JP2009067784A - Analgesic containing nitrogen-containing heterocyclic derivative substituted with cyclic group - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound with an analgesic effects. <P>SOLUTION: The analgesic comprises compounds represented by formula (I) or their pharmaceutically permissible salts, or their solvates, as effective components. (In the formula, Z is N or CR<SP>1</SP>, A<SP>1</SP>is a (substituted) nitrogen containing aromatic monocyclic group or a (substituted) nitrogen containing aromatic condensed ring group, A<SP>2</SP>are each a (substituted) aromatic hydrocarbon group or a (substituted) aromatic heterocyclic group, R<SP>1</SP>, R<SP>2</SP>, R<SP>a</SP>, R<SP>b</SP>, R<SP>c</SP>and R<SP>d</SP>are each independently H, a hydroxyl group, etc., w is 2 or 3, t is 1 or 2, X is -(CR<SP>3</SP>R<SP>4</SP>)<SB>m</SB>-, -CO(CR<SP>3</SP>R<SP>4</SP>)<SB>n</SB>-, -CONR<SP>5</SP>(CR<SP>3</SP>R<SP>4</SP>)<SB>n</SB>-, or the like, m is an integer of 1-4, n is an integer of 0-4, R<SP>3</SP>and R<SP>4</SP>are each independently a H, a halogen atom, a hydroxyl group, etc., and R<SP>5</SP>are each independently H or a lower alkyl). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an analgesic containing a nitrogen-containing heterocyclic derivative. It exhibits specific antagonism to glutamate receptors in central neurons, particularly NR1 / NR2B receptor, which is one of NMDA receptors, preferably motor function (eg, sensory abnormalities), psychiatric symptoms (eg, mental) The present invention relates to an analgesic containing a nitrogen-containing heterocyclic derivative with less side effects on (division) and the like.

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 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.
Patent Documents 1 to 9 describe that a compound similar to the compound contained in the analgesic of the present invention exhibits analgesic action or NMDA receptor antagonistic action, but any compound contained in the analgesic of the present invention is described. Therefore, it is not known that the compound contained in the analgesic of the present invention has an analgesic action.
International Publication WO02 / 068409 Pamphlet International Publication WO02 / 080928 Pamphlet International Publication WO02 / 40466 Pamphlet International Publication WO2003 / 076420 Pamphlet International Publication WO2003 / 010159 Pamphlet International Publication WO2006 / 010968 Pamphlet International Publication WO2006 / 010964 Pamphlet International Publication WO2004 / 103954 Pamphlet International Publication WO2006 / 058338 Pamphlet

  There has been a need for an analgesic that is an NMDA receptor antagonist that is highly active and has a high affinity for NMDA receptors, more preferably a high affinity for subtypes, particularly NR1 / NR2B receptors.

（式中、
ＺはＮまたはＣＲ^１であり、
Ａ^１は置換基を有していてもよい含窒素芳香族単環式基または置換基を有していてもよい含窒素芳香族縮合環式基であり、
該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は以下の条件：
i) 保護されていてもよいヒドロキシ、保護されていてもよいアミノおよび置換されていてもよいアミノオキシから選択される少なくとも１個の基を有する
または
ii) 環内に−ＮＨ−を含有する
の少なくとも一方を満たすものであり、
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およびＲ^２は各々独立して水素、ヒドロキシまたは低級アルキルであり、Ｒ^１およびＲ^２は一緒になって単結合を形成していてもよく、
Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃおよびＲ^ｄは各々独立して水素または低級アルキルであり、複数のＲ^ａ、複数のＲ^ｂ、複数のＲ^ｃまたは複数のＲ^ｄが存在するときは、それぞれが異なっていてもよく、
ｗは２または３であり、ｔは１または２であり、
Ｘは
−（ＣＲ^３Ｒ^４）ｍ−、
−ＣＯＮＲ^５（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）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−、
−（ＣＲ^３Ｒ^４）ｍＣ（＝Ｎ−ＯＲ^７）−、
−ＣＨ（ＯＲ^８）（ＣＲ^３Ｒ^４）ｎ−、
−（ＣＲ^３Ｒ^４）ｍＣＨ（ＯＲ^８）−、
−ＮＲ^５ＣＯＣＯ（ＣＲ^３Ｒ^４）ｎ−、
−（ＣＲ^３Ｒ^４）ｍＮＲ^５ＣＯＣＯ−、
−ＣＯＣＯＮＲ^５（ＣＲ^３Ｒ^４）ｎ−、
−ＮＲ^５ＣＯＣＨ（ＯＲ^８）（ＣＲ^３Ｒ^４）ｎ−、
−ＣＨ（ＯＲ^８）（ＣＲ^３Ｒ^４）ｎＮＲ^５ＣＯ−、
−ＮＲ^５（ＣＲ^３Ｒ^４）ｍＣＯ−、
−Ａ^３−（ＣＲ^３Ｒ^４）ｎ−、
−（ＣＲ^３Ｒ^４）ｍ−Ａ^３−、
−Ａ^３−ＣＲ^１０＝ＣＲ^１１（ＣＲ^３Ｒ^４）ｎ−、
−ＣＲ^１０＝ＣＲ^１１（ＣＲ^３Ｒ^４）ｎ−Ａ^３−、
−Ａ^３−ＮＲ^６（ＣＲ^３Ｒ^４）ｎ−、
−（ＣＲ^３Ｒ^４）ｎＮＲ^６−Ａ^３−または
−ＮＲ^６（ＣＲ^３Ｒ^４）ｍ−Ａ^３−であり、
ＺがＣＲ^１のときは
−ＣＯＮＲ^５（ＣＲ^３Ｒ^４）m−ＮＲ^６−、
−（ＣＲ^３Ｒ^４）ｍＣＯＮＲ^５−、
−（ＣＲ^３Ｒ^４）ｍＮＲ^５ＣＯＮＲ^６−、
−ＣＯ（ＣＲ^３Ｒ^４）ｍＮＲ^５−、
−Ａ^３−（ＣＲ^３Ｒ^４）ｍＮＲ^６−でもよく、
ｍは１〜４の整数であり、ｎおよびrは０〜４の整数であり、
Ａ^３は置換基を有していてもよい芳香族炭化水素環式基、置換基を有していてもよい芳香族複素環式基または置換基を有していてもよい非芳香族複素環式基であり、
Ｒ^３およびＲ^４は各々独立して水素、ハロゲン、ヒドロキシ、置換基を有していてもよい低級アルキルまたは置換基を有していてもよい低級アルコキシであり、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く、
Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は各々独立して水素または低級アルキルであり、
ｍまたはｎが１以上であるとき、Ｒ^１は、Ｒ^１が結合する炭素原子と隣接するＣＲ^３Ｒ^４上のＲ^３と一緒になって単結合を形成してもよい）
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を含有する鎮痛剤。 The present invention provides the following.
(1) Formula (I):

(Where
Z is N or CR ¹
A ¹ is a nitrogen-containing aromatic monocyclic group which may have a substituent or a nitrogen-containing aromatic condensed cyclic group which may have a substituent,
The nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group has the following conditions:
i) having at least one group selected from optionally protected hydroxy, optionally protected amino and optionally substituted aminooxy, or
ii) satisfying at least one of -NH- in the ring,
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 and R ² are each independently hydrogen, hydroxy or lower alkyl, and R ¹ and R ² may be combined to form a single bond;
R ^a , R ^b , R ^c and R ^d are each independently hydrogen or lower alkyl, and when a plurality of R ^a , a plurality of R ^b , a plurality of R ^c or a plurality of R ^d are present, May be different,
w is 2 or 3, t is 1 or 2,
X is ^{- (CR 3 R 4) m-} ,
^{-CONR 5 (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) 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-,
^{- (CR 3 R 4) mC} (= N-OR 7) -,
^{-CH (OR 8) (CR 3} R 4) n-,
^{- (CR 3 R 4) mCH} (OR 8) -,
^{-NR 5 COCO (CR 3 R 4} ) n-,
^{- (CR 3 R 4) mNR} 5 COCO-,
^{-COCONR 5 (CR 3 R 4)} n-,
^{-NR 5 COCH (OR 8) (} CR 3 R 4) n-,
^{-CH (OR 8) (CR 3} R 4) nNR 5 CO-,
^{-NR 5 (CR 3 R 4)} mCO-,
^{-A 3 - (CR 3 R 4} ) n-,
^{- (CR 3 R 4) m} -A 3 -,
^{-A 3 -CR 10 = CR 11 (} CR 3 R 4) n-,
^{-CR 10 = CR 11 (CR 3} R 4) n-A 3 -,
^{-A 3 -NR 6 (CR 3 R} 4) n-,
^{- (CR 3 R 4) nNR} 6 -A 3 - or ^{-NR 6 (CR 3 R 4)} m-A 3 - and is,
When Z is CR ¹ -CONR ⁵ (CR ³ R ⁴ ) m -NR ^6- ,
-(CR ³ R ⁴ ) mCONR ^5- ,
^{- (CR 3 R 4) mNR} 5 CONR 6 -,
^{-CO (CR 3 R 4) mNR} 5 -,
-A ^3- (CR ³ R ⁴ ) mNR ^6-
m is an integer of 1 to 4, n and r are integers of 0 to 4,
A ³ is an aromatic hydrocarbon cyclic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent A formula group,
R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl or optionally substituted lower alkoxy, and each of R ³ and R ⁴ is a plurality of If there are any, they may be different,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or lower alkyl;
When m or n is 1 or more, R ¹ may form a single bond together with R ³ on CR ³ R ⁴ adjacent to the carbon atom to which R ¹ is bonded.
Or a pharmaceutically acceptable salt thereof or a solvate thereof.

で示される基である、上記（１）、（２）または（３）記載の鎮痛剤。 (2) The analgesic according to (1) above, wherein w is 2 or 3, and t is 1.
(3) X is ^{- (CR 3 R 4) m} -, - CONR 5 (CR 3 R 4) n -, - (CR 3 R 4) mCONR 5 -, - NR 5 CONR 6 (CR 3 R 4) n ^{-, - C (= n-} OR 7) (CR 3 R 4) n -, - CH (OR 8) (CR 3 R 4) n -, - NR 5 COCO (CR 3 R 4) n -, - NR ^{5 COCH (OR 8) (CR} 3 R 4) n -, - NR 5 (CR 3 R 4) mCO -, - A 3 - (CR 3 R 4) n -, - A 3 -CR 10 = CR 11 ( CR ³ R ⁴ ) n- or -A ^3- (CR ³ R ⁴ ) nNR ^6- , the compound according to the above (1) or (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof. Contains analgesics.
(4) pyridyl A ¹ is substituted with at least hydroxy, quinolyl substituted with at least hydroxy, at least hydroxy substituted benzoxazolyl, at least hydroxy substituted benzimidazolyl, optionally at least protected amino 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-described (1), (2) or (3), which is an indolyl group in which an atom may be substituted Painkiller.
(5) ^{A 1} is

The analgesic according to (1), (2) or (3) above, which is a group represented by

(6) X is ^{-CONH (CHR 3) n -,} - NHCONH (CHR 3) n -, - NHCOCO (CHR 3) n- or ^-NR 5 ^{(CR 3} R 4) is MCO-, the (1) The analgesic according to any one of to (5).
(7) X is —CO (CHR ³ ) ₂ —, —CONHCHR ³ —, —CONH (CHR ³ ) ₂ —, —NHCOCHR ³ —, —NHCO (CHR ³ ) ₂ —, —NHCONH—, —NHCOCO— or The analgesic according to any one of (1) to (5), which is —NHCH ₂ CO—.
(8) Z is CR ¹ and R ¹ and R ² are each independently hydrogen or hydroxy, R ¹ and R ² together form a single bond, or m or n is 1 or more when, ^{R 1} forms a single bond together with ^{R 3} on ^CR 3 ^{R 4} and the adjacent carbon atom ^{to which R 1} is bonded, analgesia according to any one of (1) to (7) Agent.
(9) The analgesic according to any one of (1) to (7), wherein Z is N.
(10) The above (1), wherein A ² is phenyl or pyridyl each optionally substituted with one or more groups selected from halogen, cyano, lower alkyl, halogeno lower alkyl, lower alkoxy and halogeno lower alkoxy The analgesic according to any one of to (9).
(11) The analgesia according to any one of (1) to (9), wherein A ² is para-substituted phenyl, meta, para-disubstituted phenyl or meta, para-tri-substituted phenyl (3,4,5-tri-substituted phenyl). Agent.
(12) The analgesic according to any one of (1) to (11) above.

  The analgesic of the present invention is useful as a pharmaceutical product because of its excellent analgesic effect, excellent pharmacokinetics, excellent safety, and / or few side effects (somnolence, dizziness, ataxia, fatigue, etc.) It is. The analgesic of the present invention can be used as an analgesic for pain caused by inflammatory pain, nociceptive pain, neuropathic pain, and / or cancer pain. Useful as. Furthermore, the analgesic of the present invention is associated with headache, lower back pain, OA pain, RA pain, postoperative pain, cancer pain, DNP (diabetic neuropathic pain), PHN (postherpetic neuralgia), HIV. Useful for pain and / or pain caused by anticancer agents. It is especially useful for DNP, PHN, and back and back pain.

  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.). Butyldimethylsilyl, 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- -Yl, 4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl, etc.), tetrahydrofuranyl (tetrahydrofuran-2-yl, etc.), tetrahydrothiofuranyl (tetrahydrothiofuran- 2-yl etc.), aryl lower alkoxy lower alkyl (benzyloxymethyl etc.), lower alkylsulfonyl, arylsulfonyl, lower alkylarylsulfonyl (p-toluenesulfonyl etc.) and a protecting group selected from acyl etc. Also includes good hydroxy. Preferred protecting groups are lower alkyl, aryl lower alkyl, lower alkylsulfonyl and the like.

In the present specification, “optionally protected amino” means, for example, lower alkoxycarbonyl (such as tert-butyloxycarbonyl), lower alkenyloxycarbonyl (such as vinyloxycarbonyl, allyloxycarbonyl), halogeno lower alkoxycarbonyl (such as 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), aryl lower alkoxycarbonyl (benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenyl) Oxycarbonyl, etc.), tri-lower alkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc.), diazo, acyl (formyl, acetyl, pivaloyl, benzoyl) ), Halogenoacyl (such as trifluoroacetyl), lower alkylsulfonyl (such as methanesulfonyl), halogeno lower alkylsulfonyl (such as trifluoroethanesulfonyl), arylsulfonyl, lower alkylarylsulfonyl (toluenesulfonyl, 4-tert-butylbenzenesulfonyl, etc.) ), An amino optionally protected with a protecting group selected from aryl lower alkyl (such as triphenylmethyl) and the like. Preferred protecting groups are acyl, lower alkylsulfonyl and the like.
Examples of the substituent of “optionally substituted aminooxy” include lower alkyl, acyl and the like.

等で示される基である。 In the present specification, the “nitrogen-containing aromatic monocyclic group” means a 5- to 6-membered aromatic cyclic group having at least one N in the ring and further having O or S. Includes groups. For example,

And the like.

で示される基が挙げられる。結合手はいずれの環に存在していてもよい。 In the present specification, “nitrogen-containing aromatic fused cyclic group” means
a) a 5- to 6-membered aromatic ring group having at least one N in the ring and further having O or S, preferably one or two aromatic or non-aromatic rings (preferably Is a benzene ring or an aromatic heterocycle) condensed group, and
b) a 5- to 7-membered non-aromatic cyclic group having at least one N in the ring and optionally having O or S, one or two benzene rings or aromatic heterocycles Includes a fused group, and is preferably a). For example,

The group shown by these is mentioned. The bond may be present in any ring.

"Having at least one group selected from hydroxy that may be protected, amino that may be protected and aminooxy that may be substituted" A nitrogen-containing aromatic monocyclic group which may optionally have a substituent or a nitrogen-containing aromatic condensed cyclic group which may have a substituent, "hydroxy which may be protected, amino which may be protected or substituted A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group which has at least one aminooxy which may be optionally substituted with another group,
The ring has at least one group selected from hydroxy which may be protected, amino which may be protected and aminooxy which may be substituted, and further selected from the substituent group α. On the above-mentioned “nitrogen-containing aromatic monocyclic group” which may be substituted with one or more groups and on the ring, hydroxy which may be protected, amino which may be protected and amino which may be substituted The above “nitrogen-containing aromatic fused cyclic group” which has at least one group selected from oxy and may be further substituted with one or more groups selected from substituent group α is included.
Here, the substituent group α is a group consisting of halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino, carboxy, lower alkoxycarbonyl, cyano and nitro.

In the present specification, "pyridyl substituted with at least hydroxy", "quinolyl substituted with at least hydroxy", "benzoxazolyl substituted with at least hydroxy" and "benzimidazolyl substituted with at least hydroxy" , Each of which includes pyridyl, quinolyl, benzoxazolyl and benzimidazolyl, each having at least one hydroxy 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. .
In the present specification, “pyridyl substituted with at least amino optionally protected” has at least one amino or protected amino as a substituent, and is further selected from substituent group α. Including pyridyl which may be substituted with the above groups.

等で示される基が挙げられる。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。
本明細書中、「−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。 “Ii) a nitrogen-containing aromatic monocyclic group optionally having substituent (s) or a nitrogen-containing aromatic condensation optionally having substituent (s) that satisfies the condition of“ containing —NH— in the ring ” A cyclic group "," other than those containing -NH- in the ring and other ring member atoms being optionally protected hydroxy, optionally protected amino and optionally substituted aminooxy ". The nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group optionally substituted with a substituent is the above-mentioned “nitrogen-containing aromatic monocyclic group” and “nitrogen-containing aromatic condensed cyclic group”. Among the “groups”, groups containing a —NH— group in the ring are included. For example,

And the like are exemplified. 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.
In the present specification, “ringyl other than —NH— which may be substituted by a ring atom”, “pyrrolyl which may be substituted for a ring atom other than —NH—”, “ring other than —NH—” "Pyrazolyl optionally substituted with a constituent atom", "Benzpyrazolyl optionally substituted with a ring atom other than -NH-", "Benzimidazolyl optionally substituted with a ring atom other than -NH-" And “an indolyl group in which a ring member atom other than —NH— may be substituted” means that any ring member atom other than —NH— is substituted with one or more groups selected from substituent group β. Imidazolyl, pyrrolyl, pyrazolyl, benzpyrazolyl, benzimidazolyl and indolyl which may be optionally included.

In the present specification, the “aromatic hydrocarbon cyclic group” includes phenyl, naphthyl, phenanthryl and the like.
In the present specification, the substituent of the “optionally substituted aromatic hydrocarbon cyclic group” includes halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, lower alkylsulfonyl. Oxy, halogeno lower alkylsulfonyloxy, acyl, acyloxy, amino, lower alkylamino, acylamino, nitro, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, substituted with one or more groups selected from substituent group γ An aromatic hydrocarbon cyclic group which may be substituted, an arylthio which may be substituted with one or more groups selected from the substituent group γ, and a substituent substituted with one or more groups selected from the substituent group γ Optionally substituted by aryloxy, one or more groups selected from substituent group γ Aryl amino optionally include one or more aryl sulfonyloxy such as optionally substituted with a group selected from the substituent group gamma.
Here, the substituent group γ is composed of halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, amino, lower alkylamino, acylamino, carboxy, lower alkoxycarbonyl, cyano and nitro. A group.
Preferable examples of the “optionally substituted aromatic hydrocarbon cyclic group” are phenyl substituted at the para position or phenyl substituted at the meta position and the para position, and the substituent is halogen and / Or halogeno lower alkyl etc. are preferable.
“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.

（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） In the present specification, the “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, etc.) and aromatic condensed cyclic groups (eg indolyl, isoindolyl, indolizinyl) , Benzimidazolyl, benzpyrazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzof , Isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridinyl and pyrazinopyr Dazinyl and the like).
In the present specification, the “non-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, Thiranyl, oxiranyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, oxadiazolinyl, oxathiolanyl, oxothiolanyl, oxothiolanyl Dihydrothienyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydropyranyl, thianyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, Including Omoruhorino, a dihydropyridyl, etc.).
In particular, "aromatic hydrocarbon cyclic group" in A ^3, "aromatic heterocyclic group" and "non-aromatic heterocyclic group" above "aromatic hydrocarbon cyclic group", "aromatic heterocyclic The divalent group of “formula group” and “non-aromatic heterocyclic group” is included. The bond may be present at any possible position, and specific examples include the following groups.

(Where the dashed line indicates the presence or absence of a bond and R ^x is hydrogen or lower alkyl)

In the present specification, substituents of “aromatic heterocyclic group optionally having substituent (s)” and “non-aromatic heterocyclic group optionally having substituent (s)” Is the same as the substituent of the above-mentioned “aromatic hydrocarbon cyclic group which may have a substituent”.
A preferred example of the “optionally substituted aromatic heterocyclic group” for A ² is pyridyl which may have a substituent, and preferred substituents are halogen, halogeno lower alkyl, lower alkoxy. , Halogeno lower alkoxy and the like.

In the present specification, “halogen” includes F, Cl, Br, and I.
In the present specification, the lower alkyl part and halogen part of “halogeno lower alkyl”, “halogeno lower alkoxy”, “halogeno lower alkoxycarbonyl”, “halogenoacyl”, “halogeno lower alkylsulfonyl”, and “halogeno lower alkylsulfonyloxy” The same as the above “halogen”.
In the present specification, “lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. , 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, n-decyl and the like are exemplified. Particularly preferred is methyl or ethyl.
In the present specification, examples of the substituent of “optionally substituted lower alkyl” include halogen, hydroxy, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, amino, lower alkylamino, acylamino, carboxy, Lower alkoxycarbonyl, cyano, nitro and the like can be mentioned. Preferred examples of substituted lower alkyl include trihalogeno lower alkyl.
In the present specification, “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", "to Lower alkyl moiety of the aryl-lower alkylsilyl "is the same as the above" lower alkyl ".
In the present specification, the substituent of “optionally substituted lower alkoxy” is the same as the above-described substituent of “optionally substituted lower alkyl”.

In the present specification, “lower alkenyl” means a straight chain 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. Includes branched alkenyl. Specific examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
In the present specification, the lower alkenyl part of “lower alkenyloxycarbonyl” is the same as the above “lower alkenyl”.

であることを意味する。 In the present specification, “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.
In the present specification, the acyl moiety of “acyloxy”, “acylamino” and “halogenoacyl” is the same as the above “acyl”.
“R ¹ and R ² together form a single bond”

It means that.

（式中、Ｘ^ａは−ＣＯ−、−ＣＯＮＲ^５−、−ＮＲ^５ＣＯ−、−ＮＲ^５ＣＯＮＲ^６−、−Ｃ（＝Ｎ−ＯＲ^７）−、−（ＣＲ^８Ｒ^９）ｒＯ−、−（ＣＲ^８Ｒ^９）ｒＳ−、−（ＣＲ^８Ｒ^９）ｒＳＯ−、−（ＣＲ^８Ｒ^９）ｒＳＯ_２−、−ＣＲ^９＝Ｎ−Ｏ−、−Ｃ（＝Ｏ）Ｏ−、−ＣＨ（ＯＲ^８）−、−ＮＲ^５ＣＯＣＯ−、−ＣＯＣＯＮＲ^５−、−ＮＲ^５ＣＯＣＨ（ＯＲ^８）−、−Ａ^３−、−Ａ^３ＮＲ^６−または−Ａ^３−ＣＲ^１０＝ＣＲ^１１−であり、その他の記号は前記と同義）
であることを意味する。 “When m or n is 1 or more, R ¹ forms a single bond with R ³ on CR ³ R ⁴ adjacent to the carbon atom to which R ¹ is bonded”.

(In the formula, X ^a represents —CO—, —CONR ⁵ —, —NR ⁵ CO—, —NR ⁵ CONR ⁶ —, —C (═N—OR ⁷ ) —, — (CR ⁸ R ⁹ ) rO—, ^{- (CR 8 R 9) rS} -, - (CR 8 R 9) rSO -, - (CR 8 R 9) rSO 2 -, - CR 9 = N-O -, - C (= O) O -, - ^{CH (oR 8) -, -} NR 5 COCO -, - COCONR 5 -, - NR 5 COCH (oR 8) -, - A 3 -, - A 3 NR 6 - or ^-A 3 ^-CR 10 = ^{CR 11} - And other symbols are as defined above)
It means that.

The compound represented by the formula (I) contained in the analgesic of the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. For example, it contains tautomers as follows.

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

（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または−Ａ^３−（ＣＲ^３Ｒ^４）ｓであり、ｓは０〜３の整数、Ｚは塩素原子又は臭素原子であり、波線はシスまたはトランス体であることを示し、その他の各記号は前記と同意義である）
一般式（ＩＩ）で示されるケトンは、後述の参考例８〜９に記載の方法、ならびにそれらに準ずる方法で合成することができる。また、一般式（ＩＩＩ）および（ＩＶ）で示される有機リン化合物は、新実験化学講座１４, 丸善株式会社 （１９７７）．に記載の方法、ならびにそれに準ずる方法で合成することができる。
一般式（ＩＩ）で示される化合物に対して、一般式（ＩＩＩ）または（ＩＶ）で示される有機リン化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、液体アンモニア等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド等が挙げられる。一般式（ＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
得られた一般式（Ｉ−ａ）で示される化合物は、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 (II) In the presence of a base, a ketone represented by general formula (II) and an organophosphorus compound represented by general formula (III) or (IV) are condensed to form a general formula A compound represented by (Ia) can be synthesized.

(In the formula, X ¹ is optionally substituted lower alkenylene or -A ^3- (CR ³ R ⁴ ) s, s is an integer of 0 to 3, and Z is a chlorine atom or a bromine atom. The wavy line indicates cis or trans form, and other symbols are as defined above)
The ketone represented by the general formula (II) can be synthesized by the method described in Reference Examples 8 to 9 described later and a method analogous thereto. In addition, organophosphorus compounds represented by the general formulas (III) and (IV) are disclosed in New Experimental Chemistry Course 14, Maruzen Co., Ltd. (1977). Can be synthesized by the method described in 1) and a method analogous thereto.
The organic phosphorus compound represented by the general formula (III) or (IV) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia, and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (II).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Ia) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
反応溶媒としては、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
金属触媒としては、５％パラジウム−炭素、１０％パラジウム−炭素、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）が挙げられ、一般式（Ｉ−ａ）で示される化合物に対して０．０１〜０．５重量パーセント用いることができる。
水素圧は１〜５０気圧が挙げられる。
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。
得られた一般式（Ｉ−ｂ）で示される化合物は、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 (Ia) By reducing the compound represented by the general formula (Ia) with hydrogen in the presence of a metal catalyst, it is represented by the general formula (Ib). Compounds can be synthesized.

(Wherein each symbol is as defined above)
Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, and chlorotris (triphenylphosphine) rhodium (I). 01-0.5 weight percent can be used.
As for hydrogen pressure, 1-50 atmospheres is mentioned.
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 resulting compound represented by the general formula (Ib) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｘ^２は置換基を有していてもよい低級アルケニレンまたは−Ａ^３−（ＣＲ^３Ｒ^４）ｎであり、Ｌ^１はリチウム、ＭｇＣｌ、ＭｇＢｒまたはＭｇＩであり、その他の各記号は前記と同意義である）
一般式（ＩＩ）で示されるケトンに対して、一般式（Ｖ）で示される化合物を１〜３モル当量用いることができる。
反応溶媒としては、ジエチルエーテル、テトラヒドロフラン等が挙げられる。
反応温度としては−７０〜５０℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（Ｉ−ｃ）で示される化合物は、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 (II) Compound represented by general formula (Ic) by reacting a ketone represented by general formula (II) with an organometallic compound represented by general formula (V) Can be synthesized.

(In the formula, X ² is optionally substituted lower alkenylene or -A ^3- (CR ³ R ⁴ ) n, L ¹ is lithium, MgCl, MgBr or MgI, and other symbols. Is as defined above)
The compound represented by the general formula (V) can be used at 1 to 3 molar equivalents relative to the ketone represented by the general formula (II).
Examples of the reaction solvent include diethyl ether and tetrahydrofuran.
An example of a reaction temperature is -70 to 50 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (Ic) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｒ^１３はＣ_１−４アルキルであり、その他の各記号は前記と同意義である）
一般式（ＶＩ）および（ＶＩＩ）で示される化合物は、後述の参考例１１に記載の方法、ならびにそれらに準ずる方法で合成することができる。

（ＶＩ）から（ＶＩＩ）の合成
一般式（ＶＩ）で示される化合物を加水分解することにより、一般式（ＶＩＩ）で示されるカルボン酸を合成することができる。
一般式（ＶＩ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウムまたは水酸化カリウムを１〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＶＩＩ）で示される化合物は、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。

（ＶＩＩ）から（Ｉ−ｄ）の合成
縮合剤存在下、一般式（ＶＩＩ）で示されるカルボン酸と一般式（ＶＩＩＩ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｄ）で示されるアミド化合物を合成することができる。
一般式（ＶＩＩ）で示される化合物に対して、一般式（ＶＩＩＩ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＶＩＩ）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、Ｎ−メチルモルホリン、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。一般式（ＶＩＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｄ）で示される化合物は、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 D: Synthesis of (Id) from Compound (VI)

(Wherein R ¹³ is C _1-4 alkyl, and other symbols are as defined above)
The compounds represented by the general formulas (VI) and (VII) can be synthesized by the method described in Reference Example 11 described later and a method analogous thereto.

Synthesis of (VII) from (VI) A carboxylic acid represented by the general formula (VII) can be synthesized by hydrolyzing the compound represented by the general formula (VI).
Lithium hydroxide, sodium hydroxide or potassium hydroxide can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (VI).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (Id) from (VII) In the presence of a condensing agent, the carboxylic acid represented by the general formula (VII) and the amine compound represented by the general formula (VIII) are condensed to form a compound represented by the general formula (Id). The amide compounds shown can be synthesized.
The compound represented by the general formula (VIII) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (VII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (VII). You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (VII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Id) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＩＸ）で示されるアルコールは、後述の参考例１〜７に記載の方法、ならびにそれらに準ずる方法で合成することができる。

（ＩＸ）から（Ｘ）の合成
アゾ化合物と３価のリン化合物の存在下、一般式（ＩＸ）で示されるアルコールとフタルイミドを縮合して、一般式（Ｘ）で示される化合物を合成することができる。
一般式（ＩＸ）で示される化合物に対して、フタルイミドを１〜３モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル等が挙げられる。
アゾ化合物としては、アゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル等が挙げられ、一般式（ＩＸ）で示される化合物に対して１〜３モル当量用いることができる。
３価のリン化合物としては、トリフェニルホスフィン、トリブチルホスフィン等が挙げられ、一般式（ＩＸ）で示される化合物に対して１〜３モル当量用いることができる。
反応温度としては０℃〜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。
得られた一般式（Ｘ）で示される化合物は、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。

（Ｘ）から（ＸＩ）の合成
一般式（ＸＩ）で示される化合物をヒドラジン水和物と処理することにより、一般式（ＸＩ）で示されるアミン化合物を合成することができる。
一般式（Ｘ）で示される化合物に対して、ヒドラジン水和物を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
反応温度としては０〜１００℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＩ）で示される化合物は、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。

（ＸＩ）から（Ｉ−ｅ）の合成
縮合剤存在下、一般式（ＸＩＩ）で示されるアミン化合物と一般式（Ｘ）で示されるカルボン酸を縮合して、一般式（Ｉ−ｅ）で示されるアミド化合物を合成することができる。
一般式（ＸＩＩ）で示される化合物に対して、一般式（Ｘ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＩＩ）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、Ｎ−メチルモルホリン、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。一般式（ＸＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｅ）で示される化合物は、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 E: Synthesis of (Ie) from Compound (VII)

(Wherein each symbol is as defined above)
The alcohol represented by the general formula (IX) can be synthesized by the method described in Reference Examples 1 to 7 described later and a method analogous thereto.

Synthesis of (X) from (IX) Synthesis of a compound represented by general formula (X) by condensing an alcohol represented by general formula (IX) and phthalimide in the presence of an azo compound and a trivalent phosphorus compound. Can do.
1 to 3 molar equivalents of phthalimide can be used with respect to the compound represented by the general formula (IX).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, and the like.
Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).
Examples of the trivalent phosphorus compound include triphenylphosphine, tributylphosphine, and the like, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (X) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (XI) from (X) By treating the compound represented by the general formula (XI) with hydrazine hydrate, the amine compound represented by the general formula (XI) can be synthesized.
Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (X).
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 resulting compound represented by the general formula (XI) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (Ie) from (XI) In the presence of a condensing agent, the amine compound represented by the general formula (XII) and the carboxylic acid represented by the general formula (X) are condensed to form a compound represented by the general formula (Ie). The amide compounds shown can be synthesized.
The compound represented by the general formula (X) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride, and the like, which are represented by the general formula (XII). 0.5 to 2 molar equivalents can be used with respect to the compound to be obtained. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Ie) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｒ^１４はフェニル、４−ニトロフェニルであり、その他の各記号は前記と同意義である）
一般式（ＸＩ）で示される化合物に対して、一般式（ＸＩＩＩ）または（ＸＩＶ）で示される化合物を０．５〜３モル当量用いることができる。
反応溶媒としては、塩化メチレン、１，２−ジクロロエタン、トルエン、アセトニトリル、テトラヒドロフラン等が挙げられる。
必要であれば、トリエチルアミン、ジイソプロピルエチルアミン等のアミンを一般式（ＸＩＩ）で示される化合物に対して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。
得られた一般式（Ｉ−ｆ）で示される化合物は、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 F: Synthesis of (If) from Compound (XI) The amine represented by the general formula (XI) is reacted with an isocyanate represented by the general formula (XIII) or a carbamate represented by (XIV), The compound represented by If) can be synthesized.

