisition, and the NR1 / NR2B receptor is said to be involved in neurodegenerative cell death and pain transmission during cerebral ischemia. Therefore, a drug showing high affinity for the NR1 / NR2B receptor is likely to be an effective analgesic with few side effects.
In addition, although the compound similar to the nitrogen-containing heterocyclic derivative of this invention is described in patent documents 1-12, none of the compounds which concern on this invention are described.
International Publication No. 2004/11430 Pamphlet International Publication No. 2003/084948 Pamphlet Japanese Patent Laid-Open No. 8-22569 International Publication No. 98/18793 Pamphlet International Publication No. 2003/010159 Pamphlet International Publication No. 2004/054579 pamphlet JP-A-11-71350 International Publication No. 99/45925 Pamphlet Japanese Patent Laid-Open No. 3-206086 International Publication No. 03/035641 Pamphlet International Publication No. 2005/030720 Pamphlet International Publication No. 2002/50070 Pamphlet

  Provided are NMDA receptor antagonists, particularly analgesics for cancer pain and the like, which are highly active and more preferably have a high affinity for subtypes, particularly NR1 / NR2B receptors.

（式中、
Ａ^１は
保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基または
環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基であり、
Ａ^２は
置換基を有していてもよい芳香族炭化水素環式基または置換基を有していてもよい芳香族複素環式基であり、
Ｒ^１は水素、ヒドロキシ、アシルオキシ、低級アルコキシまたは低級アルキルであり、
Ｒ^２は水素、ヒドロキシまたは低級アルキルであり、
Ｒ^１およびＲ^２が一緒になって単結合を形成していてもよく、
ｍは０または１であり、
Ｘは
置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｎ−ＯＲ^７）（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ_２（ＣＲ^３Ｒ^４）ｎ−、−ＣＲ^９＝Ｎ−Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｏ）Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−ＣＲ^１０＝ＣＲ^１１（ＣＲ^３Ｒ^４）ｎ−であり、
ｍ＝１のとき、Ｘはヒドロキシで置換されていてもよい低級アルキレンであってもよく、
ｎおよびｒは各々独立して０〜４の整数であり、ｎ＋ｒは４以下であり、
Ａ^３は

（式中、破線は結合の存在または不存在を示し、Ｒ^ｘは水素または低級アルキルである）
であり、
−Ｘ−（ＣＯ）ｍ−が置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^６ＣＯ（ＣＲ^３Ｒ^４）ｎ’−（ここでｎ’は１または２）、−ＮＲ^６ＣＯＣＯ−、−ＮＲ^６（ＣＲ^３Ｒ^４）ｎＣＯ−、−Ｓ（ＣＲ^３Ｒ^４）ｎ−、−ＳＯ（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−である場合、
Ａ^１は保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基または環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい芳香族単環式基であり、
−Ｘ−（ＣＯ）ｍ−が−Ｓ（ＣＲ^３Ｒ^４）ｎ−である場合、−Ｙ−Ａ^２は無置換ベンジルではなく、
Ｙは
i)ｍ＝０のとき、単結合、−ＣＲ^１２Ｒ^１３−、−Ｏ−、−Ｓ−、−Ｃ（＝Ｎ−ＯＲ^１７）−、−Ｃ（＝Ｏ）−、−ＣH（ＯＲ^１７）−または−ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−を形成してもよく、
ii)ｍ＝１のとき、単結合、低級アルキレン、低級アルケニレン、低級アルキニレン、−Ｏ−、−Ｓ−、−ＮＲ^１５−、−ＣＲ^１２Ｒ^１３Ｏ−、−ＣＲ^１２Ｒ^１３Ｓ−または−ＣＲ^１２Ｒ^１３ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−（ＣＲ^１５Ｒ^１６）ｐ−を形成してもよく、ｐは０〜５の整数であり、
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１６およびＲ^１７は各々独立して水素または置換基を有していてもよい低級アルキルであり、Ｒ^３およびＲ^４が各々複数個存在する場合には各々異なっていてもよい）で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１’）式（Ｉ）：

（式中、
Ａ^１は
保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基または
環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基であり、
Ａ^２は
置換基を有していてもよい芳香族炭化水素環式基または置換基を有していてもよい芳香族複素環式基であり、
Ｒ^１は水素またはヒドロキシであり、
Ｒ^２は水素、ヒドロキシまたは低級アルキルであり、
Ｒ^１およびＲ^２が一緒になって単結合を形成していてもよく、
ｍは０または１であり、
Ｘは
置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｎ−ＯＲ^７）（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ_２（ＣＲ^３Ｒ^４）ｎ−、−ＣＲ^９＝Ｎ−Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｏ）Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−ＣＲ^１０＝ＣＲ^１１（ＣＲ^３Ｒ^４）ｎ−であり、
ｍ＝１のとき、Ｘはヒドロキシで置換されていてもよい低級アルキレンであってもよく、ｎおよびｒは各々独立して０〜４の整数であり、ｎ＋ｒは４以下であり、
Ａ^３は

（式中、破線は結合の存在または不存在を示し、Ｒ^Ｘは水素または低級アルキルである）
であり、
−Ｘ−（ＣＯ）ｍ−が置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^６ＣＯ（ＣＲ^３Ｒ^４）ｎ’−（ここでｎ’は１または２）、−ＮＲ^６ＣＯＣＯ−、−ＮＲ^６（ＣＲ^３Ｒ^４）ｎＣＯ−、−Ｓ（ＣＲ^３Ｒ^４）ｎ−、−ＳＯ（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−である場合、
Ａ^１は保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基または環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい芳香族単環式基であり、
−Ｘ−（ＣＯ）ｍ−が−Ｓ（ＣＲ^３Ｒ^４）ｎ−である場合、−Ｙ−Ａ^２は無置換ベンジルではなく、
Ｙは
i)ｍ＝０のとき、単結合、−ＣＲ^１２Ｒ^１３−、−Ｏ−、−Ｓ−または−ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−を形成してもよく、
ii)ｍ＝１のとき、単結合、低級アルキレン、低級アルケニレン、低級アルキニレン、−Ｏ−、−Ｓ−、−ＮＲ^１５−、−ＣＲ^１２Ｒ^１３Ｏ−、−ＣＲ^１２Ｒ^１３Ｓ−または−ＣＲ^１２Ｒ^１３ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−（ＣＲ^１５Ｒ^１６）ｐ−を形成してもよく、ｐは０〜５の整数であり、
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５およびＲ^１６は各々独立して水素または置換基を有していてもよい低級アルキルであり、Ｒ^３およびＲ^４が各々複数個存在する場合には各々異なっていてもよい）
で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１’’）式（Ｉ）：

（式中、
Ａ^１は
保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基または
環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい含窒素芳香族単環式基もしくは含窒素芳香族縮合環式基であり、
Ａ^２は
置換基を有していてもよい芳香族炭化水素環式基または置換基を有していてもよい芳香族複素環式基であり、
Ｒ^１は水素またはヒドロキシであり、
Ｒ^２は水素、ヒドロキシまたは低級アルキルであり、
Ｒ^１およびＲ^２が一緒になって単結合を形成していてもよく、
ｍは０または１であり、
Ｘは
置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｎ−ＯＲ^７）（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ（ＣＲ^３Ｒ^４）ｎ−、−（ＣＲ^８Ｒ^９）ｒＳＯ_２（ＣＲ^３Ｒ^４）ｎ−、−ＣＲ^９＝Ｎ−Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ｃ（＝Ｏ）Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−ＣＲ^１０＝ＣＲ^１１−であり、
ｍ＝１のとき、Ｘはヒドロキシで置換されていてもよい低級アルキレンであってもよく、ｎおよびｒは各々独立して０〜４の整数であり、ｎ＋ｒは４以下であり、
Ａ^３は

（式中、破線は結合の存在または不存在を示す）
であり、
−Ｘ−（ＣＯ）ｍ−が置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^６ＣＯ（ＣＲ^３Ｒ^４）ｎ’−（ここでｎ’は１または２）、−ＮＲ^６ＣＯＣＯ−、−ＮＲ^６（ＣＲ^３Ｒ^４）ｎＣＯ−、−Ｓ（ＣＲ^３Ｒ^４）ｎ−、−ＳＯ（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−である場合、
Ａ^１は保護されていてもよいヒドロキシおよび／または保護されていてもよいアミノを少なくとも１個有し、さらに他の基で置換されていてもよい含窒素芳香族単環式基または環内に−ＮＨ−を含有し、かつその他の環構成原子が、保護されていてもよいヒドロキシおよび保護されていてもよいアミノ以外の置換基で置換されていてもよい芳香族単環式基であり、
−Ｘ−（ＣＯ）ｍ−が−Ｓ（ＣＲ^３Ｒ^４）ｎ−である場合、−Ｙ−Ａ^２は無置換ベンジルではなく、
Ｙは
i)ｍ＝０のとき、単結合、−ＣＲ^１２Ｒ^１３−、−Ｏ−、−Ｓ−または−ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−を形成してもよく、
ii)ｍ＝１のとき、単結合、低級アルキレン、低級アルケニレン、低級アルキニレン、−Ｏ−、−Ｓ−、−ＮＲ^１５−、−ＣＲ^１２Ｒ^１３Ｏ−、−ＣＲ^１２Ｒ^１３Ｓ−または−ＣＲ^１２Ｒ^１３ＮＲ^１５−であり、Ｒ^２と一緒になって＝ＣＲ^１４−（ＣＲ^１５Ｒ^１６）ｐ−を形成してもよく、ｐは０〜５の整数であり、
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５およびＲ^１６は各々独立して水素または置換基を有していてもよい低級アルキルであり、Ｒ^３およびＲ^４が各々複数個存在する場合には各々異なっていてもよい）
で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。The present invention
Formula (I):

(Where
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and may further be substituted with another group, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aroma Group-containing cyclic group or -NH- in the ring, and other ring atoms may be substituted with a substituent other than hydroxy which may be protected and amino which may be protected A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
A ² is an aromatic hydrocarbon cyclic group which may have a substituent or an aromatic heterocyclic group which may have a substituent,
R ¹ is hydrogen, hydroxy, acyloxy, lower alkoxy or lower alkyl,
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
m is 0 or 1,
X represents a lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - CONR 5 (CR 3 R 4) n -, - ^{NR 5 CO (CR 3 R 4} ) n -, - NR 5 CONR 6 (CR 3 R 4) n -, - C (= n-OR 7) (CR 3 R 4) n -, - (CR 8 R 9 ^{) rO (CR 3 R 4)} n -, - (CR 8 R 9) rS (CR 3 R 4) n -, - (CR 8 R 9) rNR 6 (CR 3 R 4) n -, - (CR 8 ^{R 9) rSO (CR 3 R} 4) n -, - (CR 8 R 9) rSO 2 (CR 3 R 4) n -, - CR 9 = n-O (CR 3 R 4) n -, - C ( ^{= O) O (CR 3 R} 4) n -, - A 3 - (CR 3 R 4) n- or ^{-A 3 -CR 10 = CR 11 (} CR 3 R ⁴ ) n-
When m = 1, X may be lower alkylene which may be substituted with hydroxy,
n and r are each independently an integer of 0 to 4, n + r is 4 or less,
A ³ is

(Where the dashed line indicates the presence or absence of a bond and R ^x is hydrogen or lower alkyl)
And
-X- (CO) m-good lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - NR 6 CO (CR ³ R ⁴⁾ n '- (where n' is 1 or ^{2), - NR 6 COCO -} , - NR 6 (CR 3 R 4) nCO -, - S (CR 3 R 4) n -, - SO ( CR ³ R ⁴ ) n- or -A ^3- (CR ³ R ⁴ ) n-
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and further contains a nitrogen-containing aromatic monocyclic group or ring which may be substituted with another group. An aromatic monocyclic group containing -NH- and other ring member atoms optionally substituted with a substituent other than hydroxy which may be protected and amino which may be protected;
-X- (CO) when m- is -S ^{(CR 3} R 4) is a n-, ^{-Y-A 2} is not unsubstituted benzyl,
Y is
i) When m = 0, a single bond, —CR ¹² R ¹³ —, —O—, —S—, —C (═N—OR ¹⁷ ) —, —C (═O) —, —CH (OR ¹⁷ ) - or ^{-NR 15} - and is, together with ^{R 2} = ^{CR 14} - may be formed,
When ii) m = 1, a single bond, lower alkylene, lower alkenylene, lower ^{alkynylene, -O -, - S -,} - NR 15 -, - CR 12 R 13 O -, - CR 12 R 13 S- or - CR ¹² R ¹³ NR ¹⁵ - a and, together with ^{R 2 = CR 14 - (CR} 15 R 16) may form a p-, p is an integer from 0 to 5,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently hydrogen Or a lower alkyl which may have a substituent, and when there are a plurality of R ³ and R ^{4 s,} they may be different from each other) or a pharmaceutically acceptable salt thereof, or Solvates.
(1 ′) Formula (I):

(Where
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and may further be substituted with another group, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aroma Group-containing cyclic group or -NH- in the ring, and other ring atoms may be substituted with a substituent other than hydroxy which may be protected and amino which may be protected A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
A ² is an aromatic hydrocarbon cyclic group which may have a substituent or an aromatic heterocyclic group which may have a substituent,
R ¹ is hydrogen or hydroxy;
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
m is 0 or 1,
X represents a lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - CONR 5 (CR 3 R 4) n -, - ^{NR 5 CO (CR 3 R 4} ) n -, - NR 5 CONR 6 (CR 3 R 4) n -, - C (= n-OR 7) (CR 3 R 4) n -, - (CR 8 R 9 ^{) rO (CR 3 R 4)} n -, - (CR 8 R 9) rS (CR 3 R 4) n -, - (CR 8 R 9) rNR 6 (CR 3 R 4) n -, - (CR 8 ^{R 9) rSO (CR 3 R} 4) n -, - (CR 8 R 9) rSO 2 (CR 3 R 4) n -, - CR 9 = n-O (CR 3 R 4) n -, - C ( ^{= O) O (CR 3 R} 4) n -, - A 3 - (CR 3 R 4) n- or ^{-A 3 -CR 10 = CR 11 (} CR 3 R ⁴ ) n-
when m = 1, X may be lower alkylene which may be substituted with hydroxy, n and r are each independently an integer of 0 to 4, n + r is 4 or less,
A ³ is

(Where the dashed line indicates the presence or absence of a bond and R ^X is hydrogen or lower alkyl)
And
-X- (CO) m-good lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - NR 6 CO (CR ³ R ⁴⁾ n '- (where n' is 1 or ^{2), - NR 6 COCO -} , - NR 6 (CR 3 R 4) nCO -, - S (CR 3 R 4) n -, - SO ( CR ³ R ⁴ ) n- or -A ^3- (CR ³ R ⁴ ) n-
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and further contains a nitrogen-containing aromatic monocyclic group or ring which may be substituted with another group. An aromatic monocyclic group containing -NH- and other ring member atoms optionally substituted with a substituent other than hydroxy which may be protected and amino which may be protected;
-X- (CO) when m- is -S ^{(CR 3} R 4) is a n-, ^{-Y-A 2} is not unsubstituted benzyl,
Y is
i) When m = 0, it is a single bond, —CR ¹² R ¹³ —, —O—, —S— or —NR ¹⁵ —, and may form together with R ² ═CR ¹⁴ —. ,
When ii) m = 1, a single bond, lower alkylene, lower alkenylene, lower ^{alkynylene, -O -, - S -,} - NR 15 -, - CR 12 R 13 O -, - CR 12 R 13 S- or - CR ¹² R ¹³ NR ¹⁵ - a and, together with ^{R 2 = CR 14 - (CR} 15 R 16) may form a p-, p is an integer from 0 to 5,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen or a substituent. And may be different when there are a plurality of each of R ³ and R ⁴ )
Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(1 ″) Formula (I):

(Where
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and may further be substituted with another group, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aroma Group-containing cyclic group or -NH- in the ring, and other ring atoms may be substituted with a substituent other than hydroxy which may be protected and amino which may be protected A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
A ² is an aromatic hydrocarbon cyclic group which may have a substituent or an aromatic heterocyclic group which may have a substituent,
R ¹ is hydrogen or hydroxy;
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
m is 0 or 1,
X represents a lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - CONR 5 (CR 3 R 4) n -, - ^{NR 5 CO (CR 3 R 4} ) n -, - NR 5 CONR 6 (CR 3 R 4) n -, - C (= n-OR 7) (CR 3 R 4) n -, - (CR 8 R 9 ^{) rO (CR 3 R 4)} n -, - (CR 8 R 9) rS (CR 3 R 4) n -, - (CR 8 R 9) rNR 6 (CR 3 R 4) n -, - (CR 8 ^{R 9) rSO (CR 3 R} 4) n -, - (CR 8 R 9) rSO 2 (CR 3 R 4) n -, - CR 9 = n-O (CR 3 R 4) n -, - C ( ^{= O) O (CR 3 R} 4) n -, - a 3 - (CR 3 R 4) n- or ^-A 3 ^-CR 10 = ^{CR 11} - and is
when m = 1, X may be lower alkylene which may be substituted with hydroxy, n and r are each independently an integer of 0 to 4, n + r is 4 or less,
A ³ is

(In the formula, a broken line indicates the presence or absence of a bond)
And
-X- (CO) m-good lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - NR 6 CO (CR ³ R ⁴⁾ n '- (where n' is 1 or ^{2), - NR 6 COCO -} , - NR 6 (CR 3 R 4) nCO -, - S (CR 3 R 4) n -, - SO ( CR ³ R ⁴ ) n- or -A ^3- (CR ³ R ⁴ ) n-
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and further contains a nitrogen-containing aromatic monocyclic group or ring which may be substituted with another group. An aromatic monocyclic group containing -NH- and other ring member atoms optionally substituted with a substituent other than hydroxy which may be protected and amino which may be protected;
-X- (CO) when m- is -S ^{(CR 3} R 4) is a n-, ^{-Y-A 2} is not unsubstituted benzyl,
Y is
i) When m = 0, it is a single bond, —CR ¹² R ¹³ —, —O—, —S— or —NR ¹⁵ —, and may form together with R ² ═CR ¹⁴ —. ,
When ii) m = 1, a single bond, lower alkylene, lower alkenylene, lower ^{alkynylene, -O -, - S -,} - NR 15 -, - CR 12 R 13 O -, - CR 12 R 13 S- or - CR ¹² R ¹³ NR ¹⁵ - a and, together with ^{R 2 = CR 14 - (CR} 15 R 16) may form a p-, p is an integer from 0 to 5,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen or a substituent. And may be different when there are a plurality of each of R ³ and R ⁴ )
Or a pharmaceutically acceptable salt thereof or a solvate thereof.

（式中、Ｍｓはメタンスルホニル）
である、（１）、（１’）または（１’’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（４）−Ｘ−が、−ＣＯ（ＣＨＲ^３）ｎ−、−ＣＯＮＨ（ＣＨＲ^３）ｎ−、−ＮＨＣＯ（ＣＨＲ^３）ｎ−、−Ｏ（ＣＨＲ^３）ｎ−、−ＳＯ（ＣＨＲ^３）ｎ−、−ＳＯ_２（ＣＨＲ^３）ｎ−、−ＣＨ＝ＮＯ（ＣＨＲ^３）ｎ−、−Ｃ（＝Ｏ）Ｏ（ＣＨＲ^３）ｎ−、−Ａ^３−ＣＨＲ^３−または−Ａ^３−Ｃ_２Ｈ_４−である、上記（１）、（１’）または（１’’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（４’）−Ｘ−が、−ＣＯ（ＣＨ_２）ｎ−、−ＣＯＮＨ（ＣＨ_２）ｎ−、−ＮＨＣＯ（ＣＨ_２）ｎ−、−Ｏ（ＣＨ_２）ｎ−、−ＳＯ（ＣＨ_２）ｎ−、−ＳＯ_２（ＣＨ_２）ｎ−、−ＣＨ＝ＮＯ（ＣＨ_２）ｎ−または−Ｃ（＝Ｏ）Ｏ（ＣＨ_２）ｎ−である、上記（１）、（１’）または（１’’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（５）ｎが２または３である、上記（４）または（４’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（６）ｍが０である、上記（１）〜（４’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（７）Ｒ^１が水素であり、Ｒ^２が水素またはヒドロキシであるか、Ｒ^１およびＲ^２が一緒になって単結合を形成する、上記（１）〜（４’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（８）Ｙが単結合または−ＣＨ_２−であるか、Ｒ^２と一緒になって＝ＣＨ−を形成する、上記（１）〜（４’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（９）Ａ^２がハロゲン、シアノ、低級アルキル、ハロゲノ低級アルキル、低級アルコキシおよびハロゲノ低級アルコキシから選択される１以上の基で置換されていてもよいフェニルである、上記（１）〜（４’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１０）Ａ^２がパラ置換フェニルである、上記（１）〜（４’）および（９）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１１）上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１２）ＮＭＤＡ受容体拮抗作用を有する、上記（１１）記載の医薬組成物。
（１３）ＮＲ１／ＮＲ２Ｂ受容体拮抗作用を有する、上記（１２）記載の医薬組成物。
（１４）鎮痛剤または片頭痛、脳卒中、頭部外傷、アルツハイマー病、パーキンソン病、耳鳴り、てんかん、ハンチントン病、運動障害もしくはアルコール依存症の治療剤である、上記（１３）記載の医薬組成物。
（１５）上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、痛みの軽減方法または片頭痛、脳卒中、頭部外傷、アルツハイマー病、パーキンソン病、耳鳴り、てんかん、ハンチントン病、運動障害もしくはアルコール依存症の治療方法。
（１６）鎮痛剤または片頭痛、脳卒中、頭部外傷、アルツハイマー病、パーキンソン病、耳鳴り、てんかん、ハンチントン病、運動障害もしくはアルコール依存症の治療剤の製造のための、上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
（１７）鎮痛剤である、上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１８）上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ＮＭＤＡ受容体に起因する疾患の予防または治療方法。
（１９）ＮＭＤＡ受容体に起因する疾患の治療剤の製造のための、上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
（２０）上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、痛みの軽減方法。
（２１）鎮痛剤の製造のための、上記（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
を提供する。(2) A ¹ is pyridyl substituted with at least hydroxy, quinolyl substituted with at least hydroxy, benzoxazolyl substituted with at least hydroxy, benzimidazolyl substituted with at least hydroxy, amino optionally protected A ring member other than -NH- may be substituted, pyrrolyl other than -NH- may be substituted, or a ring member other than -NH- may be substituted. A ring member other than -NH- may be substituted with a ring atom other than -NH-, and a ring member other than -NH- may be substituted with a ring atom other than -NH-. The above (1), (1 ′) or (1 ″) description, wherein the atom is an indolyl which may be substituted Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(3) ^{A 1} is

(Where Ms is methanesulfonyl)
Or a pharmaceutically acceptable salt or solvate thereof according to (1), (1 ′) or (1 ″).
(4) -X- ^{is, -CO (CHR 3) n -} , - CONH (CHR 3) n -, - NHCO (CHR 3) n -, - O (CHR 3) n -, - SO (CHR 3) _{^{n -, - SO 2 (CHR}} 3) n -, - CH = NO (CHR 3) n -, - C (= O) O (CHR 3) n -, - A 3 -CHR 3 - or -A ³ - The compound of the above (1), (1 ′) or (1 ″), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is C ₂ H ₄ —.
(4 ′)-X— represents —CO (CH ₂ ) n—, —CONH (CH ₂ ) n—, —NHCO (CH ₂ ) n—, —O (CH ₂ ) n—, —SO (CH _{2 ) n -, - SO 2 (} CH 2) n -, - CH = NO (CH 2) n- or _{-C (= O) O (CH} 2) a n-, (1), (1 ') Or the compound according to (1 ″) or a pharmaceutically acceptable salt thereof or a solvate thereof.
(5) The compound according to (4) or (4 ′) above, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(6) The compound according to any one of (1) to (4 ′) above, wherein m is 0, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(7) R ¹ is hydrogen and R ² is hydrogen or hydroxy, or R ¹ and R ² are combined to form a single bond, according to any one of (1) to (4 ′) above Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(8) The compound according to any one of (1) to (4 ′) above or a pharmaceutically acceptable salt thereof, wherein Y is a single bond or —CH ₂ —, or together with R ² forms ═CH—. Acceptable salts or solvates thereof.
(9) The above (1) to (4 ′), wherein A ² is phenyl optionally substituted with one or more groups selected from halogen, cyano, lower alkyl, halogeno lower alkyl, lower alkoxy and halogeno lower alkoxy. ) Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(10) The compound according to any one of the above (1) to (4 ′) and (9), wherein A ² is para-substituted phenyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(11) A pharmaceutical composition comprising the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.
(12) The pharmaceutical composition according to the above (11), which has an NMDA receptor antagonistic action.
(13) The pharmaceutical composition according to the above (12), which has an NR1 / NR2B receptor antagonistic action.
(14) The pharmaceutical composition according to the above (13), which is an analgesic or a therapeutic agent for migraine, stroke, head injury, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.
(15) A method for alleviating pain, migraine or stroke, which comprises administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof. , Treatment of head injury, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorders or alcoholism.
(16) The above (1) to (10) for producing an analgesic or a therapeutic agent for migraine, stroke, head injury, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism ) Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(17) A pharmaceutical composition comprising the compound according to any one of (1) to (10) above, which is an analgesic, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(18) Prevention of a disease caused by the NMDA receptor, comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof. Or treatment method.
(19) Use of the compound according to any one of (1) to (10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for a disease caused by an NMDA receptor. .
(20) A method for alleviating pain, comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.
(21) Use of the compound according to any one of (1) to (10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of an analgesic.
I will provide a.