(Wherein R ¹⁴ is phenyl, 4-nitrophenyl, and other symbols are as defined above)
The compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 mole equivalent based on the compound represented by the general formula (XI).
Examples of the reaction solvent include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran and the like.
If necessary, an amine such as triethylamine or diisopropylethylamine can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (If) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｘ^３は（ＣＲ^３Ｒ^４）ｓ；その他の各記号前記と同意義である）

（ＩＩ）から（ＸＶＩＩ）の合成
塩基存在下、一般式（ＩＩ）で示されるケトンと一般式（ＸＶ）または（ＸＶＩ）で示される有機リン化合物を縮合して、一般式（ＸＶＩＩ）で示される化合物を合成することができる。
一般式（ＩＩ）で示される化合物に対して、一般式（ＸＶ）または（ＸＶＩ）で示される有機リン化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、液体アンモニア等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド等が挙げられる。一般式（ＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
得られた一般式（ＸＶＩＩ）で示される化合物は、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。

（ＸＶＩＩ）から（ＸＶＩＩＩ）の合成
一般式（ＸＶＩＩ）で示される化合物を加水分解することにより、一般式（ＸＶＩＩＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＶＩＩ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＶＩＩＩ）で示される化合物は、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。

（ＸＶＩＩＩ）から（Ｉ−ｇ）の合成
縮合剤存在下、一般式（ＸＶＩＩＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｇ）で示されるアミド化合物を合成することができる。
一般式（ＸＶＩＩＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＶＩＩＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＶＩＩＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｇ）で示される化合物は、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 G: Synthesis of (Ig) from Compound (II)

(Wherein X ³ is (CR ³ R ⁴ ) s; other symbols are as defined above)

Synthesis of (XVII) from (II) In the presence of a base, a ketone represented by general formula (II) and an organophosphorus compound represented by general formula (XV) or (XVI) are condensed to form a compound represented by general formula (XVII). Can be synthesized.
The organic phosphorus compound represented by the general formula (XV) or (XVI) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia, and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (II).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XVII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XVIII) from (XVII) A carboxylic acid represented by the general formula (XVIII) can be synthesized by hydrolyzing the compound represented by the general formula (XVII).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XVII).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XVIII) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Synthesis of (Ig) from (XVIII) In the presence of a condensing agent, the carboxylic acid represented by the general formula (XVIII) and the amine compound represented by the general formula (XIX) are condensed to form a compound represented by the general formula (Ig). The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XVIII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XVIII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XVIII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Ig) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）

（ＸＶＩＩ）から（ＸＸ）の合成
金属触媒存在下、一般式（ＸＶＩＩ）で示される化合物を水素で還元することにより、一般式（ＸＸ）で示される化合物を合成することができる。
反応溶媒としては、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
金属触媒としては、５％パラジウム−炭素、１０％パラジウム−炭素、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）等が挙げられ、一般式（ＸＶＩＩ）で示される化合物に対して０．０１〜０．５重量パーセント用いることができる。
水素圧は１気圧〜５０気圧が挙げられる。
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。
得られた一般式（ＸＸ）で示される化合物は、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。

（ＸＸ）から（ＸＸＩ）の合成
一般式（ＸＸＩ）で示される化合物を加水分解することにより、一般式（ＸＸＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＩ）で示される化合物は、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。

（ＸＸＩ）から（Ｉ−ｈ）の合成
縮合剤存在下、一般式（ＸＸＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｈ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｈ）で示される化合物は、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 H: Synthesis of (Ih) from Compound (XVII)

(Wherein each symbol is as defined above)

Synthesis of (XX) from (XVII) The compound represented by the general formula (XX) can be synthesized by reducing the compound represented by the general formula (XVII) with hydrogen in the presence of a metal catalyst.
Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, chlorotris (triphenylphosphine) rhodium (I) and the like, and 0.01% relative to the compound represented by the general formula (XVII). Up to 0.5 weight percent can be used.
As for hydrogen pressure, 1 atmosphere-50 atmospheres are mentioned.
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 resulting compound represented by the general formula (XX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXI) from (XX) A carboxylic acid represented by the general formula (XXI) can be synthesized by hydrolyzing the compound represented by the general formula (XXI).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XX).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ih) from (XXI) In the presence of a condensing agent, a carboxylic acid represented by the general formula (XXI) and an amine compound represented by the general formula (XIX) are condensed to form a compound represented by the general formula (Ih). The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXI). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Ih) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｘ^４は（ＣＲ^３Ｒ^４）ｖであり、ｖは０〜２の整数であり、点線は結合の存在または不存在を示し、その他の各記号は前記と同意義である）

（ＸＶＩＩ−ａ）または（ＸＸ−ａ）から（ＸＸＩＩ）の合成
還元剤存在下、一般式（ＸＶＩＩ−ａ）または（ＸＸ−ａ）で示される化合物を還元して、一般式（ＸＸＩＩ）で示されるアルコールを合成することができる。
反応溶媒としては、ジエチルエーテル、テトラヒドロフラン、トルエン、エタノール等が挙げられ、単独または混合して用いることができる。
還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウム等が挙げられ、一般式（ＸＶＩＩ−ａ）または（ＸＸ−ａ）で示される化合物に対して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℃〜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。
得られた一般式（ＸＸＩＩ）で示される化合物は、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。

（ＸＸＩＩ）から（ＸＸＩＩＩ）の合成
アゾ化合物と３価のリン化合物の存在下、一般式（ＸＸＩＩ）で示されるアルコールとフタルイミドを縮合して、一般式（ＸＸＩＩＩ）で示される化合物を合成することができる。
一般式（ＸＸＩＩ）で示される化合物に対して、フタルイミドを１〜３モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル等が挙げられる。
アゾ化合物としては、アゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル等が挙げられ、一般式（ＸＸＩＩ）で示される化合物に対して１〜３モル当量用いることができる。
３価のリン化合物としては、トリフェニルホスフィン、トリブチルホスフィン等が挙げられ、一般式（ＸＸＩＩ）で示される化合物に対して１〜３モル当量用いることができる。
反応温度としては０℃〜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。
得られた一般式（ＸＸＩＩＩ）で示される化合物は、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。

（ＸＸＩＩＩ）から（ＸＸＩＶ）の合成
一般式（ＸＸＩＩＩ）で示される化合物をヒドラジン水和物と処理することにより、一般式（ＸＸＩＶ）で示されるアミン化合物を合成することができる。
一般式（ＸＸＩＩＩ）で示される化合物に対して、ヒドラジン水和物を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
反応温度としては０〜１００℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＩＶ）で示される化合物は、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。

（ＸＸＩＶ）から（Ｉ−ｉ）の合成
縮合剤存在下、一般式（ＸＸＩＶ）で示されるアミン化合物と一般式（ＸＩＩ）で示されるカルボン酸を縮合して、一般式（Ｉ−ｉ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＩＶ）で示される化合物に対して、一般式（ＸＩＩ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＩＶ）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、Ｎ−メチルモルホリン、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。一般式（ＸＸＩＶ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｉ）で示される化合物は、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 I: Synthesis of (Ii) from Compound (XVII-a) or (XX-a)

(Wherein, X ⁴ is (CR ³ R ⁴ ) v, v is an integer of 0 to 2, a dotted line indicates the presence or absence of a bond, and other symbols are as defined above)

Synthesis of (XXII) from (XVII-a) or (XX-a) In the presence of a reducing agent, the compound represented by the general formula (XVII-a) or (XX-a) is reduced to give the general formula (XXII) The indicated alcohol can be synthesized.
Examples of the reaction solvent include diethyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 0 for the compound represented by the general formula (XVII-a) or (XX-a). 0.5-6 molar equivalents can be used.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXIII) from (XXII) Synthesis of a compound represented by general formula (XXIII) by condensing an alcohol represented by general formula (XXII) and phthalimide in the presence of an azo compound and a trivalent phosphorus compound. Can do.
1 to 3 molar equivalents of phthalimide can be used with respect to the compound represented by the general formula (XXII).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, and the like.
Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXII).
Examples of the trivalent phosphorus compound include triphenylphosphine, tributylphosphine, and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXII).
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXIV) from (XXIII) An amine compound represented by the general formula (XXIV) can be synthesized by treating the compound represented by the general formula (XXIII) with hydrazine hydrate.
Hydrazine hydrate can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXIII).
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 resulting compound represented by the general formula (XXIV) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ii) from (XXIV) In the presence of a condensing agent, an amine compound represented by the general formula (XXIV) and a carboxylic acid represented by the general formula (XII) are condensed to form a compound represented by the general formula (Ii). The indicated amide compounds can be synthesized.
The compound represented by the general formula (XII) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXIV).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride, and the like, represented by the general formula (XXIV) 0.5 to 2 molar equivalents can be used with respect to the compound to be obtained. You may use 0.5-2 molar equivalent of 1-hydroxybenzotriazole as a condensation adjuvant.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXIV).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Ii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＸＸＩＶ）で示される化合物に対して、一般式（ＸＩＩＩ）または（ＸＩＶ）で示される化合物を０．５〜３モル当量用いることができる。
反応溶媒としては、塩化メチレン、１，２−ジクロロエタン、トルエン、アセトニトリル、テトラヒドロフラン等が挙げられる。
必要であれば、トリエチルアミン、ジイソプロピルエチルアミン等のアミンを一般式（ＸＸＶ）で示される化合物に対して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。
得られた一般式（Ｉ−ｊ）で示される化合物は、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 J: Synthesis of (Ij) from Compound (XXIV) The amine represented by the general formula (XXIV) is reacted with an isocyanate represented by the general formula (XIII) or a carbamate represented by (XIV), A compound represented by Ij) can be synthesized.

(Wherein each symbol is as defined above)
The compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 mole equivalent based on the compound represented by the general formula (XXIV).
Examples of the reaction solvent include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran and the like.
If necessary, an amine such as triethylamine or diisopropylethylamine can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XXV).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Ij) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、Ｌ^２はハロゲン原子、Ｃ_１−４アルキルスルホニルオキシ、Ｃ_６−９アリールスルホニルオキシであり、その他の各記号は前記と同意義である）

（ＸＸＩＩ）から（ＸＸＶ）の合成
一般式（ＸＸＩＩ）で示される化合物とハロゲン化剤、塩化アルキルスルホニルまたは塩化アリールスルホニルを反応して、一般式（ＸＸＶ）で示される化合物を合成することができる。
反応溶媒としては、アセトニトリル、塩化メチレン、テトラヒドロフラン、トルエン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
ハロゲン化剤としては、四塩化炭素／トリフェニルホスフィン、四臭化炭素／トリフェニルホスフィン等が挙げられ、一般式（ＸＸＩＩ）で示される化合物に対して、四塩化炭素または四臭化炭素は０．５〜４モル当量、トリフェニルホスフィンは０．５〜２モル当量用いることができる。
塩化アルキルスルホニル、塩化アリールスルホニルとしては、メタンスルホニルクロリド、ベンゼンスルホニルクロリド、トルエンスルホニルクロリド等が挙げられ、一般式（ＸＸＸ）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。この時、塩基としては、トリエチルアミン等を、一般式（ＸＸＩＩ）で示される化合物に対して１〜６モル当量用いることができる。
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。
得られた一般式（ＸＸＶ）で示される化合物は、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。

（ＸＸＶ）から（ＸＸＶＩ）の合成
一般式（ＸＸＶ）で示される化合物とシアン化剤を反応して、一般式（ＸＸＶＩ）で示されるシアン化合物を合成することができる。
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、ジメチルスルホキシド等が挙げられ、単独または混合して用いることができる。
シアン化剤としては、シアン化ナトリウム、シアン化カリウム、シアン化テトラブチルアンモニウム、シアン化テトラメチルアンモニウム等が挙げられ、一般式（ＸＸＶ）で示される化合物に対して、１〜３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。
得られた一般式（ＸＸＶＩ）で示される化合物は、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。

（ＸＸＶＩ）から（ＸＸＶＩＩ）の合成
一般式（ＸＸＶＩ）で示される化合物を加水分解することにより、一般式（ＸＸＶＩＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＶＩ）で示される化合物に対して、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜４８時間が挙げられる。
得られた一般式（ＸＸＶＩＩ）で示される化合物は、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。

（ＸＸＶＩＩ）から（Ｉ−ｋ）の合成
縮合剤存在下、一般式（ＸＸＶＩＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｋ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＶＩＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＶＩＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＶＩＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｋ）で示される化合物は、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 K: Synthesis of (Ik) from Compound (XXII)

(Wherein L ² represents a halogen atom, C _1-4 alkylsulfonyloxy, C _6-9 arylsulfonyloxy, and other symbols are as defined above)

Synthesis of (XXV) from (XXII) A compound represented by general formula (XXV) can be synthesized by reacting a compound represented by general formula (XXII) with a halogenating agent, alkylsulfonyl chloride or arylsulfonyl chloride. .
Examples of the reaction solvent include acetonitrile, methylene chloride, tetrahydrofuran, toluene, N, N-dimethylformamide and the like.
Examples of the halogenating agent include carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine, and the like. In the compound represented by the general formula (XXII), carbon tetrachloride or carbon tetrabromide is 0. 0.5-4 molar equivalents, and 0.5-2 molar equivalents of triphenylphosphine can be used.
Examples of the alkylsulfonyl chloride and arylsulfonyl chloride include methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXX). At this time, triethylamine or the like can be used as the base in an amount of 1 to 6 molar equivalents relative to the compound represented by the general formula (XXII).
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 resulting compound represented by the general formula (XXV) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXVI) from (XXV) A cyanide compound represented by the general formula (XXVI) can be synthesized by reacting a compound represented by the general formula (XXV) with a cyanating agent.
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these can be used alone or in combination.
Examples of the cyanating agent include sodium cyanide, potassium cyanide, tetrabutylammonium cyanide, tetramethylammonium cyanide and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXV). .
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXVI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXVII) from (XXVI) A carboxylic acid represented by the general formula (XXVII) can be synthesized by hydrolyzing the compound represented by the general formula (XXVI).
Sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXVI).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
The reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (XXVII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ik) from (XXVII) In the presence of a condensing agent, a carboxylic acid represented by general formula (XXVII) and an amine compound represented by general formula (XIX) are condensed to form (Ik) The indicated amide compounds can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXVII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXVII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXVII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Ik) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）

（ＸＸＩＩ）から（ＸＸＶＩＩＩ）の合成
一般式（ＸＸＩＩ）で示される化合物を酸化剤と反応させ一般式（ＸＸＶＩＩＩ）で示される化合物を合成することができる。
反応溶媒としては、酢酸エチル、塩化メチレン、ジメチルスルホキシド等が挙げられる。
酸化剤としては１−ヒドロキシ−１，２−ベンズヨードオキソール−３（１Ｈ）−オン １−オキシド、１，１−ジヒドロ−１，１，１−トリアセトキシ−１，２−ベンズヨードオキソール−３（１Ｈ）−オン等が挙げられ、一般式（ＸＸＩＩ）で示される化合物に対して１〜５モル当量用いることができる。
反応温度としては０〜５０℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＶＩＩＩ）で示される化合物は、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。

（ＸＸＶＩＩＩ）から（ＸＸＸ）の合成
塩基存在下、一般式（ＸＸＶＩＩＩ）で示される化合物と、一般式（ＸＸＩＸ）で示される有機リン化合物を縮合して、一般式（ＸＸＸ）で示される化合物を合成することができる。
一般式（ＸＸＶＩＩＩ）で示される化合物に対して、一般式（ＸＸＩＸ）で示される有機リン化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、液体アンモニア等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド等が挙げられる。一般式（ＸＸＶＩＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
得られた一般式（ＸＸＸ）で示される化合物は、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。

（ＸＸＸ）から（ＸＸＸＩ）の合成
一般式（ＸＸＸ）で示される化合物を加水分解することにより、一般式（ＸＸＸＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＸ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＩ）で示される化合物は、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。

（ＸＸＸＩ）から（Ｉ−ｌ）の合成
縮合剤存在下、一般式（ＸＸＸＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｌ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｌ）で示される化合物は、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 L: Synthesis of (I-1) from Compound (XXII)

(Wherein each symbol is as defined above)

Synthesis of (XXVIII) from (XXII) A compound represented by the general formula (XXVIII) can be synthesized by reacting a compound represented by the general formula (XXII) with an oxidizing agent.
Examples of the reaction solvent include ethyl acetate, methylene chloride, dimethyl sulfoxide and the like.
1-hydroxy-1,2-benziodooxol-3 (1H) -one 1-oxide, 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodooxol as the oxidizing agent -3 (1H) -one and the like, and can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (XXII).
As reaction temperature, 0-50 degreeC is mentioned.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXVIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXX) from (XXVIII) In the presence of a base, a compound represented by the general formula (XXVIII) and an organophosphorus compound represented by the general formula (XXIX) are condensed to give a compound represented by the general formula (XXX). Can be synthesized.
The organic phosphorus compound represented by the general formula (XXIX) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (XXVIII).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia, and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXVIII).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXXI) from (XXX) A carboxylic acid represented by the general formula (XXXI) can be synthesized by hydrolyzing the compound represented by the general formula (XXX).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXX).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Il) from (XXXI) In the presence of a condensing agent, the carboxylic acid represented by the general formula (XXXI) and the amine compound represented by the general formula (XIX) are condensed to form the general formula (Il). The indicated amide compounds can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXXI). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (I-1) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＸＸＸＩＩ）で示される化合物は、後述の参考例４〜７に記載の方法、ならびにそれらに準ずる方法で合成することができる。

（ＸＸＸＩＩ）から（ＸＸＸＩＩＩ）の合成
アゾ化合物と３価のリン化合物の存在下、一般式（ＸＸＸＩＩ）で示されるアルコールとフタルイミドを縮合して、一般式（ＸＸＸＩＩＩ）で示される化合物を合成することができる。
一般式（ＸＸＸＩＩ）で示される化合物に対して、フタルイミドを１〜３モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル等が挙げられる。
アゾ化合物としては、アゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル等が挙げられ、一般式（ＸＸＸＩＩ）で示される化合物に対して１〜３モル当量用いることができる。
３価のリン化合物としては、トリフェニルホスフィン、トリブチルホスフィン等が挙げられ、一般式（ＸＸＸＩＩ）で示される化合物に対して１〜３モル当量用いることができる。
反応温度としては０℃〜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。
得られた一般式（ＸＸＸＩＩＩ）で示される化合物は、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。

（ＸＸＸＩＩＩ）から（ＸＸＸＩＶ）の合成
一般式（ＸＸＸＩＩＩ）で示される化合物をヒドラジン水和物と処理することにより、一般式（ＸＸＸＩＶ）で示されるアミン化合物を合成することができる。
一般式（ＸＸＸＩＩＩ）で示される化合物に対して、ヒドラジン水和物を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
反応温度としては０〜１００℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＩＶ）で示される化合物は、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。

（ＸＸＸＩＶ）から（Ｉ−ｍ）の合成
縮合剤存在下、一般式（ＸＸＸＩＶ）で示されるアミン化合物と一般式（ＸＸＸＶ）で示されるカルボン酸を縮合して、一般式（Ｉ−ｍ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＩＶ）で示される化合物に対して、一般式（ＸＸＸＶ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＩＶ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＩＶ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｍ）で示される化合物は、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 M: Synthesis of (Im) from Compound (XXXII)

(Wherein each symbol is as defined above)
The compound represented by the general formula (XXXII) can be synthesized by the method described in Reference Examples 4 to 7 described later and a method analogous thereto.

Synthesis of (XXXIII) from (XXXII) In the presence of an azo compound and a trivalent phosphorus compound, an alcohol represented by general formula (XXXII) and phthalimide are condensed to synthesize a compound represented by general formula (XXXIII). Can do.
1 to 3 molar equivalents of phthalimide can be used with respect to the compound represented by the general formula (XXXII).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, and the like.
Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like, and can be used at 1 to 3 mole equivalents relative to the compound represented by the general formula (XXXII).
Examples of the trivalent phosphorus compound include triphenylphosphine, tributylphosphine, and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXXII).
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXXIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXXIV) from (XXXIII) By treating a compound represented by the general formula (XXXIII) with hydrazine hydrate, an amine compound represented by the general formula (XXXIV) can be synthesized.
Hydrazine hydrate can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXIII).
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 resulting compound represented by the general formula (XXXIV) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Im) from (XXXIV) In the presence of a condensing agent, an amine compound represented by general formula (XXXIV) and a carboxylic acid represented by general formula (XXXV) are condensed to form general formula (Im) The indicated amide compounds can be synthesized.
The compound represented by the general formula (XXXV) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXIV).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride, and the like, represented by the general formula (XXXIV) 0.5 to 2 molar equivalents can be used with respect to the compound to be obtained. 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXIV).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound represented by the general formula (Im) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）

（ＸＶＩＩＩ）から（ＸＸＸＶＩ）の合成
縮合剤存在下、一般式（ＸＶＩＩＩ）で示されるカルボン酸とＮ，Ｏ−ジメチルヒドロキシルアミン塩酸塩を縮合して、一般式（ＸＸＸＶＩ）で示されるアミド化合物を合成することができる。
一般式（ＸＶＩＩＩ）で示される化合物に対して、Ｎ，Ｏ−ジメチルヒドロキシルアミン塩酸塩等を０．５〜３モル当量用いることができる。
反応溶媒としては、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、単独または混合して用いることができる。
縮合剤としては、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＶＩＩＩ）で示される化合物に対して、１〜３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等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、Ｎ−メチルモルホリン、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。一般式（ＸＶＩＩＩ）で示される化合物に対して、それぞれ０．０５〜３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。
反応時間としては０．５〜７２時間が挙げられる。
得られた一般式（ＸＸＸＶＩ）で示される化合物は、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。

（ＸＸＸＶＩ）から（Ｉ−ｎ）の合成
一般式（ＸＸＸＶＩ）で示されるアミド化合物に一般式（ＸＸＸＶＩＩ）で示される有機金属化合物を反応させ、一般式（Ｉ−ｎ）で示される化合物を合成することができる。
一般式（ＸＸＸＶＩ）で示されるアミド化合物に対して、一般式（ＸＸＸＶＩＩ）で示される化合物を１〜３モル当量用いることができる。
反応溶媒としては、ジエチルエーテル、テトラヒドロフラン等が挙げられる。
反応温度としては−７０〜５０℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（Ｉ−ｎ）で示される化合物は、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 N: Synthesis of (In) from Compound (XVIII)

(Wherein each symbol is as defined above)

Synthesis of (XXXVI) from (XVIII) In the presence of a condensing agent, a carboxylic acid represented by general formula (XVIII) and N, O-dimethylhydroxylamine hydrochloride are condensed to form an amide compound represented by general formula (XXXVI). Can be synthesized.
N, O-dimethylhydroxylamine hydrochloride or the like can be used at 0.5 to 3 mole equivalent based on the compound represented by the general formula (XVIII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like, and these can be used alone or in combination.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XVIII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 3 mole equivalent based on the compound represented by the general formula (XVIII).
Examples of the reaction temperature include 0 to 80 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXXVI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (In) from (XXXVI) The amide compound represented by the general formula (XXXVI) is reacted with the organometallic compound represented by the general formula (XXXVII) to synthesize the compound represented by the general formula (In). can do.
The compound represented by the general formula (XXXVII) can be used at 1 to 3 mole equivalents relative to the amide compound represented by the general formula (XXXVI).
Examples of the reaction solvent include diethyl ether and tetrahydrofuran.
An example of a reaction temperature is -70 to 50 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (In) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
反応溶媒としては、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
金属触媒としては、５％パラジウム−炭素、１０％パラジウム−炭素、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）が挙げられ、一般式（Ｉ−ｎ）で示される化合物に対して０．０１〜０．５重量パーセント用いることができる。
水素圧は１〜５０気圧が挙げられる。
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。
得られた一般式（Ｉ−ｏ）で示される化合物は、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 O: Synthesis of (Io) from Compound (In) The compound represented by General Formula (Io) is synthesized by reducing the compound represented by General Formula (In) with hydrogen. be able to.

(Wherein each symbol is as defined above)
Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, and chlorotris (triphenylphosphine) rhodium (I). 01-0.5 weight percent can be used.
As for hydrogen pressure, 1-50 atmospheres is mentioned.
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 resulting compound represented by the general formula (Io) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（Ｉ−ｎ）または（Ｉ−ｏ）で示されるケトンに対して、一般式（ＸＸＸＶＩＩＩ）で示される化合物を０．５〜３モル当量用いることができる。一般式（ＸＸＸＶＩＩＩ）で示される化合物の塩酸塩または硫酸塩を用いてもよい。
反応溶媒としては、メタノール、エタノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
トリエチルアミンなどの塩基や、酢酸ナトリウム、酢酸カリウム等の塩を一般式（Ｉ−ｎ）または（Ｉ−ｏ）で示されるケトンに対して０．５〜５モル当量用いてもよい。
反応温度としては０〜８０℃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。
得られた一般式（Ｉ−ｐ）で示される化合物は、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 P: Synthesis of (Ip) from Compound (In) or (Io) Compound represented by General Formula (XXXVIII) as a ketone represented by General Formula (In) or (Io) Can be synthesized to synthesize an oxime compound represented by the general formula (Ip).

(Wherein each symbol is as defined above)
The compound represented by the general formula (XXXVIII) can be used at 0.5 to 3 molar equivalents relative to the ketone represented by the general formula (In) or (Io). Hydrochloride or sulfate of the compound represented by the general formula (XXXVIII) may be used.
Examples of the reaction solvent include methanol, ethanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
A base such as triethylamine or a salt such as sodium acetate or potassium acetate may be used in an amount of 0.5 to 5 molar equivalents relative to the ketone represented by the general formula (In) or (Io).
Examples of the reaction temperature include 0 to 80 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Ip) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
反応溶媒としては、ジエチルエーテル、テトラヒドロフラン、トルエン、エタノール等が挙げられ、単独または混合して用いることができる。
還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウム等が挙げられ、一般式（Ｉ−ｎ）または（Ｉ−ｏ）で示される化合物に対して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℃〜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。
得られた一般式（Ｉ−ｑ）で示される化合物は、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 Q: Synthesis of Compound (In) or (Io) to (Iq) In the presence of a reducing agent, the compound represented by formula (In) or (Io) is reduced, Alcohols represented by general formula (Iq) can be synthesized.

(Wherein each symbol is as defined above)
Examples of the reaction solvent include diethyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 0 for the compound represented by the general formula (In) or (Io). 0.5-6 molar equivalents can be used.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Iq) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＸＸＸＩＸ）で示される化合物は、特開昭６２−２５８３４２に記載の方法、ならびにそれらに準ずる方法で合成することができる。

（ＩＩ）から（ＸＸＸＸ）の合成
塩基存在下、一般式（ＩＩ）で示される化合物と、一般式（ＸＸＸＩＸ）で示される有機リン化合物を縮合した後、酸処理することにより一般式（ＸＸＸＸ）で示される化合物を合成することができる。
一般式（ＩＩ）で示される化合物に対して、一般式（ＸＸＸＩＸ）で示される有機リン化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、液体アンモニア等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド等が挙げられる。一般式（ＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
酸処理で用いる酸としてはｐ−トルエンスルホン酸、ベンゼンスルホン酸、塩酸、硫酸等が挙げられ、（ＩＩ）で示される化合物に対して０．１〜１０モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、トルエン、水等が挙げられ、単独または混合して用いることができる。
反応温度としては２０〜１００℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸ）で示される化合物は、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。

（ＸＸＸＸ）から（ＸＸＸＸＩ）の合成
一般式（ＸＸＸＸ）で示される化合物を加水分解することにより、一般式（ＸＸＸＸＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＸＸ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸＩ）で示される化合物は、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。

（ＸＸＸＸＩ）から（Ｉ−ｒ）の合成
縮合剤存在下、一般式（ＸＸＸＸＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｒ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＸＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＸＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＸＩ）で示される化合物に対して、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。
なお縮合剤として、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等を使用した場合は、反応時間が短縮されうる。
得られた一般式（Ｉ−ｒ）で示される化合物は、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 R: Synthesis of (Ir) from Compound (II)

(Wherein each symbol is as defined above)
The compound represented by the general formula (XXXIX) can be synthesized by the method described in JP-A-62-258342 and a method analogous thereto.

Synthesis of (XXXX) from (II) In the presence of a base, the compound represented by the general formula (II) and the organophosphorus compound represented by the general formula (XXXIX) are condensed and then treated with an acid to give the general formula (XXXX) Can be synthesized.
The organophosphorus compound represented by the general formula (XXXIX) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia, and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (II).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
Examples of the acid used in the acid treatment include p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like, and can be used in an amount of 0.1 to 10 molar equivalents relative to the compound represented by (II).
Examples of the reaction solvent include methanol, ethanol, toluene, water and the like, and these can be used alone or in combination.
An example of a reaction temperature is 20 to 100 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXXXI) from (XXXX) The carboxylic acid represented by the general formula (XXXXI) can be synthesized by hydrolyzing the compound represented by the general formula (XXXX).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXX).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXXI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Ir) from (XXXXI) In the presence of a condensing agent, the carboxylic acid represented by the general formula (XXXXI) and the amine compound represented by the general formula (XIX) are condensed to form the general formula (Ir). The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXXI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXXXI). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXXI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The reaction time can be shortened when ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride or the like is used as the condensing agent.
The resulting compound represented by the general formula (Ir) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
（ＸＸＸＸ）から（ＸＸＸＸＩＩ）の合成
還元剤存在下、一般式（ＸＸＸＸ）で示される化合物を還元して、一般式（ＸＸＸＸＩＩ）で示されるアルコールを合成することができる。
反応溶媒としては、ジエチルエーテル、テトラヒドロフラン、トルエン、エタノール等が挙げられ、単独または混合して用いることができる。
還元剤としては、水素化ホウ素ナトリウム等が挙げられ、一般式（ＸＸＸＸ）で示される化合物に対して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℃〜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。
得られた一般式（ＸＸＸＸＩＩ）で示される化合物は、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。

（ＸＸＸＸＩＩ）から（ＸＸＸＸＩＩＩ）の合成
一般式（ＸＸＸＸＩＩ）で示される化合物を加水分解することにより、一般式（ＸＸＸＸＩＩＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＸＸＩＩ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸＩＩＩ）で示される化合物は、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。

（ＸＸＸＸＩＩＩ）から（Ｉ−ｓ）の合成
縮合剤存在下、一般式（ＸＸＸＸＩＩＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｓ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＸＩＩＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＸＩＩＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＸＩＩＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｓ）で示される化合物は、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 S: Synthesis of (Is) from compound (XXXX)

(Wherein each symbol is as defined above)
Synthesis of (XXXXII) from (XXXX) In the presence of a reducing agent, the compound represented by the general formula (XXXX) can be reduced to synthesize the alcohol represented by the general formula (XXXXII).
Examples of the reaction solvent include diethyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium borohydride and the like, and it can be used at 0.5 to 6 molar equivalents relative to the compound represented by the general formula (XXXX).
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXXXII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (XXXXIII) from (XXXXII) A carboxylic acid represented by the general formula (XXXXIII) can be synthesized by hydrolyzing the compound represented by the general formula (XXXXII).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXXII).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXXIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Is) from (XXXXIII) In the presence of a condensing agent, a carboxylic acid represented by general formula (XXXXIII) and an amine compound represented by general formula (XIX) are condensed to form general formula (Is). The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXXIII).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXXXIII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXXIII).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (I-s) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
（ＸＸＸＸＩＩ）から（ＸＸＸＸＶ）の合成
塩基存在下、一般式（ＸＸＸＸＩＩ）で示される化合物と、一般式（ＸＸＸＸＩＶ）で示される化合物を反応することにより、一般式（ＸＸＸＸＶ）で示される化合物を合成することができる。
一般式（ＸＸＸＸＩＩ）で示される化合物に対して、一般式（ＸＸＸＸＩＶ）で示される化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等が挙げられる。一般式（ＸＸＸＸＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
得られた一般式（ＸＸＸＸＶ）で示される化合物は、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。

（ＸＸＸＸＶ）から（ＸＸＸＸＶＩ）の合成
一般式（ＸＸＸＸＶ）で示される化合物を加水分解することにより、一般式（ＸＸＸＸＶＩ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＸＸＶ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸＶＩ）で示される化合物は、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。

（ＸＸＸＸＶＩ）から（Ｉ−ｔ）の合成
縮合剤存在下、一般式（ＸＸＸＸＶＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｔ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＸＶＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＸＶＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＸＶＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｔ）で示される化合物は、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 T: Synthesis of (It) from compound (XXXXII)

(Wherein each symbol is as defined above)
Synthesis of (XXXXV) from (XXXXII) By reacting a compound represented by general formula (XXXXII) with a compound represented by general formula (XXXXIV) in the presence of a base, a compound represented by general formula (XXXXV) is synthesized. can do.
The compound represented by the general formula (XXXXIV) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (XXXXII).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido and potassium hexamethyldisilazide. The base can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXXII).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (XXXXV) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXXXVI) from (XXXXV) A carboxylic acid represented by the general formula (XXXXVI) can be synthesized by hydrolyzing the compound represented by the general formula (XXXXV).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXXV).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXXVI) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (It) from (XXXXVI) In the presence of a condensing agent, a carboxylic acid represented by the general formula (XXXXVI) and an amine compound represented by the general formula (XIX) are condensed to form a compound represented by the general formula (It). The indicated amide compounds can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXXVI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXXXVI). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXXVI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (It) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
（ＩＩ）から（ＸＸＸＸＶＩＩＩ）の合成
塩基存在下、一般式（ＩＩ）で示される化合物と、一般式（ＸＸＸＸＶＩＩ）で示される化合物を縮合することにより、一般式（ＸＸＸＸＶＩＩＩ）で示される化合物を合成することができる。
一般式（ＩＩ）で示される化合物に対して、一般式（ＸＸＸＸＶＩＩ）で示される化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等が挙げられる。
塩基としては、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムジイソプロピルアミン、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等が挙げられる。一般式（ＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−１００〜２０℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸＶＩＩＩ）で示される化合物は、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。

（ＸＸＸＸＶＩＩＩ）から（ＸＸＸＸＩＸ）の合成
一般式（ＸＸＸＸＶＩＩＩ）で示される化合物を加水分解することにより、一般式（ＸＸＸＸＩＸ）で示されるカルボン酸を合成することができる。
一般式（ＸＸＸＸＶＩＩＩ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＸＸＸＸＩＸ）で示される化合物は、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。

（ＸＸＸＸＩＸ）から（Ｉ−ｕ）の合成
縮合剤存在下、一般式（ＸＸＸＸＩＸ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｕ）で示されるアミド化合物を合成することができる。
一般式（ＸＸＸＸＩＸ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＸＸＸＸＩＸ）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等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、Ｎ−メチルモルホリン、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。一般式（ＸＸＸＸＩＸ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｕ）で示される化合物は、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 U: Synthesis of (Iu) from Compound (II)

(Wherein each symbol is as defined above)
Synthesis of (XXXXVIII) from (II) In the presence of a base, a compound represented by general formula (XXXXVIII) is synthesized by condensing a compound represented by general formula (II) and a compound represented by general formula (XXXXVII). can do.
The compound represented by the general formula (XXXXVII) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like.
Bases include sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide Etc. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction temperature include −100 to 20 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXXVIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (XXXXIX) from (XXXXVIII) A carboxylic acid represented by the general formula (XXXXIX) can be synthesized by hydrolyzing the compound represented by the general formula (XXXXVIII).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (XXXXVIII).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (XXXIX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Iu) from (XXXIX) In the presence of a condensing agent, a carboxylic acid represented by the general formula (XXXIX) and an amine compound represented by the general formula (XIX) are condensed to form a compound represented by the general formula (Iu). The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXIX).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXXIX). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXIX).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Iu) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
（ＸＶＩＩ−ａ）から（Ｌ）の合成
一般式（ＸＶＩＩ−ａ）で示される化合物を塩基と処理することにより、一般式（Ｌ）で示される化合物を合成することができる。
一般式（ＸＶＩＩ−ａ）で示される化合物に対して、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ｎ−ブチルリチウム、カリウムtert−ブトキシド、１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン等の塩基を０．１〜１０モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、トルエン等が挙げられる。
反応温度としては−７０〜１００℃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。
得られた一般式（Ｌ）で示される化合物は、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。

（Ｌ）から（ＬＩ）の合成
一般式（Ｌ）で示される化合物を加水分解することにより、一般式（ＬＩ）で示されるカルボン酸を合成することができる。
一般式（Ｌ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＬＩ）で示される化合物は、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。

（ＬＩ）から（Ｉ−ｖ）の合成
縮合剤存在下、一般式（ＬＩ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｖ）で示されるアミド化合物を合成することができる。
一般式（ＬＩ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＬＩ）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等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、Ｎ−メチルモルホリン、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。一般式（ＬＩ）で示される化合物に対して、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。
得られた一般式（Ｉ−ｖ）で示される化合物は、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 V: Synthesis of (Iv) from Compound (XVII-a)

(Wherein each symbol is as defined above)
Synthesis of (L) from (XVII-a) The compound represented by the general formula (L) can be synthesized by treating the compound represented by the general formula (XVII-a) with a base.
Lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium, potassium tert-butoxide, 1,8-diazabicyclo [5.4.0] undeca with respect to the compound represented by the general formula (XVII-a) A base such as 7-ene can be used in an amount of 0.1 to 10 molar equivalents.
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, toluene and the like.
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (L) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).

Synthesis of (LI) from (L) The carboxylic acid represented by the general formula (LI) can be synthesized by hydrolyzing the compound represented by the general formula (L).
Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (L).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (LI) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (Iv) from (LI) In the presence of a condensing agent, a carboxylic acid represented by the general formula (LI) and an amine compound represented by the general formula (XIX) are condensed to form a compound represented by the general formula (Iv). The indicated amide compounds can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (LI).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (LI). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (LI).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Iv) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＸＸＸＩＩ）で示される化合物は、後述の参考例１０に記載の方法、ならびにそれらに準ずる方法で合成することができる。また、一般式（ＬＩＩＩ）および（ＬＩＶ）で示される有機リン化合物は、新実験化学講座１４, 丸善株式会社 （１９７７）に記載の方法、ならびにそれに準ずる方法で合成することができる。
一般式（ＬＩＩ）で示される化合物に対して、一般式（ＬＩＩＩ）または（ＬＩＶ）で示される有機リン化合物を１〜５モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、液体アンモニア等が挙げられる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、n−ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド等が挙げられる。一般式（ＬＩＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−７０〜１００℃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。
得られた一般式（Ｉ−ｗ）で示される化合物は、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 W: Synthesis of (Iw) from Compound (LII) In the presence of a base, an aldehyde represented by General Formula (LII) and an organic phosphorus compound represented by General Formula (LIII) or (LIV) are condensed to form A compound represented by the formula (Iw) can be synthesized.

(Wherein each symbol is as defined above)
The compound represented by the general formula (XXXII) can be synthesized by the method described in Reference Example 10 described later and a method analogous thereto. In addition, the organophosphorus compounds represented by the general formulas (LIII) and (LIV) can be synthesized by the method described in New Experimental Chemistry Course 14, Maruzen Co., Ltd. (1977) and a method analogous thereto.
The organophosphorus compound represented by the general formula (LIII) or (LIV) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (LII).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia, and the like.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Examples thereof include zido, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (LII).
An example of a reaction temperature is -70 to 100 ° C.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Iw) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
反応溶媒としては、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。
金属触媒としては、５％パラジウム−炭素、１０％パラジウム−炭素、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）が挙げられ、一般式（Ｉ−ａ）で示される化合物に対して０．０１〜０．５重量パーセント用いることができる。
水素圧は１〜５０気圧が挙げられる。
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。
得られた一般式（Ｉ−ｘ）で示される化合物は、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 X: Synthesis of Compound (Iw) from Compound (Iw) In the presence of a metal catalyst, the compound represented by Formula (Iw) is reduced with hydrogen to give a compound represented by Formula (Ix). Can be synthesized.

(Wherein each symbol is as defined above)
Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, and chlorotris (triphenylphosphine) rhodium (I). 01-0.5 weight percent can be used.
As for hydrogen pressure, 1-50 atmospheres is mentioned.
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 resulting compound represented by the general formula (Ix) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
一般式（ＩＩ）で示される化合物に対して、一般式（ＬＶ）で示される化合物を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等が挙げられ、一般式（ＩＩ）で示される化合物に対して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、酸として酢酸等を一般式（ＩＩ）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。
反応時間としては０．５〜７２時間が挙げられる。
得られた一般式（Ｉ−ｙ）で示される化合物は、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 Y: Synthesis of (Iy) from Compound (II) A compound represented by general formula (II) and a compound represented by general formula (LV) are reductively condensed to form general formula (Iy) The compounds shown can be synthesized.

(Wherein each symbol is as defined above)
The compound represented by the general formula (LV) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (II).
Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
Examples of the reducing agent include sodium triacetoxyborohydride and the like, and 0.5 to 6 molar equivalents can be used with respect to the compound represented by the general formula (II).
Examples of the reaction temperature include 0 to 80 ° C.
If necessary, acetic acid or the like as an acid can be used in an amount of 0.5 to 2 molar equivalents relative to the compound represented by the general formula (II).
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (Iy) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

（式中、各記号は前記と同意義である）
（ＬＶＩ）から（ＬＶＩＩＩ）の合成
塩基存在下、一般式（ＬＶＩ）で示される化合物と、一般式（ＬＶＩＩ）で示される化合物を縮合することにより、一般式（ＬＶＩＩＩ）で示される化合物を合成することができる。
一般式（ＬＶＩ）で示される化合物に対して、一般式（ＬＶＩＩ）で示される化合物を１〜３モル当量用いることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、塩化メチレン、クロロホルム、トルエン、水等が挙げられ、単独または混合して用いることができる。
塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、水素化カリウム、トリエチルアミン、モルホリン、Ｎ−メチルモルホリン等が挙げられる。一般式（ＬＶＩ）で示される化合物に対して、１．０〜５モル当量用いることができる。
反応温度としては−１０〜５０℃が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＬＶＩＩＩ）で示される化合物は、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。

（ＬＶＩＩＩ）から（ＬＩＸ）の合成
一般式（ＬＶＩＩＩ）で示される化合物を加水分解することにより、一般式（ＬＩＸ）で示されるカルボン酸を合成することができる。
一般式（ＬＶＩＩＩ）で示される化合物に対して、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等を１．０〜５モル当量用いることができる。
反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
反応温度としては０℃〜溶媒の還流温度が挙げられる。
反応時間としては０．５〜２４時間が挙げられる。
得られた一般式（ＬＩＸ）で示される化合物は、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。

（ＬＩＸ）から（Ｉ−ｚ）の合成
縮合剤存在下、一般式（ＬＩＸ）で示されるカルボン酸と一般式（ＸＩＸ）で示されるアミン化合物を縮合して、一般式（Ｉ−ｚ）で示されるアミド化合物を合成することができる。
一般式（ＬＩＸ）で示される化合物に対して、一般式（ＸＩＸ）で示される化合物を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、Ｎ，Ｎ−ジメチルアセトアミド、１，３−ジメチル−２−イミダゾリジノン、Ｎ−メチル−2−ピロリドン等が挙げられる。
縮合剤としては、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩、Ｎ，Ｎ’−カルボニルジイミダゾール、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等が挙げられ、一般式（ＬＩＸ）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等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、Ｎ−メチルモルホリン、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。一般式（ＬＩＸ）で示される化合物に対して、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。
なお縮合剤として、クロロ炭酸エチル、クロロ炭酸イソブチル、塩化チオニル、塩化オキサリル等を使用した場合は、反応時間が短縮されうる。
得られた一般式（Ｉ−ｚ）で示される化合物は、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 Z: Synthesis of (Iz) from Compound (LVI)

(Wherein each symbol is as defined above)
Synthesis of (LVIII) from (LVI) In the presence of a base, a compound represented by general formula (LVIII) is synthesized by condensing a compound represented by general formula (LVI) and a compound represented by general formula (LVII). can do.
The compound represented by the general formula (LVII) can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (LVI).
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, acetonitrile, methylene chloride, chloroform, toluene, water and the like, and these can be used alone or in combination.
Examples of the base include sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, triethylamine, morpholine, N-methylmorpholine and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (LVI).
Examples of the reaction temperature include -10 to 50 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (LVIII) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (LIX) from (LVIII) A carboxylic acid represented by the general formula (LIX) can be synthesized by hydrolyzing the compound represented by the general formula (LVIII).
Lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like can be used at 1.0 to 5 mole equivalent based on the compound represented by the general formula (LVIII).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and they can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (LIX) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Synthesis of (Iz) from (LIX) In the presence of a condensing agent, a carboxylic acid represented by general formula (LIX) and an amine compound represented by general formula (XIX) are condensed to form (Iz) The amide compounds shown can be synthesized.
The compound represented by the general formula (XIX) can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (LIX).
Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, N-methyl-2-pyrrolidone and the like.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride and the like. And 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (LIX). 1-Hydroxybenzotriazole or the like may be used as a condensation aid at 0.5 to 2 molar equivalents.
Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (LIX).
As reaction temperature, 0-100 degreeC is mentioned.
An example of the reaction time is 0.5 to 72 hours.
The reaction time can be shortened when ethyl chlorocarbonate, isobutyl chlorocarbonate, thionyl chloride, oxalyl chloride or the like is used as the condensing agent.
The resulting compound represented by the general formula (Iz) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Note that a least one of the amino being hydroxy and / or protected A ¹ is protected, yet another nitrogen-containing aromatic substituted with a group monocyclic group or a nitrogen-containing aromatic fused 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 Synthesis, Second Edition, John Wiley & Sons (1991)). The protecting group can be deprotected.

  When the compound contained in the analgesic of the present invention contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these isomers are also used as a compound contained in the analgesic of the present invention. Each of the isomers can be obtained as a single product by a known synthesis method or separation method. For example, when an optical isomer exists in a compound contained in the analgesic of the present invention, an optical isomer resolved from the compound is also included in the compound contained in the analgesic 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 method Racemate and optically active compound (for example, (+)-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. .
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to 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 the 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 made into a mixture of diastereomers by a 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.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction. For example, when the compound contained in the analgesic 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) phenyl Acetic acid], (-)-menthoxyacetic acid and the like) are subjected to a condensation reaction, whereby ester or amide diastereomers can be obtained, respectively. On the other hand, when the compound contained in the analgesic agent 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.

As the salt of the compound contained in the analgesic of the present invention, a pharmaceutically acceptable salt can be used. Examples of the basic addition salt include alkali metal salts such as sodium salt and potassium salt; for example calcium salt and magnesium salt Alkaline earth metal salts such as ammonium salts; trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts; Aralkylamine salts such as benzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt Umushio, benzyl tributyl ammonium 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 acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates and perchlorates; for example, oxalates, acetates, propionates and lactates. , 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, acetone, ethyl acetate, methanol, ethanol and the like. The solvation number of the solvate of the compound contained in the analgesic of the present invention can usually vary depending on the synthesis method, purification method, crystallization conditions, etc. It is.

Of the compounds (I) contained in the analgesic of the present invention, the following compounds are particularly preferred.
In formula (I), (CR ^a R ^b ) w is (CH ₂ ) ₂ or (CH ₂ ) ₃ , (CR ^c R ^d ) t is CH ₂ or CHMe,
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- A compound (hereinafter, A ¹ is a1), which is benzimidazolyl, which may be substituted with a ring-constituting atom other than NH-;
2) A compound in which A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, benzpyrazolyl, benzimidazolyl, unsubstituted imidazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl or unsubstituted benzimidazolyl (hereinafter A ¹ is a2 ),
3) A compound in which A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, unsubstituted imidazolyl, unsubstituted pyrazolyl or unsubstituted pyrrolyl (hereinafter, A ¹ is assumed to be a3),
4) A compound in which A ¹ is hydroxybenzoxazolyl (hereinafter, A ¹ is a4),

5) X is ^{- (CHR 3) m -,} - CO (CHR 3) n -, - CONH (CHR 3) n -, - NHCO (CHR 3) n -, - NHCONH -, - NHCOCO- or -NH ( CHR ³ ) mCO— (each R ³ may be different), Z is N or CR ¹ , and R ¹ and R ² are each independently hydrogen, hydroxy or methyl, or R ¹ and R ² may form a single bond together, when m or n is 1 or more, together with R ¹ is CR ³ R ⁴ on the R ³ and the adjacent carbon atom to which R ¹ is attached To form a single bond (when Z is N, R ¹ is absent. The same applies hereinafter) Compound (hereinafter, X, R ¹ and R ² are assumed to be xr1),
6) X is ^{-CO (CHR 3) n -,} - CONH (CHR 3) n -, - NHCO (CHR 3) n -, - NHCOCO- or ^-NH (CHR 3) a MCO-, Z is N or A compound wherein CR ¹ is R ¹ is hydrogen or hydroxy, and R ² is hydrogen or methyl (hereinafter, X is xr 2),
7) X is ^{-CO (CHR 3) n -,} - CONH (CHR 3) n- or -NHCO ^(CHR 3) a n-, Z is CR ^{1, R 1} and ^{R 2} together A compound forming a single bond (hereinafter, X is xr3),
8) X is ^{-CO (CHR 3) n -,} - CONH (CHR 3) n- or -NHCO ^(CHR 3) a n-, carbon Z is CR ^{1, R 1} is ^{wherein R 1} is attached A compound that forms a single bond with R ³ on CR ³ R ⁴ adjacent to the atom and R ² is hydrogen (hereinafter, X is xr 4),
9) X is _{^{-CO (CHR 3) 3 -,}} - CONH (CHR 3) 2 -, - NHCO (CHR 3) 2 -, - NHCOCO- or -NHCHR ³ is CO-, in ^{R 3} is hydrogen or methyl Yes (each R ³ may be different), Z is N or CR ¹ , R ¹ is hydrogen or hydroxy, R ² is hydrogen or methyl (hereinafter X is xr5) )
10) X is _{^{-CO (CHR 3) 3 -,}} - CONH (CHR 3) 2 - or -NHCO ^(CHR _{3) 2} - a and, ^{R 3} is hydrogen or methyl (each ^{R 3} differ A compound in which Z is CR ¹ and R ¹ and R ² are combined to form a single bond (hereinafter, X is xr6),
11) X is _{^{-CO (CHR 3) 3 -,}} - CONH (CHR 3) 2 - or -NHCO ^(CHR _{3) 2} - a and, ^{R 3} is hydrogen or methyl (each ^{R 3} differ Z is CR ¹ and R ¹ is taken together with R ³ on the adjacent CR ³ R ⁴ with the carbon atom to which R ¹ is bonded to form a single bond and R ² is hydrogen A compound (hereinafter, X is xr7),
12) X is _{^{-CO (CHR 3) 3 -,}} - CONH (CHR 3) 2 -, - NHCO (CHR 3) 2 -, - NHCOCO- or -NHCHR ³ is CO-, in ^{R 3} is hydrogen or methyl A compound in which each R ³ may be different, Z is N or CH, and R ² is hydrogen (hereinafter, X is xr8);
13) X is _{^{-CO (CHR 3) 3 -,}} - CONH (CHR 3) 2 -, - NHCO (CHR 3) 2 -, - NHCOCO- or -NHCHR ³ is CO-, in ^{R 3} is hydrogen or methyl Yes (each R ³ may be different), Z is CR ¹ or N (hereinafter, X is xr9),

14) A ² is halogen, respectively, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy and halogeno substituted with one or more groups selected from lower alkoxy and also phenyl or pyridyl compounds (hereinafter, A ² is a5),
15) ^{A 2} are each halogen, C1 to C3 alkyl, halogeno C1 to C3 alkyl, the compound is one or more phenyl or pyridyl optionally substituted by a group selected from C1 to C3 alkoxy and halogeno C1 to C3 alkoxy (hereinafter referred to as ^{a 2} is a6),
16) A ² is phenyl or pyridyl each substituted in the para position with one or more groups selected from halogen, C1-C3 alkyl, halogeno C1-C3 alkyl, C1-C3 alkoxy or halogeno C1-C3 alkoxy compound (hereinafter, ^{a 2} is assumed to be a7),
17) A ² is phenyl substituted at the meta and para positions with one or more groups selected from halogen, C1-C3 alkyl, halogeno C1-C3 alkyl, C1-C3 alkoxy or halogeno C1-C3 alkoxy, respectively. a compound (hereinafter, a ² is assumed to be a8),

18) A compound in which the combination (A ¹ , xr, A ² ) of A ¹ , X, R ¹ , R ² , A ² is as follows:
(A ¹ , xr, A ² ) = (a1, xr1, a5), (a1, xr1, a6), (a1, xr1, a7), (a1, xr1, a8), (a1, xr2, a5), (a1, xr2, a6), (a1, xr2, a7), (a1, xr2, a8), (a1, xr3, a5), (a1, xr3, a6), (a1, xr3, a7), (a1 , xr3, a8), (a1, xr4, a5), (a1, xr4, a6), (a1, xr4, a7), (a1, xr4, a8), (a1, xr5, a5), (a1, xr5 , a6), (a1, xr5, a7), (a1, xr5, a8), (a1, xr6, a5), (a1, xr6, a6), (a1, xr6, a7), (a1, xr6, a8 ), (a1, xr7, a5), (a1, xr7, a6), (a1, xr7, a7), (a1, xr7, a8), (a1, xr8, a5), (a1, xr8, a6), (a1, xr8, a7), (a1, xr8, a8), (a1, xr9, a5), (a1, xr9, a6), (a1, xr9, a7), (a1, xr9, a8),
(a2, xr1, a5), (a2, xr1, a6), (a2, xr1, a7), (a2, xr1, a8), (a2, xr2, a5), (a2, xr2, a6), (a2 , xr2, a7), (a2, xr2, a8), (a2, xr3, a5), (a2, xr3, a6), (a2, xr3, a7), (a2, xr4, a5), (a2, xr4 , a6), (a2, xr4, a7), (a2, xr4, a8), (a2, xr5, a5), (a2, xr5, a6), (a2, xr5, a7), (a2, xr5, a8 ), (a2, xr6, a5), (a2, xr6, a6), (a2, xr6, a7), (a2, xr6, a8), (a2, xr7, a5), (a2, xr7, a6), (a2, xr7, a7), (a2, xr7, a8), (a2, xr8, a5), (a2, xr8, a6), (a2, xr8, a7), (a2, xr8, a8), (a2 , xr9, a5), (a2, xr9, a6), (a2, xr9, a7), (a2, xr9, a8),
(a3, xr1, a5), (a3, xr1, a6), (a3, xr1, a7), (a3, xr1, a8), (a3, xr2, a5), (a3, xr2, a6), (a3 , xr2, a7), (a3, xr2, a8), (a3, xr3, a5), (a3, xr3, a6), (a3, xr3, a7), (a3, xr3, a8), (a3, xr4 , a5), (a3, xr4, a6), (a3, xr4, a7), (a3, xr4, a8), (a3, xr5, a5), (a3, xr5, a6), (a3, xr5, a7 ), (a3, xr5, a8), (a3, xr6, a5), (a3, xr6, a6), (a3, xr6, a7), (a3, xr6, a8), (a3, xr7, a5), (a3, xr7, a6), (a3, xr7, a7), (a3, xr7, a8), (a3, xr8, a5), (a3, xr8, a6), (a3, xr8, a7), (a3 , xr8, a8), (a3, xr9, a5), (a3, xr9, a6), (a3, xr9, a7), (a3, xr9, a8),
(a4, xr1, a5), (a4, xr1, a6), (a4, xr1, a7), (a4, xr1, a8), (a4, xr2, a5), (a4, xr2, a6), (a4 , xr2, a7), (a4, xr2, a8), (a4, xr3, a5), (a4, xr3, a6), (a4, xr3, a7), (a4, xr3, a8), (a4, xr4 , a5), (a4, xr4, a6), (a4, xr4, a7), (a4, xr4, a8), (a4, xr5, a5), (a4, xr5, a6), (a4, xr5, a7 ), (a4, xr5, a8), (a4, xr6, a5), (a4, xr6, a6), (a4, xr6, a7), (a4, xr6, a8), (a4, xr7, a5), (a4, xr7, a6), (a4, xr7, a7), (a4, xr7, a8), (a4, xr8, a5), (a4, xr8, a6), (a4, xr8, a7), (a4 , xr8, a8), (a4, xr9, a5), (a4, xr9, a6), (a4, xr9, a7), (a4, xr9, a8)

In formula (I) or (I ′) 16) A ¹ is pyridyl having at least one optionally protected hydroxy or optionally protected amino, and —X— is —CONH (CHR ³ ) n-, -NHCO (CHR ³ ) n- or -NHCOCO-, wherein n is 2 or more,
17) A ¹ is benzoxazolyl or benzimidazolyl having at least one optionally protected hydroxy or optionally protected amino, and X is —CONH (CHR ³ ) n—, — ^{NR 5 CO (CR 3 R 4} ) n -, - NR 5 CONR 6 - , or compounds which are -NHCOCO-,
Or a pharmaceutically acceptable salt thereof or a solvate thereof.

In the following formulas ^{(1) ~ (7),} A 1, A 2, X a combination ^{(A 1, A 2, X} ) is the following compound, its pharmaceutically acceptable salt or solvate thereof Is also a preferred embodiment of the compound contained in the analgesic of the present invention.

（表中、Msはメタンスルホニル、Meはメチル、iPrはイソプロピルを示す）
（Ａ^１、Ａ^２、Ｘ）＝(a1,b1,X1),(a1,b1,X2),(a1,b1,X3),(a1,b1,X4),(a1,b1,X5),(a1,b1,X6),(a1,b1,X7),(a1,b1,X8),(a1,b1,X9),(a1,b1,X10),(a1,b1,X11),(a1,b1,X12),(a1,b1,X13),(a1,b1,X14),(a1,b1,X15),(a1,b1,X16),(a1,b1,X17),(a1,b1,X18),(a1,b2,X1),(a1,b2,X2),(a1,b2,X3),(a1,b2,X4),(a1,b2,X5),(a1,b2,X6),(a1,b2,X7),(a1,b2,X8),(a1,b2,X9),(a1,b2,X10),(a1,b2,X11),(a1,b2,X12),(a1,b2,X13),(a1,b2,X14),(a1,b2,X15),(a1,b2,X16),(a1,b2,X17),(a1,b2,X18),(a1,b3,X1),(a1,b3,X2),(a1,b3,X3),(a1,b3,X4),(a1,b3,X5),(a1,b3,X6),(a1,b3,X7),(a1,b3,X8),(a1,b3,X9),(a1,b3,X10),(a1,b3,X11),(a1,b3,X12),(a1,b3,X13),(a1,b3,X14),(a1,b3,X15),(a1,b3,X16),(a1,b3,X17),(a1,b3,X18),(a1,b4,X1),(a1,b4,X2),(a1,b4,X3),(a1,b4,X4),(a1,b4,X5),(a1,b4,X6),(a1,b4,X7),(a1,b4,X8),(a1,b4,X9),(a1,b4,X10),(a1,b4,X11),(a1,b4,X12),(a1,b4,X13),(a1,b4,X14),(a1,b4,X15),(a1,b4,X16),(a1,b4,X17),(a1,b4,X18),(a1,b5,X1),(a1,b5,X2),(a1,b5,X3),(a1,b5,X4),(a1,b5,X5),(a1,b5,X6),(a1,b5,X7),(a1,b5,X8),(a1,b5,X9),(a1,b5,X10),(a1,b5,X11),(a1,b5,X12),(a1,b5,X13),(a1,b5,X14),(a1,b5,X15),(a1,b5,X16),(a1,b5,X17),(a1,b5,X18),(a1,b6,X1),(a1,b6,X2),(a1,b6,X3),(a1,b6,X4),(a1,b6,X5),(a1,b6,X6),(a1,b6,X7),(a1,b6,X8),(a1,b6,X9),(a1,b6,X10),(a1,b6,X11),(a1,b6,X12),(a1,b6,X13),(a1,b6,X14),(a1,b6,X15),(a1,b6,X16),(a1,b6,X17),(a1,b6,X18),(a1,b7,X1),(a1,b7,X2),(a1,b7,X3),(a1,b7,X4),(a1,b7,X5),(a1,b7,X6),(a1,b7,X7),(a1,b7,X8),(a1,b7,X9),(a1,b7,X10),(a1,b7,X11),(a1,b7,X12),(a1,b7,X13),(a1,b7,X14),(a1,b7,X15),(a1,b7,X16),(a1,b7,X17),(a1,b7,X18),(a1,b8,X1),(a1,b8,X2),(a1,b8,X3),(a1,b8,X4),(a1,b8,X5),(a1,b8,X6),(a1,b8,X7),(a1,b8,X8),(a1,b8,X9),(a1,b8,X10),(a1,b8,X11),(a1,b8,X12),(a1,b8,X13),(a1,b8,X14),(a1,b8,X15),(a1,b8,X16),(a1,b8,X17),(a1,b8,X18),(a1,b9,X1),(a1,b9,X2),(a1,b9,X3),(a1,b9,X4),(a1,b9,X5),(a1,b9,X6),(a1,b9,X7),(a1,b9,X8),(a1,b9,X9),(a1,b9,X10),(a1,b9,X11),(a1,b9,X12),(a1,b9,X13),(a1,b9,X14),(a1,b9,X15),(a1,b9,X16),(a1,b9,X17),(a1,b9,X18),(a1,b10,X1),(a1,b10,X2),(a1,b10,X3),(a1,b10,X4),(a1,b10,X5),(a1,b10,X6),(a1,b10,X7),(a1,b10,X8),(a1,b10,X9),(a1,b10,X10),(a1,b10,X11),(a1,b10,X12),(a1,b10,X13),(a1,b10,X14),(a1,b10,X15),(a1,b10,X16),(a1,b10,X17),(a1,b10,X18),(a1,b11,X1),(a1,b11,X2),(a1,b11,X3),(a1,b11,X4),(a1,b11,X5),(a1,b11,X6),(a1,b11,X7),(a1,b11,X8),(a1,b11,X9),(a1,b11,X10),(a1,b11,X11),(a1,b11,X12),(a1,b11,X13),(a1,b11,X14),(a1,b11,X15),(a1,b11,X16),(a1,b11,X17),(a1,b11,X18),(a1,b12,X1),(a1,b12,X2),(a1,b12,X3),(a1,b12,X4),(a1,b12,X5),(a1,b12,X6),(a1,b12,X7),(a1,b12,X8),(a1,b12,X9),(a1,b12,X10),(a1,b12,X11),(a1,b12,X12),(a1,b12,X13),(a1,b12,X14),(a1,b12,X15),(a1,b12,X16),(a1,b12,X17),(a1,b12,X18),(a1,b13,X1),(a1,b13,X2),(a1,b13,X3),(a1,b13,X4),(a1,b13,X5),(a1,b13,X6),(a1,b13,X7),(a1,b13,X8),(a1,b13,X9),(a1,b13,X10),(a1,b13,X11),(a1,b13,X12),(a1,b13,X13),(a1,b13,X14),(a1,b13,X15),(a1,b13,X16),(a1,b13,X17),(a1,b13,X18),(a1,b14,X1),(a1,b14,X2),(a1,b14,X3),(a1,b14,X4),(a1,b14,X5),(a1,b14,X6),(a1,b14,X7),(a1,b14,X8),(a1,b14,X9),(a1,b14,X10),(a1,b14,X11),(a1,b14,X12),(a1,b14,X13),(a1,b14,X14),(a1,b14,X15),(a1,b14,X16),(a1,b14,X17),(a1,b14,X18),(a1,b15,X1),(a1,b15,X2),(a1,b15,X3),(a1,b15,X4),(a1,b15,X5),(a1,b15,X6),(a1,b15,X7),(a1,b15,X8),(a1,b15,X9),(a1,b15,X10),(a1,b15,X11),(a1,b15,X12),(a1,b15,X13),(a1,b15,X14),(a1,b15,X15),(a1,b15,X16),(a1,b15,X17),(a1,b15,X18),(a1,b16,X1),(a1,b16,X2),(a1,b16,X3),(a1,b16,X4),(a1,b16,X5),(a1,b16,X6),(a1,b16,X7),(a1,b16,X8),(a1,b16,X9),(a1,b16,X10),(a1,b16,X11),(a1,b16,X12),(a1,b16,X13),(a1,b16,X14),(a1,b16,X15),(a1,b16,X16),(a1,b16,X17),(a1,b16,X18),(a1,b17,X1),(a1,b17,X2),(a1,b17,X3),(a1,b17,X4),(a1,b17,X5),(a1,b17,X6),(a1,b17,X7),(a1,b17,X8),(a1,b17,X9),(a1,b17,X10),(a1,b17,X11),(a1,b17,X12),(a1,b17,X13),(a1,b17,X14),(a1,b17,X15),(a1,b17,X16),(a1,b17,X17),(a1,b17,X18),(a1,b18,X1),(a1,b18,X2),(a1,b18,X3),(a1,b18,X4),(a1,b18,X5),(a1,b18,X6),(a1,b18,X7),(a1,b18,X8),(a1,b18,X9),(a1,b18,X10),(a1,b18,X11),(a1,b18,X12),(a1,b18,X13),(a1,b18,X14),(a1,b18,X15),(a1,b18,X16),(a1,b18,X17),(a1,b18,X18),(a1,b19,X1),(a1,b19,X2),(a1,b19,X3),(a1,b19,X4),(a1,b19,X5),(a1,b19,X6),(a1,b19,X7),(a1,b19,X8),(a1,b19,X9),(a1,b19,X10),(a1,b19,X11),(a1,b19,X12),(a1,b19,X13),(a1,b19,X14),(a1,b19,X15),(a1,b19,X16),(a1,b19,X17),(a1,b19,X18),(a1,b20,X1),(a1,b20,X2),(a1,b20,X3),(a1,b20,X4),(a1,b20,X5),(a1,b20,X6),(a1,b20,X7),(a1,b20,X8),(a1,b20,X9),(a1,b20,X10),(a1,b20,X11),(a1,b20,X12),(a1,b20,X13),(a1,b20,X14),(a1,b20,X15),(a1,b20,X16),(a1,b20,X17),(a1,b20,X18),(a1,b21,X1),(a1,b21,X2),(a1,b21,X3),(a1,b21,X4),(a1,b21,X5),(a1,b21,X6),(a1,b21,X7),(a1,b21,X8),(a1,b21,X9),(a1,b21,X10),(a1,b21,X11),(a1,b21,X12),(a1,b21,X13),(a1,b21,X14),(a1,b21,X15),(a1,b21,X16),(a1,b21,X17),(a1,b21,X18),(a1,b22,X1),(a1,b22,X2),(a1,b22,X3),(a1,b22,X4),(a1,b22,X5),(a1,b22,X6),(a1,b22,X7),(a1,b22,X8),(a1,b22,X9),(a1,b22,X10),(a1,b22,X11),(a1,b22,X12),(a1,b22,X13),(a1,b22,X14),(a1,b22,X15),(a1,b22,X16),(a1,b22,X17),(a1,b22,X18),(a1,b23,X1),(a1,b23,X2),(a1,b23,X3),(a1,b23,X4),(a1,b23,X5),(a1,b23,X6),(a1,b23,X7),(a1,b23,X8),(a1,b23,X9),(a1,b23,X10),(a1,b23,X11),(a1,b23,X12),(a1,b23,X13),(a1,b23,X14),(a1,b23,X15),(a1,b23,X16),(a1,b23,X17),(a1,b23,X18),(a1,b24,X1),(a1,b24,X2),(a1,b24,X3),(a1,b24,X4),(a1,b24,X5),(a1,b24,X6),(a1,b24,X7),(a1,b24,X8),(a1,b24,X9),(a1,b24,X10),(a1,b24,X11),(a1,b24,X12),(a1,b24,X13),(a1,b24,X14),(a1,b24,X15),(a1,b24,X16),(a1,b24,X17),(a1,b24,X18),(a1,b25,X1),(a1,b25,X2),(a1,b25,X3),(a1,b25,X4),(a1,b25,X5),(a1,b25,X6),(a1,b25,X7),(a1,b25,X8),(a1,b25,X9),(a1,b25,X10),(a1,b25,X11),(a1,b25,X12),(a1,b25,X13),(a1,b25,X14),(a1,b25,X15),(a1,b25,X16),(a1,b25,X17),(a1,b25,X18),(a1,b26,X1),(a1,b26,X2),(a1,b26,X3),(a1,b26,X4),(a1,b26,X5),(a1,b26,X6),(a1,b26,X7),(a1,b26,X8),(a1,b26,X9),(a1,b26,X10),(a1,b26,X11),(a1,b26,X12),(a1,b26,X13),(a1,b26,X14),(a1,b26,X15),(a1,b26,X16),(a1,b26,X17),(a1,b26,X18),(a1,b27,X1),(a1,b27,X2),(a1,b27,X3),(a1,b27,X4),(a1,b27,X5),(a1,b27,X6),(a1,b27,X7),(a1,b27,X8),(a1,b27,X9),(a1,b27,X10),(a1,b27,X11),(a1,b27,X12),(a1,b27,X13),(a1,b27,X14),(a1,b27,X15),(a1,b27,X16),(a1,b27,X17),(a1,b27,X18),