  The compound of the present invention is not only used for neurodegenerative treatment such as stroke and brain trauma, but also useful as an analgesic (eg, cancer pain analgesic) having few side effects.

  In the present specification, “optionally protected hydroxy” means, for example, lower alkyl (methyl, tert-butyl, etc.), aryl lower alkyl (triphenylmethyl, benzyl, etc.), tri-lower alkylsilyl (trimethylsilyl, tert-butyl, etc.) Dimethylsilyl, triethylsilyl, triisopropylsilyl, etc.), lower alkyldiarylsilyl (tert-butyldiphenylsilyl etc.), triaryl lower alkylsilyl (tribenzylsilyl etc.), lower alkoxy lower alkyl (methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl etc.), lower alkoxy lower alkoxy lower alkyl (methoxyethoxymethyl etc.), lower alkylthio lower alkyl (methylthiomethyl etc.), tetrahydropyranyl (tetrahydropyran-2) Yl, 4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl etc.), tetrahydrofuranyl (tetrahydrofuran-2-yl etc.), tetrahydrothiofuranyl (tetrahydrothiofuran-2) -Yl and the like, aryl lower alkoxy lower alkyl (benzyloxymethyl and the like), lower alkylsulfonyl, arylsulfonyl, lower alkylarylsulfonyl (p-toluenesulfonyl and the like) and acyl and the like. Includes good hydroxy. Preferred protecting groups are lower alkyl, aryl lower alkyl, lower alkylsulfonyl and the like.

  The “optionally protected amino” includes, for example, lower alkoxycarbonyl (tert-butyloxycarbonyl etc.), lower alkenyloxycarbonyl (vinyloxycarbonyl, allyloxycarbonyl etc.), halogeno lower alkoxycarbonyl (2-iodoethoxycarbonyl). , 2,2,2-trichloroethoxycarbonyl, etc.), aryl lower alkoxycarbonyl (benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenyloxycarbonyl, etc.), tri Lower alkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc.), diazo, acyl (formyl, acetyl, pivaloyl, benzoyl, etc.), halogeno Sil (trifluoroacetyl etc.), lower alkylsulfonyl (methanesulfonyl etc.), halogeno lower alkylsulfonyl (trifluoroethanesulfonyl etc.), arylsulfonyl, lower alkylarylsulfonyl (toluenesulfonyl, 4-tert-butylbenzenesulfonyl etc.), Amino optionally protected with a protecting group selected from aryl lower alkyl (such as triphenylmethyl) and the like is included. Preferred protecting groups are acyl or lower alkylsulfonyl.

等である。The “nitrogen-containing aromatic monocyclic group” includes a 5- to 6-membered aromatic cyclic group having at least one N in the ring and optionally having O or S. For example

Etc.

等が挙げられる。結合手はいずれの環に存在していてもよい。The “nitrogen-containing aromatic condensed cyclic group” is a 5- to 6-membered aromatic cyclic group which has at least one N in the ring and may further have O or S. It includes a group in which two benzene rings or aromatic heterocycles are condensed. For example

Etc. The bond may be present in any ring.

“Nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensation which has at least one hydroxy which may be protected and / or amino which may be protected, and may be further substituted with another group The term “cyclic group” refers to the above-mentioned “nitrogen-containing aromatic monocyclic group” or “nitrogen-containing aromatic fused cyclic group” which may be protected on the ring and / or amino which may be protected. And a cyclic group which may be substituted with one or more groups selected from substituent group α.
Here, the substituent group α is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino, carboxy, lower alkoxycarbonyl, cyano, or nitro.

“At least hydroxy-substituted pyridyl”, “at least hydroxy-substituted quinolyl”, “at least hydroxy-substituted benzoxazolyl” and “at least hydroxy-substituted benzimidazolyl” are each at least 1 It includes pyridyl, quinolyl, benzoxazolyl and benzimidazolyl, each having a hydroxy group as a substituent and further substituted with one or more groups selected from substituent group α. For example, 6-hydroxypyridin-3-yl, 2-hydroxypyridin-3-yl, 6-hydroxy-4-methyl-pyridin-3-yl, 4-acetyl-2-hydroxy-benzoxazol-6-yl, etc. .
“Pyridyl substituted with at least amino optionally protected” has at least one amino or protected amino as a substituent, and is further substituted with one or more groups selected from substituent group α Including pyridyl, which may be

等が挙げられる。結合手はいずれの環に存在していてもよく、−ＮＨ−以外の任意の環構成原子が置換基群βから選択される１以上の基で置換されていてもよい。
ここで置換基群βとはハロゲン、低級アルキル、ハロゲノ低級アルキル、アシル、カルボキシ、低級アルコキシカルボニル、シアノおよびニトロである。
「−ＮＨ−以外の環構成原子が置換されていてもよいイミダゾリル」、「−ＮＨ−以外の環構成原子が置換されていてもよいピロリル」、「−ＮＨ−以外の環構成原子が置換されていてもよいピラゾリル」、「−ＮＨ−以外の環構成原子が置換されていてもよいベンズピラゾリル」、「−ＮＨ−以外の環構成原子が置換されていてもよいベンズイミダゾリル」および「−ＮＨ−以外の環構成原子が置換されていてもよいインドリル」とは、それぞれ−ＮＨ−以外の任意の環構成原子が置換基群βから選択される１以上の基で置換されていてもよいイミダゾリル、ピロリル、ピラゾリル、ベンズピラゾリル、ベンズイミダゾリルおよびインドリルを包含する。"Nitrogen-containing aromatic group containing -NH- in the ring and other ring-constituting atoms optionally substituted with a substituent other than hydroxy which may be protected and amino which may be protected The term “cyclic group or nitrogen-containing aromatic condensed cyclic group” means that among the above “nitrogen-containing aromatic monocyclic group” and “nitrogen-containing aromatic condensed cyclic group”, the ring contains an —NH— group. Including groups. For example

Etc. The bond may exist in any ring, and any ring member atom other than —NH— may be substituted with one or more groups selected from the substituent group β.
Here, the substituent group β is halogen, lower alkyl, halogeno lower alkyl, acyl, carboxy, lower alkoxycarbonyl, cyano and nitro.
“Imidazolyl in which ring atoms other than —NH— may be substituted”, “pyrrolyl in which ring atoms other than —NH— may be substituted”, “ring atoms other than —NH— are substituted Optionally substituted pyrazolyl ”,“ benzpyrazolyl optionally substituted with a ring atom other than —NH— ”,“ benzimidazolyl optionally substituted with a ring atom other than —NH— ”and“ —NH ”. The term “indolyl in which a ring member atom other than — may be substituted” means that any ring member atom other than —NH— may be substituted with one or more groups selected from the substituent group β. , Pyrrolyl, pyrazolyl, benzpyrazolyl, benzimidazolyl and indolyl.

“Aromatic hydrocarbon cyclic group” includes phenyl, naphthyl, phenanthryl and the like.
Examples of the substituent of the “optionally substituted aromatic hydrocarbon cyclic group” include halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, lower alkylsulfonyloxy, halogeno lower alkyl. It may be substituted with one or more groups selected from sulfonyloxy, acyl, acyloxy, amino, lower alkylamino, acylamino, nitro, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, substituent group γ. From aryl, arylthio optionally substituted with one or more groups selected from substituent group γ, aryloxy optionally substituted with one or more groups selected from substituent group γ, from substituent group γ Arylamino optionally substituted with one or more selected groups Optionally substituted with one or more groups selected from substituent group γ is also good arylsulfonyloxy.
Here, the substituent group γ is halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, amino, lower alkylamino, acylamino, carboxy, lower alkoxycarbonyl, cyano, nitro. .
“Arylsulfonyl”, “arylsulfonyloxy”, “aryloxy”, “arylthio”, “arylamino”, “aryl lower alkyl”, “lower alkyldiarylsilyl”, “triaryl lower alkylsilyl”, “aryl lower alkoxy” The aryl part of “lower alkyl”, “lower alkylarylsulfonyl” and “aryl lower alkoxycarbonyl” is the same as the above “aromatic hydrocarbon cyclic group”. Preferred is phenyl.

“Aromatic heterocyclic group” means a 5- to 6-membered aromatic monocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (for example, pyrrolyl, imidazolyl, pyrazolyl, Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl, and aromatic condensed cyclic groups (e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzimidazolyl, Pyrazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isova Zofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridinyl and pyrazinopyridazinyl, etc. ).
The substituent of the “aromatic heterocyclic group which may have a substituent” is the same as the substituent of the “aromatic hydrocarbon cyclic group which may have a substituent”.

“Halogen” includes F, Cl, Br and the like.
The lower alkyl part and the halogen part of “halogeno lower alkyl”, “halogeno lower alkoxy”, “halogeno lower alkoxycarbonyl”, “halogenoacyl” and “halogeno lower alkylsulfonyl” are the same as the above “halogen”.
The “lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and includes methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl Etc. are exemplified. Particularly preferred is methyl or ethyl.
The lower alkyl part of “lower alkyl optionally having substituent (s)” is the same as the above “lower alkyl”. Examples of the substituent include halogen, hydroxy, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, amino, lower alkylamino, acylamino, carboxy, lower alkoxycarbonyl, cyano, nitro and the like, and the substituted lower alkyl is preferable. Examples include trihalogeno lower alkyl.
“Halogeno lower alkyl”, “lower alkoxy lower alkyl”, “lower alkoxy lower alkoxy lower alkyl”, “lower alkylthio lower alkyl”, “aryl lower alkoxy lower alkyl”, “lower alkoxy”, “halogeno lower alkoxy”, “lower “Alkoxycarbonyl”, “halogeno lower alkoxycarbonyl”, “aryl lower alkoxycarbonyl”, “lower alkylcarbamoyl”, “lower alkylsulfonyl”, “lower alkylarylsulfonyl”, “lower alkylsulfonyloxy”, “halogeno lower alkylsulfonyl” , “Halogeno lower alkylsulfonyloxy”, “lower alkylamino”, “aryl lower alkyl”, “tri lower alkylsilyl”, “lower alkyldiarylsilyl”, “triaryl low” Lower alkyl moiety of the alkyl silyl "is the same as the above" lower alkyl ".

“Lower alkenyl” is a straight or branched alkenyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at any position. Is included. Specific examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
The lower alkenyl part of “lower alkenyloxycarbonyl” is the same as the above “lower alkenyl”.

The “lower alkylene” includes a divalent carbon chain having 1 to 6 carbon atoms, preferably alkylene having 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms.
The “lower alkenylene” includes a linear or branched divalent carbon chain having 2 to 6 carbon atoms having a double bond at an arbitrary position. Preferably it is C2-C4, More preferably, it is C2-C3. Specific examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene, hexenylene, and the like, preferably vinylene.
Examples of the substituent of the “optionally substituted lower alkenylene” include the same substituents as the above “optionally substituted lower alkyl”, preferably halogen and hydroxy.
“Lower alkynylene” includes a straight or branched divalent carbon chain having 2 to 6 carbon atoms which has a triple bond at an arbitrary position and may further have a double bond. . Preferably it is C2-C4, More preferably, it is C2-C3. Specific examples include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
Examples of the substituent of the “optionally substituted lower alkynylene” include the same substituents as the above “optionally substituted lower alkyl”, preferably halogen and hydroxy.

であることを意味する。“Acyl” includes aliphatic acyl having 1 to 7 carbon atoms and aroyl. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioroyl, methacryloyl, crotonoyl and benzoyl.
The acyl part of “acyloxy”, “acylamino” and “halogenoacyl” is the same as the above “acyl”.
The case where “R ¹ and R ² together form a single bond”

It means that.

（式中、各記号は前記と同義）
であることを意味する。また、Ｙが「Ｒ^２と一緒になって＝ＣＲ^１４−（ＣＲ^１５Ｒ^１６）ｐ−を形成する」とは、

（式中、各記号は前記と同義）
であることを意味する。Y is - a "taken together with ^{R 2} = ^{CR 14} forms a" is

(Wherein each symbol is as defined above)
It means that. Y is “to form R = CR ¹⁴ − (CR ¹⁵ R ¹⁶ ) p− together with R ² ”.

(Wherein each symbol is as defined above)
It means that.

The compound (I) of the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. For example, it contains keto-enol tautomers as follows.

  The general synthesis method of the compound of the present invention is shown below, but is not limited to this synthesis method.

（式中、Ａ^１、Ａ^２、Ｒ^１、Ｒ^２、ＸおよびＹは前記と同意義である）
化合物（ＩＩ）は、T. KumagaiらBioorg. Med. Chem., 9, 1357 (2001)、S. ImamuraらBioorg. Med. Chem., 13, 397 (2005)、S. SakamuriらBioorg. Med. Chem. Lett., 11, 495 (2001)、Z.-L. ZhouらJ. Org. Chem., 64, 3763 (1999)、S. M. N. EfangeらJ. Med. Chem., 33, 3133 (1990)に記載の方法、参考例１〜３に記載の方法、およびそれらに準ずる方法で合成することができる。また、化合物（ＩＩＩ）は、参考例４、５に記載の方法、およびそれに準ずる方法で合成することができる。
化合物（ＩＩ）に対して、化合物（ＩＩＩ）を０．５〜２モル当量用いることができる。
反応溶媒としては、塩化メチレン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
縮合剤としては、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール等が挙げられ、式（Ｖ）で示される化合物に対して、０．５〜２モル当量用いることができる。１−ヒドロキシベンゾトリアゾールを縮合補助剤として０．５〜２モル当量用いてもよい。
塩基としては、トリエチルアミン、４−ジメチルアミノピリジン等が挙げられ、単独または混合して用いることができる。化合物（ＩＩ）に対して、それぞれ０．０５〜２モル当量用いることができる。
反応温度としては０〜１００℃が挙げられる。
反応時間としては０．５〜７２時間が挙げられる。
得られた化合物（Ｉａ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）で単離精製することができる。Method A: Synthesis of (Ia) from Compound (II) (m = 1)
In the presence of a condensing agent, an amine compound represented by formula (II) (hereinafter referred to as compound (II)) and a carboxylic acid compound represented by formula (III) (hereinafter referred to as compound (III)) are condensed to form a compound represented by formula (Ia) Can be synthesized (hereinafter, referred to as compound (Ia)).

(Wherein A ¹ , A ² , R ¹ , R ² , X and Y are as defined above)
Compound (II) is described in T. Kumagai et al. Bioorg. Med. Chem., 9 , 1357 (2001), S. Imamura et al. Bioorg. Med. Chem., 13 , 397 (2005), S. Sakamuri et al. Bioorg. Med. Chem. Lett., 11 , 495 (2001), Z.-L.Zhou et al. J. Org. Chem., 64 , 3763 (1999), SMN Efange et al. J. Med. Chem., 33 , 3133 (1990) It can synthesize | combine by the method of description, the method of the reference examples 1-3, and the method according to them. Compound (III) can be synthesized by the methods described in Reference Examples 4 and 5 and a method analogous thereto.
Compound (III) can be used at 0.5 to 2 molar equivalents relative to compound (II).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like, and 0.5% relative to the compound represented by the formula (V). ˜2 molar equivalents can be used. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to compound (II).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ia) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｌ^１はハロゲンまたはＣ１−４アルキルスルホニルオキシ；Ａ^１、Ａ^２、Ｒ^１、Ｒ^２、ＸおよびＹは前記と同意義である）
化合物（ＩＩ）に対して化合物（ＩＶ）を０．５〜３モル当量用いることができる。
反応溶媒としては、アセトニトリル、アセトン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド等が挙げられる。
塩基としては、炭酸カリウム、炭酸ナトリウム、トリエチルアミン、ジイソプロピルエチルアミン等が挙げられ、化合物（ＩＩ）に対して０．５〜２モル当量用いることができる。
ヨウ化カリウム、ヨウ化ナトリウムを化合物（ＩＩ）に対して０．０５〜１．５モル当量用いてもよい。
反応温度としては２０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜７２時間が挙げられる。
得られた化合物（Ｉｂ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）で単離精製することができる。Method B: Synthesis of (Ib) from Compound (II) (m = 0)
Compound (II) and a compound represented by formula (IV) (hereinafter referred to as compound (IV)) are condensed in the presence of a base to synthesize an amine compound represented by formula (Ib) (hereinafter referred to as compound (Ib)). be able to.

(Wherein L ¹ is halogen or C 1-4 alkylsulfonyloxy; A ¹ , A ² , R ¹ , R ² , X and Y are as defined above)
Compound (IV) can be used at 0.5 to 3 molar equivalents relative to compound (II).
Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and the base can be used at 0.5 to 2 molar equivalents relative to the compound (II).
You may use 0.05-1.5 molar equivalent of potassium iodide and sodium iodide with respect to compound (II).
Examples of the reaction temperature include 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ib) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｘ^１は置換基を有していてもよい低級アルケニレン、置換基を有していてもよい低級アルキニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｐ−、−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｑ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｐ−、−ＮＲ^５ＣＯＮＲ^６（ＣＲ^３Ｒ^４）ｑ−、−Ｃ（＝Ｎ−ＯＲ^７）（ＣＲ^３Ｒ^４）ｐ−、−（ＣＲ^８Ｒ^９）ｒＯ（ＣＲ^３Ｒ^４）ｑ−、−（ＣＲ^８Ｒ^９）ｒＳ（ＣＲ^３Ｒ^４）ｑ−、−（ＣＲ^８Ｒ^９）ｒＮＲ^６（ＣＲ^３Ｒ^４）ｑ−、−（ＣＲ^８Ｒ^９）ｒＳＯ（ＣＲ^３Ｒ^４）ｐ−、−（ＣＲ^８Ｒ^９）ｒＳＯ_２（ＣＲ^３Ｒ^４）ｐ−、−ＣＲ^９＝Ｎ−Ｏ（ＣＲ^３Ｒ^４）ｐ−、−Ｃ（＝Ｏ）Ｏ（ＣＲ^３Ｒ^４）ｑ−または−Ａ^３−（ＣＲ^３Ｒ^４）ｐ−であり、
ｐは０〜３の整数、ｑは１〜３の整数；
Ａ^１、Ａ^２、Ｒ^１、Ｒ^２、Ｒ^３及びＹは前記と同意義である）
化合物（ＩＩ）に対して、化合物（Ｖ）を０．５〜２モル当量用いることができる。
反応溶媒としては、１，２−ジクロロエタン、テトラヒドロフラン等が挙げられる。
還元剤としては、トリアセトキシ水素化ホウ素ナトリウム、シアノトリヒドロホウ素ナトリウム等が挙げられ、化合物（ＩＩ）に対して０．５〜６モル当量用いることができる。
反応温度としては０〜８０℃が挙げられる。
必要であれば、酸として酢酸等を化合物（ＩＩ）に対して、０．５〜２モル当量用いることができる。
反応時間としては０．５〜７２時間が挙げられる。
得られた化合物（Ｉｃ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）で単離精製することができる。Method C: Synthesis of (Ic) from Compound (II) (m = 0)
In the presence of a reducing agent, compound (II) and a compound represented by formula (V) (hereinafter referred to as compound (V)) are condensed to synthesize an amine compound represented by formula (Ic) (hereinafter referred to as compound (Ic)). can do.

(In the formula, X ¹ is optionally substituted lower alkenylene, optionally substituted lower alkynylene, —CO (CR ³ R ⁴ ) p—, —CONR ⁵ (CR ³ R ^{4 ) q -, - NR 5 CO} (CR 3 R 4) p -, - NR 5 CONR 6 (CR 3 R 4) q -, - C (= N-OR 7) (CR 3 R 4) p -, - ^{(CR 8 R 9) rO (} CR 3 R 4) q -, - (CR 8 R 9) rS (CR 3 R 4) q -, - (CR 8 R 9) rNR 6 (CR 3 R 4) q- ^{, - (CR 8 R 9)} rSO (CR 3 R 4) p -, - (CR 8 R 9) rSO 2 (CR 3 R 4) p -, - CR 9 = N-O (CR 3 R 4) p -, - C (= O) O (CR 3 R 4) q- or ^{-A 3 - (CR 3 R 4} ) a p-,
p is an integer of 0 to 3, q is an integer of 1 to 3;
A ¹ , A ² , R ¹ , R ² , R ³ and Y are as defined above)
Compound (V) can be used at 0.5 to 2 molar equivalents relative to compound (II).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanotrihydroborohydride and the like, and 0.5 to 6 molar equivalents can be used with respect to compound (II).
Examples of the reaction temperature include 0 to 80 ° C.
If necessary, acetic acid or the like can be used as an acid in an amount of 0.5 to 2 molar equivalents relative to compound (II).
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ic) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｚ^１はＣ１−３アルキルカルボニル又はｔｅｒｔ−ブトキシカルボニル、ｔは２〜４の整数；Ａ^１、Ａ^２、Ｌ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＹは前記と同意義である）Method D: Synthesis of (Id) from Compound (II) (X = CONR ⁵ (CR ³ R ⁴ ) n, n = 2 to 4)

Wherein Z ¹ is C 1-3 alkylcarbonyl or tert-butoxycarbonyl, t is an integer of 2-4; A ¹ , A ² , L ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y is as defined above)

Synthesis of Compound (VII) from Compound (II) In the presence of a base, compound (II) and a compound represented by formula (VI) (hereinafter, compound (VI)) are condensed to form an amine compound represented by formula (VII) ( Hereinafter, compound (VII)) can be synthesized.
Compound (VI) can be used at 0.5 to 3 molar equivalents relative to compound (II).
Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and the base can be used at 0.5 to 2 molar equivalents relative to the compound (II).
You may use 0.05-1.5 molar equivalent of potassium iodide and sodium iodide with respect to compound (II).
Examples of the reaction temperature include 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (VIII) from Compound (VII) Compound (VII) can be acid-treated to synthesize a compound represented by Formula (VIII) (hereinafter, Compound (VIII)).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran, dioxane, and no solvent.
Examples of the acid include hydrochloric acid, trifluoroacetic acid, and the like, and 2 to 100 molar equivalents can be used with respect to compound (VII).
Examples of the reaction temperature include 0 to 80 ° C.
An example of the reaction time is 0.5 to 72 hours.
After distilling off the solvent, water was added, and 1 to 5 molar equivalents of sodium carbonate with respect to compound (VIII) were used, the reaction temperature was 0 to 80 ° C., and the reaction time was 0.5 to 4 hours. Although it can be used as a body amine, it may be used in the next step as a salt.
The obtained compound (VIII) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (Id) from Compound (VIII) In the presence of a condensing agent, compound (VIII) and a carboxylic acid compound represented by formula (IX) (hereinafter referred to as compound (IX)) are condensed to obtain a compound represented by formula (Id). An amide compound (hereinafter, compound (Id)) can be synthesized.
Compound (IX) can be used at 0.5 to 2 mole equivalent based on compound (VIII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like, and 0.5 to 2 molar equivalents are used with respect to compound (VIII). be able to. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to compound (VIII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Id) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

（式中、Ａ^１、Ａ^２、Ｌ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｙ、Ｚ^１及びｑは前記と同意義である）Method E: Synthesis of (Ie) from Compound (II) (X = CONR ⁵ (CR ³ R ⁴ ) n, n = 2 to 4)

(Wherein A ¹ , A ² , L ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, Z ¹ and q are as defined above)

Synthesis of (XI) from Compound (II) An amine compound represented by Formula (XI) by condensing Compound (II) and a compound represented by Formula (X) (hereinafter, Compound (X)) in the presence of a reducing agent. (Hereinafter, compound (XI)) can be synthesized.
Compound (X) can be used at 0.5 to 2 molar equivalents relative to compound (II).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanotrihydroborohydride and the like, and 0.5 to 6 molar equivalents can be used with respect to compound (II).
Examples of the reaction temperature include 0 to 80 ° C.
If necessary, acetic acid or the like can be used as an acid in an amount of 0.5 to 2 molar equivalents relative to compound (II).
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (XI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XII) from Compound (XI) Compound (XI) can be acid-treated to synthesize a compound represented by Formula (XII) (hereinafter, Compound (XII)).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran, dioxane, and no solvent.
As the acid, hydrochloric acid, trifluoroacetic acid and the like can be mentioned, and 2 to 100 molar equivalents can be used with respect to compound (XI).
Examples of the reaction temperature include 0 to 80 ° C.
An example of the reaction time is 0.5 to 72 hours.
After distilling off the solvent, water was added, and 1 to 5 molar equivalents of sodium carbonate with respect to compound (XI) was used, the reaction temperature was 0 to 80 ° C., the reaction time was 0.5 to 4 hours, and the reaction was free. Although it can be used as a body amine, it may be used in the reaction of the next step as a salt.
The obtained compound (XII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ie) from Compound (XII) Compound (XII) and Compound (IX) are condensed in the presence of a condensing agent to synthesize an amide compound represented by Formula (Ie) (hereinafter referred to as Compound (Ie)). Can do.
Compound (IX) can be used at 0.5 to 2 molar equivalents relative to compound (XII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, etc., and 0.5% relative to the compound represented by the formula (XII). Up to 2 molar equivalents can be used. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine, and the like, and each can be used at 0.05 to 2 molar equivalents relative to compound (XII) that can be used alone or in combination.
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ie) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ａ^１、Ａ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｙ及びｔは前記と同意義である）Method F: Synthesis of (If) from compound (II) (X = CONH (CR ³ R ⁴ ) n, n = 2 to 4)

(Wherein A ¹ , A ² , R ¹ , R ² , R ³ , R ⁴ , Y and t are as defined above)

Synthesis of (XIV) from Compound (II) In the presence of a base, a compound (II) and a phthalimide compound represented by formula (XIII) (hereinafter, compound (XIII)) are condensed to form an amine compound represented by formula (XIV) (Hereinafter, compound (XIV)) can be synthesized.
Compound (XIII) can be used at 0.5 to 3 molar equivalents relative to compound (II).
Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and the base can be used at 0.5 to 2 molar equivalents relative to the compound (II).
You may use 0.05-1.5 molar equivalent of potassium iodide and sodium iodide with respect to compound (II).
Examples of the reaction temperature include 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (XIV) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XV) from Compound (XIV) By treating compound (XIV) with hydrazine hydrate, an amine compound represented by formula (XV) (hereinafter referred to as compound (XV)) can be synthesized.
Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to compound (XV).
Examples of the reaction solvent include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 24 hours.
The obtained compound (XV) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (If) from Compound (XV) Compound (XV) and Compound (IX) are condensed in the presence of a condensing agent to synthesize an amide compound represented by Formula (If) (hereinafter referred to as Compound (If)). Can do.
Compound (IX) can be used at 0.5 to 2 molar equivalents relative to compound (XV).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like. 0.5 to 2 molar equivalents are used with respect to compound (XV). be able to. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to compound (XV).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (If) can be isolated and purified by the known means (eg, chromatography, recrystallization and the like).

（式中、Ａ^１、Ａ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｙ及びｑは前記と同意義である）Method G: Synthesis of (Ig) from Compound (II) (X = CONH (CR ³ R ⁴ ) n, n = 2 to 4)

(Wherein A ¹ , A ² , R ¹ , R ² , R ³ , R ⁴ , Y and q are as defined above)

Synthesis of (XVII) from Compound (II) In the presence of a reducing agent, compound (II) and a compound represented by formula (XVI) (hereinafter, compound (XVI)) are condensed to form an amine compound represented by formula (XVII) (Hereinafter, compound (XVII)) can be synthesized.
Compound (XVI) can be used at 0.5 to 2 molar equivalents relative to compound (II).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanotrihydroborohydride and the like, and 0.5 to 6 molar equivalents can be used with respect to compound (II).
Examples of the reaction temperature include 0 to 80 ° C.
If necessary, acetic acid or the like can be used as an acid in an amount of 0.5 to 2 molar equivalents relative to compound (II).
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (XVII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XVIII) from Compound (XVII) By treating compound (XVII) with hydrazine hydrate, an amine compound represented by formula (XVIII) (hereinafter, compound (XVIII)) can be synthesized.
Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to compound (XVII).
Examples of the reaction solvent include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 24 hours.
The obtained compound (XVIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ig) from Compound (XVII) Compound (XVIII) and Compound (IX) are condensed in the presence of a condensing agent to synthesize an amide compound represented by Formula (Ig) (hereinafter referred to as Compound (Ig)). Can do.
Compound (IX) can be used at 0.5 to 2 mole equivalent based on compound (XVIII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like, and 0.5 to 2 molar equivalents relative to compound (XVIII) Can be used. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to compound (XVIII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ig) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｚ^２はＣ１−４アルキル、ｕは１〜４の整数；Ａ^１、Ａ^２、Ｌ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＹは前記と同意義である）Method H: Synthesis of (Ih) from Compound (II) (X = NR ⁵ CO (CR ³ R ⁴ ) n, n = 1 to 4)

(In the formula, Z ² is C 1-4 alkyl, u is an integer of 1 to 4; A ¹ , A ² , L ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y are as defined above. Is)

Synthesis of (XX) from Compound (II) In the presence of a base, Compound (II) and a compound represented by Formula (XIX) (hereinafter, Compound (XIX)) are condensed to form an ester compound represented by Formula (XX) ( Hereinafter, compound (XX)) can be synthesized.
Compound (XIX) can be used at 0.5 to 3 molar equivalents relative to compound (II).
Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and the base can be used at 0.5 to 2 molar equivalents relative to the compound (II).
You may use 0.05-1.5 molar equivalent of potassium iodide and sodium iodide with respect to compound (II).
Examples of the reaction temperature include 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (XX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXI) from Compound (XX) By hydrolyzing Compound (XX), a carboxylic acid represented by Formula (XXI) (hereinafter, Compound (XXI)) can be synthesized.
Sodium hydroxide or potassium hydroxide can be used at 1.0 to 5 molar equivalents relative to the compound represented by the formula (XX).
Examples of the reaction solvent include methanol, ethanol, water and the like.
Examples of the reaction temperature include 0 to 80 ° C.
An example of the reaction time is 0.5 to 24 hours.
The obtained compound (XXI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ih) from Compound (XXI) In the presence of a condensing agent, Compound (XXI) and an amine compound represented by Formula (XXII) (hereinafter, Compound (XXII)) are condensed to form an amide represented by Formula (Ih) A compound (hereinafter, compound (Ih)) can be synthesized.
Compound (XXII) can be used at 0.5 to 2 mole equivalent based on compound (XXI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole and the like, and 0.5 to 2 molar equivalents relative to compound (XXI). Can be used. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to compound (XXI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (Ih) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

In addition, nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensation which has at least one hydroxy and / or amino which is protected for A ¹ and may be further substituted with another group A nitrogen-containing aromatic monocycle containing a cyclic group or —NH— in the ring, and other ring-constituting atoms optionally substituted with a substituent other than protected hydroxy and protected amino In the case of a formula group or a nitrogen-containing aromatic condensed cyclic group, the reaction conditions usually used (for example, the method described in TW Green et al., Protective Groups in Organic Chemistry, Second Edition, John Wiley & Sons (1991).) The protecting group can be deprotected.

  When the compound of the present invention contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compounds of the present invention, and each is separately produced by a known synthesis method and separation method. Can be obtained as For example, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from the compound is also included in the compound of the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving a final racemic mixture according to a conventional method.

As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like described in detail below are used.
1) fractional recrystallization racemate and optically active compounds (e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step. Method.
2) Chiral column method A method in which a racemate or a salt thereof is separated through a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation, and water, various buffers (for example, phosphate buffer), organic Optical isomers are separated by developing a solvent (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution. Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
3) Diastereomer method A mixture of racemates is converted into a diastereomer mixture by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). And then obtaining an optical isomer by cleaving the optically active reagent moiety by chemical treatment such as hydrolysis. For example, when the compound of the present invention has hydroxy or 1,2 secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (− ) -Menthoxyacetic acid, etc.) can be subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

A pharmaceutically acceptable salt can be used as the salt of the compound of the present invention. Examples of the basic addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth salts such as calcium salt and magnesium salt. Metal salts; for example ammonium salts; for example trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts; aralkyl such as N, N-dibenzylethylenediamine Heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt; Tributylammonium salt, methyl trioctyl ammonium salts, quaternary ammonium salts such as tetrabutylammonium salts; arginine; basic amino acid salts such as lysine salt and the like.
Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; for example, oxalate, acetate, propionate, lactate , Organic acid salts such as maleate, fumarate, tartrate, malate, citrate, ascorbate; for example, methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Examples thereof include acidic amino acids such as aspartate and glutamate.
Compound (I) may be a solvate such as water, acetonitrile, ethyl acetate, methanol, ethanol and the like. The solvation number of the solvate of the compound of the present invention can usually vary depending on the synthesis method, purification method, crystallization conditions, etc., but is, for example, in the range of 1 to 5 molecules per molecule.

Of the compounds (I) of the present invention, the following compounds are particularly preferred.
In formula (I):
1) pyridyl wherein A ¹ is substituted with at least hydroxy, benzoxazolyl substituted with at least hydroxy, benzimidazolyl substituted with at least hydroxy, pyridyl substituted with at least optionally protected amino, —NH— Other ring-constituting atoms may be substituted imidazolyl, -NH- ring-constituting atoms may be substituted pyrrolyl, -NH- ring-constituting atoms may be substituted, or- NH- optionally be ring-constituting atom substitution than is also good benzimidazolyl (hereinafter, a ¹ is assumed to be a1) compound,
2) A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, aminopyridyl, lower alkylsulfonylaminopyridyl, unsubstituted imidazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl or unsubstituted benzimidazolyl (hereinafter referred to as A ^1). A)
3) A compound in which A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, unsubstituted imidazolyl, unsubstituted pyrazolyl or unsubstituted pyrrolyl (hereinafter referred to as A ¹ is a3),
4) A compound in which A ¹ is hydroxypyridyl, unsubstituted imidazolyl or unsubstituted pyrrolyl (hereinafter referred to as A ¹ is a4),

5) X is a lower ^{alkenylene, -CO (CHR 3) n -} , - CONH (CHR 3) n -, - NHCO (CHR 3) n -, - O (CHR 3) n -, - S (CHR 3) n _{^{-, - SO (CHR 3)}} n -, - SO 2 (CHR 3) n -, - CH = NO (CH 2 R 3) n -, - C (= O) O (CHR 3) n- or -A ^A compound that is ^3- CHR ³ — (each R ³ may be different) (hereinafter, X is x1),
6) X is ^{-CO (CHR 3) n -,} - CONH (CHR 3) n -, - NHCO (CHR 3) n- or ^-A 3 -CHR ³ - (hereinafter, X is assumed to be x2 )Compound,
7) X is ^{-CO (CHR 3) n -,} - CONH (CHR 3) n -, - NHCO (CHR 3) n- or ^-A 3 -CHR ³ - is and, n is 1 to 3, R ^A compound in which ³ is hydrogen or methyl (each R ³ may be different) (hereinafter, X is x3),
8) X is —CO (CHR ³ ) ₃ —, —CONH (CHR ³ ) ₂ —, —NHCO (CHR ³ ) ₂ — or —A ³ —CHR ³ —, and R ³ is hydrogen or methyl ( Each R ³ may be different) (hereinafter, X is assumed to be x4),

9) R ¹ is hydrogen, R ² is hydrogen, hydroxy or lower alkyl, and R ¹ and R ² may be combined to form a single bond (hereinafter, R ¹ and R ² are r1 Compound),
10) a compound wherein R ¹ is hydrogen and R ² is hydrogen or hydroxy (hereinafter R ¹ and R ² are assumed to be r ² ),
11) ^{R 1} and ^{R 2} form a single bond together (hereinafter, ^{R 1} and ^{R 2} is assumed to be r3) compound,

12) m is 0 and Y is a single bond, —CH ₂ —, —O—, —S— or —NH—, or together with R ² forms ═CH— (hereinafter m And Y is y1),
13) a compound wherein m is 0 and Y is a single bond or —CH ₂ — (hereinafter, m and Y are y2),
14) m is 1, Y is a single _{bond, -CH 2 -, - CH 2} CH 2 -, - CH = CH -, - C≡C -, - O -, - S -, - NH -, - CH ₂ O—, —CH ₂ S— or —CH ₂ NH—, or together with R ² form ═CH— or ═CHCH ₂ — (hereinafter, m and Y are y3) )Compound,
15) m is 1 and Y is a single bond, —CH ₂ —, —O—, —S— or —NH—, or together with R ² forms ═CH— (hereinafter m And Y is y4)
16) a compound wherein m is 1 and Y is a single bond or —CH ₂ — (hereinafter, m and Y are y5),