(In the table, Ms represents methanesulfonyl, Me represents methyl, and iPr represents isopropyl)
(A ¹ , A ² , X) = (a1, b1, X1), (a1, b1, X2), (a1, b1, X3), (a1, b1, X4), (a1, b1, X5), (a1, b1, X6), (a1, b1, X7), (a1, b1, X8), (a1, b1, X9), (a1, b1, X10), (a1, b1, X11), (a1 , b1, X12), (a1, b1, X13), (a1, b1, X14), (a1, b1, X15), (a1, b1, X16), (a1, b1, X17), (a1, b1 , X18), (a1, b2, X1), (a1, b2, X2), (a1, b2, X3), (a1, b2, X4), (a1, b2, X5), (a1, b2, X6 ), (a1, b2, X7), (a1, b2, X8), (a1, b2, X9), (a1, b2, X10), (a1, b2, X11), (a1, b2, X12), (a1, b2, X13), (a1, b2, X14), (a1, b2, X15), (a1, b2, X16), (a1, b2, X17), (a1, b2, X18), (a1 , b3, X1), (a1, b3, X2), (a1, b3, X3), (a1, b3, X4), (a1, b3, X5), (a1, b3, X6), (a1, b3 , X7), (a1, b3, X8), (a1, b3, X9), (a1, b3, X10), (a1, b3, X11), (a1, b3, X12), (a1, b3, X13 ), (a1, b3, X14), (a1, b3, X15), (a1, b3, X16), (a1, b3, X17), (a1, b3, X18), (a1, b4, X1), (a1, b4, X2), (a1, b4, X3), (a1, b4, X4), (a1, b4, X5), (a1, b4, X6), (a1, b4, X7), (a1 , b4, X8), (a1, b4, X9), (a1, b4, X10), (a1, b4, X11), (a1, b4, X12), (a1, b4, X13), (a1, b4 , X14), (a1, b4, X15), (a1, b4, X16), (a1, b4, X17), (a1, b4, X18), (a1, b5, X1), (a1, b5, X2 ), (a1, b5, X3), (a1, b5, X4), (a1, b5, X5), (a1, b5, X6), (a1, b5, X7), (a1, b5, X8), (a1, b5, X9), (a1, b5, X10), (a1, b5, X11), (a1, b5, X12), (a1 , b5, X13), (a1, b5, X14), (a1, b5, X15), (a1, b5, X16), (a1, b5, X17), (a1, b5, X18), (a1, b6 , X1), (a1, b6, X2), (a1, b6, X3), (a1, b6, X4), (a1, b6, X5), (a1, b6, X6), (a1, b6, X7 ), (a1, b6, X8), (a1, b6, X9), (a1, b6, X10), (a1, b6, X11), (a1, b6, X12), (a1, b6, X13), (a1, b6, X14), (a1, b6, X15), (a1, b6, X16), (a1, b6, X17), (a1, b6, X18), (a1, b7, X1), (a1 , b7, X2), (a1, b7, X3), (a1, b7, X4), (a1, b7, X5), (a1, b7, X6), (a1, b7, X7), (a1, b7 , X8), (a1, b7, X9), (a1, b7, X10), (a1, b7, X11), (a1, b7, X12), (a1, b7, X13), (a1, b7, X14 ), (a1, b7, X15), (a1, b7, X16), (a1, b7, X17), (a1, b7, X18), (a1, b8, X1), (a1, b8, X2), (a1, b8, X3), (a1, b8, X4), (a1, b8, X5), (a1, b8, X6), (a1, b8, X7), (a1, b8, X8), (a1 , b8, X9), (a1, b8, X10), (a1, b8, X11), (a1, b8, X12), (a1, b8, X13), (a1, b8, X14), (a1, b8 , X15), (a1, b8, X16), (a1, b8, X17), (a1, b8, X18), (a1, b9, X1), (a1, b9, X2), (a1, b9, X3 ), (a1, b9, X4), (a1, b9, X5), (a1, b9, X6), (a1, b9, X7), (a1, b9, X8), (a1, b9, X9), (a1, b9, X10), (a1, b9, X11), (a1, b9, X12), (a1, b9, X13), (a1, b9, X14), (a1, b9, X15), (a1 , b9, X16), (a1, b9, X17), (a1, b9, X18), (a1, b10, X1), (a1, b10, X2), (a1, b10, X3), (a1, b10 , X4), (a1, b10, X5), (a1, b10, X6), (a1, b10, X7), (a1, b10, X8), (a1, b10 , X9), (a1, b10, X10), (a1, b10, X11), (a1, b10, X12), (a1, b10, X13), (a1, b10, X14), (a1, b10, X15 ), (a1, b10, X16), (a1, b10, X17), (a1, b10, X18), (a1, b11, X1), (a1, b11, X2), (a1, b11, X3), (a1, b11, X4), (a1, b11, X5), (a1, b11, X6), (a1, b11, X7), (a1, b11, X8), (a1, b11, X9), (a1 , b11, X10), (a1, b11, X11), (a1, b11, X12), (a1, b11, X13), (a1, b11, X14), (a1, b11, X15), (a1, b11 , X16), (a1, b11, X17), (a1, b11, X18), (a1, b12, X1), (a1, b12, X2), (a1, b12, X3), (a1, b12, X4 ), (a1, b12, X5), (a1, b12, X6), (a1, b12, X7), (a1, b12, X8), (a1, b12, X9), (a1, b12, X10), (a1, b12, X11), (a1, b12, X12), (a1, b12, X13), (a1, b12, X14), (a1, b12, X15), (a1, b12, X16), (a1 , b12, X17), (a1, b12, X18), (a1, b13, X1), (a1, b13, X2), (a1, b13, X3), (a1, b13, X4), (a1, b13 , X5), (a1, b13, X6), (a1, b13, X7), (a1, b13, X8), (a1, b13, X9), (a1, b13, X10), (a1, b13, X11 ), (a1, b13, X12), (a1, b13, X13), (a1, b13, X14), (a1, b13, X15), (a1, b13, X16), (a1, b13, X17), (a1, b13, X18), (a1, b14, X1), (a1, b14, X2), (a1, b14, X3), (a1, b14, X4), (a1, b14, X5), (a1 , b14, X6), (a1, b14, X7), (a1, b14, X8), (a1, b14, X9), (a1, b14, X10), (a1, b14, X11), (a1, b14 , X12), (a1, b14, X13), (a1, b14, X14), (a1, b14, X15), (a1, b14, X16), (a1, b14, X17), (a1, b14, X18), (a1, b15, X1), (a1, b15, X2), (a1, b15, X3), (a1, b15, X4), (a1, b15, X5), (a1, b15, X6), (a1, b15, X7), (a1, b15, X8), (a1, b15, X9), (a1, b15, X10), (a1, b15, X11) , (a1, b15, X12), (a1, b15, X13), (a1, b15, X14), (a1, b15, X15), (a1, b15, X16), (a1, b15, X17), ( a1, b15, X18), (a1, b16, X1), (a1, b16, X2), (a1, b16, X3), (a1, b16, X4), (a1, b16, X5), (a1, b16, X6), (a1, b16, X7), (a1, b16, X8), (a1, b16, X9), (a1, b16, X10), (a1, b16, X11), (a1, b16, X12), (a1, b16, X13), (a1, b16, X14), (a1, b16, X15), (a1, b16, X16), (a1, b16, X17), (a1, b16, X18) , (a1, b17, X1), (a1, b17, X2), (a1, b17, X3), (a1, b17, X4), (a1, b17, X5), (a1, b17, X6), ( a1, b17, X7), (a1, b17, X8), (a1, b17, X9), (a1, b17, X10), (a1, b17, X11), (a1, b17, X12), (a1, b17, X13), (a1, b17, X14), (a1, b17, X15), (a1, b17, X16), (a1, b17, X17), (a1, b17, X18), (a1, b18, X1), (a1, b18, X2), (a1, b18, X3), (a1, b18, X4), (a1, b18, X5), (a1, b18, X6), (a1, b18, X7) , (a1, b18, X8), (a1, b18, X9), (a1, b18, X10), (a1, b18, X11), (a1, b18, X12), (a1, b18, X13), ( a1, b18, X14), (a1, b18, X15), (a1, b18, X16), (a1, b18, X17), (a1, b18, X18), (a1, b19, X1), (a1, b19, X2), (a1, b19, X3), (a1, b19, X4), (a1, b19, X5), (a1, b19, X6), (a1, b1 9, X7), (a1, b19, X8), (a1, b19, X9), (a1, b19, X10), (a1, b19, X11), (a1, b19, X12), (a1, b19, X13), (a1, b19, X14), (a1, b19, X15), (a1, b19, X16), (a1, b19, X17), (a1, b19, X18), (a1, b20, X1) , (a1, b20, X2), (a1, b20, X3), (a1, b20, X4), (a1, b20, X5), (a1, b20, X6), (a1, b20, X7), ( a1, b20, X8), (a1, b20, X9), (a1, b20, X10), (a1, b20, X11), (a1, b20, X12), (a1, b20, X13), (a1, b20, X14), (a1, b20, X15), (a1, b20, X16), (a1, b20, X17), (a1, b20, X18), (a1, b21, X1), (a1, b21, X2), (a1, b21, X3), (a1, b21, X4), (a1, b21, X5), (a1, b21, X6), (a1, b21, X7), (a1, b21, X8) , (a1, b21, X9), (a1, b21, X10), (a1, b21, X11), (a1, b21, X12), (a1, b21, X13), (a1, b21, X14), ( a1, b21, X15), (a1, b21, X16), (a1, b21, X17), (a1, b21, X18), (a1, b22, X1), (a1, b22, X2), (a1, b22, X3), (a1, b22, X4), (a1, b22, X5), (a1, b22, X6), (a1, b22, X7), (a1, b22, X8), (a1, b22, X9), (a1, b22, X10), (a1, b22, X11), (a1, b22, X12), (a1, b22, X13), (a1, b22, X14), (a1, b22, X15) , (a1, b22, X16), (a1, b22, X17), (a1, b22, X18), (a1, b23, X1), (a1, b23, X2), (a1, b23, X3), ( a1, b23, X4), (a1, b23, X5), (a1, b23, X6), (a1, b23, X7), (a1, b23, X8), (a1, b23, X9), (a1, b23, X10), (a1, b23, X11), (a1, b23, X12), (a1, b23, X13), (a1, b23, X14), (a1, b 23, X15), (a1, b23, X16), (a1, b23, X17), (a1, b23, X18), (a1, b24, X1), (a1, b24, X2), (a1, b24, X3), (a1, b24, X4), (a1, b24, X5), (a1, b24, X6), (a1, b24, X7), (a1, b24, X8), (a1, b24, X9) , (a1, b24, X10), (a1, b24, X11), (a1, b24, X12), (a1, b24, X13), (a1, b24, X14), (a1, b24, X15), ( a1, b24, X16), (a1, b24, X17), (a1, b24, X18), (a1, b25, X1), (a1, b25, X2), (a1, b25, X3), (a1, b25, X4), (a1, b25, X5), (a1, b25, X6), (a1, b25, X7), (a1, b25, X8), (a1, b25, X9), (a1, b25, X10), (a1, b25, X11), (a1, b25, X12), (a1, b25, X13), (a1, b25, X14), (a1, b25, X15), (a1, b25, X16) , (a1, b25, X17), (a1, b25, X18), (a1, b26, X1), (a1, b26, X2), (a1, b26, X3), (a1, b26, X4), ( a1, b26, X5), (a1, b26, X6), (a1, b26, X7), (a1, b26, X8), (a1, b26, X9), (a1, b26, X10), (a1, b26, X11), (a1, b26, X12), (a1, b26, X13), (a1, b26, X14), (a1, b26, X15), (a1, b26, X16), (a1, b26, X17), (a1, b26, X18), (a1, b27, X1), (a1, b27, X2), (a1, b27, X3), (a1, b27, X4), (a1, b27, X5) , (a1, b27, X6), (a1, b27, X7), (a1, b27, X8), (a1, b27, X9), (a1, b27, X10), (a1, b27, X11), ( a1, b27, X12), (a1, b27, X13), (a1, b27, X14), (a1, b27, X15), (a1, b27, X16), (a1, b27, X17), (a1, b27, X18),

(a2, b1, X1), (a2, b1, X2), (a2, b1, X3), (a2, b1, X4), (a2, b1, X5), (a2, b1, X6), (a2 , b1, X7), (a2, b1, X8), (a2, b1, X9), (a2, b1, X10), (a2, b1, X11), (a2, b1, X12), (a2, b1 , X13), (a2, b1, X14), (a2, b1, X15), (a2, b1, X16), (a2, b1, X17), (a2, b1, X18), (a2, b2, X1 ), (a2, b2, X2), (a2, b2, X3), (a2, b2, X4), (a2, b2, X5), (a2, b2, X6), (a2, b2, X7), (a2, b2, X8), (a2, b2, X9), (a2, b2, X10), (a2, b2, X11), (a2, b2, X12), (a2, b2, X13), (a2 , b2, X14), (a2, b2, X15), (a2, b2, X16), (a2, b2, X17), (a2, b2, X18), (a2, b3, X1), (a2, b3 , X2), (a2, b3, X3), (a2, b3, X4), (a2, b3, X5), (a2, b3, X6), (a2, b3, X7), (a2, b3, X8 ), (a2, b3, X9), (a2, b3, X10), (a2, b3, X11), (a2, b3, X12), (a2, b3, X13), (a2, b3, X14), (a2, b3, X15), (a2, b3, X16), (a2, b3, X17), (a2, b3, X18), (a2, b4, X1), (a2, b4, X2), (a2 , b4, X3), (a2, b4, X4), (a2, b4, X5), (a2, b4, X6), (a2, b4, X7), (a2, b4, X8), (a2, b4 , X9), (a2, b4, X10), (a2, b4, X11), (a2, b4, X12), (a2, b4, X13), (a2, b4, X14), (a2, b4, X15 ), (a2, b4, X16), (a2, b4, X17), (a2, b4, X18), (a2, b5, X1), (a2, b5, X2), (a2, b5, X3), (a2, b5, X4), (a2, b5, X5), (a2, b5, X6), (a2, b5, X7), (a2, b5, X8), (a2, b5, X9), (a2 , b5, X10), (a2, b5, X11), (a2, b5, X12), (a2, b5, X13), (a2, b5, X14), (a2, b5, X15), ( a2, b5, X16), (a2, b5, X17), (a2, b5, X18), (a2, b6, X1), (a2, b6, X2), (a2, b6, X3), (a2, b6, X4), (a2, b6, X5), (a2, b6, X6), (a2, b6, X7), (a2, b6, X8), (a2, b6, X9), (a2, b6, X10), (a2, b6, X11), (a2, b6, X12), (a2, b6, X13), (a2, b6, X14), (a2, b6, X15), (a2, b6, X16) , (a2, b6, X17), (a2, b6, X18), (a2, b7, X1), (a2, b7, X2), (a2, b7, X3), (a2, b7, X4), ( a2, b7, X5), (a2, b7, X6), (a2, b7, X7), (a2, b7, X8), (a2, b7, X9), (a2, b7, X10), (a2, b7, X11), (a2, b7, X12), (a2, b7, X13), (a2, b7, X14), (a2, b7, X15), (a2, b7, X16), (a2, b7, X17), (a2, b7, X18), (a2, b8, X1), (a2, b8, X2), (a2, b8, X3), (a2, b8, X4), (a2, b8, X5) , (a2, b8, X6), (a2, b8, X7), (a2, b8, X8), (a2, b8, X9), (a2, b8, X10), (a2, b8, X11), ( a2, b8, X12), (a2, b8, X13), (a2, b8, X14), (a2, b8, X15), (a2, b8, X16), (a2, b8, X17), (a2, b8, X18), (a2, b9, X1), (a2, b9, X2), (a2, b9, X3), (a2, b9, X4), (a2, b9, X5), (a2, b9, X6), (a2, b9, X7), (a2, b9, X8), (a2, b9, X9), (a2, b9, X10), (a2, b9, X11), (a2, b9, X12) , (a2, b9, X13), (a2, b9, X14), (a2, b9, X15), (a2, b9, X16), (a2, b9, X17), (a2, b9, X18), ( a2, b10, X1), (a2, b10, X2), (a2, b10, X3), (a2, b10, X4), (a2, b10, X5), (a2, b10, X6), (a2, b10, X7), (a2, b10, X8), (a2, b10, X9), (a2, b10, X10), (a2, b10, X11), (a2 , b10, X12), (a2, b10, X13), (a2, b10, X14), (a2, b10, X15), (a2, b10, X16), (a2, b10, X17), (a2, b10 , X18), (a2, b11, X1), (a2, b11, X2), (a2, b11, X3), (a2, b11, X4), (a2, b11, X5), (a2, b11, X6 ), (a2, b11, X7), (a2, b11, X8), (a2, b11, X9), (a2, b11, X10), (a2, b11, X11), (a2, b11, X12), (a2, b11, X13), (a2, b11, X14), (a2, b11, X15), (a2, b11, X16), (a2, b11, X17), (a2, b11, X18), (a2 , b12, X1), (a2, b12, X2), (a2, b12, X3), (a2, b12, X4), (a2, b12, X5), (a2, b12, X6), (a2, b12 , X7), (a2, b12, X8), (a2, b12, X9), (a2, b12, X10), (a2, b12, X11), (a2, b12, X12), (a2, b12, X13 ), (a2, b12, X14), (a2, b12, X15), (a2, b12, X16), (a2, b12, X17), (a2, b12, X18), (a2, b13, X1), (a2, b13, X2), (a2, b13, X3), (a2, b13, X4), (a2, b13, X5), (a2, b13, X6), (a2, b13, X7), (a2 , b13, X8), (a2, b13, X9), (a2, b13, X10), (a2, b13, X11), (a2, b13, X12), (a2, b13, X13), (a2, b13 , X14), (a2, b13, X15), (a2, b13, X16), (a2, b13, X17), (a2, b13, X18), (a2, b14, X1), (a2, b14, X2 ), (a2, b14, X3), (a2, b14, X4), (a2, b14, X5), (a2, b14, X6), (a2, b14, X7), (a2, b14, X8), (a2, b14, X9), (a2, b14, X10), (a2, b14, X11), (a2, b14, X12), (a2, b14, X13), (a2, b14, X14), (a2 , b14, X15), (a2, b14, X16), (a2, b14, X17), (a2, b14, X18), (a2, b15, X1), (a2, b15, X2), (a2, b15, X3), (a2, b15, X4), (a2, b15, X5), (a2, b15, X6), (a2, b15, X7), (a2 , b15, X8), (a2, b15, X9), (a2, b15, X10), (a2, b15, X11), (a2, b15, X12), (a2, b15, X13), (a2, b15 , X14), (a2, b15, X15), (a2, b15, X16), (a2, b15, X17), (a2, b15, X18), (a2, b16, X1), (a2, b16, X2 ), (a2, b16, X3), (a2, b16, X4), (a2, b16, X5), (a2, b16, X6), (a2, b16, X7), (a2, b16, X8), (a2, b16, X9), (a2, b16, X10), (a2, b16, X11), (a2, b16, X12), (a2, b16, X13), (a2, b16, X14), (a2 , b16, X15), (a2, b16, X16), (a2, b16, X17), (a2, b16, X18), (a2, b17, X1), (a2, b17, X2), (a2, b17 , X3), (a2, b17, X4), (a2, b17, X5), (a2, b17, X6), (a2, b17, X7), (a2, b17, X8), (a2, b17, X9 ), (a2, b17, X10), (a2, b17, X11), (a2, b17, X12), (a2, b17, X13), (a2, b17, X14), (a2, b17, X15), (a2, b17, X16), (a2, b17, X17), (a2, b17, X18), (a2, b18, X1), (a2, b18, X2), (a2, b18, X3), (a2 , b18, X4), (a2, b18, X5), (a2, b18, X6), (a2, b18, X7), (a2, b18, X8), (a2, b18, X9), (a2, b18 , X10), (a2, b18, X11), (a2, b18, X12), (a2, b18, X13), (a2, b18, X14), (a2, b18, X15), (a2, b18, X16 ), (a2, b18, X17), (a2, b18, X18), (a2, b19, X1), (a2, b19, X2), (a2, b19, X3), (a2, b19, X4), (a2, b19, X5), (a2, b19, X6), (a2, b19, X7), (a2, b19, X8), (a2, b19, X9), (a2, b19, X10), (a2, b19, X11), (a2, b19, X12), (a2, b19, X13), (a2, b19, X14), (a2, b19, X15), (a2, b19, X16), (a2, b19, X17), (a2, b19, X18), (a2, b20, X1), (a2, b20, X2), (a2, b20, X3), (a2, b20, X4) , (a2, b20, X5), (a2, b20, X6), (a2, b20, X7), (a2, b20, X8), (a2, b20, X9), (a2, b20, X10), ( a2, b20, X11), (a2, b20, X12), (a2, b20, X13), (a2, b20, X14), (a2, b20, X15), (a2, b20, X16), (a2, b20, X17), (a2, b20, X18), (a2, b21, X1), (a2, b21, X2), (a2, b21, X3), (a2, b21, X4), (a2, b21, X5), (a2, b21, X6), (a2, b21, X7), (a2, b21, X8), (a2, b21, X9), (a2, b21, X10), (a2, b21, X11) , (a2, b21, X12), (a2, b21, X13), (a2, b21, X14), (a2, b21, X15), (a2, b21, X16), (a2, b21, X17), ( a2, b21, X18), (a2, b22, X1), (a2, b22, X2), (a2, b22, X3), (a2, b22, X4), (a2, b22, X5), (a2, b22, X6), (a2, b22, X7), (a2, b22, X8), (a2, b22, X9), (a2, b22, X10), (a2, b22, X11), (a2, b22, X12), (a2, b22, X13), (a2, b22, X14), (a2, b22, X15), (a2, b22, X16), (a2, b22, X17), (a2, b22, X18) , (a2, b23, X1), (a2, b23, X2), (a2, b23, X3), (a2, b23, X4), (a2, b23, X5), (a2, b23, X6), ( a2, b23, X7), (a2, b23, X8), (a2, b23, X9), (a2, b23, X10), (a2, b23, X11), (a2, b23, X12), (a2, b23, X13), (a2, b23, X14), (a2, b23, X15), (a2, b23, X16), (a2, b23, X17), (a2, b23, X18), (a2, b24, X1), (a2, b24, X2), (a2, b24, X3), (a2, b24, X4), (a2, b24, X5), (a2 , b24, X6), (a2, b24, X7), (a2, b24, X8), (a2, b24, X9), (a2, b24, X10), (a2, b24, X11), (a2, b24 , X12), (a2, b24, X13), (a2, b24, X14), (a2, b24, X15), (a2, b24, X16), (a2, b24, X17), (a2, b24, X18 ), (a2, b25, X1), (a2, b25, X2), (a2, b25, X3), (a2, b25, X4), (a2, b25, X5), (a2, b25, X6), (a2, b25, X7), (a2, b25, X8), (a2, b25, X9), (a2, b25, X10), (a2, b25, X11), (a2, b25, X12), (a2 , b25, X13), (a2, b25, X14), (a2, b25, X15), (a2, b25, X16), (a2, b25, X17), (a2, b25, X18), (a2, b26 , X1), (a2, b26, X2), (a2, b26, X3), (a2, b26, X4), (a2, b26, X5), (a2, b26, X6), (a2, b26, X7 ), (a2, b26, X8), (a2, b26, X9), (a2, b26, X10), (a2, b26, X11), (a2, b26, X12), (a2, b26, X13), (a2, b26, X14), (a2, b26, X15), (a2, b26, X16), (a2, b26, X17), (a2, b26, X18), (a2, b27, X1), (a2 , b27, X2), (a2, b27, X3), (a2, b27, X4), (a2, b27, X5), (a2, b27, X6), (a2, b27, X7), (a2, b27 , X8), (a2, b27, X9), (a2, b27, X10), (a2, b27, X11), (a2, b27, X12), (a2, b27, X13), (a2, b27, X14 ), (a2, b27, X15), (a2, b27, X16), (a2, b27, X17), (a2, b27, X18),

(a3, b1, X1), (a3, b1, X2), (a3, b1, X3), (a3, b1, X4), (a3, b1, X5), (a3, b1, X6), (a3 , b1, X7), (a3, b1, X8), (a3, b1, X9), (a3, b1, X10), (a3, b1, X11), (a3, b1, X12), (a3, b1 , X13), (a3, b1, X14), (a3, b1, X15), (a3, b1, X16), (a3, b1, X17), (a3, b1, X18), (a3, b2, X1 ), (a3, b2, X2), (a3, b2, X3), (a3, b2, X4), (a3, b2, X5), (a3, b2, X6), (a3, b2, X7), (a3, b2, X8), (a3, b2, X9), (a3, b2, X10), (a3, b2, X11), (a3, b2, X12), (a3, b2, X13), (a3 , b2, X14), (a3, b2, X15), (a3, b2, X16), (a3, b2, X17), (a3, b2, X18), (a3, b3, X1), (a3, b3 , X2), (a3, b3, X3), (a3, b3, X4), (a3, b3, X5), (a3, b3, X6), (a3, b3, X7), (a3, b3, X8 ), (a3, b3, X9), (a3, b3, X10), (a3, b3, X11), (a3, b3, X12), (a3, b3, X13), (a3, b3, X14), (a3, b3, X15), (a3, b3, X16), (a3, b3, X17), (a3, b3, X18), (a3, b4, X1), (a3, b4, X2), (a3 , b4, X3), (a3, b4, X4), (a3, b4, X5), (a3, b4, X6), (a3, b4, X7), (a3, b4, X8), (a3, b4 , X9), (a3, b4, X10), (a3, b4, X11), (a3, b4, X12), (a3, b4, X13), (a3, b4, X14), (a3, b4, X15 ), (a3, b4, X16), (a3, b4, X17), (a3, b4, X18), (a3, b5, X1), (a3, b5, X2), (a3, b5, X3), (a3, b5, X4), (a3, b5, X5), (a3, b5, X6), (a3, b5, X7), (a3, b5, X8), (a3, b5, X9), (a3 , b5, X10), (a3, b5, X11), (a3, b5, X12), (a3, b5, X13), (a3, b5, X14), (a3, b5, X15), ( a3, b5, X16), (a3, b5, X17), (a3, b5, X18), (a3, b6, X1), (a3, b6, X2), (a3, b6, X3), (a3, b6, X4), (a3, b6, X5), (a3, b6, X6), (a3, b6, X7), (a3, b6, X8), (a3, b6, X9), (a3, b6, X10), (a3, b6, X11), (a3, b6, X12), (a3, b6, X13), (a3, b6, X14), (a3, b6, X15), (a3, b6, X16) , (a3, b6, X17), (a3, b6, X18), (a3, b7, X1), (a3, b7, X2), (a3, b7, X3), (a3, b7, X4), ( a3, b7, X5), (a3, b7, X6), (a3, b7, X7), (a3, b7, X8), (a3, b7, X9), (a3, b7, X10), (a3, b7, X11), (a3, b7, X12), (a3, b7, X13), (a3, b7, X14), (a3, b7, X15), (a3, b7, X16), (a3, b7, X17), (a3, b7, X18), (a3, b8, X1), (a3, b8, X2), (a3, b8, X3), (a3, b8, X4), (a3, b8, X5) , (a3, b8, X6), (a3, b8, X7), (a3, b8, X8), (a3, b8, X9), (a3, b8, X10), (a3, b8, X11), ( a3, b8, X12), (a3, b8, X13), (a3, b8, X14), (a3, b8, X15), (a3, b8, X16), (a3, b8, X17), (a3, b8, X18), (a3, b9, X1), (a3, b9, X2), (a3, b9, X3), (a3, b9, X4), (a3, b9, X5), (a3, b9, X6), (a3, b9, X7), (a3, b9, X8), (a3, b9, X9), (a3, b9, X10), (a3, b9, X11), (a3, b9, X12) , (a3, b9, X13), (a3, b9, X14), (a3, b9, X15), (a3, b9, X16), (a3, b9, X17), (a3, b9, X18), ( a3, b10, X1), (a3, b10, X2), (a3, b10, X3), (a3, b10, X4), (a3, b10, X5), (a3, b10, X6), (a3, b10, X7), (a3, b10, X8), (a3, b10, X9), (a3, b10, X10), (a3, b10, X11), (a3 , b10, X12), (a3, b10, X13), (a3, b10, X14), (a3, b10, X15), (a3, b10, X16), (a3, b10, X17), (a3, b10 , X18), (a3, b11, X1), (a3, b11, X2), (a3, b11, X3), (a3, b11, X4), (a3, b11, X5), (a3, b11, X6 ), (a3, b11, X7), (a3, b11, X8), (a3, b11, X9), (a3, b11, X10), (a3, b11, X11), (a3, b11, X12), (a3, b11, X13), (a3, b11, X14), (a3, b11, X15), (a3, b11, X16), (a3, b11, X17), (a3, b11, X18), (a3 , b12, X1), (a3, b12, X2), (a3, b12, X3), (a3, b12, X4), (a3, b12, X5), (a3, b12, X6), (a3, b12 , X7), (a3, b12, X8), (a3, b12, X9), (a3, b12, X10), (a3, b12, X11), (a3, b12, X12), (a3, b12, X13 ), (a3, b12, X14), (a3, b12, X15), (a3, b12, X16), (a3, b12, X17), (a3, b12, X18), (a3, b13, X1), (a3, b13, X2), (a3, b13, X3), (a3, b13, X4), (a3, b13, X5), (a3, b13, X6), (a3, b13, X7), (a3 , b13, X8), (a3, b13, X9), (a3, b13, X10), (a3, b13, X11), (a3, b13, X12), (a3, b13, X13), (a3, b13 , X14), (a3, b13, X15), (a3, b13, X16), (a3, b13, X17), (a3, b13, X18), (a3, b14, X1), (a3, b14, X2 ), (a3, b14, X3), (a3, b14, X4), (a3, b14, X5), (a3, b14, X6), (a3, b14, X7), (a3, b14, X8), (a3, b14, X9), (a3, b14, X10), (a3, b14, X11), (a3, b14, X12), (a3, b14, X13), (a3, b14, X14), (a3 , b14, X15), (a3, b14, X16), (a3, b14, X17), (a3, b14, X18), (a3, b15, X1), (a3, b15, X2), (a3, b15, X3), (a3, b15, X4), (a3, b15, X5), (a3, b15, X6), (a3, b15, X7), (a3 , b15, X8), (a3, b15, X9), (a3, b15, X10), (a3, b15, X11), (a3, b15, X12), (a3, b15, X13), (a3, b15 , X14), (a3, b15, X15), (a3, b15, X16), (a3, b15, X17), (a3, b15, X18), (a3, b16, X1), (a3, b16, X2 ), (a3, b16, X3), (a3, b16, X4), (a3, b16, X5), (a3, b16, X6), (a3, b16, X7), (a3, b16, X8), (a3, b16, X9), (a3, b16, X10), (a3, b16, X11), (a3, b16, X12), (a3, b16, X13), (a3, b16, X14), (a3 , b16, X15), (a3, b16, X16), (a3, b16, X17), (a3, b16, X18), (a3, b17, X1), (a3, b17, X2), (a3, b17 , X3), (a3, b17, X4), (a3, b17, X5), (a3, b17, X6), (a3, b17, X7), (a3, b17, X8), (a3, b17, X9 ), (a3, b17, X10), (a3, b17, X11), (a3, b17, X12), (a3, b17, X13), (a3, b17, X14), (a3, b17, X15), (a3, b17, X16), (a3, b17, X17), (a3, b17, X18), (a3, b18, X1), (a3, b18, X2), (a3, b18, X3), (a3 , b18, X4), (a3, b18, X5), (a3, b18, X6), (a3, b18, X7), (a3, b18, X8), (a3, b18, X9), (a3, b18 , X10), (a3, b18, X11), (a3, b18, X12), (a3, b18, X13), (a3, b18, X14), (a3, b18, X15), (a3, b18, X16 ), (a3, b18, X17), (a3, b18, X18), (a3, b19, X1), (a3, b19, X2), (a3, b19, X3), (a3, b19, X4), (a3, b19, X5), (a3, b19, X6), (a3, b19, X7), (a3, b19, X8), (a3, b19, X9), (a3, b19, X10), (a3, b19, X11), (a3, b19, X12), (a3, b19, X13), (a3, b19, X14), (a3, b19, X15), (a3, b19, X16), (a3, b19, X17), (a3, b19, X18), (a3, b20, X1), (a3, b20, X2), (a3, b20, X3), (a3, b20, X4) , (a3, b20, X5), (a3, b20, X6), (a3, b20, X7), (a3, b20, X8), (a3, b20, X9), (a3, b20, X10), ( a3, b20, X11), (a3, b20, X12), (a3, b20, X13), (a3, b20, X14), (a3, b20, X15), (a3, b20, X16), (a3, b20, X17), (a3, b20, X18), (a3, b21, X1), (a3, b21, X2), (a3, b21, X3), (a3, b21, X4), (a3, b21, X5), (a3, b21, X6), (a3, b21, X7), (a3, b21, X8), (a3, b21, X9), (a3, b21, X10), (a3, b21, X11) , (a3, b21, X12), (a3, b21, X13), (a3, b21, X14), (a3, b21, X15), (a3, b21, X16), (a3, b21, X17), ( a3, b21, X18), (a3, b22, X1), (a3, b22, X2), (a3, b22, X3), (a3, b22, X4), (a3, b22, X5), (a3, b22, X6), (a3, b22, X7), (a3, b22, X8), (a3, b22, X9), (a3, b22, X10), (a3, b22, X11), (a3, b22, X12), (a3, b22, X13), (a3, b22, X14), (a3, b22, X15), (a3, b22, X16), (a3, b22, X17), (a3, b22, X18) , (a3, b23, X1), (a3, b23, X2), (a3, b23, X3), (a3, b23, X4), (a3, b23, X5), (a3, b23, X6), ( a3, b23, X7), (a3, b23, X8), (a3, b23, X9), (a3, b23, X10), (a3, b23, X11), (a3, b23, X12), (a3, b23, X13), (a3, b23, X14), (a3, b23, X15), (a3, b23, X16), (a3, b23, X17), (a3, b23, X18), (a3, b24, X1), (a3, b24, X2), (a3, b24, X3), (a3, b24, X4), (a3, b24, X5), (a3 , b24, X6), (a3, b24, X7), (a3, b24, X8), (a3, b24, X9), (a3, b24, X10), (a3, b24, X11), (a3, b24 , X12), (a3, b24, X13), (a3, b24, X14), (a3, b24, X15), (a3, b24, X16), (a3, b24, X17), (a3, b24, X18 ), (a3, b25, X1), (a3, b25, X2), (a3, b25, X3), (a3, b25, X4), (a3, b25, X5), (a3, b25, X6), (a3, b25, X7), (a3, b25, X8), (a3, b25, X9), (a3, b25, X10), (a3, b25, X11), (a3, b25, X12), (a3 , b25, X13), (a3, b25, X14), (a3, b25, X15), (a3, b25, X16), (a3, b25, X17), (a3, b25, X18), (a3, b26 , X1), (a3, b26, X2), (a3, b26, X3), (a3, b26, X4), (a3, b26, X5), (a3, b26, X6), (a3, b26, X7 ), (a3, b26, X8), (a3, b26, X9), (a3, b26, X10), (a3, b26, X11), (a3, b26, X12), (a3, b26, X13), (a3, b26, X14), (a3, b26, X15), (a3, b26, X16), (a3, b26, X17), (a3, b26, X18), (a3, b27, X1), (a3 , b27, X2), (a3, b27, X3), (a3, b27, X4), (a3, b27, X5), (a3, b27, X6), (a3, b27, X7), (a3, b27 , X8), (a3, b27, X9), (a3, b27, X10), (a3, b27, X11), (a3, b27, X12), (a3, b27, X13), (a3, b27, X14 ), (a3, b27, X15), (a3, b27, X16), (a3, b27, X17), (a3, b27, X18),

(a4, b1, X1), (a4, b1, X2), (a4, b1, X3), (a4, b1, X4), (a4, b1, X5), (a4, b1, X6), (a4 , b1, X7), (a4, b1, X8), (a4, b1, X9), (a4, b1, X10), (a4, b1, X11), (a4, b1, X12), (a4, b1 , X13), (a4, b1, X14), (a4, b1, X15), (a4, b1, X16), (a4, b1, X17), (a4, b1, X18), (a4, b2, X1 ), (a4, b2, X2), (a4, b2, X3), (a4, b2, X4), (a4, b2, X5), (a4, b2, X6), (a4, b2, X7), (a4, b2, X8), (a4, b2, X9), (a4, b2, X10), (a4, b2, X11), (a4, b2, X12), (a4, b2, X13), (a4 , b2, X14), (a4, b2, X15), (a4, b2, X16), (a4, b2, X17), (a4, b2, X18), (a4, b3, X1), (a4, b3 , X2), (a4, b3, X3), (a4, b3, X4), (a4, b3, X5), (a4, b3, X6), (a4, b3, X7), (a4, b3, X8 ), (a4, b3, X9), (a4, b3, X10), (a4, b3, X11), (a4, b3, X12), (a4, b3, X13), (a4, b3, X14), (a4, b3, X15), (a4, b3, X16), (a4, b3, X17), (a4, b3, X18), (a4, b4, X1), (a4, b4, X2), (a4 , b4, X3), (a4, b4, X4), (a4, b4, X5), (a4, b4, X6), (a4, b4, X7), (a4, b4, X8), (a4, b4 , X9), (a4, b4, X10), (a4, b4, X11), (a4, b4, X12), (a4, b4, X13), (a4, b4, X14), (a4, b4, X15 ), (a4, b4, X16), (a4, b4, X17), (a4, b4, X18), (a4, b5, X1), (a4, b5, X2), (a4, b5, X3), (a4, b5, X4), (a4, b5, X5), (a4, b5, X6), (a4, b5, X7), (a4, b5, X8), (a4, b5, X9), (a4 , b5, X10), (a4, b5, X11), (a4, b5, X12), (a4, b5, X13), (a4, b5, X14), (a4, b5, X15), ( a4, b5, X16), (a4, b5, X17), (a4, b5, X18), (a4, b6, X1), (a4, b6, X2), (a4, b6, X3), (a4, b6, X4), (a4, b6, X5), (a4, b6, X6), (a4, b6, X7), (a4, b6, X8), (a4, b6, X9), (a4, b6, X10), (a4, b6, X11), (a4, b6, X12), (a4, b6, X13), (a4, b6, X14), (a4, b6, X15), (a4, b6, X16) , (a4, b6, X17), (a4, b6, X18), (a4, b7, X1), (a4, b7, X2), (a4, b7, X3), (a4, b7, X4), ( a4, b7, X5), (a4, b7, X6), (a4, b7, X7), (a4, b7, X8), (a4, b7, X9), (a4, b7, X10), (a4, b7, X11), (a4, b7, X12), (a4, b7, X13), (a4, b7, X14), (a4, b7, X15), (a4, b7, X16), (a4, b7, X17), (a4, b7, X18), (a4, b8, X1), (a4, b8, X2), (a4, b8, X3), (a4, b8, X4), (a4, b8, X5) , (a4, b8, X6), (a4, b8, X7), (a4, b8, X8), (a4, b8, X9), (a4, b8, X10), (a4, b8, X11), ( a4, b8, X12), (a4, b8, X13), (a4, b8, X14), (a4, b8, X15), (a4, b8, X16), (a4, b8, X17), (a4, b8, X18), (a4, b9, X1), (a4, b9, X2), (a4, b9, X3), (a4, b9, X4), (a4, b9, X5), (a4, b9, X6), (a4, b9, X7), (a4, b9, X8), (a4, b9, X9), (a4, b9, X10), (a4, b9, X11), (a4, b9, X12) , (a4, b9, X13), (a4, b9, X14), (a4, b9, X15), (a4, b9, X16), (a4, b9, X17), (a4, b9, X18), ( a4, b10, X1), (a4, b10, X2), (a4, b10, X3), (a4, b10, X4), (a4, b10, X5), (a4, b10, X6), (a4, b10, X7), (a4, b10, X8), (a4, b10, X9), (a4, b10, X10), (a4, b10, X11), (a4 , b10, X12), (a4, b10, X13), (a4, b10, X14), (a4, b10, X15), (a4, b10, X16), (a4, b10, X17), (a4, b10 , X18), (a4, b11, X1), (a4, b11, X2), (a4, b11, X3), (a4, b11, X4), (a4, b11, X5), (a4, b11, X6 ), (a4, b11, X7), (a4, b11, X8), (a4, b11, X9), (a4, b11, X10), (a4, b11, X11), (a4, b11, X12), (a4, b11, X13), (a4, b11, X14), (a4, b11, X15), (a4, b11, X16), (a4, b11, X17), (a4, b11, X18), (a4 , b12, X1), (a4, b12, X2), (a4, b12, X3), (a4, b12, X4), (a4, b12, X5), (a4, b12, X6), (a4, b12 , X7), (a4, b12, X8), (a4, b12, X9), (a4, b12, X10), (a4, b12, X11), (a4, b12, X12), (a4, b12, X13 ), (a4, b12, X14), (a4, b12, X15), (a4, b12, X16), (a4, b12, X17), (a4, b12, X18), (a4, b13, X1), (a4, b13, X2), (a4, b13, X3), (a4, b13, X4), (a4, b13, X5), (a4, b13, X6), (a4, b13, X7), (a4 , b13, X8), (a4, b13, X9), (a4, b13, X10), (a4, b13, X11), (a4, b13, X12), (a4, b13, X13), (a4, b13 , X14), (a4, b13, X15), (a4, b13, X16), (a4, b13, X17), (a4, b13, X18), (a4, b14, X1), (a4, b14, X2 ), (a4, b14, X3), (a4, b14, X4), (a4, b14, X5), (a4, b14, X6), (a4, b14, X7), (a4, b14, X8), (a4, b14, X9), (a4, b14, X10), (a4, b14, X11), (a4, b14, X12), (a4, b14, X13), (a4, b14, X14), (a4 , b14, X15), (a4, b14, X16), (a4, b14, X17), (a4, b14, X18), (a4, b15, X1), (a4, b15, X2), (a4, b15, X3), (a4, b15, X4), (a4, b15, X5), (a4, b15, X6), (a4, b15, X7), (a4 , b15, X8), (a4, b15, X9), (a4, b15, X10), (a4, b15, X11), (a4, b15, X12), (a4, b15, X13), (a4, b15 , X14), (a4, b15, X15), (a4, b15, X16), (a4, b15, X17), (a4, b15, X18), (a4, b16, X1), (a4, b16, X2 ), (a4, b16, X3), (a4, b16, X4), (a4, b16, X5), (a4, b16, X6), (a4, b16, X7), (a4, b16, X8), (a4, b16, X9), (a4, b16, X10), (a4, b16, X11), (a4, b16, X12), (a4, b16, X13), (a4, b16, X14), (a4 , b16, X15), (a4, b16, X16), (a4, b16, X17), (a4, b16, X18), (a4, b17, X1), (a4, b17, X2), (a4, b17 , X3), (a4, b17, X4), (a4, b17, X5), (a4, b17, X6), (a4, b17, X7), (a4, b17, X8), (a4, b17, X9 ), (a4, b17, X10), (a4, b17, X11), (a4, b17, X12), (a4, b17, X13), (a4, b17, X14), (a4, b17, X15), (a4, b17, X16), (a4, b17, X17), (a4, b17, X18), (a4, b18, X1), (a4, b18, X2), (a4, b18, X3), (a4 , b18, X4), (a4, b18, X5), (a4, b18, X6), (a4, b18, X7), (a4, b18, X8), (a4, b18, X9), (a4, b18 , X10), (a4, b18, X11), (a4, b18, X12), (a4, b18, X13), (a4, b18, X14), (a4, b18, X15), (a4, b18, X16 ), (a4, b18, X17), (a4, b18, X18), (a4, b19, X1), (a4, b19, X2), (a4, b19, X3), (a4, b19, X4), (a4, b19, X5), (a4, b19, X6), (a4, b19, X7), (a4, b19, X8), (a4, b19, X9), (a4, b19, X10), (a4, b19, X11), (a4, b19, X12), (a4, b19, X13), (a4, b19, X14), (a4, b19, X15), (a4, b19, X16), (a4, b19, X17), (a4, b19, X18), (a4, b20, X1), (a4, b20, X2), (a4, b20, X3), (a4, b20, X4) , (a4, b20, X5), (a4, b20, X6), (a4, b20, X7), (a4, b20, X8), (a4, b20, X9), (a4, b20, X10), ( a4, b20, X11), (a4, b20, X12), (a4, b20, X13), (a4, b20, X14), (a4, b20, X15), (a4, b20, X16), (a4, b20, X17), (a4, b20, X18), (a4, b21, X1), (a4, b21, X2), (a4, b21, X3), (a4, b21, X4), (a4, b21, X5), (a4, b21, X6), (a4, b21, X7), (a4, b21, X8), (a4, b21, X9), (a4, b21, X10), (a4, b21, X11) , (a4, b21, X12), (a4, b21, X13), (a4, b21, X14), (a4, b21, X15), (a4, b21, X16), (a4, b21, X17), ( a4, b21, X18), (a4, b22, X1), (a4, b22, X2), (a4, b22, X3), (a4, b22, X4), (a4, b22, X5), (a4, b22, X6), (a4, b22, X7), (a4, b22, X8), (a4, b22, X9), (a4, b22, X10), (a4, b22, X11), (a4, b22, X12), (a4, b22, X13), (a4, b22, X14), (a4, b22, X15), (a4, b22, X16), (a4, b22, X17), (a4, b22, X18) , (a4, b23, X1), (a4, b23, X2), (a4, b23, X3), (a4, b23, X4), (a4, b23, X5), (a4, b23, X6), ( a4, b23, X7), (a4, b23, X8), (a4, b23, X9), (a4, b23, X10), (a4, b23, X11), (a4, b23, X12), (a4, b23, X13), (a4, b23, X14), (a4, b23, X15), (a4, b23, X16), (a4, b23, X17), (a4, b23, X18), (a4, b24, X1), (a4, b24, X2), (a4, b24, X3), (a4, b24, X4), (a4, b24, X5), (a4 , b24, X6), (a4, b24, X7), (a4, b24, X8), (a4, b24, X9), (a4, b24, X10), (a4, b24, X11), (a4, b24 , X12), (a4, b24, X13), (a4, b24, X14), (a4, b24, X15), (a4, b24, X16), (a4, b24, X17), (a4, b24, X18 ), (a4, b25, X1), (a4, b25, X2), (a4, b25, X3), (a4, b25, X4), (a4, b25, X5), (a4, b25, X6), (a4, b25, X7), (a4, b25, X8), (a4, b25, X9), (a4, b25, X10), (a4, b25, X11), (a4, b25, X12), (a4 , b25, X13), (a4, b25, X14), (a4, b25, X15), (a4, b25, X16), (a4, b25, X17), (a4, b25, X18), (a4, b26 , X1), (a4, b26, X2), (a4, b26, X3), (a4, b26, X4), (a4, b26, X5), (a4, b26, X6), (a4, b26, X7 ), (a4, b26, X8), (a4, b26, X9), (a4, b26, X10), (a4, b26, X11), (a4, b26, X12), (a4, b26, X13), (a4, b26, X14), (a4, b26, X15), (a4, b26, X16), (a4, b26, X17), (a4, b26, X18), (a4, b27, X1), (a4 , b27, X2), (a4, b27, X3), (a4, b27, X4), (a4, b27, X5), (a4, b27, X6), (a4, b27, X7), (a4, b27 , X8), (a4, b27, X9), (a4, b27, X10), (a4, b27, X11), (a4, b27, X12), (a4, b27, X13), (a4, b27, X14 ), (a4, b27, X15), (a4, b27, X16), (a4, b27, X17), (a4, b27, X18),

(a5, b1, X1), (a5, b1, X2), (a5, b1, X3), (a5, b1, X4), (a5, b1, X5), (a5, b1, X6), (a5 , b1, X7), (a5, b1, X8), (a5, b1, X9), (a5, b1, X10), (a5, b1, X11), (a5, b1, X12), (a5, b1 , X13), (a5, b1, X14), (a5, b1, X15), (a5, b1, X16), (a5, b1, X17), (a5, b1, X18), (a5, b2, X1 ), (a5, b2, X2), (a5, b2, X3), (a5, b2, X4), (a5, b2, X5), (a5, b2, X6), (a5, b2, X7), (a5, b2, X8), (a5, b2, X9), (a5, b2, X10), (a5, b2, X11), (a5, b2, X12), (a5, b2, X13), (a5 , b2, X14), (a5, b2, X15), (a5, b2, X16), (a5, b2, X17), (a5, b2, X18), (a5, b3, X1), (a5, b3 , X2), (a5, b3, X3), (a5, b3, X4), (a5, b3, X5), (a5, b3, X6), (a5, b3, X7), (a5, b3, X8 ), (a5, b3, X9), (a5, b3, X10), (a5, b3, X11), (a5, b3, X12), (a5, b3, X13), (a5, b3, X14), (a5, b3, X15), (a5, b3, X16), (a5, b3, X17), (a5, b3, X18), (a5, b4, X1), (a5, b4, X2), (a5 , b4, X3), (a5, b4, X4), (a5, b4, X5), (a5, b4, X6), (a5, b4, X7), (a5, b4, X8), (a5, b4 , X9), (a5, b4, X10), (a5, b4, X11), (a5, b4, X12), (a5, b4, X13), (a5, b4, X14), (a5, b4, X15 ), (a5, b4, X16), (a5, b4, X17), (a5, b4, X18), (a5, b5, X1), (a5, b5, X2), (a5, b5, X3), (a5, b5, X4), (a5, b5, X5), (a5, b5, X6), (a5, b5, X7), (a5, b5, X8), (a5, b5, X9), (a5 , b5, X10), (a5, b5, X11), (a5, b5, X12), (a5, b5, X13), (a5, b5, X14), (a5, b5, X15), ( a5, b5, X16), (a5, b5, X17), (a5, b5, X18), (a5, b6, X1), (a5, b6, X2), (a5, b6, X3), (a5, b6, X4), (a5, b6, X5), (a5, b6, X6), (a5, b6, X7), (a5, b6, X8), (a5, b6, X9), (a5, b6, X10), (a5, b6, X11), (a5, b6, X12), (a5, b6, X13), (a5, b6, X14), (a5, b6, X15), (a5, b6, X16) , (a5, b6, X17), (a5, b6, X18), (a5, b7, X1), (a5, b7, X2), (a5, b7, X3), (a5, b7, X4), ( a5, b7, X5), (a5, b7, X6), (a5, b7, X7), (a5, b7, X8), (a5, b7, X9), (a5, b7, X10), (a5, b7, X11), (a5, b7, X12), (a5, b7, X13), (a5, b7, X14), (a5, b7, X15), (a5, b7, X16), (a5, b7, X17), (a5, b7, X18), (a5, b8, X1), (a5, b8, X2), (a5, b8, X3), (a5, b8, X4), (a5, b8, X5) , (a5, b8, X6), (a5, b8, X7), (a5, b8, X8), (a5, b8, X9), (a5, b8, X10), (a5, b8, X11), ( a5, b8, X12), (a5, b8, X13), (a5, b8, X14), (a5, b8, X15), (a5, b8, X16), (a5, b8, X17), (a5, b8, X18), (a5, b9, X1), (a5, b9, X2), (a5, b9, X3), (a5, b9, X4), (a5, b9, X5), (a5, b9, X6), (a5, b9, X7), (a5, b9, X8), (a5, b9, X9), (a5, b9, X10), (a5, b9, X11), (a5, b9, X12) , (a5, b9, X13), (a5, b9, X14), (a5, b9, X15), (a5, b9, X16), (a5, b9, X17), (a5, b9, X18), ( a5, b10, X1), (a5, b10, X2), (a5, b10, X3), (a5, b10, X4), (a5, b10, X5), (a5, b10, X6), (a5, b10, X7), (a5, b10, X8), (a5, b10, X9), (a5, b10, X10), (a5, b10, X11), (a5 , b10, X12), (a5, b10, X13), (a5, b10, X14), (a5, b10, X15), (a5, b10, X16), (a5, b10, X17), (a5, b10 , X18), (a5, b11, X1), (a5, b11, X2), (a5, b11, X3), (a5, b11, X4), (a5, b11, X5), (a5, b11, X6 ), (a5, b11, X7), (a5, b11, X8), (a5, b11, X9), (a5, b11, X10), (a5, b11, X11), (a5, b11, X12), (a5, b11, X13), (a5, b11, X14), (a5, b11, X15), (a5, b11, X16), (a5, b11, X17), (a5, b11, X18), (a5 , b12, X1), (a5, b12, X2), (a5, b12, X3), (a5, b12, X4), (a5, b12, X5), (a5, b12, X6), (a5, b12 , X7), (a5, b12, X8), (a5, b12, X9), (a5, b12, X10), (a5, b12, X11), (a5, b12, X12), (a5, b12, X13 ), (a5, b12, X14), (a5, b12, X15), (a5, b12, X16), (a5, b12, X17), (a5, b12, X18), (a5, b13, X1), (a5, b13, X2), (a5, b13, X3), (a5, b13, X4), (a5, b13, X5), (a5, b13, X6), (a5, b13, X7), (a5 , b13, X8), (a5, b13, X9), (a5, b13, X10), (a5, b13, X11), (a5, b13, X12), (a5, b13, X13), (a5, b13 , X14), (a5, b13, X15), (a5, b13, X16), (a5, b13, X17), (a5, b13, X18), (a5, b14, X1), (a5, b14, X2 ), (a5, b14, X3), (a5, b14, X4), (a5, b14, X5), (a5, b14, X6), (a5, b14, X7), (a5, b14, X8), (a5, b14, X9), (a5, b14, X10), (a5, b14, X11), (a5, b14, X12), (a5, b14, X13), (a5, b14, X14), (a5 , b14, X15), (a5, b14, X16), (a5, b14, X17), (a5, b14, X18), (a5, b15, X1), (a5, b15, X2), (a5, b15, X3), (a5, b15, X4), (a5, b15, X5), (a5, b15, X6), (a5, b15, X7), (a5 , b15, X8), (a5, b15, X9), (a5, b15, X10), (a5, b15, X11), (a5, b15, X12), (a5, b15, X13), (a5, b15 , X14), (a5, b15, X15), (a5, b15, X16), (a5, b15, X17), (a5, b15, X18), (a5, b16, X1), (a5, b16, X2 ), (a5, b16, X3), (a5, b16, X4), (a5, b16, X5), (a5, b16, X6), (a5, b16, X7), (a5, b16, X8), (a5, b16, X9), (a5, b16, X10), (a5, b16, X11), (a5, b16, X12), (a5, b16, X13), (a5, b16, X14), (a5 , b16, X15), (a5, b16, X16), (a5, b16, X17), (a5, b16, X18), (a5, b17, X1), (a5, b17, X2), (a5, b17 , X3), (a5, b17, X4), (a5, b17, X5), (a5, b17, X6), (a5, b17, X7), (a5, b17, X8), (a5, b17, X9 ), (a5, b17, X10), (a5, b17, X11), (a5, b17, X12), (a5, b17, X13), (a5, b17, X14), (a5, b17, X15), (a5, b17, X16), (a5, b17, X17), (a5, b17, X18), (a5, b18, X1), (a5, b18, X2), (a5, b18, X3), (a5 , b18, X4), (a5, b18, X5), (a5, b18, X6), (a5, b18, X7), (a5, b18, X8), (a5, b18, X9), (a5, b18 , X10), (a5, b18, X11), (a5, b18, X12), (a5, b18, X13), (a5, b18, X14), (a5, b18, X15), (a5, b18, X16 ), (a5, b18, X17), (a5, b18, X18), (a5, b19, X1), (a5, b19, X2), (a5, b19, X3), (a5, b19, X4), (a5, b19, X5), (a5, b19, X6), (a5, b19, X7), (a5, b19, X8), (a5, b19, X9), (a5, b19, X10), (a5, b19, X11), (a5, b19, X12), (a5, b19, X13), (a5, b19, X14), (a5, b19, X15), (a5, b19, X16), (a5, b19, X17), (a5, b19, X18), (a5, b20, X1), (a5, b20, X2), (a5, b20, X3), (a5, b20, X4) , (a5, b20, X5), (a5, b20, X6), (a5, b20, X7), (a5, b20, X8), (a5, b20, X9), (a5, b20, X10), ( a5, b20, X11), (a5, b20, X12), (a5, b20, X13), (a5, b20, X14), (a5, b20, X15), (a5, b20, X16), (a5, b20, X17), (a5, b20, X18), (a5, b21, X1), (a5, b21, X2), (a5, b21, X3), (a5, b21, X4), (a5, b21, X5), (a5, b21, X6), (a5, b21, X7), (a5, b21, X8), (a5, b21, X9), (a5, b21, X10), (a5, b21, X11) , (a5, b21, X12), (a5, b21, X13), (a5, b21, X14), (a5, b21, X15), (a5, b21, X16), (a5, b21, X17), ( a5, b21, X18), (a5, b22, X1), (a5, b22, X2), (a5, b22, X3), (a5, b22, X4), (a5, b22, X5), (a5, b22, X6), (a5, b22, X7), (a5, b22, X8), (a5, b22, X9), (a5, b22, X10), (a5, b22, X11), (a5, b22, X12), (a5, b22, X13), (a5, b22, X14), (a5, b22, X15), (a5, b22, X16), (a5, b22, X17), (a5, b22, X18) , (a5, b23, X1), (a5, b23, X2), (a5, b23, X3), (a5, b23, X4), (a5, b23, X5), (a5, b23, X6), ( a5, b23, X7), (a5, b23, X8), (a5, b23, X9), (a5, b23, X10), (a5, b23, X11), (a5, b23, X12), (a5, b23, X13), (a5, b23, X14), (a5, b23, X15), (a5, b23, X16), (a5, b23, X17), (a5, b23, X18), (a5, b24, X1), (a5, b24, X2), (a5, b24, X3), (a5, b24, X4), (a5, b24, X5), (a5 , b24, X6), (a5, b24, X7), (a5, b24, X8), (a5, b24, X9), (a5, b24, X10), (a5, b24, X11), (a5, b24 , X12), (a5, b24, X13), (a5, b24, X14), (a5, b24, X15), (a5, b24, X16), (a5, b24, X17), (a5, b24, X18 ), (a5, b25, X1), (a5, b25, X2), (a5, b25, X3), (a5, b25, X4), (a5, b25, X5), (a5, b25, X6), (a5, b25, X7), (a5, b25, X8), (a5, b25, X9), (a5, b25, X10), (a5, b25, X11), (a5, b25, X12), (a5 , b25, X13), (a5, b25, X14), (a5, b25, X15), (a5, b25, X16), (a5, b25, X17), (a5, b25, X18), (a5, b26 , X1), (a5, b26, X2), (a5, b26, X3), (a5, b26, X4), (a5, b26, X5), (a5, b26, X6), (a5, b26, X7 ), (a5, b26, X8), (a5, b26, X9), (a5, b26, X10), (a5, b26, X11), (a5, b26, X12), (a5, b26, X13), (a5, b26, X14), (a5, b26, X15), (a5, b26, X16), (a5, b26, X17), (a5, b26, X18), (a5, b27, X1), (a5 , b27, X2), (a5, b27, X3), (a5, b27, X4), (a5, b27, X5), (a5, b27, X6), (a5, b27, X7), (a5, b27 , X8), (a5, b27, X9), (a5, b27, X10), (a5, b27, X11), (a5, b27, X12), (a5, b27, X13), (a5, b27, X14 ), (a5, b27, X15), (a5, b27, X16), (a5, b27, X17), (a5, b27, X18),