17) A ² is halogen, cyano, halogeno-lower alkyl, and halogeno substituted with one or more groups selected from lower alkoxy and also phenyl (hereinafter, referred to as A ² is a5) compound,
18) A compound wherein A ² is phenyl optionally substituted with one or more groups selected from halogen, trifluoromethyl and trifluoromethoxy (hereinafter, A ² is a6),
19) A ² is para halogen, phenyl substituted with one or more groups selected from trifluoromethyl and trifluoromethoxy (hereinafter, A ² is assumed to be a7) compound,
20) A compound in which the combination of A ¹ , X, R ¹ , R ² , m, Y, and A ² is as follows (A ¹ , X, R ¹ and R ² , m and Y, A ² ) = (a1 , x1, r1, y1, a5), (a1, x1, r1, y1, a6), (a1, x1, r1, y1, a7), (a1, x1, r1, y2, a5), (a1, x1 , r1, y2, a6), (a1, x1, r1, y2, a7), (a1, x1, r1, y3, a5), (a1, x1, r1, y3, a6), (a1, x1, r1 , y3, a7), (a1, x1, r1, y4, a5), (a1, x1, r1, y4, a6), (a1, x1, r1, y4, a7), (a1, x1, r1, y5 , a5), (a1, x1, r1, y5, a6), (a1, x1, r1, y5, a7), (a1, x1, r2, y1, a5), (a1, x1, r2, y1, a6 ), (a1, x1, r2, y1, a7), (a1, x1, r2, y2, a5), (a1, x1, r2, y2, a6), (a1, x1, r2, y2, a7), (a1, x1, r2, y3, a5), (a1, x1, r2, y3, a6), (a1, x1, r2, y3, a7), (a1, x1, r2, y4, a5), (a1 , x1, r2, y4, a6), (a1, x1, r2, y4, a7), (a1, x1, r2, y5, a5), (a1, x1, r2, y5, a6), (a1, x1 , r2, y5, a7), (a1, x1, r3, y1, a5), (a1, x1, r3, y1, a6), (a1, x1, r3, y1, a7), (a1, x1, r3 , y2, a5), (a1, x1, r3, y2, a6), (a1, x1, r3, y2, a7), (a1, x1, r3, y3, a5), (a1, x1, r3, y3 , a6), (a1, x1, r3, y3, a7), (a1, x1, r3, y4, a5), (a1, x1, r3, y4, a6), (a1, x1, r3, y4, a7 ), (a1, x1, r3, y5, a5), (a1, x1, r3, y5, a6), (a1, x1, r3, y5, a7), (a1, x2, r1, y1, a5), (a1, x2, r1, y1, a6), ( a1, x2, r1, y1, a7), (a1, x2, r1, y2, a5), (a1, x2, r1, y2, a6), (a1, x2, r1, y2, a7), (a1, x2, r1, y3, a5), (a1, x2, r1, y3, a6), (a1, x2, r1, y3, a7), (a1, x2, r1, y4, a5), (a1, x2, r1, y4, a6), (a1, x2, r1, y4, a7), (a1, x2, r1, y5, a5), (a1, x2, r1, y5, a6), (a1, x2, r1, y5, a7), (a1, x2, r2, y1, a5), (a1, x2, r2, y1, a6), (a1, x2, r2, y1, a7), (a1, x2, r2, y2, a5), (a1, x2, r2, y2, a6), (a1, x2, r2, y2, a7), (a1, x2, r2, y3, a5), (a1, x2, r2, y3, a6) , (a1, x2, r2, y3, a7), (a1, x2, r2, y4, a5), (a1, x2, r2, y4, a6), (a1, x2, r2, y4, a7), ( a1, x2, r2, y5, a5), (a1, x2, r2, y5, a6), (a1, x2, r2, y5, a7), (a1, x2, r3, y1, a5), (a1, x2, r3, y1, a6), (a1, x2, r3, y1, a7), (a1, x2, r3, y2, a5), (a1, x2, r3, y2, a6), (a1, x2, r3, y2, a7), (a1, x2, r3, y3, a5), (a1, x2, r3, y3, a6), (a1, x2, r3, y3, a7), (a1, x2, r3, y4, a5), (a1, x2, r3, y4, a6), (a1, x2, r3, y4, a7), (a1, x2, r3, y5, a5), (a1, x2, r3, y5, a6), (a1, x2, r3, y5, a7), (a1, x3, r1, y1, a5), (a1, x3, r1, y1, a6), (a1, x3, r1, y1, a7) , (a1, x3, r1, y2, a5), (a1, x3, r1, y2, a6), (a1, x3, r1, y2, a7), (a1, x3, r1, y3, a5), ( a1, x3, r1, y3, a6), (a1, x3, r1, y3, a7), (a1, x3, r1, y4, a5), (a1, x3, r1, y4, a6), (a1, x3, r1, y4, a7), (a1, x3, r1, y5, a5), (a1, x3, r1, y5, a6), (a1, x3, r1, y5, a7), (a1, x3, r2, y1, a5 ), (a1, x3, r2, y1, a6), (a1, x3, r2, y1, a7), (a1, x3, r2, y2, a5), (a1, x3, r2, y2, a6), (a1, x3, r2, y2, a7), (a1, x3, r2, y3, a5), (a1, x3, r2, y3, a6), (a1, x3, r2, y3, a7), (a1 , x3, r2, y4, a5), (a1, x3, r2, y4, a6), (a1, x3, r2, y4, a7), (a1, x3, r2, y5, a5), (a1, x3 , r2, y5, a6), (a1, x3, r2, y5, a7), (a1, x3, r3, y1, a5), (a1, x3, r3, y1, a6), (a1, x3, r3 , y1, a7), (a1, x3, r3, y2, a5), (a1, x3, r3, y2, a6), (a1, x3, r3, y2, a7), (a1, x3, r3, y3 , a5), (a1, x3, r3, y3, a6), (a1, x3, r3, y3, a7), (a1, x3, 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y4, a5), (a3, x2, r3, y4, a6 ), (a3, x2, r3, y4, a7), (a3, x2, r3, y5, a5), (a3, x2, r3, y5, a6), (a3, x2, r3, y5, a7), (a3, x3, r1, y1, a5), (a3, x3, r1, y1, a6), (a3, x3, r1, y1, a7), (a3, x3, r1, y2, a5), (a3 , x3, r1, y2, a6), (a3, x3, r1, y2, a7), (a3, x3, r1, y3, a5), (a3, x3, r1, y3, a6), (a3, x3 , r1, y3, a 7), (a3, x3, r1, y4, a5), (a3, x3, r1, y4, a6), (a3, x3, r1, y4, a7), (a3, x3, r1, y5, a5) , (a3, x3, r1, y5, a6), (a3, x3, r1, y5, a7), (a3, x3, r2, y1, a5), (a3, x3, r2, y1, a6), ( a3, x3, r2, y1, a7), (a3, x3, r2, y2, a5), (a3, x3, r2, y2, a6), (a3, x3, r2, y2, a7), (a3, x3, r2, y3, a5), (a3, x3, r2, y3, a6), (a3, x3, r2, y3, a7), (a3, x3, r2, y4, a5), (a3, x3, r2, y4, a6), (a3, x3, r2, y4, a7), (a3, x3, r2, y5, a5), (a3, x3, r2, y5, a6), (a3, x3, r2, y5, a7), (a3, x3, r3, y1, a5), (a3, x3, r3, y1, a6), (a3, x3, r3, y1, a7), (a3, x3, r3, y2, a5), (a3, x3, r3, y2, a6), (a3, x3, r3, y2, a7), (a3, x3, r3, y3, a5), (a3, x3, r3, y3, a6) , (a3, x3, r3, y3, a7), (a3, x3, r3, y4, a5), (a3, x3, r3, y4, a6), (a3, x3, r3, y4, a7), ( a3, x3, r3, y5, a5), (a3, x3, r3, y5, a6), (a3, x3, r3, y5, a7), (a3, x4, r1, y1, a5), (a3, x4, r1, y1, a6), (a3, x4, r1, y1, a7), (a3, x4, r1, y2, a5), (a3, x4, r1, y2, a6), (a3, x4, r1, y2, a7), (a3, x4, r1, y3, a5), (a3, x4, r1, y3, a6), (a3, x4, r1, y3, a7), (a3, x4, r1, y4, a5), (a3, x4, r1, y4, a6), (a3, x4, r1, y4, a7), (a3, x4, r1, y5, a5), (a3, x4, r1, y5, a6), (a3, x4, r1, y5, a7), (a3, x4, r2, y1, a5), (a3, x4, r2, y1, a6), (a3, x4, r2, y1, a7) , (a3, x4, r2, y2, a5), (a3, x4, r2, y2, a6), (a3, x4, r2, y2, a7), (a3, x4, r2, y3, a5), ( a3, x4, r2, y 3, a6), (a3, x4, r2, y3, a7), (a3, x4, r2, y4, a5), (a3, x4, r2, y4, a6), (a3, x4, r2, y4, a7), (a3, x4, r2, y5, a5), (a3, x4, r2, y5, a6), (a3, x4, r2, y5, a7), (a3, x4, r3, y1, a5) , (a3, x4, r3, y1, a6), (a3, x4, r3, y1, a7), (a3, x4, r3, y2, a5), (a3, x4, r3, y2, a6), ( a3, x4, r3, y2, a7), (a3, x4, r3, y3, a5), (a3, x4, r3, y3, a6), (a3, x4, r3, y3, a7), (a3, x4, r3, y4, a5), (a3, x4, r3, y4, a6), (a3, x4, r3, y4, a7), (a3, x4, r3, y5, a5), (a3, x4, r3, y5, a6), (a3, x4, r3, y5, a7), (a4, x1, r1, y1, a5), (a4, x1, r1, y1, a6), (a4, x1, r1, y1, a7), (a4, x1, r1, y2, a5), (a4, x1, r1, y2, a6), (a4, x1, r1, y2, a7), (a4, x1, r1, y3, a5), (a4, x1, r1, y3, a6), (a4, x1, r1, y3, a7), (a4, x1, r1, y4, a5), (a4, x1, r1, y4, a6) , (a4, x1, r1, y4, a7), (a4, x1, r1, y5, a5), (a4, x1, r1, y5, a6), (a4, x1, r1, y5, a7), ( a4, x1, r2, y1, a5), (a4, x1, r2, y1, a6), (a4, x1, r2, y1, a7), (a4, x1, r2, y2, a5), (a4, x1, r2, y2, a6), (a4, x1, r2, y2, a7), (a4, x1, r2, y3, a5), (a4, x1, r2, y3, a6), (a4, x1, r2, y3, a7), (a4, x1, r2, y4, a5), (a4, x1, r2, y4, a6), (a4, x1, r2, y4, a7), (a4, x1, r2, y5, a5), (a4, x1, r2, y5, a6), (a4, x1, r2, y5, a7), (a4, x1, r3, y1, a5), (a4, x1, r3, y1, a6), (a4, x1, r3, y1, a7), (a4, x1, r3, y2, a5), (a4, x1, r3, y2, a6), (a4, x1, r3, y2, a7) , (a4, x1, r 3, y3, a5), (a4, x1, r3, y3, a6), (a4, x1, r3, y3, a7), (a4, x1, r3, y4, a5), (a4, x1, r3, y4, a6), (a4, x1, r3, y4, a7), (a4, x1, r3, y5, a5), (a4, x1, r3, y5, a6), (a4, x1, r3, y5, a7), (a4, x2, r1, y1, a5), (a4, x2, r1, y1, a6), (a4, x2, r1, y1, a7), (a4, x2, r1, y2, a5) , (a4, x2, r1, y2, a6), (a4, x2, r1, y2, a7), (a4, x2, r1, y3, a5), (a4, x2, r1, y3, a6), ( a4, x2, r1, y3, a7), (a4, x2, r1, y4, a5), (a4, x2, r1, y4, a6), (a4, x2, r1, y4, a7),
(a4, x2, r1, y5, a5), (a4, x2, r1, y5, a6), (a4, x2, r1, y5, a7), (a4, x2, r2, y1, a5), (a4 , x2, r2, y1, a6), (a4, x2, r2, y1, a7), (a4, x2, r2, y2, a5), (a4, x2, r2, y2, a6), (a4, x2 , r2, y2, a7), (a4, x2, r2, y3, a5), (a4, x2, r2, y3, a6), (a4, x2, r2, y3, a7), (a4, x2, r2 , y4, a5), (a4, x2, r2, y4, a6), (a4, x2, r2, y4, a7), (a4, x2, r2, y5, a5), (a4, x2, r2, y5 , a6), (a4, x2, r2, y5, a7), (a4, x2, r3, y1, a5), (a4, x2, r3, y1, a6), (a4, x2, r3, y1, a7 ), (a4, x2, r3, y2, a5), (a4, x2, r3, y2, a6), (a4, x2, r3, y2, a7), (a4, x2, r3, y3, a5), (a4, x2, r3, y3, a6), (a4, x2, r3, y3, a7), (a4, x2, r3, y4, a5), (a4, x2, r3, y4, a6), (a4 , x2, r3, y4, a7), (a4, x2, r3, y5, a5), (a4, x2, r3, y5, a6), (a4, x2, r3, y5, a7), (a4, x3 , r1, y1, a5), (a4, x3, r1, y1, a6), (a4, x3, r1, y1, a7), (a4, x3, r1, y2, a5), (a4, x3, r1 , y2, a6), (a4, x3, r1, y2, a7), (a4, x3, r1, y3, a5), (a4, x3, r1, y3, a6), (a4, x3, r1, y3 , a7), (a4, x3, r1, y4, a5), (a4, x3, r1, y4, a6), (a4, x3, r1, y4, a7), (a4, x3, r1, y5, a5 ), (a4, x3, r1, y5, a6), (a4, x3, r1, y5, a7), (a4, x3, r2, y1, a5), (a4, x3, r2, y1, a6), (a4, x3, r2, y1, a7), (a4, x3, r2, y2, a5), (a4, x3, r2, y2, a6), (a4, x3, r2, y2, a7), (a4 , x3, r2, y3, a5), (a4, x3, r2, y3, a6), (a4, x3, r2, y3, a7), (a4, x3, r2, y4, a5), (a4, x3 , r2, y4, a 6), (a4, x3, r2, y4, a7), (a4, x3, r2, y5, a5), (a4, x3, r2, y5, a6), (a4, x3, r2, y5, a7) , (a4, x3, r3, y1, a5), (a4, x3, r3, y1, a6), (a4, x3, r3, y1, a7), (a4, x3, r3, y2, a5), ( a4, x3, r3, y2, a6), (a4, x3, r3, y2, a7), (a4, x3, r3, y3, a5), (a4, x3, r3, y3, a6), (a4, x3, r3, y3, a7), (a4, x3, r3, y4, a5), (a4, x3, r3, y4, a6), (a4, x3, r3, y4, a7), (a4, x3, r3, y5, a5), (a4, x3, r3, y5, a6), (a4, x3, r3, y5, a7), (a4, x4, r1, y1, a5), (a4, x4, r1, y1, a6), (a4, x4, r1, y1, a7), (a4, x4, r1, y2, a5), (a4, x4, r1, y2, a6), (a4, x4, r1, y2, a7), (a4, x4, r1, y3, a5), (a4, x4, r1, y3, a6), (a4, x4, r1, y3, a7), (a4, x4, r1, y4, a5) , (a4, x4, r1, y4, a6), (a4, x4, r1, y4, a7), (a4, x4, r1, y5, a5), (a4, x4, r1, y5, a6), ( a4, x4, r1, y5, a7), (a4, x4, r2, y1, a5), (a4, x4, r2, y1, a6), (a4, x4, r2, y1, a7), (a4, x4, r2, y2, a5), (a4, x4, r2, y2, a6), (a4, x4, r2, y2, a7), (a4, x4, r2, y3, a5), (a4, x4, r2, y3, a6), (a4, x4, r2, y3, a7), (a4, x4, r2, y4, a5), (a4, x4, r2, y4, a6), (a4, x4, r2, y4, a7), (a4, x4, r2, y5, a5), (a4, x4, r2, y5, a6), (a4, x4, r2, y5, a7), (a4, x4, r3, y1, a5), (a4, x4, r3, y1, a6), (a4, x4, r3, y1, a7), (a4, x4, r3, y2, a5), (a4, x4, r3, y2, a6) , (a4, x4, r3, y2, a7), (a4, x4, r3, y3, a5), (a4, x4, r3, y3, a6), (a4, x4, r3, y3, a7), ( a4, x4, r3, y 4, a5), (a4, x4, r3, y4, a6), (a4, x4, r3, y4, a7), (a4, x4, r3, y5, a5), (a4, x4, r3, y5, a6), (a4, x4, r3, y5, a7).

で示される化合物において、それぞれ
Ｒ^Ａがヒドロキシ、アミノ、低級アルキルアミノまたはアシルアミノであり、
Ｘが置換基を有していてもよい低級アルケニレン、−ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｎ−、−Ｏ（ＣＲ^３Ｒ^４）ｎ−、−Ｓ（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、−ＳＯ（ＣＲ^３Ｒ^４）ｎ−、−ＳＯ_２（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−ＣＲ^３Ｒ^４−であり、
ｎは０〜４の整数であり、
Ｒ^１は水素であり、
Ｒ^２は水素、ヒドロキシまたは低級アルキルであり、
Ｒ^１およびＲ^２が一緒になって単結合を形成していてもよく、
Ｒ^３、Ｒ^４およびＲ^６は各々独立して水素または低級アルキルであり、
Ｙは単結合または−ＣＲ^１２Ｒ^１３−であり、Ｒ^２と一緒になって＝ＣＲ^１４−を形成してもよく、
Ｒは水素、ハロゲン、低級アルコキシ、ハロゲノ低級アルキル、ハロゲノ低級アルコキシまたはシアノである化合物、
好ましくは
Ｒ^Ａがヒドロキシであり、
Ｘが−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、−ＮＲ^５ＣＯ（ＣＲ^３Ｒ^４）ｎ−または−Ａ^３−ＣＲ^３Ｒ^４−であり、
ｎは０〜４の整数であり、
Ｒ^１およびＲ^２が共に水素であるか、一緒になって単結合を形成していてもよく、
Ｒ^３、Ｒ^４およびＲ^６は各々独立して水素または低級アルキルであり、
Ｙは単結合または−ＣH_２−であり、
Ｒは水素、ハロゲン、低級アルコキシ、ハロゲノ低級アルキル、ハロゲノ低級アルコキシまたはシアノである化合物、
Ｑ^１はＯ、ＮＨまたはＣＲ^ＢＲ^Ｃ（ここでＲ^ＢおよびＲ^Ｃは各々独立して水素または置換基群αから選択される基である）であり、
Ｑ^２がＮまたはＣＨであり、
Ｑ^３がＮまたはＣＨである化合物、21) The following formulas (Ii) to (Im):

In which each R ^A is hydroxy, amino, lower alkylamino or acylamino,
X is optionally substituted lower alkenylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - CONR 5 (CR 3 R 4) n -, - NR 5 CO (CR 3 R 4) n-, ^{-O (CR 3 R 4) n} -, - S (CR 3 R 4) n -, - NR 6 (CR 3 R 4) n -, - SO (CR 3 R 4) n -, - SO 2 (CR ³ R ⁴⁾ n-or ^-A 3 ^-CR 3 ^{R 4} - a and,
n is an integer from 0 to 4,
R ¹ is hydrogen;
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
R ³ , R ⁴ and R ⁶ are each independently hydrogen or lower alkyl,
Y is a single bond or —CR ¹² R ¹³ —, and together with R ² may form ═CR ¹⁴ —,
A compound wherein R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl, halogeno lower alkoxy or cyano;
Preferably R ^A is hydroxy,
X is ^{-CONR 5 (CR 3 R 4)} n -, - NR 5 CO (CR 3 R 4) n- or ^-A 3 ^-CR 3 ^{R 4} - a and,
n is an integer from 0 to 4,
R ¹ and R ² may both be hydrogen or together form a single bond;
R ³ , R ⁴ and R ⁶ are each independently hydrogen or lower alkyl,
Y is a single bond or —CH ₂ —;
A compound wherein R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl, halogeno lower alkoxy or cyano;
Q ¹ is O, NH or CR ^B R ^C (wherein R ^B and R ^C are each independently a group selected from hydrogen or substituent group α);
Q ² is N or CH,
A compound wherein Q ³ is N or CH;

で示される化合物において、Ｙは単結合、低級アルキレン、低級アルケニレン、低級アルキニレン、−Ｏ−または−ＣＲ^１２Ｒ^１３Ｏ−であり、Ｒ^２と一緒になって＝ＣＲ^１４−（ＣＲ^１５Ｒ^１６）ｐ−を形成してもよく、その他の記号は上記２０）と同様である化合物、22) Formulas (In) to (Iq):

Y is a single bond, lower alkylene, lower alkenylene, lower alkynylene, —O— or —CR ¹² R ¹³ O—, and together with R ² ═CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) P- may be formed, and other symbols are the same as in 20) above,

23) In formula (Ii), R ^A is hydroxy or amino;
X is a lower ^{alkenylene, -CO (CHR 3) n -} , - CONR 5 (CHR 3) n -, - NR 5 CO (CHR 3) n- or ^-A 3 -CHR ³ - is and,
n is 2 or 3,
R ¹ is hydrogen;
R ² is hydrogen, hydroxy or methyl;
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond or —CH ₂ —, and together with R ² may form ═CH—,
A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

24) In formula (Ij):
R ^A is hydroxy or amino;
Q ¹ is O or NH;
X is ^{-CONR 5 (CHR 3) n -} , - NR 5 CO (CHR 3) 2 - or ^-A 3 -CHR ³ - is and,
R ¹ is hydrogen;
R ² is hydrogen or hydroxy;
R ¹ and R ² may be combined to form a single bond, R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond or —CH ₂ —;
A compound wherein R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl or halogeno lower alkoxy;

25) In formula (Ik):
Q ² is N or CH,
X is —CO (CHR ³ ) ₂ —, —CONR ⁵ (CHR ³ ) ₂ —, —NR ⁵ CO (CH ₂ ) ₂ — or —A ³ —CHR ³ —,
R ¹ is hydrogen;
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different), R ⁵ is hydrogen or lower alkyl,
Y is a single bond or —CH ₂ —;
A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

26) In formula (Im):
Q ³ is N or CH,
X is —CONR ⁵ (CHR ³ ) ₂ —, —NR ⁵ CO (CHR ³ ) ₂ — or —A ³ —CHR ³ —,
R ¹ is hydrogen;
R ² is hydrogen or hydroxy;
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different), R ⁵ is hydrogen or lower alkyl,
Y is a single bond or —CR ¹² R ¹³ —;
A compound wherein R is hydrogen, halogen, halogeno lower alkyl or lower alkoxy;

27) In formula (In):
R ^A is hydroxy or amino;
X is lower alkylene optionally substituted with hydroxy, optionally substituted lower alkenylene, optionally substituted lower alkynylene, —CO (CHR ³ ) n—, —CONR ⁵ ( ^{CHR 3) n -, - NR} 5 CO (CHR 3) n -, - O (CHR 3) n -, - CH = n-O (CHR 3) n -, - C (= O) O (CHR 3) ^{n -, - a 3 - (} CHR 3) n- or ^{-A 3 -CH = CH (CHR 3} ) is n-,
n is 0-3,
A ³ is phenylene,
R ¹ is hydrogen;
R ² is hydrogen or hydroxy;
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond, lower alkylene, lower alkenylene, lower alkynylene, —O— or —CR ¹² R ¹³ O—, and together with R ² forms ═CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p—. You can,
A compound wherein R is hydrogen, halogen, halogeno lower alkyl or cyano;

28) In formula (Io), R ^A is hydroxy or amino;
Q ¹ is O, NH or CH ₂
X is ^{-CO (CHR 3) n -,} - CONR 5 (CHR 3) n -, - NR 5 CO (CHR 3) n- or ^-A 3 -CHR ³ - is and,
n is 1 or 2,
R ¹ is hydrogen;
R ² is hydrogen or hydroxy;
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond or lower alkylene,
A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

29) In formula (Ip):
Q ² is N or CH,
X is ^{-CO (CHR 3) n -,} - CONR 5 (CHR 3) n -, - NR 5 CO (CHR 3) n- or ^-A 3 -CHR ³ - is and,
n is 0-2,
R ¹ is hydrogen;
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond or lower alkylene,
A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

30) In formula (Iq):
Q ³ is N or CH,
X is ^{-CO (CHR 3) n -,} - CONR 5 (CHR 3) n -, - NR 5 CO (CHR 3) n'- or ^-A 3 -CHR ³ - is and,
n is 1 or 2,
R ¹ is hydrogen;
R ² is hydrogen or hydroxy;
R ¹ and R ² may be combined to form a single bond,
R ³ is hydrogen or lower alkyl (each R ³ may be different),
R ⁵ is hydrogen or lower alkyl,
Y is a single bond or lower alkylene,
A compound wherein R is hydrogen, halogen, halogeno lower alkyl or lower alkoxy.

In the following formula (Ir), (Is), (It) or (Iu), a compound in which the combination of A ¹ , X, Y and R is as follows is also a preferred embodiment of the present invention.

(A1-1, X1, Y1, R-1), (A1-1, X1, Y1, R-2), (A1-1, X1, Y1, R-3), (A1-1, X1, Y1 , R-4), (A1-1, X1, Y1, R-5), (A1-1, X1, Y1, R-6), (A1-1, X1, Y2, R-1), (A1 -1, X1, Y2, R-2), (A1-1, X1, Y2, R-3), (A1-1, X1, Y2, R-4), (A1-1, X1, Y2, R -5), (A1-1, X1, Y2, R-6), (A1-1, X2, Y1, R-1), (A1-1, X2, Y1, R-2), (A1-1 , X2, Y1, R-3), (A1-1, X2, Y1, R-4), (A1-1, X2, Y1, R-5), (A1-1, X2, Y1, R-6) ), (A1-1, X2, Y2, R-1), (A1-1, X2, Y2, R-2), (A1-1, X2, Y2, R-3), (A1-1, X2 , Y2, R-4), (A1-1, X2, Y2, R-5), (A1-1, X2, Y2, R-6), (A1-1, X3, Y1, R-1), (A1-1, X3, Y1, R-2), (A1-1, X3, Y1, R-3), (A1-1, X3, Y1, R-4), (A1-1, X3, Y1 , R-5), (A1-1, X3, Y1, R-6), (A1-1, X3, Y2, R-1), (A1-1, X3, Y2, R-2), (A1 -1, X3, Y2, R-3), (A1-1, X3, Y2, R-4), (A1-1, X3, Y2, R-5), (A1-1, X3, Y2, R -6), (A1-1, X4, Y1, R-1), (A1-1, X4, Y1, R-2), (A1-1, X4, Y1, R-3), (A1-1 , X4, Y1, R-4), (A1-1, X4, Y1, R-5), (A1-1, X4, Y1, R-6), (A1-1, X4, Y2, R-1 ), (A1-1, X4, Y2, R-2), (A1-1, X4, Y2, R-3), (A1-1, X4, Y2, R-4), (A1-1, X4 , Y2, R-5), (A1-1, X4, Y2, R-6), (A1-1, X5, Y1, R-1), (A1-1, X5, Y1, R-2), (A1-1, X5, Y1, R-3), (A1-1, X5, Y1, R-4), (A1-1, X5, Y1, R-5), (A1-1, X5, Y1 , R-6), (A1-1, X5, Y2, R-1), (A1-1, X5, Y2, R-2), (A1-1, X5, Y2, R-3), (A1 -1, X5, Y2, R-4), (A1-1, X5, Y2, R- 5), (A1-1, X5, Y2, R-6), (A1-1, X6, Y1, R-1), (A1-1, X6, Y1, R-2), (A1-1, X6, Y1, R-3), (A1-1, X6, Y1, R-4), (A1-1, X6, Y1, R-5), (A1-1, X6, Y1, R-6) , (A1-1, X6, Y2, R-1), (A1-1, X6, Y2, R-2), (A1-1, X6, Y2, R-3), (A1-1, X6, Y2, R-4), (A1-1, X6, Y2, R-5), (A1-1, X6, Y2, R-6), (A1-1, X7, Y1, R-1), ( A1-1, X7, Y1, R-2), (A1-1, X7, Y1, R-3), (A1-1, X7, Y1, R-4), (A1-1, X7, Y1, R-5), (A1-1, X7, Y1, R-6), (A1-1, X7, Y2, R-1), (A1-1, X7, Y2, R-2), (A1- 1, X7, Y2, R-3), (A1-1, X7, Y2, R-4), (A1-1, X7, Y2, R-5), (A1-1, X7, Y2, R- 6), (A1-1, X8, Y1, R-1), (A1-1, X8, Y1, R-2), (A1-1, X8, Y1, R-3), (A1-1, X8, Y1, R-4), (A1-1, X8, Y1, R-5), (A1-1, X8, Y1, R-6), (A1-1, X8, Y2, R-1) , (A1-1, X8, Y2, R-2), (A1-1, X8, Y2, R-3), (A1-1, X8, Y2, R-4), (A1-1, X8, Y2, R-5), (A1-1, X8, Y2, R-6), (A1-1, X9, Y1, R-1), (A1-1, X9, Y1, R-2), ( A1-1, X9, Y1, R-3), (A1-1, X9, Y1, R-4), (A1-1, X9, Y1, R-5), (A1-1, X9, Y1, R-6), (A1-1, X9, Y2, R-1), (A1-1, X9, Y2, R-2), (A1-1, X9, Y2, R-3), (A1- 1, X9, Y2, R-4), (A1-1, X9, Y2, R-5), (A1-1, X9, Y2, R-6), (A1-1, X10, Y1, R- 1), (A1-1, X10, Y1, R-2), (A1-1, X10, Y1, R-3), (A1-1, X10, Y1, R-4), (A1-1, X10, Y1, R-5), (A1-1, X10, Y1, R-6), (A1-1, X10, Y2, R-1), (A1-1, X10, Y2, R-2) , (A1-1, X10, Y2, R-3), (A 1-1, X10, Y2, R-4), (A1-1, X10, Y2, R-5), (A1-1, X10, Y2, R-6),
(A1-1, X11, Y1, R-1), (A1-1, X11, Y1, R-2), (A1-1, X11, Y1, R-3), (A1-1, X11, Y1 , R-4), (A1-1, X11, Y1, R-5), (A1-1, X11, Y1, R-6), (A1-1, X11, Y2, R-1), (A1 -1, X11, Y2, R-2), (A1-1, X11, Y2, R-3), (A1-1, X11, Y2, R-4), (A1-1, X11, Y2, R -5), (A1-1, X11, Y2, R-6),
(A1-1, X12, Y1, R-1), (A1-1, X12, Y1, R-2), (A1-1, X12, Y1, R-3), (A1-1, X12, Y1 , R-4), (A1-1, X12, Y1, R-5), (A1-1, X12, Y1, R-6), (A1-1, X12, Y2, R-1), (A1 -1, X12, Y2, R-2), (A1-1, X12, Y2, R-3), (A1-1, X12, Y2, R-4), (A1-1, X12, Y2, R -5), (A1-1, X12, Y2, R-6),
(A1-1, X13, Y1, R-1), (A1-1, X13, Y1, R-2), (A1-1, X13, Y1, R-3), (A1-1, X13, Y1 , R-4), (A1-1, X13, Y1, R-5), (A1-1, X13, Y1, R-6), (A1-1, X13, Y2, R-1), (A1 -1, X13, Y2, R-2), (A1-1, X13, Y2, R-3), (A1-1, X13, Y2, R-4), (A1-1, X13, Y2, R -5), (A1-1, X13, Y2, R-6),
(A1-1, X14, Y1, R-1), (A1-1, X14, Y1, R-2), (A1-1, X14, Y1, R-3), (A1-1, X14, Y1 , R-4), (A1-1, X14, Y1, R-5), (A1-1, X14, Y1, R-6), (A1-1, X14, Y2, R-1), (A1 -1, X14, Y2, R-2), (A1-1, X14, Y2, R-3), (A1-1, X14, Y2, R-4), (A1-1, X14, Y2, R -5), (A1-1, X14, Y2, R-6),
(A1-1, X15, Y1, R-1), (A1-1, X15, Y1, R-2), (A1-1, X15, Y1, R-3), (A1-1, X15, Y1 , R-4), (A1-1, X15, Y1, R-5), (A1-1, X15, Y1, R-6), (A1-1, X15, Y2, R-1), (A1 -1, X15, Y2, R-2), (A1-1, X15, Y2, R-3), (A1-1, X15, Y2, R-4), (A1-1, X15, Y2, R -5), (A1-1, X15, Y2, R-6),
(A1-1, X16, Y1, R-1), (A1-1, X16, Y1, R-2), (A1-1, X16, Y1, R-3), (A1-1, X16, Y1 , R-4), (A1-1, X16, Y1, R-5), (A1-1, X16, Y1, R-6), (A1-1, X16, Y2, R-1), (A1 -1, X16, Y2, R-2), (A1-1, X16, Y2, R-3), (A1-1, X16, Y2, R-4), (A1-1, X16, Y2, R -5), (A1-1, X16, Y2, R-6),
(A1-1, X17, Y1, R-1), (A1-1, X17, Y1, R-2), (A1-1, X17, Y1, R-3), (A1-1, X17, Y1 , R-4), (A1-1, X17, Y1, R-5), (A1-1, X17, Y1, R-6), (A1-1, X17, Y2, R-1), (A1 -1, X17, Y2, R-2), (A1-1, X17, Y2, R-3), (A1-1, X17, Y2, R-4), (A1-1, X17, Y2, R -5), (A1-1, X17, Y2, R-6),
(A1-1, X18, Y1, R-1), (A1-1, X18, Y1, R-2), (A1-1, X18, Y1, R-3), (A1-1, X18, Y1 , R-4), (A1-1, X18, Y1, R-5), (A1-1, X18, Y1, R-6), (A1-1, X18, Y2, R-1), (A1 -1, X18, Y2, R-2), (A1-1, X18, Y2, R-3), (A1-1, X18, Y2, R-4), (A1-1, X18, Y2, R -5), (A1-1, X18, Y2, R-6),

(A1-2, X1, Y1, R-1), (A1-2, X1, Y1, R-2), (A1-2, X1, Y1, R-3), (A1-2, X1, Y1 , R-4), (A1-2, X1, Y1, R-5), (A1-2, X1, Y1, R-6), (A1-2, X1, Y2, R-1), (A1 -2, X1, Y2, R-2), (A1-2, X1, Y2, R-3), (A1-2, X1, Y2, R-4), (A1-2, X1, Y2, R -5), (A1-2, X1, Y2, R-6), (A1-2, X2, Y1, R-1), (A1-2, X2, Y1, R-2), (A1-2 , X2, Y1, R-3), (A1-2, X2, Y1, R-4), (A1-2, X2, Y1, R-5), (A1-2, X2, Y1, R-6 ), (A1-2, X2, Y2, R-1), (A1-2, X2, Y2, R-2), (A1-2, X2, Y2, R-3), (A1-2, X2 , Y2, R-4), (A1-2, X2, Y2, R-5), (A1-2, X2, Y2, R-6), (A1-2, X3, Y1, R-1), (A1-2, X3, Y1, R-2), (A1-2, X3, Y1, R-3), (A1-2, X3, Y1, R-4), (A1-2, X3, Y1 , R-5), (A1-2, X3, Y1, R-6), (A1-2, X3, Y2, R-1), (A1-2, X3, Y2, R-2), (A1 -2, X3, Y2, R-3), (A1-2, X3, Y2, R-4), (A1-2, X3, Y2, R-5), (A1-2, X3, Y2, R -6), (A1-2, X4, Y1, R-1), (A1-2, X4, Y1, R-2), (A1-2, X4, Y1, R-3), (A1-2 , X4, Y1, R-4), (A1-2, X4, Y1, R-5), (A1-2, X4, Y1, R-6), (A1-2, X4, Y2, R-1 ), (A1-2, X4, Y2, R-2), (A1-2, X4, Y2, R-3), (A1-2, X4, Y2, R-4), (A1-2, X4 , Y2, R-5), (A1-2, X4, Y2, R-6), (A1-2, X5, Y1, R-1), (A1-2, X5, Y1, R-2), (A1-2, X5, Y1, R-3), (A1-2, X5, Y1, R-4), (A1-2, X5, Y1, R-5), (A1-2, X5, Y1 , R-6), (A1-2, X5, Y2, R-1), (A1-2, X5, Y2, R-2), (A1-2, X5, Y2, R-3), (A1 -2, X5, Y2, R-4), (A1-2, X5, Y2, R- 5), (A1-2, X5, Y2, R-6), (A1-2, X6, Y1, R-1), (A1-2, X6, Y1, R-2), (A1-2, X6, Y1, R-3), (A1-2, X6, Y1, R-4), (A1-2, X6, Y1, R-5), (A1-2, X6, Y1, R-6) , (A1-2, X6, Y2, R-1), (A1-2, X6, Y2, R-2), (A1-2, X6, Y2, R-3), (A1-2, X6, Y2, R-4), (A1-2, X6, Y2, R-5), (A1-2, X6, Y2, R-6), (A1-2, X7, Y1, R-1), ( A1-2, X7, Y1, R-2), (A1-2, X7, Y1, R-3), (A1-2, X7, Y1, R-4), (A1-2, X7, Y1, R-5), (A1-2, X7, Y1, R-6), (A1-2, X7, Y2, R-1), (A1-2, X7, Y2, R-2), (A1- 2, X7, Y2, R-3), (A1-2, X7, Y2, R-4), (A1-2, X7, Y2, R-5), (A1-2, X7, Y2, R- 6), (A1-2, X8, Y1, R-1), (A1-2, X8, Y1, R-2), (A1-2, X8, Y1, R-3), (A1-2, X8, Y1, R-4), (A1-2, X8, Y1, R-5), (A1-2, X8, Y1, R-6), (A1-2, X8, Y2, R-1) , (A1-2, X8, Y2, R-2), (A1-2, X8, Y2, R-3), (A1-2, X8, Y2, R-4), (A1-2, X8, Y2, R-5), (A1-2, X8, Y2, R-6), (A1-2, X9, Y1, R-1), (A1-2, X9, Y1, R-2), ( A1-2, X9, Y1, R-3), (A1-2, X9, Y1, R-4), (A1-2, X9, Y1, R-5), (A1-2, X9, Y1, R-6), (A1-2, X9, Y2, R-1), (A1-2, X9, Y2, R-2), (A1-2, X9, Y2, R-3), (A1- 2, X9, Y2, R-4), (A1-2, X9, Y2, R-5), (A1-2, X9, Y2, R-6), (A1-2, X10, Y1, R- 1), (A1-2, X10, Y1, R-2), (A1-2, X10, Y1, R-3), (A1-2, X10, Y1, R-4), (A1-2, X10, Y1, R-5), (A1-2, X10, Y1, R-6), (A1-2, X10, Y2, R-1), (A1-2, X10, Y2, R-2) , (A1-2, X10, Y2, R-3), (A 1-2, X10, Y2, R-4), (A1-2, X10, Y2, R-5), (A1-2, X10, Y2, R-6), (A1-2, X11, Y1, R-1), (A1-2, X11, Y1, R-2), (A1-2, X11, Y1, R-3), (A1-2, X11, Y1, R-4), (A1- 2, X11, Y1, R-5), (A1-2, X11, Y1, R-6), (A1-2, X11, Y2, R-1), (A1-2, X11, Y2, R- 2), (A1-2, X11, Y2, R-3), (A1-2, X11, Y2, R-4), (A1-2, X11, Y2, R-5), (A1-2, X11, Y2, R-6),
(A1-2, X12, Y1, R-1), (A1-2, X12, Y1, R-2), (A1-2, X12, Y1, R-3), (A1-2, X12, Y1 , R-4), (A1-2, X12, Y1, R-5), (A1-2, X12, Y1, R-6), (A1-2, X12, Y2, R-1), (A1 -2, X12, Y2, R-2), (A1-2, X12, Y2, R-3), (A1-2, X12, Y2, R-4), (A1-2, X12, Y2, R -5), (A1-2, X12, Y2, R-6),
(A1-2, X13, Y1, R-1), (A1-2, X13, Y1, R-2), (A1-2, X13, Y1, R-3), (A1-2, X13, Y1 , R-4), (A1-2, X13, Y1, R-5), (A1-2, X13, Y1, R-6), (A1-2, X13, Y2, R-1), (A1 -2, X13, Y2, R-2), (A1-2, X13, Y2, R-3), (A1-2, X13, Y2, R-4), (A1-2, X13, Y2, R -5), (A1-2, X13, Y2, R-6),
(A1-2, X14, Y1, R-1), (A1-2, X14, Y1, R-2), (A1-2, X14, Y1, R-3), (A1-2, X14, Y1 , R-4), (A1-2, X14, Y1, R-5), (A1-2, X14, Y1, R-6), (A1-2, X14, Y2, R-1), (A1 -2, X14, Y2, R-2), (A1-2, X14, Y2, R-3), (A1-2, X14, Y2, R-4), (A1-2, X14, Y2, R -5), (A1-2, X14, Y2, R-6),
(A1-2, X15, Y1, R-1), (A1-2, X15, Y1, R-2), (A1-2, X15, Y1, R-3), (A1-2, X15, Y1 , R-4), (A1-2, X15, Y1, R-5), (A1-2, X15, Y1, R-6), (A1-2, X15, Y2, R-1), (A1 -2, X15, Y2, R-2), (A1-2, X15, Y2, R-3), (A1-2, X15, Y2, R-4), (A1-2, X15, Y2, R -5), (A1-2, X15, Y2, R-6),
(A1-2, X16, Y1, R-1), (A1-2, X16, Y1, R-2), (A1-2, X16, Y1, R-3), (A1-2, X16, Y1 , R-4), (A1-2, X16, Y1, R-5), (A1-2, X16, Y1, R-6), (A1-2, X16, Y2, R-1), (A1 -2, X16, Y2, R-2), (A1-2, X16, Y2, R-3), (A1-2, X16, Y2, R-4), (A1-2, X16, Y2, R -5), (A1-2, X16, Y2, R-6),
(A1-2, X17, Y1, R-1), (A1-2, X17, Y1, R-2), (A1-2, X17, Y1, R-3), (A1-2, X17, Y1 , R-4), (A1-2, X17, Y1, R-5), (A1-2, X17, Y1, R-6), (A1-2, X17, Y2, R-1), (A1 -2, X17, Y2, R-2), (A1-2, X17, Y2, R-3), (A1-2, X17, Y2, R-4), (A1-2, X17, Y2, R -5), (A1-2, X17, Y2, R-6), (A1-2, X18, Y1, R-1), (A1-2, X18, Y1, R-2), (A1-2 , X18, Y1, R-3), (A1-2, X18, Y1, R-4), (A1-2, X18, Y1, R-5), (A1-2, X18, Y1, R-6 ), (A1-2, X18, Y2, R-1), (A1-2, X18, Y2, R-2), (A1-2, X18, Y2, R-3), (A1-2, X18 , Y2, R-4), (A1-2, X18, Y2, R-5), (A1-2, X18, Y2, R-6),

(A1-3, X1, Y1, R-1), (A1-3, X1, Y1, R-2), (A1-3, X1, Y1, R-3), (A1-3, X1, Y1 , R-4), (A1-3, X1, Y1, R-5), (A1-3, X1, Y1, R-6), (A1-3, X1, Y2, R-1), (A1 -3, X1, Y2, R-2), (A1-3, X1, Y2, R-3), (A1-3, X1, Y2, R-4), (A1-3, X1, Y2, R -5), (A1-3, X1, Y2, R-6), (A1-3, X2, Y1, R-1), (A1-3, X2, Y1, R-2), (A1-3 , X2, Y1, R-3), (A1-3, X2, Y1, R-4), (A1-3, X2, Y1, R-5), (A1-3, X2, Y1, R-6 ), (A1-3, X2, Y2, R-1), (A1-3, X2, Y2, R-2), (A1-3, X2, Y2, R-3), (A1-3, X2 , Y2, R-4), (A1-3, X2, Y2, R-5), (A1-3, X2, Y2, R-6), (A1-3, X3, Y1, R-1), (A1-3, X3, Y1, R-2), (A1-3, X3, Y1, R-3), (A1-3, X3, Y1, R-4), (A1-3, X3, Y1 , R-5), (A1-3, X3, Y1, R-6), (A1-3, X3, Y2, R-1), (A1-3, X3, Y2, R-2), (A1 -3, X3, Y2, R-3), (A1-3, X3, Y2, R-4), (A1-3, X3, Y2, R-5), (A1-3, X3, Y2, R -6), (A1-3, X4, Y1, R-1), (A1-3, X4, Y1, R-2), (A1-3, X4, Y1, R-3), (A1-3 , X4, Y1, R-4), (A1-3, X4, Y1, R-5), (A1-3, X4, Y1, R-6), (A1-3, X4, Y2, R-1 ), (A1-3, X4, Y2, R-2), (A1-3, X4, Y2, R-3), (A1-3, X4, Y2, R-4), (A1-3, X4 , Y2, R-5), (A1-3, X4, Y2, R-6), (A1-3, X5, Y1, R-1), (A1-3, X5, Y1, R-2), (A1-3, X5, Y1, R-3), (A1-3, X5, Y1, R-4), (A1-3, X5, Y1, R-5), (A1-3, X5, Y1 , R-6), (A1-3, X5, Y2, R-1), (A1-3, X5, Y2, R-2), (A1-3, X5, Y2, R-3), (A1 -3, X5, Y2, R-4), (A1-3, X5, Y2, R- 5), (A1-3, X5, Y2, R-6), (A1-3, X6, Y1, R-1), (A1-3, X6, Y1, R-2), (A1-3, X6, Y1, R-3), (A1-3, X6, Y1, R-4), (A1-3, X6, Y1, R-5), (A1-3, X6, Y1, R-6) , (A1-3, X6, Y2, R-1), (A1-3, X6, Y2, R-2), (A1-3, X6, Y2, R-3), (A1-3, X6, Y2, R-4), (A1-3, X6, Y2, R-5), (A1-3, X6, Y2, R-6), (A1-3, X7, Y1, R-1), ( A1-3, X7, Y1, R-2), (A1-3, X7, Y1, R-3), (A1-3, X7, Y1, R-4), (A1-3, X7, Y1, R-5), (A1-3, X7, Y1, R-6), (A1-3, X7, Y2, R-1), (A1-3, X7, Y2, R-2), (A1- 3, X7, Y2, R-3), (A1-3, X7, Y2, R-4), (A1-3, X7, Y2, R-5), (A1-3, X7, Y2, R- 6), (A1-3, X8, Y1, R-1), (A1-3, X8, Y1, R-2), (A1-3, X8, Y1, R-3), (A1-3, X8, Y1, R-4), (A1-3, X8, Y1, R-5), (A1-3, X8, Y1, R-6), (A1-3, X8, Y2, R-1) , (A1-3, X8, Y2, R-2), (A1-3, X8, Y2, R-3), (A1-3, X8, Y2, R-4), (A1-3, X8, Y2, R-5), (A1-3, X8, Y2, R-6), (A1-3, X9, Y1, R-1), (A1-3, X9, Y1, R-2), ( A1-3, X9, Y1, R-3), (A1-3, X9, Y1, R-4), (A1-3, X9, Y1, R-5), (A1-3, X9, Y1, R-6), (A1-3, X9, Y2, R-1), (A1-3, X9, Y2, R-2), (A1-3, X9, Y2, R-3), (A1- 3, X9, Y2, R-4), (A1-3, X9, Y2, R-5), (A1-3, X9, Y2, R-6), (A1-3, X10, Y1, R- 1), (A1-3, X10, Y1, R-2), (A1-3, X10, Y1, R-3), (A1-3, X10, Y1, R-4), (A1-3, X10, Y1, R-5), (A1-3, X10, Y1, R-6), (A1-3, X10, Y2, R-1), (A1-3, X10, Y2, R-2) , (A1-3, X10, Y2, R-3), (A 1-3, X10, Y2, R-4), (A1-3, X10, Y2, R-5), (A1-3, X10, Y2, R-6), (A1-3, X11, Y1, R-1), (A1-3, X11, Y1, R-2), (A1-3, X11, Y1, R-3), (A1-3, X11, Y1, R-4), (A1- 3, X11, Y1, R-5), (A1-3, X11, Y1, R-6), (A1-3, X11, Y2, R-1), (A1-3, X11, Y2, R- 2), (A1-3, X11, Y2, R-3), (A1-3, X11, Y2, R-4), (A1-3, X11, Y2, R-5), (A1-3, X11, Y2, R-6),
(A1-3, X12, Y1, R-1), (A1-3, X12, Y1, R-2), (A1-3, X12, Y1, R-3), (A1-3, X12, Y1 , R-4), (A1-3, X12, Y1, R-5), (A1-3, X12, Y1, R-6), (A1-3, X12, Y2, R-1), (A1 -3, X12, Y2, R-2), (A1-3, X12, Y2, R-3), (A1-3, X12, Y2, R-4), (A1-3, X12, Y2, R -5), (A1-3, X12, Y2, R-6),
(A1-3, X13, Y1, R-1), (A1-3, X13, Y1, R-2), (A1-3, X13, Y1, R-3), (A1-3, X13, Y1 , R-4), (A1-3, X13, Y1, R-5), (A1-3, X13, Y1, R-6), (A1-3, X13, Y2, R-1), (A1 -3, X13, Y2, R-2), (A1-3, X13, Y2, R-3), (A1-3, X13, Y2, R-4), (A1-3, X13, Y2, R -5), (A1-3, X13, Y2, R-6),
(A1-3, X14, Y1, R-1), (A1-3, X14, Y1, R-2), (A1-3, X14, Y1, R-3), (A1-3, X14, Y1 , R-4), (A1-3, X14, Y1, R-5), (A1-3, X14, Y1, R-6), (A1-3, X14, Y2, R-1), (A1 -3, X14, Y2, R-2), (A1-3, X14, Y2, R-3), (A1-3, X14, Y2, R-4), (A1-3, X14, Y2, R -5), (A1-3, X14, Y2, R-6),
(A1-3, X15, Y1, R-1), (A1-3, X15, Y1, R-2), (A1-3, X15, Y1, R-3), (A1-3, X15, Y1 , R-4), (A1-3, X15, Y1, R-5), (A1-3, X15, Y1, R-6), (A1-3, X15, Y2, R-1), (A1 -3, X15, Y2, R-2), (A1-3, X15, Y2, R-3), (A1-3, X15, Y2, R-4), (A1-3, X15, Y2, R -5), (A1-3, X15, Y2, R-6),
(A1-3, X16, Y1, R-1), (A1-3, X16, Y1, R-2), (A1-3, X16, Y1, R-3), (A1-3, X16, Y1 , R-4), (A1-3, X16, Y1, R-5), (A1-3, X16, Y1, R-6), (A1-3, X16, Y2, R-1), (A1 -3, X16, Y2, R-2), (A1-3, X16, Y2, R-3), (A1-3, X16, Y2, R-4), (A1-3, X16, Y2, R -5), (A1-3, X16, Y2, R-6),
(A1-3, X17, Y1, R-1), (A1-3, X17, Y1, R-2), (A1-3, X17, Y1, R-3), (A1-3, X17, Y1 , R-4), (A1-3, X17, Y1, R-5), (A1-3, X17, Y1, R-6), (A1-3, X17, Y2, R-1), (A1 -3, X17, Y2, R-2), (A1-3, X17, Y2, R-3), (A1-3, X17, Y2, R-4), (A1-3, X17, Y2, R -5), (A1-3, X17, Y2, R-6), (A1-3, X18, Y1, R-1), (A1-3, X18, Y1, R-2), (A1-3 , X18, Y1, R-3), (A1-3, X18, Y1, R-4), (A1-3, X18, Y1, R-5), (A1-3, X18, Y1, R-6) ), (A1-3, X18, Y2, R-1), (A1-3, X18, Y2, R-2), (A1-3, X18, Y2, R-3), (A1-3, X18 , Y2, R-4), (A1-3, X18, Y2, R-5), (A1-3, X18, Y2, R-6),