(a6, b1, X1), (a6, b1, X2), (a6, b1, X3), (a6, b1, X4), (a6, b1, X5), (a6, b1, X6), (a6 , b1, X7), (a6, b1, X8), (a6, b1, X9), (a6, b1, X10), (a6, b1, X11), (a6, b1, X12), (a6, b1 , X13), (a6, b1, X14), (a6, b1, X15), (a6, b1, X16), (a6, b1, X17), (a6, b1, X18), (a6, b2, X1 ), (a6, b2, X2), (a6, b2, X3), (a6, b2, X4), (a6, b2, X5), (a6, b2, X6), (a6, b2, X7), (a6, b2, X8), (a6, b2, X9), (a6, b2, X10), (a6, b2, X11), (a6, b2, X12), (a6, b2, X13), (a6 , b2, X14), (a6, b2, X15), (a6, b2, X16), (a6, b2, X17), (a6, b2, X18), (a6, b3, X1), (a6, b3 , X2), (a6, b3, X3), (a6, b3, X4), (a6, b3, X5), (a6, b3, X6), (a6, b3, X7), (a6, b3, X8 ), (a6, b3, X9), (a6, b3, X10), (a6, b3, X11), (a6, b3, X12), (a6, b3, X13), (a6, b3, X14), (a6, b3, X15), (a6, b3, X16), (a6, b3, X17), (a6, b3, X18), (a6, b4, X1), (a6, b4, X2), (a6 , b4, X3), (a6, b4, X4), (a6, b4, X5), (a6, b4, X6), (a6, b4, X7), (a6, b4, X8), (a6, b4 , X9), (a6, b4, X10), (a6, b4, X11), (a6, b4, X12), (a6, b4, X13), (a6, b4, X14), (a6, b4, X15 ), (a6, b4, X16), (a6, b4, X17), (a6, b4, X18), (a6, b5, X1), (a6, b5, X2), (a6, b5, X3), (a6, b5, X4), (a6, b5, X5), (a6, b5, X6), (a6, b5, X7), (a6, b5, X8), (a6, b5, X9), (a6 , b5, X10), (a6, b5, X11), (a6, b5, X12), (a6, b5, X13), (a6, b5, X14), (a6, b5, X15), ( a6, b5, X16), (a6, b5, X17), (a6, b5, X18), (a6, b6, X1), (a6, b6, X2), (a6, b6, X3), (a6, b6, X4), (a6, b6, X5), (a6, b6, X6), (a6, b6, X7), (a6, b6, X8), (a6, b6, X9), (a6, b6, X10), (a6, b6, X11), (a6, b6, X12), (a6, b6, X13), (a6, b6, X14), (a6, b6, X15), (a6, b6, X16) , (a6, b6, X17), (a6, b6, X18), (a6, b7, X1), (a6, b7, X2), (a6, b7, X3), (a6, b7, X4), ( a6, b7, X5), (a6, b7, X6), (a6, b7, X7), (a6, b7, X8), (a6, b7, X9), (a6, b7, X10), (a6, b7, X11), (a6, b7, X12), (a6, b7, X13), (a6, b7, X14), (a6, b7, X15), (a6, b7, X16), (a6, b7, X17), (a6, b7, X18), (a6, b8, X1), (a6, b8, X2), (a6, b8, X3), (a6, b8, X4), (a6, b8, X5) , (a6, b8, X6), (a6, b8, X7), (a6, b8, X8), (a6, b8, X9), (a6, b8, X10), (a6, b8, X11), ( a6, b8, X12), (a6, b8, X13), (a6, b8, X14), (a6, b8, X15), (a6, b8, X16), (a6, b8, X17), (a6, b8, X18), (a6, b9, X1), (a6, b9, X2), (a6, b9, X3), (a6, b9, X4), (a6, b9, X5), (a6, b9, X6), (a6, b9, X7), (a6, b9, X8), (a6, b9, X9), (a6, b9, X10), (a6, b9, X11), (a6, b9, X12) , (a6, b9, X13), (a6, b9, X14), (a6, b9, X15), (a6, b9, X16), (a6, b9, X17), (a6, b9, X18), ( a6, b10, X1), (a6, b10, X2), (a6, b10, X3), (a6, b10, X4), (a6, b10, X5), (a6, b10, X6), (a6, b10, X7), (a6, b10, X8), (a6, b10, X9), (a6, b10, X10), (a6, b10, X11), (a6 , b10, X12), (a6, b10, X13), (a6, b10, X14), (a6, b10, X15), (a6, b10, X16), (a6, b10, X17), (a6, b10 , X18), (a6, b11, X1), (a6, b11, X2), (a6, b11, X3), (a6, b11, X4), (a6, b11, X5), (a6, b11, X6 ), (a6, b11, X7), (a6, b11, X8), (a6, b11, X9), (a6, b11, X10), (a6, b11, X11), (a6, b11, X12), (a6, b11, X13), (a6, b11, X14), (a6, b11, X15), (a6, b11, X16), (a6, b11, X17), (a6, b11, X18), (a6 , b12, X1), (a6, b12, X2), (a6, b12, X3), (a6, b12, X4), (a6, b12, X5), (a6, b12, X6), (a6, b12 , X7), (a6, b12, X8), (a6, b12, X9), (a6, b12, X10), (a6, b12, X11), (a6, b12, X12), (a6, b12, X13 ), (a6, b12, X14), (a6, b12, X15), (a6, b12, X16), (a6, b12, X17), (a6, b12, X18), (a6, b13, X1), (a6, b13, X2), (a6, b13, X3), (a6, b13, X4), (a6, b13, X5), (a6, b13, X6), (a6, b13, X7), (a6 , b13, X8), (a6, b13, X9), (a6, b13, X10), (a6, b13, X11), (a6, b13, X12), (a6, b13, X13), (a6, b13 , X14), (a6, b13, X15), (a6, b13, X16), (a6, b13, X17), (a6, b13, X18), (a6, b14, X1), (a6, b14, X2 ), (a6, b14, X3), (a6, b14, X4), (a6, b14, X5), (a6, b14, X6), (a6, b14, X7), (a6, b14, X8), (a6, b14, X9), (a6, b14, X10), (a6, b14, X11), (a6, b14, X12), (a6, b14, X13), (a6, b14, X14), (a6 , b14, X15), (a6, b14, X16), (a6, b14, X17), (a6, b14, X18), (a6, b15, X1), (a6, b15, X2), (a6, b15, X3), (a6, b15, X4), (a6, b15, X5), (a6, b15, X6), (a6, b15, X7), (a6 , b15, X8), (a6, b15, X9), (a6, b15, X10), (a6, b15, X11), (a6, b15, X12), (a6, b15, X13), (a6, b15 , X14), (a6, b15, X15), (a6, b15, X16), (a6, b15, X17), (a6, b15, X18), (a6, b16, X1), (a6, b16, X2 ), (a6, b16, X3), (a6, b16, X4), (a6, b16, X5), (a6, b16, X6), (a6, b16, X7), (a6, b16, X8), (a6, b16, X9), (a6, b16, X10), (a6, b16, X11), (a6, b16, X12), (a6, b16, X13), (a6, b16, X14), (a6 , b16, X15), (a6, b16, X16), (a6, b16, X17), (a6, b16, X18), (a6, b17, X1), (a6, b17, X2), (a6, b17 , X3), (a6, b17, X4), (a6, b17, X5), (a6, b17, X6), (a6, b17, X7), (a6, b17, X8), (a6, b17, X9 ), (a6, b17, X10), (a6, b17, X11), (a6, b17, X12), (a6, b17, X13), (a6, b17, X14), (a6, b17, X15), (a6, b17, X16), (a6, b17, X17), (a6, b17, X18), (a6, b18, X1), (a6, b18, X2), (a6, b18, X3), (a6 , b18, X4), (a6, b18, X5), (a6, b18, X6), (a6, b18, X7), (a6, b18, X8), (a6, b18, X9), (a6, b18 , X10), (a6, b18, X11), (a6, b18, X12), (a6, b18, X13), (a6, b18, X14), (a6, b18, X15), (a6, b18, X16 ), (a6, b18, X17), (a6, b18, X18), (a6, b19, X1), (a6, b19, X2), (a6, b19, X3), (a6, b19, X4), (a6, b19, X5), (a6, b19, X6), (a6, b19, X7), (a6, b19, X8), (a6, b19, X9), (a6, b19, X10), (a6, b19, X11), (a6, b19, X12), (a6, b19, X13), (a6, b19, X14), (a6, b19, X15), (a6, b19, X16), (a6, b19, X17), (a6, b19, X18), (a6, b20, X1), (a6, b20, X2), (a6, b20, X3), (a6, b20, X4) , (a6, b20, X5), (a6, b20, X6), (a6, b20, X7), (a6, b20, X8), (a6, b20, X9), (a6, b20, X10), ( a6, b20, X11), (a6, b20, X12), (a6, b20, X13), (a6, b20, X14), (a6, b20, X15), (a6, b20, X16), (a6, b20, X17), (a6, b20, X18), (a6, b21, X1), (a6, b21, X2), (a6, b21, X3), (a6, b21, X4), (a6, b21, X5), (a6, b21, X6), (a6, b21, X7), (a6, b21, X8), (a6, b21, X9), (a6, b21, X10), (a6, b21, X11) , (a6, b21, X12), (a6, b21, X13), (a6, b21, X14), (a6, b21, X15), (a6, b21, X16), (a6, b21, X17), ( a6, b21, X18), (a6, b22, X1), (a6, b22, X2), (a6, b22, X3), (a6, b22, X4), (a6, b22, X5), (a6, b22, X6), (a6, b22, X7), (a6, b22, X8), (a6, b22, X9), (a6, b22, X10), (a6, b22, X11), (a6, b22, X12), (a6, b22, X13), (a6, b22, X14), (a6, b22, X15), (a6, b22, X16), (a6, b22, X17), (a6, b22, X18) , (a6, b23, X1), (a6, b23, X2), (a6, b23, X3), (a6, b23, X4), (a6, b23, X5), (a6, b23, X6), ( a6, b23, X7), (a6, b23, X8), (a6, b23, X9), (a6, b23, X10), (a6, b23, X11), (a6, b23, X12), (a6, b23, X13), (a6, b23, X14), (a6, b23, X15), (a6, b23, X16), (a6, b23, X17), (a6, b23, X18), (a6, b24, X1), (a6, b24, X2), (a6, b24, X3), (a6, b24, X4), (a6, b24, X5), (a6 , b24, X6), (a6, b24, X7), (a6, b24, X8), (a6, b24, X9), (a6, b24, X10), (a6, b24, X11), (a6, b24 , X12), (a6, b24, X13), (a6, b24, X14), (a6, b24, X15), (a6, b24, X16), (a6, b24, X17), (a6, b24, X18 ), (a6, b25, X1), (a6, b25, X2), (a6, b25, X3), (a6, b25, X4), (a6, b25, X5), (a6, b25, X6), (a6, b25, X7), (a6, b25, X8), (a6, b25, X9), (a6, b25, X10), (a6, b25, X11), (a6, b25, X12), (a6 , b25, X13), (a6, b25, X14), (a6, b25, X15), (a6, b25, X16), (a6, b25, X17), (a6, b25, X18), (a6, b26 , X1), (a6, b26, X2), (a6, b26, X3), (a6, b26, X4), (a6, b26, X5), (a6, b26, X6), (a6, b26, X7 ), (a6, b26, X8), (a6, b26, X9), (a6, b26, X10), (a6, b26, X11), (a6, b26, X12), (a6, b26, X13), (a6, b26, X14), (a6, b26, X15), (a6, b26, X16), (a6, b26, X17), (a6, b26, X18), (a6, b27, X1), (a6 , b27, X2), (a6, b27, X3), (a6, b27, X4), (a6, b27, X5), (a6, b27, X6), (a6, b27, X7), (a6, b27 , X8), (a6, b27, X9), (a6, b27, X10), (a6, b27, X11), (a6, b27, X12), (a6, b27, X13), (a6, b27, X14 ), (a6, b27, X15), (a6, b27, X16), (a6, b27, X17), (a6, b27, X18),

(a7, b1, X1), (a7, b1, X2), (a7, b1, X3), (a7, b1, X4), (a7, b1, X5), (a7, b1, X6), (a7 , b1, X7), (a7, b1, X8), (a7, b1, X9), (a7, b1, X10), (a7, b1, X11), (a7, b1, X12), (a7, b1 , X13), (a7, b1, X14), (a7, b1, X15), (a7, b1, X16), (a7, b1, X17), (a7, b1, X18), (a7, b2, X1 ), (a7, b2, X2), (a7, b2, X3), (a7, b2, X4), (a7, b2, X5), (a7, b2, X6), (a7, b2, X7), (a7, b2, X8), (a7, b2, X9), (a7, b2, X10), (a7, b2, X11), (a7, b2, X12), (a7, b2, X13), (a7 , b2, X14), (a7, b2, X15), (a7, b2, X16), (a7, b2, X17), (a7, b2, X18), (a7, b3, X1), (a7, b3 , X2), (a7, b3, X3), (a7, b3, X4), (a7, b3, X5), (a7, b3, X6), (a7, b3, X7), (a7, b3, X8 ), (a7, b3, X9), (a7, b3, X10), (a7, b3, X11), (a7, b3, X12), (a7, b3, X13), (a7, b3, X14), (a7, b3, X15), (a7, b3, X16), (a7, b3, X17), (a7, b3, X18), (a7, b4, X1), (a7, b4, X2), (a7 , b4, X3), (a7, b4, X4), (a7, b4, X5), (a7, b4, X6), (a7, b4, X7), (a7, b4, X8), (a7, b4 , X9), (a7, b4, X10), (a7, b4, X11), (a7, b4, X12), (a7, b4, X13), (a7, b4, X14), (a7, b4, X15 ), (a7, b4, X16), (a7, b4, X17), (a7, b4, X18), (a7, b5, X1), (a7, b5, X2), (a7, b5, X3), (a7, b5, X4), (a7, b5, X5), (a7, b5, X6), (a7, b5, X7), (a7, b5, X8), (a7, b5, X9), (a7 , b5, X10), (a7, b5, X11), (a7, b5, X12), (a7, b5, X13), (a7, b5, X14), (a7, b5, X15), ( a7, b5, X16), (a7, b5, X17), (a7, b5, X18), (a7, b6, X1), (a7, b6, X2), (a7, b6, X3), (a7, b6, X4), (a7, b6, X5), (a7, b6, X6), (a7, b6, X7), (a7, b6, X8), (a7, b6, X9), (a7, b6, X10), (a7, b6, X11), (a7, b6, X12), (a7, b6, X13), (a7, b6, X14), (a7, b6, X15), (a7, b6, X16) , (a7, b6, X17), (a7, b6, X18), (a7, b7, X1), (a7, b7, X2), (a7, b7, X3), (a7, b7, X4), ( a7, b7, X5), (a7, b7, X6), (a7, b7, X7), (a7, b7, X8), (a7, b7, X9), (a7, b7, X10), (a7, b7, X11), (a7, b7, X12), (a7, b7, X13), (a7, b7, X14), (a7, b7, X15), (a7, b7, X16), (a7, b7, X17), (a7, b7, X18), (a7, b8, X1), (a7, b8, X2), (a7, b8, X3), (a7, b8, X4), (a7, b8, X5) , (a7, b8, X6), (a7, b8, X7), (a7, b8, X8), (a7, b8, X9), (a7, b8, X10), (a7, b8, X11), ( a7, b8, X12), (a7, b8, X13), (a7, b8, X14), (a7, b8, X15), (a7, b8, X16), (a7, b8, X17), (a7, b8, X18), (a7, b9, X1), (a7, b9, X2), (a7, b9, X3), (a7, b9, X4), (a7, b9, X5), (a7, b9, X6), (a7, b9, X7), (a7, b9, X8), (a7, b9, X9), (a7, b9, X10), (a7, b9, X11), (a7, b9, X12) , (a7, b9, X13), (a7, b9, X14), (a7, b9, X15), (a7, b9, X16), (a7, b9, X17), (a7, b9, X18), ( a7, b10, X1), (a7, b10, X2), (a7, b10, X3), (a7, b10, X4), (a7, b10, X5), (a7, b10, X6), (a7, b10, X7), (a7, b10, X8), (a7, b10, X9), (a7, b10, X10), (a7, b10, X11), (a7 , b10, X12), (a7, b10, X13), (a7, b10, X14), (a7, b10, X15), (a7, b10, X16), (a7, b10, X17), (a7, b10 , X18), (a7, b11, X1), (a7, b11, X2), (a7, b11, X3), (a7, b11, X4), (a7, b11, X5), (a7, b11, X6 ), (a7, b11, X7), (a7, b11, X8), (a7, b11, X9), (a7, b11, X10), (a7, b11, X11), (a7, b11, X12), (a7, b11, X13), (a7, b11, X14), (a7, b11, X15), (a7, b11, X16), (a7, b11, X17), (a7, b11, X18), (a7 , b12, X1), (a7, b12, X2), (a7, b12, X3), (a7, b12, X4), (a7, b12, X5), (a7, b12, X6), (a7, b12 , X7), (a7, b12, X8), (a7, b12, X9), (a7, b12, X10), (a7, b12, X11), (a7, b12, X12), (a7, b12, X13 ), (a7, b12, X14), (a7, b12, X15), (a7, b12, X16), (a7, b12, X17), (a7, b12, X18), (a7, b13, X1), (a7, b13, X2), (a7, b13, X3), (a7, b13, X4), (a7, b13, X5), (a7, b13, X6), (a7, b13, X7), (a7 , b13, X8), (a7, b13, X9), (a7, b13, X10), (a7, b13, X11), (a7, b13, X12), (a7, b13, X13), (a7, b13 , X14), (a7, b13, X15), (a7, b13, X16), (a7, b13, X17), (a7, b13, X18), (a7, b14, X1), (a7, b14, X2 ), (a7, b14, X3), (a7, b14, X4), (a7, b14, X5), (a7, b14, X6), (a7, b14, X7), (a7, b14, X8), (a7, b14, X9), (a7, b14, X10), (a7, b14, X11), (a7, b14, X12), (a7, b14, X13), (a7, b14, X14), (a7 , b14, X15), (a7, b14, X16), (a7, b14, X17), (a7, b14, X18), (a7, b15, X1), (a7, b15, X2), (a7, b15, X3), (a7, b15, X4), (a7, b15, X5), (a7, b15, X6), (a7, b15, X7), (a7 , b15, X8), (a7, b15, X9), (a7, b15, X10), (a7, b15, X11), (a7, b15, X12), (a7, b15, X13), (a7, b15 , X14), (a7, b15, X15), (a7, b15, X16), (a7, b15, X17), (a7, b15, X18), (a7, b16, X1), (a7, b16, X2 ), (a7, b16, X3), (a7, b16, X4), (a7, b16, X5), (a7, b16, X6), (a7, b16, X7), (a7, b16, X8), (a7, b16, X9), (a7, b16, X10), (a7, b16, X11), (a7, b16, X12), (a7, b16, X13), (a7, b16, X14), (a7 , b16, X15), (a7, b16, X16), (a7, b16, X17), (a7, b16, X18), (a7, b17, X1), (a7, b17, X2), (a7, b17 , X3), (a7, b17, X4), (a7, b17, X5), (a7, b17, X6), (a7, b17, X7), (a7, b17, X8), (a7, b17, X9 ), (a7, b17, X10), (a7, b17, X11), (a7, b17, X12), (a7, b17, X13), (a7, b17, X14), (a7, b17, X15), (a7, b17, X16), (a7, b17, X17), (a7, b17, X18), (a7, b18, X1), (a7, b18, X2), (a7, b18, X3), (a7 , b18, X4), (a7, b18, X5), (a7, b18, X6), (a7, b18, X7), (a7, b18, X8), (a7, b18, X9), (a7, b18 , X10), (a7, b18, X11), (a7, b18, X12), (a7, b18, X13), (a7, b18, X14), (a7, b18, X15), (a7, b18, X16 ), (a7, b18, X17), (a7, b18, X18), (a7, b19, X1), (a7, b19, X2), (a7, b19, X3), (a7, b19, X4), (a7, b19, X5), (a7, b19, X6), (a7, b19, X7), (a7, b19, X8), (a7, b19, X9), (a7, b19, X10), (a7, b19, X11), (a7, b19, X12), (a7, b19, X13), (a7, b19, X14), (a7, b19, X15), (a7, b19, X16), (a7, b19, X17), (a7, b19, X18), (a7, b20, X1), (a7, b20, X2), (a7, b20, X3), (a7, b20, X4) , (a7, b20, X5), (a7, b20, X6), (a7, b20, X7), (a7, b20, X8), (a7, b20, X9), (a7, b20, X10), ( a7, b20, X11), (a7, b20, X12), (a7, b20, X13), (a7, b20, X14), (a7, b20, X15), (a7, b20, X16), (a7, b20, X17), (a7, b20, X18), (a7, b21, X1), (a7, b21, X2), (a7, b21, X3), (a7, b21, X4), (a7, b21, X5), (a7, b21, X6), (a7, b21, X7), (a7, b21, X8), (a7, b21, X9), (a7, b21, X10), (a7, b21, X11) , (a7, b21, X12), (a7, b21, X13), (a7, b21, X14), (a7, b21, X15), (a7, b21, X16), (a7, b21, X17), ( a7, b21, X18), (a7, b22, X1), (a7, b22, X2), (a7, b22, X3), (a7, b22, X4), (a7, b22, X5), (a7, b22, X6), (a7, b22, X7), (a7, b22, X8), (a7, b22, X9), (a7, b22, X10), (a7, b22, X11), (a7, b22, X12), (a7, b22, X13), (a7, b22, X14), (a7, b22, X15), (a7, b22, X16), (a7, b22, X17), (a7, b22, X18) , (a7, b23, X1), (a7, b23, X2), (a7, b23, X3), (a7, b23, X4), (a7, b23, X5), (a7, b23, X6), ( a7, b23, X7), (a7, b23, X8), (a7, b23, X9), (a7, b23, X10), (a7, b23, X11), (a7, b23, X12), (a7, b23, X13), (a7, b23, X14), (a7, b23, X15), (a7, b23, X16), (a7, b23, X17), (a7, b23, X18), (a7, b24, X1), (a7, b24, X2), (a7, b24, X3), (a7, b24, X4), (a7, b24, X5), (a7 , b24, X6), (a7, b24, X7), (a7, b24, X8), (a7, b24, X9), (a7, b24, X10), (a7, b24, X11), (a7, b24 , X12), (a7, b24, X13), (a7, b24, X14), (a7, b24, X15), (a7, b24, X16), (a7, b24, X17), (a7, b24, X18 ), (a7, b25, X1), (a7, b25, X2), (a7, b25, X3), (a7, b25, X4), (a7, b25, X5), (a7, b25, X6), (a7, b25, X7), (a7, b25, X8), (a7, b25, X9), (a7, b25, X10), (a7, b25, X11), (a7, b25, X12), (a7 , b25, X13), (a7, b25, X14), (a7, b25, X15), (a7, b25, X16), (a7, b25, X17), (a7, b25, X18), (a7, b26 , X1), (a7, b26, X2), (a7, b26, X3), (a7, b26, X4), (a7, b26, X5), (a7, b26, X6), (a7, b26, X7 ), (a7, b26, X8), (a7, b26, X9), (a7, b26, X10), (a7, b26, X11), (a7, b26, X12), (a7, b26, X13), (a7, b26, X14), (a7, b26, X15), (a7, b26, X16), (a7, b26, X17), (a7, b26, X18), (a7, b27, X1), (a7 , b27, X2), (a7, b27, X3), (a7, b27, X4), (a7, b27, X5), (a7, b27, X6), (a7, b27, X7), (a7, b27 , X8), (a7, b27, X9), (a7, b27, X10), (a7, b27, X11), (a7, b27, X12), (a7, b27, X13), (a7, b27, X14 ), (a7, b27, X15), (a7, b27, X16), (a7, b27, X17), (a7, b27, X18),

(a8, b1, X1), (a8, b1, X2), (a8, b1, X3), (a8, b1, X4), (a8, b1, X5), (a8, b1, X6), (a8 , b1, X7), (a8, b1, X8), (a8, b1, X9), (a8, b1, X10), (a8, b1, X11), (a8, b1, X12), (a8, b1 , X13), (a8, b1, X14), (a8, b1, X15), (a8, b1, X16), (a8, b1, X17), (a8, b1, X18), (a8, b2, X1 ), (a8, b2, X2), (a8, b2, X3), (a8, b2, X4), (a8, b2, X5), (a8, b2, X6), (a8, b2, X7), (a8, b2, X8), (a8, b2, X9), (a8, b2, X10), (a8, b2, X11), (a8, b2, X12), (a8, b2, X13), (a8 , b2, X14), (a8, b2, X15), (a8, b2, X16), (a8, b2, X17), (a8, b2, X18), (a8, b3, X1), (a8, b3 , X2), (a8, b3, X3), (a8, b3, X4), (a8, b3, X5), (a8, b3, X6), (a8, b3, X7), (a8, b3, X8 ), (a8, b3, X9), (a8, b3, X10), (a8, b3, X11), (a8, b3, X12), (a8, b3, X13), (a8, b3, X14), (a8, b3, X15), (a8, b3, X16), (a8, b3, X17), (a8, b3, X18), (a8, b4, X1), (a8, b4, X2), (a8 , b4, X3), (a8, b4, X4), (a8, b4, X5), (a8, b4, X6), (a8, b4, X7), (a8, b4, X8), (a8, b4 , X9), (a8, b4, X10), (a8, b4, X11), (a8, b4, X12), (a8, b4, X13), (a8, b4, X14), (a8, b4, X15 ), (a8, b4, X16), (a8, b4, X17), (a8, b4, X18), (a8, b5, X1), (a8, b5, X2), (a8, b5, X3), (a8, b5, X4), (a8, b5, X5), (a8, b5, X6), (a8, b5, X7), (a8, b5, X8), (a8, b5, X9), (a8 , b5, X10), (a8, b5, X11), (a8, b5, X12), (a8, b5, X13), (a8, b5, X14), (a8, b5, X15), ( a8, b5, X16), (a8, b5, X17), (a8, b5, X18), (a8, b6, X1), (a8, b6, X2), (a8, b6, X3), (a8, b6, X4), (a8, b6, X5), (a8, b6, X6), (a8, b6, X7), (a8, b6, X8), (a8, b6, X9), (a8, b6, X10), (a8, b6, X11), (a8, b6, X12), (a8, b6, X13), (a8, b6, X14), (a8, b6, X15), (a8, b6, X16) , (a8, b6, X17), (a8, b6, X18), (a8, b7, X1), (a8, b7, X2), (a8, b7, X3), (a8, b7, X4), ( a8, b7, X5), (a8, b7, X6), (a8, b7, X7), (a8, b7, X8), (a8, b7, X9), (a8, b7, X10), (a8, b7, X11), (a8, b7, X12), (a8, b7, X13), (a8, b7, X14), (a8, b7, X15), (a8, b7, X16), (a8, b7, X17), (a8, b7, X18), (a8, b8, X1), (a8, b8, X2), (a8, b8, X3), (a8, b8, X4), (a8, b8, X5) , (a8, b8, X6), (a8, b8, X7), (a8, b8, X8), (a8, b8, X9), (a8, b8, X10), (a8, b8, X11), ( a8, b8, X12), (a8, b8, X13), (a8, b8, X14), (a8, b8, X15), (a8, b8, X16), (a8, b8, X17), (a8, b8, X18), (a8, b9, X1), (a8, b9, X2), (a8, b9, X3), (a8, b9, X4), (a8, b9, X5), (a8, b9, X6), (a8, b9, X7), (a8, b9, X8), (a8, b9, X9), (a8, b9, X10), (a8, b9, X11), (a8, b9, X12) , (a8, b9, X13), (a8, b9, X14), (a8, b9, X15), (a8, b9, X16), (a8, b9, X17), (a8, b9, X18), ( a8, b10, X1), (a8, b10, X2), (a8, b10, X3), (a8, b10, X4), (a8, b10, X5), (a8, b10, X6), (a8, b10, X7), (a8, b10, X8), (a8, b10, X9), (a8, b10, X10), (a8, b10, X11), (a8 , b10, X12), (a8, b10, X13), (a8, b10, X14), (a8, b10, X15), (a8, b10, X16), (a8, b10, X17), (a8, b10 , X18), (a8, b11, X1), (a8, b11, X2), (a8, b11, X3), (a8, b11, X4), (a8, b11, X5), (a8, b11, X6 ), (a8, b11, X7), (a8, b11, X8), (a8, b11, X9), (a8, b11, X10), (a8, b11, X11), (a8, b11, X12), (a8, b11, X13), (a8, b11, X14), (a8, b11, X15), (a8, b11, X16), (a8, b11, X17), (a8, b11, X18), (a8 , b12, X1), (a8, b12, X2), (a8, b12, X3), (a8, b12, X4), (a8, b12, X5), (a8, b12, X6), (a8, b12 , X7), (a8, b12, X8), (a8, b12, X9), (a8, b12, X10), (a8, b12, X11), (a8, b12, X12), (a8, b12, X13 ), (a8, b12, X14), (a8, b12, X15), (a8, b12, X16), (a8, b12, X17), (a8, b12, X18), (a8, b13, X1), (a8, b13, X2), (a8, b13, X3), (a8, b13, X4), (a8, b13, X5), (a8, b13, X6), (a8, b13, X7), (a8 , b13, X8), (a8, b13, X9), (a8, b13, X10), (a8, b13, X11), (a8, b13, X12), (a8, b13, X13), (a8, b13 , X14), (a8, b13, X15), (a8, b13, X16), (a8, b13, X17), (a8, b13, X18), (a8, b14, X1), (a8, b14, X2 ), (a8, b14, X3), (a8, b14, X4), (a8, b14, X5), (a8, b14, X6), (a8, b14, X7), (a8, b14, X8), (a8, b14, X9), (a8, b14, X10), (a8, b14, X11), (a8, b14, X12), (a8, b14, X13), (a8, b14, X14), (a8 , b14, X15), (a8, b14, X16), (a8, b14, X17), (a8, b14, X18), (a8, b15, X1), (a8, b15, X2), (a8, b15, X3), (a8, b15, X4), (a8, b15, X5), (a8, b15, X6), (a8, b15, X7), (a8 , b15, X8), (a8, b15, X9), (a8, b15, X10), (a8, b15, X11), (a8, b15, X12), (a8, b15, X13), (a8, b15 , X14), (a8, b15, X15), (a8, b15, X16), (a8, b15, X17), (a8, b15, X18), (a8, b16, X1), (a8, b16, X2 ), (a8, b16, X3), (a8, b16, X4), (a8, b16, X5), (a8, b16, X6), (a8, b16, X7), (a8, b16, X8), (a8, b16, X9), (a8, b16, X10), (a8, b16, X11), (a8, b16, X12), (a8, b16, X13), (a8, b16, X14), (a8 , b16, X15), (a8, b16, X16), (a8, b16, X17), (a8, b16, X18), (a8, b17, X1), (a8, b17, X2), (a8, b17 , X3), (a8, b17, X4), (a8, b17, X5), (a8, b17, X6), (a8, b17, X7), (a8, b17, X8), (a8, b17, X9 ), (a8, b17, X10), (a8, b17, X11), (a8, b17, X12), (a8, b17, X13), (a8, b17, X14), (a8, b17, X15), (a8, b17, X16), (a8, b17, X17), (a8, b17, X18), (a8, b18, X1), (a8, b18, X2), (a8, b18, X3), (a8 , b18, X4), (a8, b18, X5), (a8, b18, X6), (a8, b18, X7), (a8, b18, X8), (a8, b18, X9), (a8, b18 , X10), (a8, b18, X11), (a8, b18, X12), (a8, b18, X13), (a8, b18, X14), (a8, b18, X15), (a8, b18, X16 ), (a8, b18, X17), (a8, b18, X18), (a8, b19, X1), (a8, b19, X2), (a8, b19, X3), (a8, b19, X4), (a8, b19, X5), (a8, b19, X6), (a8, b19, X7), (a8, b19, X8), (a8, b19, X9), (a8, b19, X10), (a8, b19, X11), (a8, b19, X12), (a8, b19, X13), (a8, b19, X14), (a8, b19, X15), (a8, b19, X16), (a8, b19, X17), (a8, b19, X18), (a8, b20, X1), (a8, b20, X2), (a8, b20, X3), (a8, b20, X4) , (a8, b20, X5), (a8, b20, X6), (a8, b20, X7), (a8, b20, X8), (a8, b20, X9), (a8, b20, X10), ( a8, b20, X11), (a8, b20, X12), (a8, b20, X13), (a8, b20, X14), (a8, b20, X15), (a8, b20, X16), (a8, b20, X17), (a8, b20, X18), (a8, b21, X1), (a8, b21, X2), (a8, b21, X3), (a8, b21, X4), (a8, b21, X5), (a8, b21, X6), (a8, b21, X7), (a8, b21, X8), (a8, b21, X9), (a8, b21, X10), (a8, b21, X11) , (a8, b21, X12), (a8, b21, X13), (a8, b21, X14), (a8, b21, X15), (a8, b21, X16), (a8, b21, X17), ( a8, b21, X18), (a8, b22, X1), (a8, b22, X2), (a8, b22, X3), (a8, b22, X4), (a8, b22, X5), (a8, b22, X6), (a8, b22, X7), (a8, b22, X8), (a8, b22, X9), (a8, b22, X10), (a8, b22, X11), (a8, b22, X12), (a8, b22, X13), (a8, b22, X14), (a8, b22, X15), (a8, b22, X16), (a8, b22, X17), (a8, b22, X18) , (a8, b23, X1), (a8, b23, X2), (a8, b23, X3), (a8, b23, X4), (a8, b23, X5), (a8, b23, X6), ( a8, b23, X7), (a8, b23, X8), (a8, b23, X9), (a8, b23, X10), (a8, b23, X11), (a8, b23, X12), (a8, b23, X13), (a8, b23, X14), (a8, b23, X15), (a8, b23, X16), (a8, b23, X17), (a8, b23, X18), (a8, b24, X1), (a8, b24, X2), (a8, b24, X3), (a8, b24, X4), (a8, b24, X5), (a8 , b24, X6), (a8, b24, X7), (a8, b24, X8), (a8, b24, X9), (a8, b24, X10), (a8, b24, X11), (a8, b24 , X12), (a8, b24, X13), (a8, b24, X14), (a8, b24, X15), (a8, b24, X16), (a8, b24, X17), (a8, b24, X18 ), (a8, b25, X1), (a8, b25, X2), (a8, b25, X3), (a8, b25, X4), (a8, b25, X5), (a8, b25, X6), (a8, b25, X7), (a8, b25, X8), (a8, b25, X9), (a8, b25, X10), (a8, b25, X11), (a8, b25, X12), (a8 , b25, X13), (a8, b25, X14), (a8, b25, X15), (a8, b25, X16), (a8, b25, X17), (a8, b25, X18), (a8, b26 , X1), (a8, b26, X2), (a8, b26, X3), (a8, b26, X4), (a8, b26, X5), (a8, b26, X6), (a8, b26, X7 ), (a8, b26, X8), (a8, b26, X9), (a8, b26, X10), (a8, b26, X11), (a8, b26, X12), (a8, b26, X13), (a8, b26, X14), (a8, b26, X15), (a8, b26, X16), (a8, b26, X17), (a8, b26, X18), (a8, b27, X1), (a8 , b27, X2), (a8, b27, X3), (a8, b27, X4), (a8, b27, X5), (a8, b27, X6), (a8, b27, X7), (a8, b27 , X8), (a8, b27, X9), (a8, b27, X10), (a8, b27, X11), (a8, b27, X12), (a8, b27, X13), (a8, b27, X14 ), (a8, b27, X15), (a8, b27, X16), (a8, b27, X17), (a8, b27, X18),