(A1-4, X1, Y1, R-1), (A1-4, X1, Y1, R-2), (A1-4, X1, Y1, R-3), (A1-4, X1, Y1 , R-4), (A1-4, X1, Y1, R-5), (A1-4, X1, Y1, R-6), (A1-4, X1, Y2, R-1), (A1 -4, X1, Y2, R-2), (A1-4, X1, Y2, R-3), (A1-4, X1, Y2, R-4), (A1-4, X1, Y2, R -5), (A1-4, X1, Y2, R-6), (A1-4, X2, Y1, R-1), (A1-4, X2, Y1, R-2), (A1-4 , X2, Y1, R-3), (A1-4, X2, Y1, R-4), (A1-4, X2, Y1, R-5), (A1-4, X2, Y1, R-6) ), (A1-4, X2, Y2, R-1), (A1-4, X2, Y2, R-2), (A1-4, X2, Y2, R-3), (A1-4, X2 , Y2, R-4), (A1-4, X2, Y2, R-5), (A1-4, X2, Y2, R-6), (A1-4, X3, Y1, R-1), (A1-4, X3, Y1, R-2), (A1-4, X3, Y1, R-3), (A1-4, X3, Y1, R-4), (A1-4, X3, Y1 , R-5), (A1-4, X3, Y1, R-6), (A1-4, X3, Y2, R-1), (A1-4, X3, Y2, R-2), (A1 -4, X3, Y2, R-3), (A1-4, X3, Y2, R-4), (A1-4, X3, Y2, R-5), (A1-4, X3, Y2, R -6), (A1-4, X4, Y1, R-1), (A1-4, X4, Y1, R-2), (A1-4, X4, Y1, R-3), (A1-4 , X4, Y1, R-4), (A1-4, X4, Y1, R-5), (A1-4, X4, Y1, R-6), (A1-4, X4, Y2, R-1 ), (A1-4, X4, Y2, R-2), (A1-4, X4, Y2, R-3), (A1-4, X4, Y2, R-4), (A1-4, X4 , Y2, R-5), (A1-4, X4, Y2, R-6), (A1-4, X5, Y1, R-1), (A1-4, X5, Y1, R-2), (A1-4, X5, Y1, R-3), (A1-4, X5, Y1, R-4), (A1-4, X5, Y1, R-5), (A1-4, X5, Y1 , R-6), (A1-4, X5, Y2, R-1), (A1-4, X5, Y2, R-2), (A1-4, X5, Y2, R-3), (A1 -4, X5, Y2, R-4), (A1-4, X5, Y2, R- 5), (A1-4, X5, Y2, R-6), (A1-4, X6, Y1, R-1), (A1-4, X6, Y1, R-2), (A1-4, X6, Y1, R-3), (A1-4, X6, Y1, R-4), (A1-4, X6, Y1, R-5), (A1-4, X6, Y1, R-6) , (A1-4, X6, Y2, R-1), (A1-4, X6, Y2, R-2), (A1-4, X6, Y2, R-3), (A1-4, X6, Y2, R-4), (A1-4, X6, Y2, R-5), (A1-4, X6, Y2, R-6), (A1-4, X7, Y1, R-1), ( A1-4, X7, Y1, R-2), (A1-4, X7, Y1, R-3), (A1-4, X7, Y1, R-4), (A1-4, X7, Y1, R-5), (A1-4, X7, Y1, R-6), (A1-4, X7, Y2, R-1), (A1-4, X7, Y2, R-2), (A1- 4, X7, Y2, R-3), (A1-4, X7, Y2, R-4), (A1-4, X7, Y2, R-5), (A1-4, X7, Y2, R- 6), (A1-4, X8, Y1, R-1), (A1-4, X8, Y1, R-2), (A1-4, X8, Y1, R-3), (A1-4, X8, Y1, R-4), (A1-4, X8, Y1, R-5), (A1-4, X8, Y1, R-6), (A1-4, X8, Y2, R-1) , (A1-4, X8, Y2, R-2), (A1-4, X8, Y2, R-3), (A1-4, X8, Y2, R-4), (A1-4, X8, Y2, R-5), (A1-4, X8, Y2, R-6), (A1-4, X9, Y1, R-1), (A1-4, X9, Y1, R-2), ( A1-4, X9, Y1, R-3), (A1-4, X9, Y1, R-4), (A1-4, X9, Y1, R-5), (A1-4, X9, Y1, R-6), (A1-4, X9, Y2, R-1), (A1-4, X9, Y2, R-2), (A1-4, X9, Y2, R-3), (A1- 4, X9, Y2, R-4), (A1-4, X9, Y2, R-5), (A1-4, X9, Y2, R-6), (A1-4, X10, Y1, R- 1), (A1-4, X10, Y1, R-2), (A1-4, X10, Y1, R-3), (A1-4, X10, Y1, R-4), (A1-4, X10, Y1, R-5), (A1-4, X10, Y1, R-6), (A1-4, X10, Y2, R-1), (A1-4, X10, Y2, R-2) , (A1-4, X10, Y2, R-3), (A 1-4, X10, Y2, R-4), (A1-4, X10, Y2, R-5), (A1-4, X10, Y2, R-6), (A1-4, X11, Y1, R-1), (A1-4, X11, Y1, R-2), (A1-4, X11, Y1, R-3), (A1-4, X11, Y1, R-4), (A1- 4, X11, Y1, R-5), (A1-4, X11, Y1, R-6), (A1-4, X11, Y2, R-1), (A1-4, X11, Y2, R- 2), (A1-4, X11, Y2, R-3), (A1-4, X11, Y2, R-4), (A1-4, X11, Y2, R-5), (A1-4, X11, Y2, R-6),
(A1-4, X12, Y1, R-1), (A1-4, X12, Y1, R-2), (A1-4, X12, Y1, R-3), (A1-4, X12, Y1 , R-4), (A1-4, X12, Y1, R-5), (A1-4, X12, Y1, R-6), (A1-4, X12, Y2, R-1), (A1 -4, X12, Y2, R-2), (A1-4, X12, Y2, R-3), (A1-4, X12, Y2, R-4), (A1-4, X12, Y2, R -5), (A1-4, X12, Y2, R-6),
(A1-4, X13, Y1, R-1), (A1-4, X13, Y1, R-2), (A1-4, X13, Y1, R-3), (A1-4, X13, Y1 , R-4), (A1-4, X13, Y1, R-5), (A1-4, X13, Y1, R-6), (A1-4, X13, Y2, R-1), (A1 -4, X13, Y2, R-2), (A1-4, X13, Y2, R-3), (A1-4, X13, Y2, R-4), (A1-4, X13, Y2, R -5), (A1-4, X13, Y2, R-6),
(A1-4, X14, Y1, R-1), (A1-4, X14, Y1, R-2), (A1-4, X14, Y1, R-3), (A1-4, X14, Y1 , R-4), (A1-4, X14, Y1, R-5), (A1-4, X14, Y1, R-6), (A1-4, X14, Y2, R-1), (A1 -4, X14, Y2, R-2), (A1-4, X14, Y2, R-3), (A1-4, X14, Y2, R-4), (A1-4, X14, Y2, R -5), (A1-4, X14, Y2, R-6),
(A1-4, X15, Y1, R-1), (A1-4, X15, Y1, R-2), (A1-4, X15, Y1, R-3), (A1-4, X15, Y1 , R-4), (A1-4, X15, Y1, R-5), (A1-4, X15, Y1, R-6), (A1-4, X15, Y2, R-1), (A1 -4, X15, Y2, R-2), (A1-4, X15, Y2, R-3), (A1-4, X15, Y2, R-4), (A1-4, X15, Y2, R -5), (A1-4, X15, Y2, R-6),
(A1-4, X16, Y1, R-1), (A1-4, X16, Y1, R-2), (A1-4, X16, Y1, R-3), (A1-4, X16, Y1 , R-4), (A1-4, X16, Y1, R-5), (A1-4, X16, Y1, R-6), (A1-4, X16, Y2, R-1), (A1 -4, X16, Y2, R-2), (A1-4, X16, Y2, R-3), (A1-4, X16, Y2, R-4), (A1-4, X16, Y2, R -5), (A1-4, X16, Y2, R-6),
(A1-4, X17, Y1, R-1), (A1-4, X17, Y1, R-2), (A1-4, X17, Y1, R-3), (A1-4, X17, Y1 , R-4), (A1-4, X17, Y1, R-5), (A1-4, X17, Y1, R-6), (A1-4, X17, Y2, R-1), (A1 -4, X17, Y2, R-2), (A1-4, X17, Y2, R-3), (A1-4, X17, Y2, R-4), (A1-4, X17, Y2, R -5), (A1-4, X17, Y2, R-6),
(A1-4, X18, Y1, R-1), (A1-4, X18, Y1, R-2), (A1-4, X18, Y1, R-3), (A1-4, X18, Y1 , R-4), (A1-4, X18, Y1, R-5), (A1-4, X18, Y1, R-6), (A1-4, X18, Y2, R-1), (A1 -4, X18, Y2, R-2), (A1-4, X18, Y2, R-3), (A1-4, X18, Y2, R-4), (A1-4, X18, Y2, R -5), (A1-4, X18, Y2, R-6).

Since compound (I) has high affinity for NMDA receptors, particularly NR1 / NR2B receptors and high receptor selectivity, it can be a pharmaceutical with reduced side effects. It also has advantages such as high stability, high oral absorption, good BA, low clearance, high brain migration, long half-life, and high non-protein binding rate.
Compound (I) is a prophylactic / therapeutic agent for various central diseases (eg, stroke, cerebral infarction, brain trauma, chronic neurodegenerative disease) caused by drugs, particularly NMDA receptors, especially NR1 / NR2B receptors, or cancer As an analgesic for pain and the like, it can be administered orally or parenterally to animals including humans. Examples of the dosage form include granules, tablets, capsules, injections and the like. In formulation, various additives such as excipients, disintegrants, binders, lubricants, stabilizers, colorants, and coating agents can be used as desired. The dose varies depending on the age, weight, symptom and administration method of the subject and is not particularly limited, but is usually about 1 mg to about 5000 mg per day for an adult and about 0 for parenteral administration. .1 mg to about 1000 mg.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited at all by these Examples. Melting points listed in the text are uncorrected values. ¹ H-NMR was measured in a deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-d ₆ ) solvent using tetramethylsilane as an internal standard. The δ value is expressed in ppm, and the coupling constant (J) is expressed in Hz. In the data, s is single line, d is double line, t is triple line, q is quadruple line, quint is quintet line, m is multi-line, br is wide line, brs is wide single line, brt is wide Means a triple line.
Each abbreviation has the meaning shown below.
Boc: tert-butoxycarbonyl Et: ethyl THF: tetrahydrofuran LDA: lithium diisopropylamide DIBAL: diisobutylaluminum hydride DMSO: dimethyl sulfoxide Bn: benzyl DMF: N, N-dimethylformamide HOBt: 1-hydroxybenzotriazole DMAP: 4-dimethyl Aminopyridine EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

ａ）化合物2の合成
窒素雰囲気下、P. J. GilliganらJ. Med. Chem., 37, 364 (1994)に記載の方法により調製したエステル1（5.15 g, 20.0 mmol)をＴＨＦ（80 ml)に溶解し、ドライアイス−アセトン浴で-78℃に冷却した。ＬＤＡ（2.0Ｍヘプタン/ＴＨＦ/ベンゼン溶液, 11 ml, 22.0 mmol）を滴下後、-70℃以下で1時間撹拌した。4-フルオロベンジルブロミド（3.97 g，21.0 mmol)の20mlＴＨＦ溶液を滴下し-70℃以下で1時間、室温で16時間撹拌した。氷水中に反応液を注ぎ、酢酸エチルで抽出した。有機層を水、10%クエン酸水溶液、水、飽和重曹水、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 2（7.17 g, 収率98%)を淡黄色油状物として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.19 (t, J = 7.3Hz, 3H), 1.35-1.45 (m, 2H), 1.44 (s, 9H), 2.03-2.12 (m, 2H), 2.75-2.85 (m, 2H), 2.79 (s, 2H), 3.87-3.98 (m, 2H), 4.10 (q, J = 7.3Hz, 2H), 6.90-7.04 (m, 4H).
ｂ）化合物3の合成
窒素雰囲気下、化合物 2（3.14 g, 8.59 mmol)を塩化メチレン（100 ml)に溶解し、ドライアイス−アセトン浴で-78℃に冷却した。-70℃以下でＤＩＢＡＬ（1.0 Ｍトルエン溶液, 25.8 ml, 25.8 mmol）を滴下し、-70℃以下で1時間撹拌した。メタノール10 mlを加えた後、ジエチルエーテル−飽和酒石酸ナトリウムカリウム水溶液の混液中に反応液を注ぎ、室温で16時間撹拌した。ジエチルエーテルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 3（1.66 g, 収率60%)を白色固体として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.30 (t, J = 4.6Hz, 1H), 1.38-1.50 (m, 4H), 1.46 (s, 9H), 2.70 (s, 2H), 3.33-3.42 (m, 4H), 3.45-3.58 (m, 2H), 6.97 (t, J = 8.6Hz, 2H), 7.14 (dd, J = 8.6, 5.3Hz, 2H).
ｃ）化合物4の合成
化合物 3（0.22 g, 0.68 mmol)を塩化メチレン（8 ml)に溶解し、トリエチルアミン（0.14 g, 1.36 mmol)、三酸化硫黄ピリジン錯体（0.22 g, 1.36 mmol)、ＤＭＳＯ（0.53 g, 6.8 mmol)を加え、室温で48時間撹拌した。溶媒を減圧留去し、残渣に水を加えジエチルエーテルで抽出した。有機層を１ mol/L塩酸、水、飽和重曹水、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 4（0.09 g, 収率41%)を無色油状物として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.44 (s, 9H), 1.45-1.57 (m, 2H), 1.88-1.97 (m, 2H), 2.76 (s, 2H), 2.78-2.93 (m, 2H), 3.83-3.94 (m, 2H), 6.92-7.04 (m, 4H), 9.56 (s, 1H).
ｄ）化合物5の合成
化合物 4（0.17 g, 0.53 mmol)、エチレングリコール(5 ml)、ヒドラジン一水和物（0.53 g, 10.6 mmol)を混合し160℃で4時間撹拌した。室温まで放冷した後、水酸化ナトリウム（0.47 g, 11.7 mmol)を加え180℃で2時間撹拌した。室温まで放冷した後、水、１ mol/L塩酸を加え塩化メチレンで抽出した。無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン−メタノール）により精製した。化合物 5（0.05 g, 収率46%)を淡黄色油状物として得た。
^１H-NMR（CDCl₃ / TMS）δppm：0.89 (s, 3H), 1.20-1.32 (m, 2H), 1.37-1.50 (m, 2H), 1.63 (br, 1H), 2.54 (s, 2H), 2.74-2.94 (m, 4H), 6.95 (t, J = 8.6Hz, 2H), 7.04-7.10 (m, 2H).Reference Example 1 Synthesis of Compound 5

a) Synthesis of Compound 2 Ester 1 (5.15 g, 20.0 mmol) prepared by the method described in PJ Gilligan et al., J. Med. Chem., 37 , 364 (1994) was dissolved in THF (80 ml) under a nitrogen atmosphere. And cooled to -78 ° C in a dry ice-acetone bath. After dropwise addition of LDA (2.0 M heptane / THF / benzene solution, 11 ml, 22.0 mmol), the mixture was stirred at −70 ° C. or lower for 1 hour. A solution of 4-fluorobenzyl bromide (3.97 g, 21.0 mmol) in 20 ml THF was added dropwise, and the mixture was stirred at -70 ° C or lower for 1 hour and at room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 2 (7.17 g, yield 98%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.19 (t, J = 7.3 Hz, 3H), 1.35-1.45 (m, 2H), 1.44 (s, 9H), 2.03-2.12 (m, 2H), 2.75 -2.85 (m, 2H), 2.79 (s, 2H), 3.87-3.98 (m, 2H), 4.10 (q, J = 7.3Hz, 2H), 6.90-7.04 (m, 4H).
b) Synthesis of Compound 3 Compound 2 (3.14 g, 8.59 mmol) was dissolved in methylene chloride (100 ml) under a nitrogen atmosphere and cooled to −78 ° C. in a dry ice-acetone bath. DIBAL (1.0 M toluene solution, 25.8 ml, 25.8 mmol) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −70 ° C. or lower for 1 hour. After adding 10 ml of methanol, the reaction solution was poured into a mixed solution of diethyl ether-saturated sodium potassium tartrate aqueous solution and stirred at room temperature for 16 hours. After extraction with diethyl ether, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 3 (1.66 g, yield 60%) as a white solid.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.30 (t, J = 4.6 Hz, 1H), 1.38-1.50 (m, 4H), 1.46 (s, 9H), 2.70 (s, 2H), 3.33-3.42 (m, 4H), 3.45-3.58 (m, 2H), 6.97 (t, J = 8.6Hz, 2H), 7.14 (dd, J = 8.6, 5.3Hz, 2H).
c) Synthesis of Compound 4 Compound 3 (0.22 g, 0.68 mmol) was dissolved in methylene chloride (8 ml), triethylamine (0.14 g, 1.36 mmol), sulfur trioxide pyridine complex (0.22 g, 1.36 mmol), DMSO ( 0.53 g, 6.8 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 mol / L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 4 (0.09 g, yield 41%) as a colorless oil.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.44 (s, 9H), 1.45-1.57 (m, 2H), 1.88-1.97 (m, 2H), 2.76 (s, 2H), 2.78-2.93 (m, 2H), 3.83-3.94 (m, 2H), 6.92-7.04 (m, 4H), 9.56 (s, 1H).
d) Synthesis of Compound 5 Compound 4 (0.17 g, 0.53 mmol), ethylene glycol (5 ml), and hydrazine monohydrate (0.53 g, 10.6 mmol) were mixed and stirred at 160 ° C. for 4 hours. After allowing to cool to room temperature, sodium hydroxide (0.47 g, 11.7 mmol) was added and stirred at 180 ° C. for 2 hours. After allowing to cool to room temperature, water and 1 mol / L hydrochloric acid were added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride-methanol). Compound 5 (0.05 g, yield 46%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 0.89 (s, 3H), 1.20-1.32 (m, 2H), 1.37-1.50 (m, 2H), 1.63 (br, 1H), 2.54 (s, 2H) , 2.74-2.94 (m, 4H), 6.95 (t, J = 8.6Hz, 2H), 7.04-7.10 (m, 2H).

ａ）化合物7の合成
窒素雰囲気下、4-クロロベンジルトリフェニルホスホニウムクロリド（12.70 g, 30.0 mmol)をＴＨＦ（80 ml)に懸濁し、氷浴で冷却した。1.58Ｍ n-ブチルリチウム−ヘキサン溶液（20.9 ml, 33.0 mmol）を滴下後、化合物 6（5.98 g，30.0 mmol)の20mlＴＨＦ溶液を加え、室温で16時間撹拌した。水を加え、ジエチルエーテルで抽出し、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 7（7.56 g, 収率82%)を淡黄色油状物として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.48 (s, 9H), 2.32 (t, J = 5.6Hz, 2H), 2.42 (t, J = 5.6Hz, 2H), 3.40 (t, J = 5.6Hz, 2H), 3.50 (t, J = 5.6Hz, 2H), 6.30 (s, 1H), 7.11 (d, J = 8.6Hz, 2H), 7.28 (d, J = 8.6Hz, 2H).
ｂ）化合物8の合成
化合物 7（7.56 g, 24.6 mmol)をトルエン（100 ml)に溶解し、クロロ（トリフェニルホスフィン）ロジウム（I）（0.52 g, 0.56 mmol）を加え、水素ガス4気圧下、70〜80℃で48時間撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 8（7.02 g, 収率92%)を淡黄色固体として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.05-1.17 (m, 2H), 1.45 (s, 9H), 1.55-1.65 (m, 3H), 2.50 (d, J = 6.9Hz, 2H), 2.55-2.70 (m, 2H), 4.02-4.15 (m, 2H), 7.06 (d, J = 8.6Hz, 2H), 7.24 (d, J = 8.6Hz, 2H).
ｃ）化合物9の合成
化合物 8（7.02 g, 22.7 mmol)に10％塩酸−メタノール（30 ml)を加え室温で1時間、50℃で0.5時間撹拌した。溶媒を減圧留去し、残渣をエタノール−ジエチルエーテルより再結晶して、化合物 9（5.34 g, 収率96%)を白色結晶として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：1.30-1.50 (m, 2H), 1.66-1.86 (m, 3H), 2.52 (d, J = 6.9Hz, 2H), 2.76 (dd, J = 10.2, 2.3Hz, 2H), 3.19 (d, J = 10.2Hz, 2H), 7.21 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.3Hz, 2H), 8.96 (brs, 2H).Reference Example 2 Synthesis of Compound 9

a) Synthesis of Compound 7 Under a nitrogen atmosphere, 4-chlorobenzyltriphenylphosphonium chloride (12.70 g, 30.0 mmol) was suspended in THF (80 ml) and cooled in an ice bath. A 1.58M n-butyllithium-hexane solution (20.9 ml, 33.0 mmol) was added dropwise, and then a 20 ml THF solution of compound 6 (5.98 g, 30.0 mmol) was added, followed by stirring at room temperature for 16 hours. Water was added, the mixture was extracted with diethyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 7 (7.56 g, yield 82%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.48 (s, 9H), 2.32 (t, J = 5.6Hz, 2H), 2.42 (t, J = 5.6Hz, 2H), 3.40 (t, J = 5.6 Hz, 2H), 3.50 (t, J = 5.6Hz, 2H), 6.30 (s, 1H), 7.11 (d, J = 8.6Hz, 2H), 7.28 (d, J = 8.6Hz, 2H).
b) Synthesis of Compound 8 Compound 7 (7.56 g, 24.6 mmol) was dissolved in toluene (100 ml), chloro (triphenylphosphine) rhodium (I) (0.52 g, 0.56 mmol) was added, and hydrogen gas was at 4 atm. , And stirred at 70-80 ° C. for 48 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 8 (7.02 g, yield 92%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.05-1.17 (m, 2H), 1.45 (s, 9H), 1.55-1.65 (m, 3H), 2.50 (d, J = 6.9Hz, 2H), 2.55 -2.70 (m, 2H), 4.02-4.15 (m, 2H), 7.06 (d, J = 8.6Hz, 2H), 7.24 (d, J = 8.6Hz, 2H).
c) Synthesis of Compound 9 10% hydrochloric acid-methanol (30 ml) was added to Compound 8 (7.02 g, 22.7 mmol), and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-diethyl ether to obtain Compound 9 (5.34 g, yield 96%) as white crystals.
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.30-1.50 (m, 2H), 1.66-1.86 (m, 3H), 2.52 (d, J = 6.9 Hz, 2H), 2.76 (dd, J = 10.2, 2.3Hz, 2H), 3.19 (d, J = 10.2Hz, 2H), 7.21 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.3Hz, 2H), 8.96 (brs, 2H) .

ａ）化合物11の合成
化合物 10（4.07 g，20.0 mmol)をアセトン（50 ml)に溶解し、塩化ベンジル（2.53 g, 20.0 mmol）を加え室温で18時間撹拌した後、48時間還流した。室温まで放冷した後、ジエチルエーテルを加え析出した固体を濾取した。乾燥後、化合物 11（4.73 g, 収率72%)を淡黄色固体として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：4.28 (s, 2H), 5.79 (s, 2H), 7.35-7.55 (m, 9H), 8.02 (d, J = 6.6Hz, 2H), 9.10 (d, J = 6.6Hz, 2H).
ｂ）化合物12の合成
化合物 11（4.73 g，14.3 mmol)をエタノール（50 ml)に溶解し、氷浴で冷却した。水素化ホウ素ナトリウム（2.17 g, 57.4 mmol）を少量ずつ加え、室温で3時間撹拌した。溶媒を減圧留去し、残渣に２ mol/L塩酸を加え酸性とした後、重曹でアルカリ性に戻し酢酸エチルで抽出した。水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 12（3.40 g, 収率80%)を黄色油状物として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.98-2.08 (m, 2H), 2.52 (t, J = 5.6Hz, 2H), 2.94-3.03 (m, 2H), 3.20-3.29 (m, 2H), 3.56 (s, 2H), 5.32-5.38 (m, 1H), 7.09 (d, J = 8.6Hz, 2H), 7.20-7.38 (m, 7H).
ｃ）化合物13の合成
化合物 12（3.40 g, 11.4 mmol)を1,2-ジクロロエタン（50 ml)に溶解し、氷浴で冷却した。クロロ炭酸（1-クロロエチル）（1.96 g, 13.7 mmol）を加え2時間還流した。溶媒を減圧留去し、残渣をメタノール（50 ml)に溶解して16時間還流した。溶媒を減圧留去し、残渣をメタノール−ジエチルエーテルより再結晶して、化合物 13（2.33 g, 収率84%)を白色結晶として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：2.08-2.18 (m, 2H), 3.09 (t, J = 5.9Hz, 2H), 3.33-3.36 (m, 2H), 3.49-3.53 (m, 2H), 5.45-5.49 (m, 1H), 7.23 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.6Hz, 2H), 9.20 (brs, 2H).Reference Example 3 Synthesis of Compound 13

a) Synthesis of Compound 11 Compound 10 (4.07 g, 20.0 mmol) was dissolved in acetone (50 ml), benzyl chloride (2.53 g, 20.0 mmol) was added, and the mixture was stirred at room temperature for 18 hours and then refluxed for 48 hours. After cooling to room temperature, diethyl ether was added and the precipitated solid was collected by filtration. After drying, compound 11 (4.73 g, yield 72%) was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 4.28 (s, 2H), 5.79 (s, 2H), 7.35-7.55 (m, 9H), 8.02 (d, J = 6.6 Hz, 2H), 9.10 (d, J = 6.6Hz, 2H).
b) Synthesis of Compound 12 Compound 11 (4.73 g, 14.3 mmol) was dissolved in ethanol (50 ml) and cooled in an ice bath. Sodium borohydride (2.17 g, 57.4 mmol) was added in small portions and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was acidified with 2 mol / L hydrochloric acid, made alkaline with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 12 (3.40 g, yield 80%) as a yellow oil.
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.98-2.08 (m, 2H), 2.52 (t, J = 5.6Hz, 2H), 2.94-3.03 (m, 2H), 3.20-3.29 (m, 2H) , 3.56 (s, 2H), 5.32-5.38 (m, 1H), 7.09 (d, J = 8.6Hz, 2H), 7.20-7.38 (m, 7H).
c) Synthesis of Compound 13 Compound 12 (3.40 g, 11.4 mmol) was dissolved in 1,2-dichloroethane (50 ml) and cooled in an ice bath. Chlorocarbonic acid (1-chloroethyl) (1.96 g, 13.7 mmol) was added and refluxed for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (50 ml) and refluxed for 16 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol-diethyl ether to obtain Compound 13 (2.33 g, yield 84%) as white crystals.
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 2.08-2.18 (m, 2H), 3.09 (t, J = 5.9Hz, 2H), 3.33-3.36 (m, 2H), 3.49-3.53 (m, 2H), 5.45-5.49 (m, 1H), 7.23 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.6Hz, 2H), 9.20 (brs, 2H).

ａ）化合物15の合成
カルボン酸 14（2.48 g, 17.8 mmol)にＤＭＦ（100 ml）、4-アミノ酪酸エチル（3.29 g, 19.6 mmol)、ＨＯＢｔ一水和物（3.00 g, 19.6 mmol)、トリエチルアミン（4.33 g, 19.6 mmol)、ＤＭＡＰ（0.22 g， 1.8 mmol)、ＥＤＣ（3.76 g, 19.6 mmol)を加え、室温で24時間撹拌した。ＤＭＦを減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン−メタノール）により精製し、酢酸エチル−ヘキサンより再結晶を行ない、化合物 16（3.41 g, 収率76%)を白色固体として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.26 (t, J = 7.3Hz, 3H), 1.95 (q, J = 6.6Hz, 2H), 2.46 (t, J = 6.6Hz, 2H), 3.47 (dt, J = 5.3, 6.6Hz, 2H), 4.15 (q, J = 7.3Hz, 2H), 6.58 (d, J = 9.6Hz, 1H), 6.89 (t, J = 5.3Hz, 1H), 7.84 (dd, J = 9.6, 2.6Hz, 1H), 8.09 (d, J = 2.6Hz, 1H), 12.56 (brs, 1H).
ｂ）化合物16の合成
化合物 15（3.41 g, 13.5 mmol)にエタノール（50 ml）、１ mol/L水酸化ナトリウム水溶液（30 ml, 30.0 mmol)を加え、室温で18時間撹拌した。１ mol/L塩酸（32 ml, 32.0 mmol)を加えた後、溶媒を減圧濃縮し、氷浴で冷却して析出した固体を濾取した。水、酢酸エチルで洗浄後、乾燥し、化合物 16（2.71 g, 収率89%)を白色固体として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：1.70 (quint, J = 7.3Hz, 2H), 2.25 (t, J = 7.3Hz, 2H), 3.21 (dt, J = 5.3, 7.3Hz, 2H), 6.33 (d, J = 9.6Hz, 1H), 7.85 (dd, J = 9.6, 2.6Hz, 1H), 7.97 (d, J = 2.6Hz, 1H), 8.22 (t, J = 5.3Hz, 1H), 12.00 (brs, 2H).Reference Example 4 Synthesis of Compound 16

a) Synthesis of Compound 15 Carboxylic acid 14 (2.48 g, 17.8 mmol) to DMF (100 ml), ethyl 4-aminobutyrate (3.29 g, 19.6 mmol), HOBt monohydrate (3.00 g, 19.6 mmol), triethylamine (4.33 g, 19.6 mmol), DMAP (0.22 g, 1.8 mmol), EDC (3.76 g, 19.6 mmol) were added, and the mixture was stirred at room temperature for 24 hours. DMF was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride-methanol) and recrystallized from ethyl acetate-hexane to give compound 16 (3.41 g, yield 76%) as a white solid Got as.
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.26 (t, J = 7.3Hz, 3H), 1.95 (q, J = 6.6Hz, 2H), 2.46 (t, J = 6.6Hz, 2H), 3.47 ( dt, J = 5.3, 6.6Hz, 2H), 4.15 (q, J = 7.3Hz, 2H), 6.58 (d, J = 9.6Hz, 1H), 6.89 (t, J = 5.3Hz, 1H), 7.84 ( dd, J = 9.6, 2.6Hz, 1H), 8.09 (d, J = 2.6Hz, 1H), 12.56 (brs, 1H).
b) Synthesis of Compound 16 Ethanol (50 ml) and 1 mol / L aqueous sodium hydroxide solution (30 ml, 30.0 mmol) were added to Compound 15 (3.41 g, 13.5 mmol) and stirred at room temperature for 18 hours. After adding 1 mol / L hydrochloric acid (32 ml, 32.0 mmol), the solvent was concentrated under reduced pressure, cooled in an ice bath, and the precipitated solid was collected by filtration. The extract was washed with water and ethyl acetate and dried to give Compound 16 (2.71 g, yield 89%) as a white solid.
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 1.70 (quint, J = 7.3Hz, 2H), 2.25 (t, J = 7.3Hz, 2H), 3.21 (dt, J = 5.3, 7.3Hz, 2H ), 6.33 (d, J = 9.6Hz, 1H), 7.85 (dd, J = 9.6, 2.6Hz, 1H), 7.97 (d, J = 2.6Hz, 1H), 8.22 (t, J = 5.3Hz, 1H ), 12.00 (brs, 2H).

ａ）化合物18の合成
化合物 17（0.81 g, 4.05 mmol)を塩化メチレン（10 ml）に溶解し、トリエチルアミン（0.61 g, 0.60 mmol)を加えた。氷浴で冷却し、こはく酸モノエチルクロライド（0.73 g, 4.44 mmol)の塩化メチレン（5 ml）溶液を滴下し、0℃で1時間撹拌した。溶媒を減圧留去し、残渣に水を加え酢酸エチルで抽出した。有機層を10％クエン酸水溶液、水、飽和重曹水、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 18（1.19 g, 収率90%)を橙色固体として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.27 (t, J = 7.3Hz, 3H), 2.62-2.79 (m, 4H), 4.17 (q, J = 7.3Hz, 2H), 5.34 (s, 2H), 6.78 (d, J = 8.9Hz, 1H), 7.26-7.46 (m, 5H), 7.61 (brs, 1H), 7.90 (dd, J = 8.9, 2.6Hz, 1H), 8.16 (d, J = 2.6Hz, 1H).
ｂ）化合物19の合成
化合物 18（0.45 g, 1.37 mmol)をエタノール（50 ml）に溶解し、10％パラジウム−炭素（80 mg)を加えた。系内を水素ガスで置換し、室温で18時間撹拌した。セライトを用いて反応液を濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン−メタノール）により精製し、化合物 19（0.33 g, 収率100%)を白色固体として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.27 (t, J = 7.3Hz, 3H), 2.63-2.77 (m, 4H), 4.16 (q, J = 7.3Hz, 2H), 6.51 (d, J = 9.6Hz, 1H), 7.40 (dd, J = 9.6, 2.3Hz, 1H), 7.88 (s, 1H), 8.19 (d, J = 2.3Hz, 1H), 12.32 (br, 1H).
ｃ）化合物20の合成
化合物 19（0.33 g, 1.39 mmol)にメタノール（15 ml）、１ mol/L水酸化ナトリウム水溶液（4.2 ml, 4.2 mmol)を加え、室温で5時間撹拌した。１ mol/L塩酸（4.3 ml, 4.3 mmol)を加えた後、溶媒を減圧濃縮し、氷浴で冷却して析出した固体を濾取した。水、酢酸エチルで洗浄後、乾燥し、化合物 16（0.24 g, 収率89%)を白色固体として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：2.45-2.55 (m, 4H), 6.34 (d, J = 9.6Hz, 1H), 7.41 (dd, J = 9.6, 2.6Hz, 1H), 7.83 (d, J = 2.6Hz, 1H), 9.71 (s, 1H), 11.71 (brs, 1H).Reference Example 5 Synthesis of Compound 20

a) Synthesis of Compound 18 Compound 17 (0.81 g, 4.05 mmol) was dissolved in methylene chloride (10 ml), and triethylamine (0.61 g, 0.60 mmol) was added. The mixture was cooled in an ice bath, a solution of succinic acid monoethyl chloride (0.73 g, 4.44 mmol) in methylene chloride (5 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 18 (1.19 g, yield 90%) as an orange solid.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.27 (t, J = 7.3Hz, 3H), 2.62-2.79 (m, 4H), 4.17 (q, J = 7.3Hz, 2H), 5.34 (s, 2H ), 6.78 (d, J = 8.9Hz, 1H), 7.26-7.46 (m, 5H), 7.61 (brs, 1H), 7.90 (dd, J = 8.9, 2.6Hz, 1H), 8.16 (d, J = 2.6Hz, 1H).
b) Synthesis of Compound 19 Compound 18 (0.45 g, 1.37 mmol) was dissolved in ethanol (50 ml), and 10% palladium-carbon (80 mg) was added. The system was replaced with hydrogen gas and stirred at room temperature for 18 hours. The reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol) to obtain Compound 19 (0.33 g, yield 100%) as a white solid.
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.27 (t, J = 7.3Hz, 3H), 2.63-2.77 (m, 4H), 4.16 (q, J = 7.3Hz, 2H), 6.51 (d, J = 9.6Hz, 1H), 7.40 (dd, J = 9.6, 2.3Hz, 1H), 7.88 (s, 1H), 8.19 (d, J = 2.3Hz, 1H), 12.32 (br, 1H).
c) Synthesis of Compound 20 Methanol (15 ml) and 1 mol / L aqueous sodium hydroxide solution (4.2 ml, 4.2 mmol) were added to Compound 19 (0.33 g, 1.39 mmol) and stirred at room temperature for 5 hours. After adding 1 mol / L hydrochloric acid (4.3 ml, 4.3 mmol), the solvent was concentrated under reduced pressure, cooled in an ice bath, and the precipitated solid was collected by filtration. The extract was washed with water and ethyl acetate and dried to give Compound 16 (0.24 g, yield 89%) as a white solid.
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.45-2.55 (m, 4H), 6.34 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 9.6, 2.6 Hz, 1H), 7.83 (d, J = 2.6Hz, 1H), 9.71 (s, 1H), 11.71 (brs, 1H).

参考例３で得られたアミン13（100 mg, 0.41 mmol)にＤＭＦ（10 ml）、参考例４で得られたカルボン酸 16（100 mg, 0.45 mmol)、ＨＯＢｔ一水和物（68 mg, 0.45 mmol)、トリエチルアミン（99 mg, 0.98 mmol)、ＤＭＡＰ（5 mg， 0.04 mmol)、ＥＤＣ（86 mg, 0.45 mmol)を加え、室温で6時間撹拌した。ＤＭＦを減圧留去し、残渣に飽和重曹水を加え酢酸エチルで抽出した。有機層を水、10％クエン酸水溶液、水、飽和重曹水、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣を酢酸エチル−ヘキサンより再結晶し、化合物（Ｉ−９５）（117 mg, 収率69%)を白色固体として得た。
mp 200 201℃
^１H-NMR（DMSO-d₆ / TMS）δppm：0.84-1.15 (m, 2H), 1.48-1.58 (m, 2H), 1.62-1.80 (m, 3H), 2.31 (t, J = 7.3Hz, 2H), 2.37-2.47 (m, 1H), 2.82-2.93 (m, 1H), 3.20 (q, J = 6.6Hz, 2H), 3.74-3.84 (m, 1H), 4.28-4.38 (m, 1H), 6.33 (d, J = 9.6Hz, 1H), 7.19 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 7.84 (dd, J = 9.6, 2.6Hz, 1H), 7.96 (d, J = 2.6Hz, 1H), 8.19 (t, J = 6.6Hz, 1H), 11.92 (brs, 1H).Synthesis of Compound (I-95)

The amine 13 (100 mg, 0.41 mmol) obtained in Reference Example 3 was added to DMF (10 ml), the carboxylic acid 16 (100 mg, 0.45 mmol) obtained in Reference Example 4, and HOBt monohydrate (68 mg, 0.45 mmol), triethylamine (99 mg, 0.98 mmol), DMAP (5 mg, 0.04 mmol), EDC (86 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature for 6 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give compound (I-95) (117 mg, yield 69%) as a white solid.
mp 200 201 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 0.84-1.15 (m, 2H), 1.48-1.58 (m, 2H), 1.62-1.80 (m, 3H), 2.31 (t, J = 7.3 Hz, 2H), 2.37-2.47 (m, 1H), 2.82-2.93 (m, 1H), 3.20 (q, J = 6.6Hz, 2H), 3.74-3.84 (m, 1H), 4.28-4.38 (m, 1H) , 6.33 (d, J = 9.6Hz, 1H), 7.19 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 7.84 (dd, J = 9.6, 2.6Hz, 1H) , 7.96 (d, J = 2.6Hz, 1H), 8.19 (t, J = 6.6Hz, 1H), 11.92 (brs, 1H).

参考例３で得られたアミン13（110 mg, 0.45 mmol)にＤＭＦ（10 ml）、参考例５で得られたカルボン酸 20（103 mg, 0.49 mmol)、ＨＯＢｔ一水和物（75 mg, 0.49 mmol)、トリエチルアミン（109 mg, 1.08 mmol)、ＤＭＡＰ（5 mg， 0.04 mmol)、ＥＤＣ（94 mg, 0.49 mmol)を加え、室温で16時間撹拌した。ＤＭＦを減圧留去し、残渣に飽和重曹水を加え酢酸エチルで抽出した。有機層を水、10％クエン酸水溶液、水、飽和重曹水、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をメタノール−水より再結晶し、化合物（Ｉ−１０１）（82 mg, 収率46%)を白色固体として得た。
mp 221 222℃
^１H-NMR（DMSO-d₆ / TMS）δppm：0.85-1.18 (m, 2H), 1.49-1.62 (m, 2H), 1.65-1.80 (m, 1H), 2.38-2.60 (m, 7H), 2.91 (t, J = 12.2Hz, 1H), 3.80-3.90 (m, 1H), 4.27-4.37 (m, 1H), 6.34 (d, J = 9.6Hz, 1H), 7.20 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 7.41 (dd, J = 9.6, 2.6Hz, 1H), 7.84 (d, J = 2.6Hz, 1H), 9.68 (s, 1H), 11.27 (br, 1H).Synthesis of Compound (I-101)

To amine 13 (110 mg, 0.45 mmol) obtained in Reference Example 3, DMF (10 ml), carboxylic acid 20 (103 mg, 0.49 mmol) obtained in Reference Example 5, HOBt monohydrate (75 mg, 0.49 mmol), triethylamine (109 mg, 1.08 mmol), DMAP (5 mg, 0.04 mmol), EDC (94 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for 16 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from methanol-water to obtain compound (I-101) (82 mg, yield 46%) as a white solid.
mp 221 222 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 0.85-1.18 (m, 2H), 1.49-1.62 (m, 2H), 1.65-1.80 (m, 1H), 2.38-2.60 (m, 7H), 2.91 (t, J = 12.2Hz, 1H), 3.80-3.90 (m, 1H), 4.27-4.37 (m, 1H), 6.34 (d, J = 9.6Hz, 1H), 7.20 (d, J = 8.2Hz , 2H), 7.33 (d, J = 8.2Hz, 2H), 7.41 (dd, J = 9.6, 2.6Hz, 1H), 7.84 (d, J = 2.6Hz, 1H), 9.68 (s, 1H), 11.27 (br, 1H).

ａ）化合物22の合成
化合物21（3.14 g, 13.6 mmol)をアセトニトリル（100 ml)に溶解し、Ｎ-Ｂｏｃ-2-クロロエチルアミン（2.70 g, 15.0 mmol)、炭酸カリウム（5.66 g, 41.0 mmol)、ヨウ化カリウム（0.23 g, 1.4 mmol)を加え3日間還流した。溶媒を減圧留去し、残渣に水を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、さらに酢酸エチル−ヘキサンより再結晶して、化合物22（1.79 g， 収率39%)を淡黄色固体として得た。
^１H-NMR（CDCl₃）δppm：1.45 (s, 9H), 2.48-2.60 (m, 4H), 2.71 (t, J = 5.6Hz, 2H), 3.13-3.18 (m, 2H), 3.26-3.36 (m, 2H), 5.03 (br, 1H), 6.06 (brs, 1H), 7.29 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H).
ｂ）化合物23の合成
化合物22（2.50 g, 7.42 mmol)をメタノール（10 ml)に溶解し、10％塩酸−メタノール（20 ml)を加え、50℃で20時間撹拌した。溶媒を減圧濃縮し、酢酸エチルを加えて結晶化し結晶を濾取して、化合物23（2.29 g, 収率100%)を白色結晶として得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：2.78-2.89 (m, 2H), 3.38-3.47 (m, 6H), 3.72-4.04 (m, 2H), 6.24 (s, 1H), 7.45 (d, J = 8.6Hz, 2H), 7.53 (d, J = 8.6Hz, 2H), 8.51 (br, 3H), 11.37 (br, 1H).
ｃ）化合物（Ｉ−６）の合成
化合物23（150 mg, 0.45 mmol)にＤＭＦ（10 ml）、6-ヒドロキシニコチン酸（74 mg, 0.53 mmol)、ＨＯＢｔ一水和物（89 mg, 0.58 mmol)、トリエチルアミン（175 mg, 1.73 mmol)、ＤＭＡＰ（6 mg， 0.05 mmol)、ＥＤＣ（111 mg, 0.58 mmol)を加え、室温で22時間撹拌した。ＤＭＦを減圧留去し、残渣に飽和重曹水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン−メタノール）により精製し、ヘキサンを加えて結晶化して結晶を濾取し、化合物（Ｉ−６）（121 mg, 収率70%)をベージュ色固体として得た。
mp 221 224℃
^１H-NMR（DMSO-d₆ / TMS）δppm：2.43-2.46 (m, 2H), 2.58 (t, J = 6.6Hz, 2H), 2.69 (t, J = 4.9Hz, 2H), 3.14-3.18 (m, 2H), 3.39 (q, J = 6.6Hz, 2H), 6.18-6.22 (m, 1H), 6.34 (d, J = 9.6Hz, 1H), 7.38 (d, J = 8.2Hz, 2H), 7.45 (d, J = 8.2Hz, 2H), 7.85 (dd, J = 9.6, 2.6Hz, 1H), 7.96-7.98 (m, 1H), 8.24 (brt, J = 6.6Hz, 1H), 11.93 (br, 1H).Synthesis of Compound (I-6)

a) Synthesis of Compound 22 Compound 21 (3.14 g, 13.6 mmol) was dissolved in acetonitrile (100 ml), N-Boc-2-chloroethylamine (2.70 g, 15.0 mmol), potassium carbonate (5.66 g, 41.0 mmol) Potassium iodide (0.23 g, 1.4 mmol) was added and refluxed for 3 days. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and further recrystallized from ethyl acetate-hexane to obtain Compound 22 (1.79 g, yield 39%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (s, 9H), 2.48-2.60 (m, 4H), 2.71 (t, J = 5.6 Hz, 2H), 3.13-3.18 (m, 2H), 3.26-3.36 (m, 2H), 5.03 (br, 1H), 6.06 (brs, 1H), 7.29 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H).
b) Synthesis of Compound 23 Compound 22 (2.50 g, 7.42 mmol) was dissolved in methanol (10 ml), 10% hydrochloric acid-methanol (20 ml) was added, and the mixture was stirred at 50 ° C. for 20 hours. The solvent was concentrated under reduced pressure, ethyl acetate was added to crystallize, and the crystals were collected by filtration to obtain Compound 23 (2.29 g, yield 100%) as white crystals.
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.78-2.89 (m, 2H), 3.38-3.47 (m, 6H), 3.72-4.04 (m, 2H), 6.24 (s, 1H), 7.45 ( d, J = 8.6Hz, 2H), 7.53 (d, J = 8.6Hz, 2H), 8.51 (br, 3H), 11.37 (br, 1H).
c) Synthesis of Compound (I-6) Compound 23 (150 mg, 0.45 mmol) was added to DMF (10 ml), 6-hydroxynicotinic acid (74 mg, 0.53 mmol), HOBt monohydrate (89 mg, 0.58 mmol). ), Triethylamine (175 mg, 1.73 mmol), DMAP (6 mg, 0.05 mmol) and EDC (111 mg, 0.58 mmol) were added, and the mixture was stirred at room temperature for 22 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol), crystallized by adding hexane, and the crystals were collected by filtration to give Compound (I-6) (121 mg, yield 70%) as beige Obtained as a solid.
mp 221 224 ℃
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.43-2.46 (m, 2H), 2.58 (t, J = 6.6Hz, 2H), 2.69 (t, J = 4.9Hz, 2H), 3.14-3.18 (m, 2H), 3.39 (q, J = 6.6Hz, 2H), 6.18-6.22 (m, 1H), 6.34 (d, J = 9.6Hz, 1H), 7.38 (d, J = 8.2Hz, 2H) , 7.45 (d, J = 8.2Hz, 2H), 7.85 (dd, J = 9.6, 2.6Hz, 1H), 7.96-7.98 (m, 1H), 8.24 (brt, J = 6.6Hz, 1H), 11.93 ( br, 1H).

実施例３で得られた化合物23（150 mg, 0.45 mmol)にＤＭＦ（20 ml）、4-イミダゾールカルボン酸（54 mg, 0.48 mmol)、ＨＯＢｔ一水和物（89 mg, 0.58 mmol)、トリエチルアミン（175 mg, 1.73 mmol)、ＤＭＡＰ（6 mg， 0.05 mmol)、ＥＤＣ（111 mg, 0.58 mmol)を加え、室温で22時間撹拌した。ＤＭＦを減圧留去し、残渣に飽和重曹水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン−メタノール）により精製し、ヘキサンを加えて結晶化して結晶を濾取し、化合物 （Ｉ−９）（56 mg, 収率35%)をベージュ色固体として得た。
mp 172 175℃
^１H-NMR（DMSO-d₆ / TMS）δppm：2.43-2.46 (m, 2H), 2.62 (t, J = 6.6Hz, 2H), 2.72(t, J = 5.3Hz, 2H), 3.16-3.21 (m, 2H), 3.43 (q, J = 6.6Hz, 2H), 6.13-6.18 (m, 1H), 7.34 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.2Hz, 2H), 7.51 (s, 1H), 7.58-7.65 (m, 2H), 12.49 (br, 1H).Synthesis of Compound (I-9)

Compound 23 (150 mg, 0.45 mmol) obtained in Example 3 was added to DMF (20 ml), 4-imidazolecarboxylic acid (54 mg, 0.48 mmol), HOBt monohydrate (89 mg, 0.58 mmol), triethylamine. (175 mg, 1.73 mmol), DMAP (6 mg, 0.05 mmol), EDC (111 mg, 0.58 mmol) were added, and the mixture was stirred at room temperature for 22 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol), crystallized by adding hexane, and the crystals were collected by filtration to give Compound (I-9) (56 mg, yield 35%) as beige Obtained as a solid.
mp 172 175 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.43-2.46 (m, 2H), 2.62 (t, J = 6.6Hz, 2H), 2.72 (t, J = 5.3Hz, 2H), 3.16-3.21 (m, 2H), 3.43 (q, J = 6.6Hz, 2H), 6.13-6.18 (m, 1H), 7.34 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.2Hz, 2H) , 7.51 (s, 1H), 7.58-7.65 (m, 2H), 12.49 (br, 1H).