(a9, b1, X1), (a9, b1, X2), (a9, b1, X3), (a9, b1, X4), (a9, b1, X5), (a9, b1, X6), (a9 , b1, X7), (a9, b1, X8), (a9, b1, X9), (a9, b1, X10), (a9, b1, X11), (a9, b1, X12), (a9, b1 , X13), (a9, b1, X14), (a9, b1, X15), (a9, b1, X16), (a9, b1, X17), (a9, b1, X18), (a9, b2, X1 ), (a9, b2, X2), (a9, b2, X3), (a9, b2, X4), (a9, b2, X5), (a9, b2, X6), (a9, b2, X7), (a9, b2, X8), (a9, b2, X9), (a9, b2, X10), (a9, b2, X11), (a9, b2, X12), (a9, b2, X13), (a9 , b2, X14), (a9, b2, X15), (a9, b2, X16), (a9, b2, X17), (a9, b2, X18), (a9, b3, X1), (a9, b3 , X2), (a9, b3, X3), (a9, b3, X4), (a9, b3, X5), (a9, b3, X6), (a9, b3, X7), (a9, b3, X8 ), (a9, b3, X9), (a9, b3, X10), (a9, b3, X11), (a9, b3, X12), (a9, b3, X13), (a9, b3, X14), (a9, b3, X15), (a9, b3, X16), (a9, b3, X17), (a9, b3, X18), (a9, b4, X1), (a9, b4, X2), (a9 , b4, X3), (a9, b4, X4), (a9, b4, X5), (a9, b4, X6), (a9, b4, X7), (a9, b4, X8), (a9, b4 , X9), (a9, b4, X10), (a9, b4, X11), (a9, b4, X12), (a9, b4, X13), (a9, b4, X14), (a9, b4, X15 ), (a9, b4, X16), (a9, b4, X17), (a9, b4, X18), (a9, b5, X1), (a9, b5, X2), (a9, b5, X3), (a9, b5, X4), (a9, b5, X5), (a9, b5, X6), (a9, b5, X7), (a9, b5, X8), (a9, b5, X9), (a9 , b5, X10), (a9, b5, X11), (a9, b5, X12), (a9, b5, X13), (a9, b5, X14), (a9, b5, X15), ( a9, b5, X16), (a9, b5, X17), (a9, b5, X18), (a9, b6, X1), (a9, b6, X2), (a9, b6, X3), (a9, b6, X4), (a9, b6, X5), (a9, b6, X6), (a9, b6, X7), (a9, b6, X8), (a9, b6, X9), (a9, b6, X10), (a9, b6, X11), (a9, b6, X12), (a9, b6, X13), (a9, b6, X14), (a9, b6, X15), (a9, b6, X16) , (a9, b6, X17), (a9, b6, X18), (a9, b7, X1), (a9, b7, X2), (a9, b7, X3), (a9, b7, X4), ( a9, b7, X5), (a9, b7, X6), (a9, b7, X7), (a9, b7, X8), (a9, b7, X9), (a9, b7, X10), (a9, b7, X11), (a9, b7, X12), (a9, b7, X13), (a9, b7, X14), (a9, b7, X15), (a9, b7, X16), (a9, b7, X17), (a9, b7, X18), (a9, b8, X1), (a9, b8, X2), (a9, b8, X3), (a9, b8, X4), (a9, b8, X5) , (a9, b8, X6), (a9, b8, X7), (a9, b8, X8), (a9, b8, X9), (a9, b8, X10), (a9, b8, X11), ( a9, b8, X12), (a9, b8, X13), (a9, b8, X14), (a9, b8, X15), (a9, b8, X16), (a9, b8, X17), (a9, b8, X18), (a9, b9, X1), (a9, b9, X2), (a9, b9, X3), (a9, b9, X4), (a9, b9, X5), (a9, b9, X6), (a9, b9, X7), (a9, b9, X8), (a9, b9, X9), (a9, b9, X10), (a9, b9, X11), (a9, b9, X12) , (a9, b9, X13), (a9, b9, X14), (a9, b9, X15), (a9, b9, X16), (a9, b9, X17), (a9, b9, X18), ( a9, b10, X1), (a9, b10, X2), (a9, b10, X3), (a9, b10, X4), (a9, b10, X5), (a9, b10, X6), (a9, b10, X7), (a9, b10, X8), (a9, b10, X9), (a9, b10, X10), (a9, b10, X11), (a9 , b10, X12), (a9, b10, X13), (a9, b10, X14), (a9, b10, X15), (a9, b10, X16), (a9, b10, X17), (a9, b10 , X18), (a9, b11, X1), (a9, b11, X2), (a9, b11, X3), (a9, b11, X4), (a9, b11, X5), (a9, b11, X6 ), (a9, b11, X7), (a9, b11, X8), (a9, b11, X9), (a9, b11, X10), (a9, b11, X11), (a9, b11, X12), (a9, b11, X13), (a9, b11, X14), (a9, b11, X15), (a9, b11, X16), (a9, b11, X17), (a9, b11, X18), (a9 , b12, X1), (a9, b12, X2), (a9, b12, X3), (a9, b12, X4), (a9, b12, X5), (a9, b12, X6), (a9, b12 , X7), (a9, b12, X8), (a9, b12, X9), (a9, b12, X10), (a9, b12, X11), (a9, b12, X12), (a9, b12, X13 ), (a9, b12, X14), (a9, b12, X15), (a9, b12, X16), (a9, b12, X17), (a9, b12, X18), (a9, b13, X1), (a9, b13, X2), (a9, b13, X3), (a9, b13, X4), (a9, b13, X5), (a9, b13, X6), (a9, b13, X7), (a9 , b13, X8), (a9, b13, X9), (a9, b13, X10), (a9, b13, X11), (a9, b13, X12), (a9, b13, X13), (a9, b13 , X14), (a9, b13, X15), (a9, b13, X16), (a9, b13, X17), (a9, b13, X18), (a9, b14, X1), (a9, b14, X2 ), (a9, b14, X3), (a9, b14, X4), (a9, b14, X5), (a9, b14, X6), (a9, b14, X7), (a9, b14, X8), (a9, b14, X9), (a9, b14, X10), (a9, b14, X11), (a9, b14, X12), (a9, b14, X13), (a9, b14, X14), (a9 , b14, X15), (a9, b14, X16), (a9, b14, X17), (a9, b14, X18), (a9, b15, X1), (a9, b15, X2), (a9, b15, X3), (a9, b15, X4), (a9, b15, X5), (a9, b15, X6), (a9, b15, X7), (a9 , b15, X8), (a9, b15, X9), (a9, b15, X10), (a9, b15, X11), (a9, b15, X12), (a9, b15, X13), (a9, b15 , X14), (a9, b15, X15), (a9, b15, X16), (a9, b15, X17), (a9, b15, X18), (a9, b16, X1), (a9, b16, X2 ), (a9, b16, X3), (a9, b16, X4), (a9, b16, X5), (a9, b16, X6), (a9, b16, X7), (a9, b16, X8), (a9, b16, X9), (a9, b16, X10), (a9, b16, X11), (a9, b16, X12), (a9, b16, X13), (a9, b16, X14), (a9 , b16, X15), (a9, b16, X16), (a9, b16, X17), (a9, b16, X18), (a9, b17, X1), (a9, b17, X2), (a9, b17 , X3), (a9, b17, X4), (a9, b17, X5), (a9, b17, X6), (a9, b17, X7), (a9, b17, X8), (a9, b17, X9 ), (a9, b17, X10), (a9, b17, X11), (a9, b17, X12), (a9, b17, X13), (a9, b17, X14), (a9, b17, X15), (a9, b17, X16), (a9, b17, X17), (a9, b17, X18), (a9, b18, X1), (a9, b18, X2), (a9, b18, X3), (a9 , b18, X4), (a9, b18, X5), (a9, b18, X6), (a9, b18, X7), (a9, b18, X8), (a9, b18, X9), (a9, b18 , X10), (a9, b18, X11), (a9, b18, X12), (a9, b18, X13), (a9, b18, X14), (a9, b18, X15), (a9, b18, X16 ), (a9, b18, X17), (a9, b18, X18), (a9, b19, X1), (a9, b19, X2), (a9, b19, X3), (a9, b19, X4), (a9, b19, X5), (a9, b19, X6), (a9, b19, X7), (a9, b19, X8), (a9, b19, X9), (a9, b19, X10), (a9, b19, X11), (a9, b19, X12), (a9, b19, X13), (a9, b19, X14), (a9, b19, X15), (a9, b19, X16), (a9, b19, X17), (a9, b19, X18), (a9, b20, X1), (a9, b20, X2), (a9, b20, X3), (a9, b20, X4) , (a9, b20, X5), (a9, b20, X6), (a9, b20, X7), (a9, b20, X8), (a9, b20, X9), (a9, b20, X10), ( a9, b20, X11), (a9, b20, X12), (a9, b20, X13), (a9, b20, X14), (a9, b20, X15), (a9, b20, X16), (a9, b20, X17), (a9, b20, X18), (a9, b21, X1), (a9, b21, X2), (a9, b21, X3), (a9, b21, X4), (a9, b21, X5), (a9, b21, X6), (a9, b21, X7), (a9, b21, X8), (a9, b21, X9), (a9, b21, X10), (a9, b21, X11) , (a9, b21, X12), (a9, b21, X13), (a9, b21, X14), (a9, b21, X15), (a9, b21, X16), (a9, b21, X17), ( a9, b21, X18), (a9, b22, X1), (a9, b22, X2), (a9, b22, X3), (a9, b22, X4), (a9, b22, X5), (a9, b22, X6), (a9, b22, X7), (a9, b22, X8), (a9, b22, X9), (a9, b22, X10), (a9, b22, X11), (a9, b22, X12), (a9, b22, X13), (a9, b22, X14), (a9, b22, X15), (a9, b22, X16), (a9, b22, X17), (a9, b22, X18) , (a9, b23, X1), (a9, b23, X2), (a9, b23, X3), (a9, b23, X4), (a9, b23, X5), (a9, b23, X6), ( a9, b23, X7), (a9, b23, X8), (a9, b23, X9), (a9, b23, X10), (a9, b23, X11), (a9, b23, X12), (a9, b23, X13), (a9, b23, X14), (a9, b23, X15), (a9, b23, X16), (a9, b23, X17), (a9, b23, X18), (a9, b24, X1), (a9, b24, X2), (a9, b24, X3), (a9, b24, X4), (a9, b24, X5), (a9 , b24, X6), (a9, b24, X7), (a9, b24, X8), (a9, b24, X9), (a9, b24, X10), (a9, b24, X11), (a9, b24 , X12), (a9, b24, X13), (a9, b24, X14), (a9, b24, X15), (a9, b24, X16), (a9, b24, X17), (a9, b24, X18 ), (a9, b25, X1), (a9, b25, X2), (a9, b25, X3), (a9, b25, X4), (a9, b25, X5), (a9, b25, X6), (a9, b25, X7), (a9, b25, X8), (a9, b25, X9), (a9, b25, X10), (a9, b25, X11), (a9, b25, X12), (a9 , b25, X13), (a9, b25, X14), (a9, b25, X15), (a9, b25, X16), (a9, b25, X17), (a9, b25, X18), (a9, b26 , X1), (a9, b26, X2), (a9, b26, X3), (a9, b26, X4), (a9, b26, X5), (a9, b26, X6), (a9, b26, X7 ), (a9, b26, X8), (a9, b26, X9), (a9, b26, X10), (a9, b26, X11), (a9, b26, X12), (a9, b26, X13), (a9, b26, X14), (a9, b26, X15), (a9, b26, X16), (a9, b26, X17), (a9, b26, X18), (a9, b27, X1), (a9 , b27, X2), (a9, b27, X3), (a9, b27, X4), (a9, b27, X5), (a9, b27, X6), (a9, b27, X7), (a9, b27 , X8), (a9, b27, X9), (a9, b27, X10), (a9, b27, X11), (a9, b27, X12), (a9, b27, X13), (a9, b27, X14 ), (a9, b27, X15), (a9, b27, X16), (a9, b27, X17), (a9, b27, X18),

(a10, b1, X1), (a10, b1, X2), (a10, b1, X3), (a10, b1, X4), (a10, b1, X5), (a10, b1, X6), (a10 , b1, X7), (a10, b1, X8), (a10, b1, X9), (a10, b1, X10), (a10, b1, X11), (a10, b1, X12), (a10, b1 , X13), (a10, b1, X14), (a10, b1, X15), (a10, b1, X16), (a10, b1, X17), (a10, b1, X18), (a10, b2, X1 ), (a10, b2, X2), (a10, b2, X3), (a10, b2, X4), (a10, b2, X5), (a10, b2, X6), (a10, b2, X7), (a10, b2, X8), (a10, b2, X9), (a10, b2, X10), (a10, b2, X11), (a10, b2, X12), (a10, b2, X13), (a10 , b2, X14), (a10, b2, X15), (a10, b2, X16), (a10, b2, X17), (a10, b2, X18), (a10, b3, X1), (a10, b3 , X2), (a10, b3, X3), (a10, b3, X4), (a10, b3, X5), (a10, b3, X6), (a10, b3, X7), (a10, b3, X8 ), (a10, b3, X9), (a10, b3, X10), (a10, b3, X11), (a10, b3, X12), (a10, b3, X13), (a10, b3, X14), (a10, b3, X15), (a10, b3, X16), (a10, b3, X17), (a10, b3, X18), (a10, b4, X1), (a10, b4, X2), (a10 , b4, X3), (a10, b4, X4), (a10, b4, X5), (a10, b4, X6), (a10, b4, X7), (a10, b4, X8), (a10, b4 , X9), (a10, b4, X10), (a10, b4, X11), (a10, b4, X12), (a10, b4, X13), (a10, b4, X14), (a10, b4, X15 ), (a10, b4, X16), (a10, b4, X17), (a10, b4, X18), (a10, b5, X1), (a10, b5, X2), (a10, b5, X3), (a10, b5, X4), (a10, b5, X5), (a10, b5, X6), (a10, b5, X7), (a10, b5, X8), (a10 , b5, X9), (a10, b5, X10), (a10, b5, X11), (a10, b5, X12), (a10, b5, X13), (a10, b5, X14), (a10, b5 , X15), (a10, b5, X16), (a10, b5, X17), (a10, b5, X18), (a10, b6, X1), (a10, b6, X2), (a10, b6, X3 ), (a10, b6, X4), (a10, b6, X5), (a10, b6, X6), (a10, b6, X7), (a10, b6, X8), (a10, b6, X9), (a10, b6, X10), (a10, b6, X11), (a10, b6, X12), (a10, b6, X13), (a10, b6, X14), (a10, b6, X15), (a10 , b6, X16), (a10, b6, X17), (a10, b6, X18), (a10, b7, X1), (a10, b7, X2), (a10, b7, X3), (a10, b7 , X4), (a10, b7, X5), (a10, b7, X6), (a10, b7, X7), (a10, b7, X8), (a10, b7, X9), (a10, b7, X10 ), (a10, b7, X11), (a10, b7, X12), (a10, b7, X13), (a10, b7, X14), (a10, b7, X15), (a10, b7, X16), (a10, b7, X17), (a10, b7, X18), (a10, b8, X1), (a10, b8, X2), (a10, b8, X3), (a10, b8, X4), (a10 , b8, X5), (a10, b8, X6), (a10, b8, X7), (a10, b8, X8), (a10, b8, X9), (a10, b8, X10), (a10, b8 , X11), (a10, b8, X12), (a10, b8, X13), (a10, b8, X14), (a10, b8, X15), (a10, b8, X16), (a10, b8, X17 ), (a10, b8, X18), (a10, b9, X1), (a10, b9, X2), (a10, b9, X3), (a10, b9, X4), (a10, b9, X5), (a10, b9, X6), (a10, b9, X7), (a10, b9, X8), (a10, b9, X9), (a10, b9, X10), (a10, b9, X11), (a10 , b9, X12), (a10, b9, X13), (a10, b9, X14), (a10, b9, X15), (a10, b9, X16), ( a10, b9, X17), (a10, b9, X18), (a10, b10, X1), (a10, b10, X2), (a10, b10, X3), (a10, b10, X4), (a10, b10, X5), (a10, b10, X6), (a10, b10, X7), (a10, b10, X8), (a10, b10, X9), (a10, b10, X10), (a10, b10, X11), (a10, b10, X12), (a10, b10, X13), (a10, b10, X14), (a10, b10, X15), (a10, b10, X16), (a10, b10, X17) , (a10, b10, X18), (a10, b11, X1), (a10, b11, X2), (a10, b11, X3), (a10, b11, X4), (a10, b11, X5), ( a10, b11, X6), (a10, b11, X7), (a10, b11, X8), (a10, b11, X9), (a10, b11, X10), (a10, b11, X11), (a10, b11, X12), (a10, b11, X13), (a10, b11, X14), (a10, b11, X15), (a10, b11, X16), (a10, b11, X17), (a10, b11, X18), (a10, b12, X1), (a10, b12, X2), (a10, b12, X3), (a10, b12, X4), (a10, b12, X5), (a10, b12, X6) , (a10, b12, X7), (a10, b12, X8), (a10, b12, X9), (a10, b12, X10), (a10, b12, X11), (a10, b12, X12), ( a10, b12, X13), (a10, b12, X14), (a10, b12, X15), (a10, b12, X16), (a10, b12, X17), (a10, b12, X18), (a10, b13, X1), (a10, b13, X2), (a10, b13, X3), (a10, b13, X4), (a10, b13, X5), (a10, b13, X6), (a10, b13, X7), (a10, b13, X8), (a10, b13, X9), (a10, b13, X10), (a10, b13, X11), (a10, b13, X12), (a10, b13, X13) , (a10, b13, X14), (a10, b13, X15), (a10, b13, X16), (a10, b13, X17), (a10, b13, X18), (a1 0, b14, X1), (a10, b14, X2), (a10, b14, X3), (a10, b14, X4), (a10, b14, X5), (a10, b14, X6), (a10, b14, X7), (a10, b14, X8), (a10, b14, X9), (a10, b14, X10), (a10, b14, X11), (a10, b14, X12), (a10, b14, X13), (a10, b14, X14), (a10, b14, X15), (a10, b14, X16), (a10, b14, X17), (a10, b14, X18), (a10, b15, X1) , (a10, b15, X2), (a10, b15, X3), (a10, b15, X4), (a10, b15, X5), (a10, b15, X6), (a10, b15, X7), ( a10, b15, X8), (a10, b15, X9), (a10, b15, X10), (a10, b15, X11), (a10, b15, X12), (a10, b15, X13), (a10, b15, X14), (a10, b15, X15), (a10, b15, X16), (a10, b15, X17), (a10, b15, X18), (a10, b16, X1), (a10, b16, X2), (a10, b16, X3), (a10, b16, X4), (a10, b16, X5), (a10, b16, X6), (a10, b16, X7), (a10, b16, X8) , (a10, b16, X9), (a10, b16, X10), (a10, b16, X11), (a10, b16, X12), (a10, b16, X13), (a10, b16, X14), ( a10, b16, X15), (a10, b16, X16), (a10, b16, X17), (a10, b16, X18), (a10, b17, X1), (a10, b17, X2), (a10, b17, X3), (a10, b17, X4), (a10, b17, X5), (a10, b17, X6), (a10, b17, X7), (a10, b17, X8), (a10, b17, X9), (a10, b17, X10), (a10, b17, X11), (a10, b17, X12), (a10, b17, X13), (a10, b17, X14), (a10, b17, X15) , (a10, b17, X16), (a10, b17, X17), (a10, b17, X18), (a10, b18, X1), (a10, b18, X2), (a10, b18, X3), (a10, b18, X4), (a10, b18, X5), (a10, b18, X6), (a10, b18, X7), (a10, b18, X8), (a10, b18, X9), (a10, b18, X10), (a10, b18, X11), (a10, b18, X12), (a10, b18, X13), (a10, b18, X14), (a10, b18, X15) , (a10, b18, X16), (a10, b18, X17), (a10, b18, X18), (a10, b19, X1), (a10, b19, X2), (a10, b19, X3), ( a10, b19, X4), (a10, b19, X5), (a10, b19, X6), (a10, b19, X7), (a10, b19, X8), (a10, b19, X9), (a10, b19, X10), (a10, b19, X11), (a10, b19, X12), (a10, b19, X13), (a10, b19, X14), (a10, b19, X15), (a10, b19, X16), (a10, b19, X17), (a10, b19, X18), (a10, b20, X1), (a10, b20, X2), (a10, b20, X3), (a10, b20, X4) , (a10, b20, X5), (a10, b20, X6), (a10, b20, X7), (a10, b20, X8), (a10, b20, X9), (a10, b20, X10), ( a10, b20, X11), (a10, b20, X12), (a10, b20, X13), (a10, b20, X14), (a10, b20, X15), (a10, b20, X16), (a10, b20, X17), (a10, b20, X18), (a10, b21, X1), (a10, b21, X2), (a10, b21, X3), (a10, b21, X4), (a10, b21, X5), (a10, b21, X6), (a10, b21, X7), (a10, b21, X8), (a10, b21, X9), (a10, b21, X10), (a10, b21, X11) , (a10, b21, X12), (a10, b21, X13), (a10, b21, X14), (a10, b21, X15), (a10, b21, X16), (a10, b21, X17), ( a10, b21, X18), (a10, b22, X1), (a10, b22, X2), (a10, b22, X3), (a10, b22, X4), (a10, b2 2, X5), (a10, b22, X6), (a10, b22, X7), (a10, b22, X8), (a10, b22, X9), (a10, b22, X10), (a10, b22, X11), (a10, b22, X12), (a10, b22, X13), (a10, b22, X14), (a10, b22, X15), (a10, b22, X16), (a10, b22, X17) , (a10, b22, X18), (a10, b23, X1), (a10, b23, X2), (a10, b23, X3), (a10, b23, X4), (a10, b23, X5), ( a10, b23, X6), (a10, b23, X7), (a10, b23, X8), (a10, b23, X9), (a10, b23, X10), (a10, b23, X11), (a10, b23, X12), (a10, b23, X13), (a10, b23, X14), (a10, b23, X15), (a10, b23, X16), (a10, b23, X17), (a10, b23, X18), (a10, b24, X1), (a10, b24, X2), (a10, b24, X3), (a10, b24, X4), (a10, b24, X5), (a10, b24, X6) , (a10, b24, X7), (a10, b24, X8), (a10, b24, X9), (a10, b24, X10), (a10, b24, X11), (a10, b24, X12), ( a10, b24, X13), (a10, b24, X14), (a10, b24, X15), (a10, b24, X16), (a10, b24, X17), (a10, b24, X18), (a10, b25, X1), (a10, b25, X2), (a10, b25, X3), (a10, b25, X4), (a10, b25, X5), (a10, b25, X6), (a10, b25, X7), (a10, b25, X8), (a10, b25, X9), (a10, b25, X10), (a10, b25, X11), (a10, b25, X12), (a10, b25, X13) , (a10, b25, X14), (a10, b25, X15), (a10, b25, X16), (a10, b25, X17), (a10, b25, X18), (a10, b26, X1), ( a10, b26, X2), (a10, b26, X3), (a10, b26, X4), (a10, b26, X5), (a10, b26, X6), (a10, b26, X7), (a10, b26, X8), (a10, b26, X9), (a10, b26, X10), (a10, b26, X11), (a10, b26, X12), (a10, b26, X13) , (a10, b26, X14), (a10, b26, X15), (a10, b26, X16), (a10, b26, X17), (a10, b26, X18), (a10, b27, X1), ( a10, b27, X2), (a10, b27, X3), (a10, b27, X4), (a10, b27, X5), (a10, b27, X6), (a10, b27, X7), (a10, b27, X8), (a10, b27, X9), (a10, b27, X10), (a10, b27, X11), (a10, b27, X12), (a10, b27, X13), (a10, b27, X14), (a10, b27, X15), (a10, b27, X16), (a10, b27, X17), (a10, b27, X18),

(a11, b1, X1), (a11, b1, X2), (a11, b1, X3), (a11, b1, X4), (a11, b1, X5), (a11, b1, X6), (a11 , b1, X7), (a11, b1, X8), (a11, b1, X9), (a11, b1, X10), (a11, b1, X11), (a11, b1, X12), (a11, b1 , X13), (a11, b1, X14), (a11, b1, X15), (a11, b1, X16), (a11, b1, X17), (a11, b1, X18), (a11, b2, X1 ), (a11, b2, X2), (a11, b2, X3), (a11, b2, X4), (a11, b2, X5), (a11, b2, X6), (a11, b2, X7), (a11, b2, X8), (a11, b2, X9), (a11, b2, X10), (a11, b2, X11), (a11, b2, X12), (a11, b2, X13), (a11 , b2, X14), (a11, b2, X15), (a11, b2, X16), (a11, b2, X17), (a11, b2, X18), (a11, b3, X1), (a11, b3 , X2), (a11, b3, X3), (a11, b3, X4), (a11, b3, X5), (a11, b3, X6), (a11, b3, X7), (a11, b3, X8 ), (a11, b3, X9), (a11, b3, X10), (a11, b3, X11), (a11, b3, X12), (a11, b3, X13), (a11, b3, X14), (a11, b3, X15), (a11, b3, X16), (a11, b3, X17), (a11, b3, X18), (a11, b4, X1), (a11, b4, X2), (a11 , b4, X3), (a11, b4, X4), (a11, b4, X5), (a11, b4, X6), (a11, b4, X7), (a11, b4, X8), (a11, b4 , X9), (a11, b4, X10), (a11, b4, X11), (a11, b4, X12), (a11, b4, X13), (a11, b4, X14), (a11, b4, X15 ), (a11, b4, X16), (a11, b4, X17), (a11, b4, X18), (a11, b5, X1), (a11, b5, X2), (a11, b5, X3), (a11, b5, X4), (a11, b5, X5), (a11, b5, X6), (a11, b5, X7), (a11, b5, X8), (a11 , b5, X9), (a11, b5, X10), (a11, b5, X11), (a11, b5, X12), (a11, b5, X13), (a11, b5, X14), (a11, b5 , X15), (a11, b5, X16), (a11, b5, X17), (a11, b5, X18), (a11, b6, X1), (a11, b6, X2), (a11, b6, X3 ), (a11, b6, X4), (a11, b6, X5), (a11, b6, X6), (a11, b6, X7), (a11, b6, X8), (a11, b6, X9), (a11, b6, X10), (a11, b6, X11), (a11, b6, X12), (a11, b6, X13), (a11, b6, X14), (a11, b6, X15), (a11 , b6, X16), (a11, b6, X17), (a11, b6, X18), (a11, b7, X1), (a11, b7, X2), (a11, b7, X3), (a11, b7 , X4), (a11, b7, X5), (a11, b7, X6), (a11, b7, X7), (a11, b7, X8), (a11, b7, X9), (a11, b7, X10 ), (a11, b7, X11), (a11, b7, X12), (a11, b7, X13), (a11, b7, X14), (a11, b7, X15), (a11, b7, X16), (a11, b7, X17), (a11, b7, X18), (a11, b8, X1), (a11, b8, X2), (a11, b8, X3), (a11, b8, X4), (a11 , b8, X5), (a11, b8, X6), (a11, b8, X7), (a11, b8, X8), (a11, b8, X9), (a11, b8, X10), (a11, b8 , X11), (a11, b8, X12), (a11, b8, X13), (a11, b8, X14), (a11, b8, X15), (a11, b8, X16), (a11, b8, X17 ), (a11, b8, X18), (a11, b9, X1), (a11, b9, X2), (a11, b9, X3), (a11, b9, X4), (a11, b9, X5), (a11, b9, X6), (a11, b9, X7), (a11, b9, X8), (a11, b9, X9), (a11, b9, X10), (a11, b9, X11), (a11 , b9, X12), (a11, b9, X13), (a11, b9, X14), (a11, b9, X15), (a11, b9, X16), ( a11, b9, X17), (a11, b9, X18), (a11, b10, X1), (a11, b10, X2), (a11, b10, X3), (a11, b10, X4), (a11, b10, X5), (a11, b10, X6), (a11, b10, X7), (a11, b10, X8), (a11, b10, X9), (a11, b10, X10), (a11, b10, X11), (a11, b10, X12), (a11, b10, X13), (a11, b10, X14), (a11, b10, X15), (a11, b10, X16), (a11, b10, X17) , (a11, b10, X18), (a11, b11, X1), (a11, b11, X2), (a11, b11, X3), (a11, b11, X4), (a11, b11, X5), ( a11, b11, X6), (a11, b11, X7), (a11, b11, X8), (a11, b11, X9), (a11, b11, X10), (a11, b11, X11), (a11, b11, X12), (a11, b11, X13), (a11, b11, X14), (a11, b11, X15), (a11, b11, X16), (a11, b11, X17), (a11, b11, X18), (a11, b12, X1), (a11, b12, X2), (a11, b12, X3), (a11, b12, X4), (a11, b12, X5), (a11, b12, X6) , (a11, b12, X7), (a11, b12, X8), (a11, b12, X9), (a11, b12, X10), (a11, b12, X11), (a11, b12, X12), ( a11, b12, X13), (a11, b12, X14), (a11, b12, X15), (a11, b12, X16), (a11, b12, X17), (a11, b12, X18), (a11, b13, X1), (a11, b13, X2), (a11, b13, X3), (a11, b13, X4), (a11, b13, X5), (a11, b13, X6), (a11, b13, X7), (a11, b13, X8), (a11, b13, X9), (a11, b13, X10), (a11, b13, X11), (a11, b13, X12), (a11, b13, X13) , (a11, b13, X14), (a11, b13, X15), (a11, b13, X16), (a11, b13, X17), (a11, b13, X18), (a1 1, b14, X1), (a11, b14, X2), (a11, b14, X3), (a11, b14, X4), (a11, b14, X5), (a11, b14, X6), (a11, b14, X7), (a11, b14, X8), (a11, b14, X9), (a11, b14, X10), (a11, b14, X11), (a11, b14, X12), (a11, b14, X13), (a11, b14, X14), (a11, b14, X15), (a11, b14, X16), (a11, b14, X17), (a11, b14, X18), (a11, b15, X1) , (a11, b15, X2), (a11, b15, X3), (a11, b15, X4), (a11, b15, X5), (a11, b15, X6), (a11, b15, X7), ( a11, b15, X8), (a11, b15, X9), (a11, b15, X10), (a11, b15, X11), (a11, b15, X12), (a11, b15, X13), (a11, b15, X14), (a11, b15, X15), (a11, b15, X16), (a11, b15, X17), (a11, b15, X18), (a11, b16, X1), (a11, b16, X2), (a11, b16, X3), (a11, b16, X4), (a11, b16, X5), (a11, b16, X6), (a11, b16, X7), (a11, b16, X8) , (a11, b16, X9), (a11, b16, X10), (a11, b16, X11), (a11, b16, X12), (a11, b16, X13), (a11, b16, X14), ( a11, b16, X15), (a11, b16, X16), (a11, b16, X17), (a11, b16, X18), (a11, b17, X1), (a11, b17, X2), (a11, b17, X3), (a11, b17, X4), (a11, b17, X5), (a11, b17, X6), (a11, b17, X7), (a11, b17, X8), (a11, b17, X9), (a11, b17, X10), (a11, b17, X11), (a11, b17, X12), (a11, b17, X13), (a11, b17, X14), (a11, b17, X15) , (a11, b17, X16), (a11, b17, X17), (a11, b17, X18), (a11, b18, X1), (a11, b18, X2), (a11, b18, X3), (a11, b18, X4), (a11, b18, X5), (a11, b18, X6), (a11, b18, X7), (a11, b18, X8), (a11, b18, X9), (a11, b18, X10), (a11, b18, X11), (a11, b18, X12), (a11, b18, X13), (a11, b18, X14), (a11, b18, X15) , (a11, b18, X16), (a11, b18, X17), (a11, b18, X18), (a11, b19, X1), (a11, b19, X2), (a11, b19, X3), ( a11, b19, X4), (a11, b19, X5), (a11, b19, X6), (a11, b19, X7), (a11, b19, X8), (a11, b19, X9), (a11, b19, X10), (a11, b19, X11), (a11, b19, X12), (a11, b19, X13), (a11, b19, X14), (a11, b19, X15), (a11, b19, X16), (a11, b19, X17), (a11, b19, X18), (a11, b20, X1), (a11, b20, X2), (a11, b20, X3), (a11, b20, X4) , (a11, b20, X5), (a11, b20, X6), (a11, b20, X7), (a11, b20, X8), (a11, b20, X9), (a11, b20, X10), ( a11, b20, X11), (a11, b20, X12), (a11, b20, X13), (a11, b20, X14), (a11, b20, X15), (a11, b20, X16), (a11, b20, X17), (a11, b20, X18), (a11, b21, X1), (a11, b21, X2), (a11, b21, X3), (a11, b21, X4), (a11, b21, X5), (a11, b21, X6), (a11, b21, X7), (a11, b21, X8), (a11, b21, X9), (a11, b21, X10), (a11, b21, X11) , (a11, b21, X12), (a11, b21, X13), (a11, b21, X14), (a11, b21, X15), (a11, b21, X16), (a11, b21, X17), ( a11, b21, X18), (a11, b22, X1), (a11, b22, X2), (a11, b22, X3), (a11, b22, X4), (a11, b2 2, X5), (a11, b22, X6), (a11, b22, X7), (a11, b22, X8), (a11, b22, X9), (a11, b22, X10), (a11, b22, X11), (a11, b22, X12), (a11, b22, X13), (a11, b22, X14), (a11, b22, X15), (a11, b22, X16), (a11, b22, X17) , (a11, b22, X18), (a11, b23, X1), (a11, b23, X2), (a11, b23, X3), (a11, b23, X4), (a11, b23, X5), ( a11, b23, X6), (a11, b23, X7), (a11, b23, X8), (a11, b23, X9), (a11, b23, X10), (a11, b23, X11), (a11, b23, X12), (a11, b23, X13), (a11, b23, X14), (a11, b23, X15), (a11, b23, X16), (a11, b23, X17), (a11, b23, X18), (a11, b24, X1), (a11, b24, X2), (a11, b24, X3), (a11, b24, X4), (a11, b24, X5), (a11, b24, X6) , (a11, b24, X7), (a11, b24, X8), (a11, b24, X9), (a11, b24, X10), (a11, b24, X11), (a11, b24, X12), ( a11, b24, X13), (a11, b24, X14), (a11, b24, X15), (a11, b24, X16), (a11, b24, X17), (a11, b24, X18), (a11, b25, X1), (a11, b25, X2), (a11, b25, X3), (a11, b25, X4), (a11, b25, X5), (a11, b25, X6), (a11, b25, X7), (a11, b25, X8), (a11, b25, X9), (a11, b25, X10), (a11, b25, X11), (a11, b25, X12), (a11, b25, X13) , (a11, b25, X14), (a11, b25, X15), (a11, b25, X16), (a11, b25, X17), (a11, b25, X18), (a11, b26, X1), ( a11, b26, X2), (a11, b26, X3), (a11, b26, X4), (a11, b26, X5), (a11, b26, X6), (a11, b26, X7), (a11, b26, X8), (a11, b26, X9), (a11, b26, X10), (a11, b26, X11), (a11, b26, X12), (a11, b26, X13) , (a11, b26, X14), (a11, b26, X15), (a11, b26, X16), (a11, b26, X17), (a11, b26, X18), (a11, b27, X1), ( a11, b27, X2), (a11, b27, X3), (a11, b27, X4), (a11, b27, X5), (a11, b27, X6), (a11, b27, X7), (a11, b27, X8), (a11, b27, X9), (a11, b27, X10), (a11, b27, X11), (a11, b27, X12), (a11, b27, X13), (a11, b27, X14), (a11, b27, X15), (a11, b27, X16), (a11, b27, X17), (a11, b27, X18),