ａ）化合物26の合成
化合物25（2.28 g, 8.28 mmol)をアセトニトリル（41 ml)に溶解し、Ｎ-(2-ブロモエチル)フタルイミド（3.16 g, 12.4 mmol)、炭酸カリウム（3.43 g, 24.8 mmol)、ヨウ化カリウム（0.69 g, 4.14 mmol)を加え22時間還流した。溶媒を減圧留去し、残渣に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、ヘキサンを加えて結晶化して結晶を濾取し、化合物26（3.25 g, 収率88%)を淡黄色固体として得た。
^１H-NMR（CDCl₃）δppm：1.13 (s, 1H), 1.43-1.53 (m, 2H), 1.58-1.70 (m, 2H), 2.35 (dt, J = 2.6, 11.5Hz, 2H), 2.64 (t, J = 6.6Hz, 2H), 2.70-2.80 (m, 2H), 2.72 (s, 2H), 3.82 (t, J = 6.6Hz, 2H), 7.14 (d, J = 8.6Hz, 2H), 7.21 (d, J = 8.6Hz, 2H), 7.71 (dd, J = 5.6, 3.0Hz, 2H), 7.84 (dd, J = 5.6, 3.0Hz, 2H).
ｂ）化合物27の合成
化合物26（3.25 g, 7.25 mmol)をエタノール（35 ml)に溶解し、ヒドラジン一水和物（0.73 g, 14.5 mmol)を加え24時間還流した。冷後、析出した結晶を濾去し、濾液を減圧濃縮して粗製の化合物27（2.35 g， 粗収率100%)を黄色油状物として得た。化合物 30は粗製物のまま次工程の反応に用いた。
ｃ）化合物（Ｉ−１５）の合成
アミン27（150 mg, 0.47 mmol)にＤＭＦ（10 ml）、6-ヒドロキシニコチン酸（72 mg, 0.52 mmol)、ＨＯＢｔ一水和物（86 mg, 0.56 mmol)、トリエチルアミン（57 mg, 0.56 mmol)、ＤＭＡＰ（6 mg， 0.05 mmol)、ＥＤＣ（107 mg, 0.56 mmol)を加え、室温で24時間撹拌した。ＤＭＦを減圧留去し、残渣に飽和重曹水を加え酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣をアルミナカラムクロマトグラフィー（酢酸エチル−メタノールから塩化メチレン−メタノール）により精製した。ヘキサンを加えて結晶化して結晶を濾取し、化合物（Ｉ−１５）（103 mg, 収率50%)を淡黄色固体として得た。
mp 98 101℃
^１H-NMR（DMSO-d₆ / TMS）δppm：1.31-1.36 (m, 2H), 1.44-1.52 (m, 2H), 2.24-2.32 (m, 2H), 2.39-2.50 (m, 2H), 2.51-2.53 (m, 2H), 2.68 (s, 2H), 3.23-3.31 (m, 2H), 4.19 (s, 1H), 6.33 (d, J = 9.6Hz, 1H), 7.24 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 7.83 (d, J = 9.6Hz, 1H), 7.95 (s, 1H), 8.14 (brt, J = 5.9Hz, 1H), 11.95 (br, 1H).Synthesis of Compound (I-15)

a) Synthesis of Compound 26 Compound 25 (2.28 g, 8.28 mmol) was dissolved in acetonitrile (41 ml), N- (2-bromoethyl) phthalimide (3.16 g, 12.4 mmol), potassium carbonate (3.43 g, 24.8 mmol) Potassium iodide (0.69 g, 4.14 mmol) was added and refluxed for 22 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), crystallized by adding hexane, and the crystals were collected by filtration to obtain Compound 26 (3.25 g, yield 88%) as a pale yellow solid. .
¹ H-NMR (CDCl ₃ ) δ ppm: 1.13 (s, 1H), 1.43-1.53 (m, 2H), 1.58-1.70 (m, 2H), 2.35 (dt, J = 2.6, 11.5Hz, 2H), 2.64 (t, J = 6.6Hz, 2H), 2.70-2.80 (m, 2H), 2.72 (s, 2H), 3.82 (t, J = 6.6Hz, 2H), 7.14 (d, J = 8.6Hz, 2H) , 7.21 (d, J = 8.6Hz, 2H), 7.71 (dd, J = 5.6, 3.0Hz, 2H), 7.84 (dd, J = 5.6, 3.0Hz, 2H).
b) Synthesis of Compound 27 Compound 26 (3.25 g, 7.25 mmol) was dissolved in ethanol (35 ml), hydrazine monohydrate (0.73 g, 14.5 mmol) was added, and the mixture was refluxed for 24 hours. After cooling, the precipitated crystals were removed by filtration, and the filtrate was concentrated under reduced pressure to give crude compound 27 (2.35 g, crude yield 100%) as a yellow oil. Compound 30 was used as a crude product in the next step.
c) Synthesis of Compound (I-15) Amine 27 (150 mg, 0.47 mmol) was added to DMF (10 ml), 6-hydroxynicotinic acid (72 mg, 0.52 mmol), HOBt monohydrate (86 mg, 0.56 mmol). ), Triethylamine (57 mg, 0.56 mmol), DMAP (6 mg, 0.05 mmol), EDC (107 mg, 0.56 mmol) were added, and the mixture was stirred at room temperature for 24 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by alumina column chromatography (ethyl acetate-methanol to methylene chloride-methanol). Hexane was added to crystallize, and the crystal was collected by filtration to obtain Compound (I-15) (103 mg, yield 50%) as a pale yellow solid.
mp 98 101 ℃
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.31-1.36 (m, 2H), 1.44-1.52 (m, 2H), 2.24-2.32 (m, 2H), 2.39-2.50 (m, 2H), 2.51-2.53 (m, 2H), 2.68 (s, 2H), 3.23-3.31 (m, 2H), 4.19 (s, 1H), 6.33 (d, J = 9.6Hz, 1H), 7.24 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 7.83 (d, J = 9.6Hz, 1H), 7.95 (s, 1H), 8.14 (brt, J = 5.9Hz, 1H), 11.95 (br, 1H).

ａ）化合物29の合成
窒素雰囲気下、化合物28（7.92 g，30.0 mmol)をＴＨＦ（100 ml)に溶解し、ドライアイス−アセトン浴で-78℃に冷却した。1.58Ｍ n-ブチルリチウム−ヘキサン溶液（20.3 ml, 32.0 mmol）を滴下後、-78℃で2時間撹拌した。4-クロロ-Ｎ-メトキシ-Ｎ-メチル酪酸アミド（3.31 g，20.0 mmol)の50mlＴＨＦ溶液を加え、-78℃で1時間撹拌した。水を加え室温に昇温し、溶媒を減圧濃縮した。残渣に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物29（4.88 g，4-クロロ-Ｎ-メトキシ-Ｎ-メチル酪酸アミドからの収率84%)を白色結晶として得た。
^１H-NMR（CDCl₃）δppm：2.23 (m, 2H), 3.13 (t, J = 7.3Hz, 2H), 3.68 (t, J = 5.9Hz, 2H), 5.48 (s, 2H), 6.85 (d, J = 8.9Hz, 1H), 7.26-7.48 (m, 5H), 8.16 (dd, J = 8.9, 2.4Hz, 1H), 8.83 (d, J = 2.4Hz, 1H).
ｂ）化合物30の合成
4-(4-フルオロベンジル)ピペリジン（0.39 g, 2.0 mmol)、化合物29（0.70 g, 2.4 mmol)をアセトニトリル（10 ml)に溶解し、炭酸カリウム（0.41 g, 3.0 mmol)、ヨウ化カリウム（33 mg, 0.2 mmol)を加え60℃で4時間、室温で60時間撹拌した。溶媒を減圧留去し、残渣に水を加え塩化メチレンで抽出した。無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をアルミナカラムクロマトグラフィー（塩化メチレン）により精製し、化合物30（0.42 g, 4-(4-フルオロベンジル)ピペリジンからの収率47%)を白色結晶として得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.18 (m, 2H), 1.36-1.58 (m, 3H), 1.80-2.01 (m, 4H), 2.35 (t, J = 6.9Hz, 2H), 2.46 (d, J = 5.7Hz, 2H), 2.83-2.94 (m, 4H), 5.46 (s, 2H), 6.83 (d, J = 8.9Hz, 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.29-7.48 (m, 5H), 8.15 (dd, J = 8.9, 2.4Hz, 1H), 8.80 (d, J = 2.4Hz, 1H).
ｃ）化合物（Ｉ−２２）の合成
化合物30（0.42 g, 0.94 mmol)をアニソール（10 ml)に溶解し、氷浴で冷却した。塩化アルミニウム（0.63 g, 4.7 mmol)を加え、室温で16時間撹拌、さらに60℃で0.5時間撹拌した。飽和重曹水を加え塩化メチレンで抽出した。無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣をアルミナカラムクロマトグラフィー（塩化メチレン−メタノール）により精製し、さらに酢酸エチル−ヘキサンより再結晶し、化合物（Ｉ−２２）（52 mg, 収率6%)を白色結晶として得た。
mp 123 126℃
^１H-NMR（CDCl₃ / TMS）δppm：1.21 (m, 2H), 1.40-1.60 (m, 3H), 1.85 (m, 4H), 2.33 (t, J = 7.0Hz, 2H), 2.48 (d, J = 6.9Hz, 2H), 2.79 (m, 4H), 6.59 (d, J = 9.9Hz, 1H), 6.92 (m, 2H), 7.09 (m, 2H), 8.06 (dd, J = 9.9, 2.3Hz, 1H), 8.19 (d, J = 2.3Hz, 1H).Synthesis of compound (I-22)

a) Synthesis of Compound 29 Under a nitrogen atmosphere, Compound 28 (7.92 g, 30.0 mmol) was dissolved in THF (100 ml) and cooled to -78 ° C in a dry ice-acetone bath. A 1.58 M n-butyllithium-hexane solution (20.3 ml, 32.0 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. 4-Chloro-N-methoxy-N-methylbutyric acid amide (3.31 g, 20.0 mmol) in 50 ml THF was added, and the mixture was stirred at -78 ° C for 1 hour. Water was added, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 29 (4.88 g, 84% yield from 4-chloro-N-methoxy-N-methylbutyric acid amide) as white crystals. It was.
¹ H-NMR (CDCl ₃ ) δ ppm: 2.23 (m, 2H), 3.13 (t, J = 7.3Hz, 2H), 3.68 (t, J = 5.9Hz, 2H), 5.48 (s, 2H), 6.85 ( d, J = 8.9Hz, 1H), 7.26-7.48 (m, 5H), 8.16 (dd, J = 8.9, 2.4Hz, 1H), 8.83 (d, J = 2.4Hz, 1H).
b) Synthesis of compound 30
4- (4-Fluorobenzyl) piperidine (0.39 g, 2.0 mmol), compound 29 (0.70 g, 2.4 mmol) was dissolved in acetonitrile (10 ml), and potassium carbonate (0.41 g, 3.0 mmol), potassium iodide ( 33 mg, 0.2 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours and at room temperature for 60 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. It was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by alumina column chromatography (methylene chloride) to give a compound 30 (0.42 g, yield from 4- (4-fluorobenzyl) piperidine 47 %) Was obtained as white crystals.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.18 (m, 2H), 1.36-1.58 (m, 3H), 1.80-2.01 (m, 4H), 2.35 (t, J = 6.9Hz, 2H), 2.46 (d, J = 5.7Hz, 2H), 2.83-2.94 (m, 4H), 5.46 (s, 2H), 6.83 (d, J = 8.9Hz, 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.29-7.48 (m, 5H), 8.15 (dd, J = 8.9, 2.4Hz, 1H), 8.80 (d, J = 2.4Hz, 1H).
c) Synthesis of Compound (I-22) Compound 30 (0.42 g, 0.94 mmol) was dissolved in anisole (10 ml) and cooled in an ice bath. Aluminum chloride (0.63 g, 4.7 mmol) was added, and the mixture was stirred at room temperature for 16 hours and further stirred at 60 ° C. for 0.5 hour. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by alumina column chromatography (methylene chloride-methanol) and recrystallized from ethyl acetate-hexane to give compound (I-22) (52 mg, yield 6%) was obtained as white crystals.
mp 123 126 ° C
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.21 (m, 2H), 1.40-1.60 (m, 3H), 1.85 (m, 4H), 2.33 (t, J = 7.0Hz, 2H), 2.48 (d , J = 6.9Hz, 2H), 2.79 (m, 4H), 6.59 (d, J = 9.9Hz, 1H), 6.92 (m, 2H), 7.09 (m, 2H), 8.06 (dd, J = 9.9, 2.3Hz, 1H), 8.19 (d, J = 2.3Hz, 1H).

  Thereafter, other compounds (I) are synthesized in the same manner. The structural formula and physical constant are shown below.

結合阻害率(%) = 100−[(被検化合物存在下の結合量−非特異的結合量) / (全結合量
−非特異的結合量)]×100

以上の結果から本発明化合物は、ＮＲ１／ＮＲ２Ｂサブタイプ受容体に強い結合性を示すことが明らかとなった。Test Example 1 Binding Experiment to NMDA Receptor (NR1 / NR2B Receptor) A receptor competition experiment with a test compound was performed using Ifenprodil which is an NR1 / NR2B subtype receptor-specific antagonist as a ligand.
The animals were male, Slc: Wistar rats, and the brains after decapitation were removed and the cerebral cortex was fractionated.
The cerebral cortex was homogenized with 20 times the amount of ice-cold 50 mM Tris · HCl buffer (pH 7.4) and centrifuged at 4 ° C. and 27,500 × g for 10 minutes. The obtained precipitate was suspended in the same buffer and centrifuged again. This operation was repeated three times, and the resulting precipitate was suspended in a buffer solution and stored at -80 ° C. Immediately before the experiment, the mixture was thawed at room temperature and centrifuged at 4 ° C. and 27,500 × g for 10 minutes, and the resulting precipitate was suspended in a buffer solution. Furthermore, it diluted 10 times with the buffer solution, and this was used for experiment as a membrane sample.
In the binding experiment, 10 μl of different concentrations of the test compound, 10 μl of labeled ligand [ ³ H] -Ifenprodil and 10 μl of GBR-12909 were added to 470 μl of the above membrane preparation and incubated at ice temperature for 120 minutes. The concentration of the labeled ligand [ ³ H] -Ifenprodil was 5 nM final, and the concentration of GBR-12909 was final 3 μM. DMSO, which is a solvent, was used to measure the total binding amount, and 100 μM Ifenprodil was used to measure the non-specific binding amount. GBR-12909 was added to block the binding of [ ³ H] -Ifenprodil to non-polyamine-sensitive sites. After incubation, the conjugate and free body were separated using Whatman GF / C filter paper (Whatman), and the filter paper was washed 4 times with 2.5 ml of ice-cold buffer. The filter paper was immersed in liquid scintillation (Clearsol I, manufactured by Nacalai Tesque) in a vial, and the radioactivity (dpm) was measured with a liquid scintillation counter. The binding inhibition rate (%) was determined from the measured value according to the following formula, and the dose (IC ₅₀ ) that suppressed binding by 50% was calculated. Table 11 shows the IC ₅₀ values of the test substances.
The formula of GBR-12909 (vanoxerin) is shown below.

Binding inhibition rate (%) = 100 − [(binding amount in the presence of test compound−nonspecific binding amount) / (total binding amount−nonspecific binding amount)] × 100

From the above results, it was clarified that the compound of the present invention exhibits strong binding to the NR1 / NR2B subtype receptor.

Test Example 2 NMDA Receptor Expression and Ca Ion Influx Measurement Complementary DNA (cDNA) of mouse NMDA receptor subunit was transiently introduced into HEK293 cells, and glutamic acid / glycine-induced intracellular Ca content one day after introduction Changes were measured using a Ca ion reactive fluorescent dye.
HEK293 cells were cultured and passaged using modified Dulbecco's Eagle medium (DMEM, low glucose).
20,000 HEK293 cells / well are seeded in a 96-well plate, and the NR1 and NR2B subunits of the NMDA receptor incorporated into the pcDAN3.1 plasmid are transiently introduced into the cell to co-express the subunits. I did it. The amount of DNA introduced was 0.025 μg of NR1 subunit and 0.075 μg of NR2B subunit per hole. The cells after introduction were inhibited from cell death using 50 μM of NMDA receptor antagonist MK-801.
A Krebs-Ringer Hepes buffer solution (KRH, Ca: 5 mM) was used for preparation of test compounds and cell washing.
One day after the introduction, the NMDA receptor antagonist MK-801 was washed away using KRH buffer, and the Ca ion-indicating fluorescent dye Fluo-3 / AM was taken up into the cells. Ca ion influx was induced by 20 μM glutamate / 2 μM glycine. The change in the amount of fluorescence due to the inflow of Ca ions into the cells was measured at 480 nm excitation using a fluorescence imaging system FDSS3000.
Usually, if the test compound shows NMDA receptor antagonism, the influx of Ca ions into the cell decreases, and the amount of fluorescence decreases.
From the measured value of the test compound, the Ca ion influx inhibition rate (%) was determined by the following formula, and the dose (IC ₅₀ ) for inhibiting inflow by 50% was calculated. Table 12 shows the IC ₅₀ values of the test substances.

Ca ion inflow inhibition rate (%) = 100 − [(fluorescence amount in the presence of test compound−background fluorescence amount) / (total fluorescence amount−background fluorescence amount)] × 100

以上の結果から、本発明化合物はＮＭＤＡ受容体拮抗作用を示すことが明らかとなった。

From the above results, it was clarified that the compound of the present invention exhibits NMDA receptor antagonistic action.

The present invention shows specific antagonism to glutamate receptors of central nerve cells, particularly NR1 / NR2B receptor, which is one of NMDA receptors, motor function (abnormal sensory), psychiatric symptoms (schizophrenia) It is useful as an analgesic and / or neuroprotective agent with few side effects.

Claims (16)

Formula (I):

(Where
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and may further be substituted with another group, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aroma Group-containing cyclic group or -NH- in the ring, and other ring atoms may be substituted with a substituent other than hydroxy which may be protected and amino which may be protected A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
A ² is an aromatic hydrocarbon cyclic group which may have a substituent or an aromatic heterocyclic group which may have a substituent,
R ¹ is hydrogen, hydroxy, acyloxy, lower alkoxy or lower alkyl,
R ² is hydrogen, hydroxy or lower alkyl,
R ¹ and R ² may be combined to form a single bond,
m is 0 or 1,
X represents a lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - CONR 5 (CR 3 R 4) n -, - ^{NR 5 CO (CR 3 R 4} ) n -, - NR 5 CONR 6 (CR 3 R 4) n -, - C (= n-OR 7) (CR 3 R 4) n -, - (CR 8 R 9 ^{) rO (CR 3 R 4)} n -, - (CR 8 R 9) rS (CR 3 R 4) n -, - (CR 8 R 9) rNR 6 (CR 3 R 4) n -, - (CR 8 ^{R 9) rSO (CR 3 R} 4) n -, - (CR 8 R 9) rSO 2 (CR 3 R 4) n -, - CR 9 = n-O (CR 3 R 4) n -, - C ( ^{= O) O (CR 3 R} 4) n -, - A 3 - (CR 3 R 4) n- or ^{-A 3 -CR 10 = CR 11 (} CR 3 R ⁴ ) n-
when m = 1, X may be lower alkylene which may be substituted with hydroxy, n and r are each independently an integer of 0 to 4, n + r is 4 or less,
A ³ is

(Where the dashed line indicates the presence or absence of a bond and R ^x is hydrogen or lower alkyl)
And
-X- (CO) m-good lower alkenylene which may have a substituent group, optionally substituted lower alkynylene which may have a ^{substituent, -CO (CR 3 R 4)} n -, - NR 6 CO (CR ³ R ⁴⁾ n '- (where n' is 1 or ^{2), - NR 6 COCO -} , - NR 6 (CR 3 R 4) nCO -, - S (CR 3 R 4) n -, - SO ( CR ³ R ⁴ ) n- or -A ^3- (CR ³ R ⁴ ) n-
A ¹ has at least one hydroxy which may be protected and / or amino which may be protected, and further contains a nitrogen-containing aromatic monocyclic group or ring which may be substituted with another group. An aromatic monocyclic group containing -NH- and other ring member atoms optionally substituted with a substituent other than hydroxy which may be protected and amino which may be protected;
-X- (CO) when m- is -S ^{(CR 3} R 4) is a n-, ^{-Y-A 2} is not unsubstituted benzyl,
Y is
i) When m = 0, a single bond, —CR ¹² R ¹³ —, —O—, —S—, —C (═N—OR ¹⁷ ) —, —C (═O) —, —CH (OR ¹⁷ ) - or ^{-NR 15} - and is, together with ^{R 2} = ^{CR 14} - may be formed,
When ii) m = 1, a single bond, lower alkylene, lower alkenylene, lower ^{alkynylene, -O -, - S -,} - NR 15 -, - CR 12 R 13 O -, - CR 12 R 13 S- or - CR ¹² R ¹³ NR ¹⁵ - a and, together with ^{R 2 = CR 14 - (CR} 15 R 16) may form a p-, p is an integer from 0 to 5,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently hydrogen Or a lower alkyl which may have a substituent, and when there are a plurality of R ³ and R ^{4 s,} they may be different from each other)
Or a pharmaceutically acceptable salt thereof or a solvate thereof. A ¹ is substituted with at least hydroxy-substituted pyridyl, at least hydroxy-substituted quinolyl, at least hydroxy-substituted benzoxazolyl, at least hydroxy-substituted benzimidazolyl, at least substituted with an optionally protected amino A ring member other than -NH- may be substituted, pyrrolyl other than -NH- may be substituted, a ring member other than -NH- may be substituted A ring member other than -NH- may be substituted, a ring member other than -NH- may be substituted, a ring atom other than -NH- may be substituted, or a ring member other than -NH- may be substituted. The compound according to claim 1, which is an indolyl which may be prepared, or a pharmaceutically acceptable product thereof Salts or solvates thereof. A ¹ is

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. -X- ^{is, -CO (CHR 3) n -} , - CONH (CHR 3) n -, - NHCO (CHR 3) n- or ^{-O (CHR 3) n -,} - SO (CHR 3) n-, _{^{-SO 2 (CHR 3) n -}} , - CH = NO (CHR 3) n -, - C (= O) O (CHR 3) n -, - A 3 -CHR 3 - or ^-A 3 _-C 2 H ₄ - is a compound or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein. The compound according to claim 4, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 0. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen and R ² is hydrogen or hydroxy, or R ¹ and R ² are combined to form a single bond. Salts or solvates thereof. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a group thereof, wherein Y is a single bond or -CH _2- , or together with R ² forms ═CH-. Solvate. The A ^{2 according} to any one of claims 1 to 4, wherein A ² is phenyl optionally substituted with one or more groups selected from halogen, cyano, lower alkyl, halogeno lower alkyl, lower alkoxy and halogeno lower alkoxy. Compound or a pharmaceutically acceptable salt thereof or a solvate thereof. The compound according to any one of claims 1 to 4 or 9, wherein A ² is para-substituted phenyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The pharmaceutical composition containing the compound in any one of Claims 1-10, its pharmaceutically acceptable salt, or those solvates. The pharmaceutical composition according to claim 11, which has an NMDA receptor antagonistic action. The pharmaceutical composition according to claim 12, which has an NR1 / NR2B receptor antagonistic action. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an analgesic. A method for preventing or treating a disease caused by an NMDA receptor, comprising administering the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for a disease caused by an NMDA receptor.