(a12, b1, X1), (a12, b1, X2), (a12, b1, X3), (a12, b1, X4), (a12, b1, X5), (a12, b1, X6), (a12 , b1, X7), (a12, b1, X8), (a12, b1, X9), (a12, b1, X10), (a12, b1, X11), (a12, b1, X12), (a12, b1 , X13), (a12, b1, X14), (a12, b1, X15), (a12, b1, X16), (a12, b1, X17), (a12, b1, X18), (a12, b2, X1 ), (a12, b2, X2), (a12, b2, X3), (a12, b2, X4), (a12, b2, X5), (a12, b2, X6), (a12, b2, X7), (a12, b2, X8), (a12, b2, X9), (a12, b2, X10), (a12, b2, X11), (a12, b2, X12), (a12, b2, X13), (a12 , b2, X14), (a12, b2, X15), (a12, b2, X16), (a12, b2, X17), (a12, b2, X18), (a12, b3, X1), (a12, b3 , X2), (a12, b3, X3), (a12, b3, X4), (a12, b3, X5), (a12, b3, X6), (a12, b3, X7), (a12, b3, X8 ), (a12, b3, X9), (a12, b3, X10), (a12, b3, X11), (a12, b3, X12), (a12, b3, X13), (a12, b3, X14), (a12, b3, X15), (a12, b3, X16), (a12, b3, X17), (a12, b3, X18), (a12, b4, X1), (a12, b4, X2), (a12 , b4, X3), (a12, b4, X4), (a12, b4, X5), (a12, b4, X6), (a12, b4, X7), (a12, b4, X8), (a12, b4 , X9), (a12, b4, X10), (a12, b4, X11), (a12, b4, X12), (a12, b4, X13), (a12, b4, X14), (a12, b4, X15 ), (a12, b4, X16), (a12, b4, X17), (a12, b4, X18), (a12, b5, X1), (a12, b5, X2), (a12, b5, X3), (a12, b5, X4), (a12, b5, X5), (a12, b5, X6), (a12, b5, X7), (a12, b5, X8), (a12 , b5, X9), (a12, b5, X10), (a12, b5, X11), (a12, b5, X12), (a12, b5, X13), (a12, b5, X14), (a12, b5 , X15), (a12, b5, X16), (a12, b5, X17), (a12, b5, X18), (a12, b6, X1), (a12, b6, X2), (a12, b6, X3 ), (a12, b6, X4), (a12, b6, X5), (a12, b6, X6), (a12, b6, X7), (a12, b6, X8), (a12, b6, X9), (a12, b6, X10), (a12, b6, X11), (a12, b6, X12), (a12, b6, X13), (a12, b6, X14), (a12, b6, X15), (a12 , b6, X16), (a12, b6, X17), (a12, b6, X18), (a12, b7, X1), (a12, b7, X2), (a12, b7, X3), (a12, b7 , X4), (a12, b7, X5), (a12, b7, X6), (a12, b7, X7), (a12, b7, X8), (a12, b7, X9), (a12, b7, X10 ), (a12, b7, X11), (a12, b7, X12), (a12, b7, X13), (a12, b7, X14), (a12, b7, X15), (a12, b7, X16), (a12, b7, X17), (a12, b7, X18), (a12, b8, X1), (a12, b8, X2), (a12, b8, X3), (a12, b8, X4), (a12 , b8, X5), (a12, b8, X6), (a12, b8, X7), (a12, b8, X8), (a12, b8, X9), (a12, b8, X10), (a12, b8 , X11), (a12, b8, X12), (a12, b8, X13), (a12, b8, X14), (a12, b8, X15), (a12, b8, X16), (a12, b8, X17 ), (a12, b8, X18), (a12, b9, X1), (a12, b9, X2), (a12, b9, X3), (a12, b9, X4), (a12, b9, X5), (a12, b9, X6), (a12, b9, X7), (a12, b9, X8), (a12, b9, X9), (a12, b9, X10), (a12, b9, X11), (a12 , b9, X12), (a12, b9, X13), (a12, b9, X14), (a12, b9, X15), (a12, b9, X16), ( a12, b9, X17), (a12, b9, X18), (a12, b10, X1), (a12, b10, X2), (a12, b10, X3), (a12, b10, X4), (a12, b10, X5), (a12, b10, X6), (a12, b10, X7), (a12, b10, X8), (a12, b10, X9), (a12, b10, X10), (a12, b10, X11), (a12, b10, X12), (a12, b10, X13), (a12, b10, X14), (a12, b10, X15), (a12, b10, X16), (a12, b10, X17) , (a12, b10, X18), (a12, b11, X1), (a12, b11, X2), (a12, b11, X3), (a12, b11, X4), (a12, b11, X5), ( a12, b11, X6), (a12, b11, X7), (a12, b11, X8), (a12, b11, X9), (a12, b11, X10), (a12, b11, X11), (a12, b11, X12), (a12, b11, X13), (a12, b11, X14), (a12, b11, X15), (a12, b11, X16), (a12, b11, X17), (a12, b11, X18), (a12, b12, X1), (a12, b12, X2), (a12, b12, X3), (a12, b12, X4), (a12, b12, X5), (a12, b12, X6) , (a12, b12, X7), (a12, b12, X8), (a12, b12, X9), (a12, b12, X10), (a12, b12, X11), (a12, b12, X12), ( a12, b12, X13), (a12, b12, X14), (a12, b12, X15), (a12, b12, X16), (a12, b12, X17), (a12, b12, X18), (a12, b13, X1), (a12, b13, X2), (a12, b13, X3), (a12, b13, X4), (a12, b13, X5), (a12, b13, X6), (a12, b13, X7), (a12, b13, X8), (a12, b13, X9), (a12, b13, X10), (a12, b13, X11), (a12, b13, X12), (a12, b13, X13) , (a12, b13, X14), (a12, b13, X15), (a12, b13, X16), (a12, b13, X17), (a12, b13, X18), (a1 2, b14, X1), (a12, b14, X2), (a12, b14, X3), (a12, b14, X4), (a12, b14, X5), (a12, b14, X6), (a12, b14, X7), (a12, b14, X8), (a12, b14, X9), (a12, b14, X10), (a12, b14, X11), (a12, b14, X12), (a12, b14, X13), (a12, b14, X14), (a12, b14, X15), (a12, b14, X16), (a12, b14, X17), (a12, b14, X18), (a12, b15, X1) , (a12, b15, X2), (a12, b15, X3), (a12, b15, X4), (a12, b15, X5), (a12, b15, X6), (a12, b15, X7), ( a12, b15, X8), (a12, b15, X9), (a12, b15, X10), (a12, b15, X11), (a12, b15, X12), (a12, b15, X13), (a12, b15, X14), (a12, b15, X15), (a12, b15, X16), (a12, b15, X17), (a12, b15, X18), (a12, b16, X1), (a12, b16, X2), (a12, b16, X3), (a12, b16, X4), (a12, b16, X5), (a12, b16, X6), (a12, b16, X7), (a12, b16, X8) , (a12, b16, X9), (a12, b16, X10), (a12, b16, X11), (a12, b16, X12), (a12, b16, X13), (a12, b16, X14), ( a12, b16, X15), (a12, b16, X16), (a12, b16, X17), (a12, b16, X18), (a12, b17, X1), (a12, b17, X2), (a12, b17, X3), (a12, b17, X4), (a12, b17, X5), (a12, b17, X6), (a12, b17, X7), (a12, b17, X8), (a12, b17, X9), (a12, b17, X10), (a12, b17, X11), (a12, b17, X12), (a12, b17, X13), (a12, b17, X14), (a12, b17, X15) , (a12, b17, X16), (a12, b17, X17), (a12, b17, X18), (a12, b18, X1), (a12, b18, X2), (a12, b18, X3), (a12, b18, X4), (a12, b18, X5), (a12, b18, X6), (a12, b18, X7), (a12, b18, X8), (a12, b18, X9), (a12, b18, X10), (a12, b18, X11), (a12, b18, X12), (a12, b18, X13), (a12, b18, X14), (a12, b18, X15) , (a12, b18, X16), (a12, b18, X17), (a12, b18, X18), (a12, b19, X1), (a12, b19, X2), (a12, b19, X3), ( a12, b19, X4), (a12, b19, X5), (a12, b19, X6), (a12, b19, X7), (a12, b19, X8), (a12, b19, X9), (a12, b19, X10), (a12, b19, X11), (a12, b19, X12), (a12, b19, X13), (a12, b19, X14), (a12, b19, X15), (a12, b19, X16), (a12, b19, X17), (a12, b19, X18), (a12, b20, X1), (a12, b20, X2), (a12, b20, X3), (a12, b20, X4) , (a12, b20, X5), (a12, b20, X6), (a12, b20, X7), (a12, b20, X8), (a12, b20, X9), (a12, b20, X10), ( a12, b20, X11), (a12, b20, X12), (a12, b20, X13), (a12, b20, X14), (a12, b20, X15), (a12, b20, X16), (a12, b20, X17), (a12, b20, X18), (a12, b21, X1), (a12, b21, X2), (a12, b21, X3), (a12, b21, X4), (a12, b21, X5), (a12, b21, X6), (a12, b21, X7), (a12, b21, X8), (a12, b21, X9), (a12, b21, X10), (a12, b21, X11) , (a12, b21, X12), (a12, b21, X13), (a12, b21, X14), (a12, b21, X15), (a12, b21, X16), (a12, b21, X17), ( a12, b21, X18), (a12, b22, X1), (a12, b22, X2), (a12, b22, X3), (a12, b22, X4), (a12, b2 2, X5), (a12, b22, X6), (a12, b22, X7), (a12, b22, X8), (a12, b22, X9), (a12, b22, X10), (a12, b22, X11), (a12, b22, X12), (a12, b22, X13), (a12, b22, X14), (a12, b22, X15), (a12, b22, X16), (a12, b22, X17) , (a12, b22, X18), (a12, b23, X1), (a12, b23, X2), (a12, b23, X3), (a12, b23, X4), (a12, b23, X5), ( a12, b23, X6), (a12, b23, X7), (a12, b23, X8), (a12, b23, X9), (a12, b23, X10), (a12, b23, X11), (a12, b23, X12), (a12, b23, X13), (a12, b23, X14), (a12, b23, X15), (a12, b23, X16), (a12, b23, X17), (a12, b23, X18), (a12, b24, X1), (a12, b24, X2), (a12, b24, X3), (a12, b24, X4), (a12, b24, X5), (a12, b24, X6) , (a12, b24, X7), (a12, b24, X8), (a12, b24, X9), (a12, b24, X10), (a12, b24, X11), (a12, b24, X12), ( a12, b24, X13), (a12, b24, X14), (a12, b24, X15), (a12, b24, X16), (a12, b24, X17), (a12, b24, X18), (a12, b25, X1), (a12, b25, X2), (a12, b25, X3), (a12, b25, X4), (a12, b25, X5), (a12, b25, X6), (a12, b25, X7), (a12, b25, X8), (a12, b25, X9), (a12, b25, X10), (a12, b25, X11), (a12, b25, X12), (a12, b25, X13) , (a12, b25, X14), (a12, b25, X15), (a12, b25, X16), (a12, b25, X17), (a12, b25, X18), (a12, b26, X1), ( a12, b26, X2), (a12, b26, X3), (a12, b26, X4), (a12, b26, X5), (a12, b26, X6), (a12, b26, X7), (a12, b26, X8), (a12, b26, X9), (a12, b26, X10), (a12, b26, X11), (a12, b26, X12), (a12, b26, X13) , (a12, b26, X14), (a12, b26, X15), (a12, b26, X16), (a12, b26, X17), (a12, b26, X18), (a12, b27, X1), ( a12, b27, X2), (a12, b27, X3), (a12, b27, X4), (a12, b27, X5), (a12, b27, X6), (a12, b27, X7), (a12, b27, X8), (a12, b27, X9), (a12, b27, X10), (a12, b27, X11), (a12, b27, X12), (a12, b27, X13), (a12, b27, X14), (a12, b27, X15), (a12, b27, X16), (a12, b27, X17), (a12, b27, X18).

The compound represented by the formula (I) contained in the analgesic of the present invention has high affinity for NMDA receptors, particularly NR1 / NR2B receptors, and has high subtype selectivity and selectivity for other receptors. It can be a pharmaceutical with excellent analgesic effect and / or reduced side effects (eg, somnolence, dizziness, ataxia and fatigue). It also has high stability, high oral absorption, good bioavailability, low clearance, high brain migration, long half-life, high non-protein binding rate, high drug efficacy and / or Or, since it also has an advantage such as low liver enzyme inhibitory activity, it can be a pharmaceutical with excellent pharmacokinetics and / or excellent safety.
The compound represented by the formula (I) contained in the analgesic of the present invention can be used as an analgesic for pain caused by inflammatory pain, nociceptive pain, neuropathic pain, and / or cancer pain. It is particularly useful as an analgesic for pain caused by neuropathic pain. 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 dosage varies depending on the age, weight, symptom, administration method, etc. 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.

Hereinafter, although the compound contained in this invention analgesic is demonstrated in more detail by an Example, the compound contained in this invention analgesic 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 a single line, d is a double line, t is a triple line, q is a quadruple line, m is a multiple line, br is a wide line, and brs is a wide single line.
Each abbreviation has the meaning shown below.
THF: Tetrahydrofuran DMF: N, N-dimethylformamide HOBt: 1-hydroxybenzotriazole DMAP: 4-dimethylaminopyridine EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride IBX: 1-hydroxy-1 , 2-benz-iodo Oki sole -3 (IH) - on 1-oxide Me: methyl Et: ethyl Bu ^t: tert-butyl Ts: p - toluenesulfonyl BINAP: 2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl Pd ₂ (dba) ₃ : bis (dibenzylideneacetone) palladium (0)
DMPO: 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone MOM: methoxymethyl

窒素雰囲気下、化合物 1（576 mg, 5.0 mmol）と化合物 2（985 mg, 6.0 mmol）をＤＭＦ（5 ml）に溶解し、炭酸カリウム（829 mg, 6.0 mmol）を加え120℃で24時間撹拌した。溶媒を減圧留去し、残渣に水を加えクロロホルムで抽出した。無水硫酸マグネシウムで乾燥後、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（クロロホルム−アセトニトリル）により精製し、化合物 3（671 mg, 収率52%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.40-1.50 (br, 3H), 1.74 (m, 2H), 1.88 (d, J = 12.3Hz, 2H), 2.85 (t, J = 12.3Hz, 2H), 3.56 (d, J = 4.2Hz, 2H), 3.83 (d, J = 12.3Hz, 2H), 7.00 (br, 2H), 7.48 (d, J = 9.0Hz, 2H). Reference Example 1 Synthesis of Compound 3

In a nitrogen atmosphere, compound 1 (576 mg, 5.0 mmol) and compound 2 (985 mg, 6.0 mmol) are dissolved in DMF (5 ml), potassium carbonate (829 mg, 6.0 mmol) is added, and the mixture is stirred at 120 ° C. for 24 hours. did. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-acetonitrile) to obtain Compound 3 (671 mg, yield 52%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.40-1.50 (br, 3H), 1.74 (m, 2H), 1.88 (d, J = 12.3Hz, 2H), 2.85 (t, J = 12.3Hz, 2H ), 3.56 (d, J = 4.2Hz, 2H), 3.83 (d, J = 12.3Hz, 2H), 7.00 (br, 2H), 7.48 (d, J = 9.0Hz, 2H).

化合物 1 の代わりに化合物 4 を用いる以外は参考例１と同様の方法で反応を行ない、化合物 5（収率47%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.26-1.39 (m, 2H), 1.56 (q, J = 6.6Hz, 2H), 1.64-1.69 (m, 1H), 1.83 (d, J = 12.6Hz, 2H), 2.87 (t, J = 12.6Hz, 2H), 3.71-3.81 (m, 4H), 6.93 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H). Reference Example 2 Synthesis of Compound 5

The reaction was conducted in the same manner as in Reference Example 1 except that compound 4 was used in place of compound 1 to obtain compound 5 (yield 47%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.26-1.39 (m, 2H), 1.56 (q, J = 6.6Hz, 2H), 1.64-1.69 (m, 1H), 1.83 (d, J = 12.6Hz , 2H), 2.87 (t, J = 12.6Hz, 2H), 3.71-3.81 (m, 4H), 6.93 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).

化合物 4（646 mg, 5.0 mmol）と化合物 6（908 mg, 5.0 mmol）をＤＭＦ（15 ml）に溶解し、炭酸水素ナトリウム（504 mg, 6.0 mmol）を加え80℃で2時間撹拌した。冷後、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 7（1.08 g, 収率78%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.16-1.32 (m, 3H), 1.50-1.60 (m, 2H), 1.68-1.86 (m, 3H), 2.84-2.97 (m, 2H), 3.69-3.78 (m, 2H), 4.34-4.44 (m, 2H), 6.63 (d, J = 9.0Hz, 1H), 7.59 (dd, J = 9.0, 1.5Hz, 1H), 8.37 (d, J = 1.5Hz, 1H). Reference Example 3 Synthesis of Compound 7

Compound 4 (646 mg, 5.0 mmol) and compound 6 (908 mg, 5.0 mmol) were dissolved in DMF (15 ml), sodium bicarbonate (504 mg, 6.0 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with 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 7 (1.08 g, yield 78%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.16-1.32 (m, 3H), 1.50-1.60 (m, 2H), 1.68-1.86 (m, 3H), 2.84-2.97 (m, 2H), 3.69- 3.78 (m, 2H), 4.34-4.44 (m, 2H), 6.63 (d, J = 9.0Hz, 1H), 7.59 (dd, J = 9.0, 1.5Hz, 1H), 8.37 (d, J = 1.5Hz , 1H).

窒素雰囲気下、ＢＩＮＡＰ（187 mg，0.3 mmol）、Ｐｄ_２(ｄｂａ)_３（92 mg，0.1 mmol）、ナトリウムtert-ブトキシド（1.19 g，12.0 mmol）、化合物 8（1.14 g，11.2 mmol）、化合物 9（1.36 ml，10.0 mmol）にトルエン（20 ml）を加え、マイクロウエーブ照射下、120℃で1時間反応させた。反応液をセライトを用いてろ過し、固体を酢酸エチルで洗浄した。ろ液、洗液を合わせ減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製して化合物 10（1.45 g，収率59%）を得た。
mp 9798℃
^１H-NMR（CDCl₃ / TMS）δppm：1.49-1.56 (m, 2H), 1.62-1.74 (m, 2H), 2.03 (brs, 2H), 3.03-3.10 (m, 2H), 3.63-3.71 (m, 2H), 3.93 (brs, 1H), 6.97 (br, 2H), 7.48 (d, J = 8.7Hz, 2H). Reference Example 4 Synthesis of Compound 10

Under a nitrogen atmosphere, BINAP (187 mg, 0.3 mmol), Pd ₂ (dba) ₃ (92 mg, 0.1 mmol), sodium tert-butoxide (1.19 g, 12.0 mmol), compound 8 (1.14 g, 11.2 mmol), compound Toluene (20 ml) was added to 9 (1.36 ml, 10.0 mmol) and reacted at 120 ° C. for 1 hour under microwave irradiation. The reaction solution was filtered using celite, and the solid was washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 10 (1.45 g, yield 59%).
mp 9798 ℃
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.49-1.56 (m, 2H), 1.62-1.74 (m, 2H), 2.03 (brs, 2H), 3.03-3.10 (m, 2H), 3.63-3.71 ( m, 2H), 3.93 (brs, 1H), 6.97 (br, 2H), 7.48 (d, J = 8.7Hz, 2H).

化合物 11（2.12 g, 15.0 mmol）と化合物 8（1.82 g, 18.0 mmol）をＤＭＦ（15 ml）に溶解し、炭酸カリウム（2.52 g, 18.0 mmol）を加え85℃で1時間撹拌した。溶媒を減圧留去し、残渣に水を加えクロロホルムで抽出した。無水硫酸マグネシウムで乾燥後、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（クロロホルム−アセトニトリル）により精製し、化合物 12（3.10 g, 収率93%）を得た。
mp 115.6117℃
^１H-NMR（CDCl₃ / TMS）δppm：1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82-3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H). Reference Example 5 Synthesis of Compound 12

Compound 11 (2.12 g, 15.0 mmol) and compound 8 (1.82 g, 18.0 mmol) were dissolved in DMF (15 ml), potassium carbonate (2.52 g, 18.0 mmol) was added, and the mixture was stirred at 85 ° C. for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-acetonitrile) to obtain Compound 12 (3.10 g, yield 93%).
mp 115.6117 ℃
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82- 3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H).

化合物 12（1.50 g，6.75 mmol）をメタノール（25 ml）に溶解し、10%パラジウム−炭素（150 mg）を加え系内を水素ガスで置換した。室温で2時間撹拌した後、セライトを用いて反応液をろ過し、メタノールで洗浄した。ろ液、洗液を合わせ溶媒を減圧留去し、化合物 13（1.28 g，収率99%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.70-1.80 (m, 2H), 2.07 (br, 2H), 2.84 (br, 2H), 3.37 (br, 3H), 3.85 (br, 1H), 6.65 (d, J = 8.4Hz, 2H), 6.91 (br, 2H). Reference Example 6 Synthesis of Compound 13

Compound 12 (1.50 g, 6.75 mmol) was dissolved in methanol (25 ml), 10% palladium-carbon (150 mg) was added, and the system was replaced with hydrogen gas. After stirring at room temperature for 2 hours, the reaction solution was filtered using celite and washed with methanol. The filtrate and washing solution were combined and the solvent was distilled off under reduced pressure to obtain Compound 13 (1.28 g, yield 99%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.70-1.80 (m, 2H), 2.07 (br, 2H), 2.84 (br, 2H), 3.37 (br, 3H), 3.85 (br, 1H), 6.65 (d, J = 8.4Hz, 2H), 6.91 (br, 2H).

化合物 13（1.28 g，6.66 mmol）を6 mol/L塩酸（26 ml）に溶解し、ドライアイス−アセトン浴で-35 〜-40℃に冷却した。亜硝酸ナトリウム（482 mg，6.99 mmol）の水溶液（5 ml）を滴下し、-35 〜-40℃で30分間撹拌した。尿素（100 mg，1.67 mmol）、塩化第一銅（725 mg，7.32 mmol）、塩化第二銅（985 mg，7.32 mmol）を加え60℃で45分間撹拌した。水浴で冷却してアンモニア水を加えアルカリ性とし、クロロホルムを加えた後、不溶物をセライトを用いてろ去した。ろ液をクロロホルムで抽出し、有機層を水で洗浄した後、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（クロロホルム−メタノール）により精製し、化合物 14（1.32 g, 収率94%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82-3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H). Reference Example 7 Synthesis of Compound 14

Compound 13 (1.28 g, 6.66 mmol) was dissolved in 6 mol / L hydrochloric acid (26 ml) and cooled to −35 to −40 ° C. in a dry ice-acetone bath. An aqueous solution (5 ml) of sodium nitrite (482 mg, 6.99 mmol) was added dropwise, and the mixture was stirred at −35 to −40 ° C. for 30 minutes. Urea (100 mg, 1.67 mmol), cuprous chloride (725 mg, 7.32 mmol) and cupric chloride (985 mg, 7.32 mmol) were added, and the mixture was stirred at 60 ° C for 45 minutes. After cooling with a water bath and adding aqueous ammonia to make it alkaline, chloroform was added, and insoluble matter was removed by filtration using Celite. The filtrate was extracted with chloroform, the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 14 (1.32 g, yield 94%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82- 3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H).

化合物 10（1.50 g，6.12 mmol）を酢酸エチル（45 ml）に溶解し、ＩＢＸ（5.14 g，18.4 mmol）を加え80℃で8時間撹拌した。氷浴で冷却し、析出した固体をろ去して酢酸エチルで洗浄した。ろ液、洗液を合わせ減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム）により精製し、化合物 15（1.34 g, 収率90%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：2.57 (t, J = 6.3Hz, 4H), 3.71 (t, J = 6.3Hz, 4H), 6.97 (d, J = 8.7Hz, 2H), 7.52 (d, J = 8.7Hz, 2H). Reference Example 8 Synthesis of Compound 15

Compound 10 (1.50 g, 6.12 mmol) was dissolved in ethyl acetate (45 ml), IBX (5.14 g, 18.4 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours. The mixture was cooled in an ice bath, and the precipitated solid was removed by filtration and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain Compound 15 (1.34 g, yield 90%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 2.57 (t, J = 6.3Hz, 4H), 3.71 (t, J = 6.3Hz, 4H), 6.97 (d, J = 8.7Hz, 2H), 7.52 ( d, J = 8.7Hz, 2H).

化合物 10 の代わりに化合物 14 を用いる以外は参考例８と同様の方法で反応を行ない、化合物 16（収率92%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：2.57 (t, J = 6.0Hz, 4H), 3.58 (t, J = 6.0Hz, 4H), 6.91 (d, J = 9.0Hz, 2H), 7.24 (d, J = 9.0Hz, 2H). Reference Example 9 Synthesis of Compound 16

The reaction was conducted in the same manner as in Reference Example 8 except that compound 14 was used instead of compound 10 to obtain compound 16 (yield 92%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 2.57 (t, J = 6.0 Hz, 4H), 3.58 (t, J = 6.0 Hz, 4H), 6.91 (d, J = 9.0 Hz, 2H), 7.24 ( d, J = 9.0Hz, 2H).

化合物 10 の代わりに化合物 3 を用いる以外は参考例８と同様の方法で反応を行ない、化合物 17（収率79%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.72-1.85 (m, 2H), 2.01-2.09 (m, 2H), 2.43-2.52 (m, 1H), 2.95-3.04 (m, 2H), 3.69-3.76 (m, 2H), 6.94 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H), 9.71 (s, 1H). Reference Example 10 Synthesis of Compound 17

The reaction was conducted in the same manner as in Reference Example 8 except that compound 3 was used instead of compound 10 to obtain compound 17 (yield 79%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.72-1.85 (m, 2H), 2.01-2.09 (m, 2H), 2.43-2.52 (m, 1H), 2.95-3.04 (m, 2H), 3.69- 3.76 (m, 2H), 6.94 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H), 9.71 (s, 1H).

化合物 2（3.28 g, 20.0 mmol）と化合物 18（3.77 g, 24.0 mmol）をＤＭＦ（10 ml）に溶解し、炭酸カリウム（3.32 g, 24.0 mmol）を加え120℃で24時間撹拌した。溶媒を減圧留去し、残渣に水を加えトルエンで抽出した。有機層を水洗した後、無水硫酸マグネシウムで乾燥後、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（トルエン−酢酸エチル）により精製し、化合物 19（2.35 g, 収率39%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.27 (t, J = 7.1Hz, 3H), 1.76-1.92 (m, 2H), 1.97-2.08 (m, 2H), 2.42-2.54 (m, 1H), 2.84-2.96 (m, 2H), 3.70-3.79 (m, 2H), 4.16 (q, J = 7.1Hz, 2H), 6.92 (d, J = 9.0Hz, 2H), 7.46 (d, J = 9.0Hz, 2H). Reference Example 11 Synthesis of Compound 19

Compound 2 (3.28 g, 20.0 mmol) and compound 18 (3.77 g, 24.0 mmol) were dissolved in DMF (10 ml), potassium carbonate (3.32 g, 24.0 mmol) was added, and the mixture was stirred at 120 ° C. for 24 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene-ethyl acetate) to obtain Compound 19 (2.35 g, yield 39%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.27 (t, J = 7.1 Hz, 3H), 1.76-1.92 (m, 2H), 1.97-2.08 (m, 2H), 2.42-2.54 (m, 1H) , 2.84-2.96 (m, 2H), 3.70-3.79 (m, 2H), 4.16 (q, J = 7.1Hz, 2H), 6.92 (d, J = 9.0Hz, 2H), 7.46 (d, J = 9.0 Hz, 2H).

1-(4-クロロフェニル)ピペラジン塩酸塩 20（1.00 g, 4.3 mmol)をトルエン（5 ml）に溶解し氷浴で冷却した。クロログリオキシ酸エチル（0.64 g, 4.7 mmol）のトルエン（2 ml）溶液を滴下し0℃で0.5時間撹拌した。反応液を酢酸エチルで抽出し、有機層を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、化合物 21（1.27 g, 収率100%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.38 (t, J = 7.1Hz, 3H), 3.15-3.20 (m, 4H), 3.60 (t, J = 5.2Hz, 2H), 3.78 (t, J = 5.2Hz, 2H), 4.36 (q, J = 7.1Hz, 2H), 6.84 (d, J = 9.1Hz, 2H), 7.22 (d, J = 9.1Hz, 2H). Reference Example 12 Synthesis of Compound 21

1- (4-Chlorophenyl) piperazine hydrochloride 20 (1.00 g, 4.3 mmol) was dissolved in toluene (5 ml) and cooled in an ice bath. A solution of ethyl chloroglyoxylate (0.64 g, 4.7 mmol) in toluene (2 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 0.5 hr. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 21 (1.27 g, yield 100%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.38 (t, J = 7.1Hz, 3H), 3.15-3.20 (m, 4H), 3.60 (t, J = 5.2Hz, 2H), 3.78 (t, J = 5.2Hz, 2H), 4.36 (q, J = 7.1Hz, 2H), 6.84 (d, J = 9.1Hz, 2H), 7.22 (d, J = 9.1Hz, 2H).

ａ）化合物23の合成
2-アミノ-5-ニトロフェノール 22（22.20 g, 144 mmol)をＴＨＦ（100 ml）に溶解し、系内を窒素ガスで置換し氷浴で冷却した。1,1'-カルボニルジイミダゾール（28.03 g, 173 mmol）のＴＨＦ懸濁液（100 ml）を0〜5℃で少量ずつ加え、室温で15時間撹拌した。溶媒を減圧留去した後、残渣に水（144 ml）を加え氷浴で冷却し、2 mol/L塩酸（144 ml, 288 mmol）を加え室温で3時間撹拌した。析出した固体をろ取し、水洗後乾燥して化合物 23（25.81 g, 収率99%)を得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：7.28 (d, J = 8.6Hz, 1H), 8.13 (dd, J = 2.0, 8.6Hz, 1H), 8.19 (d, J = 2.0Hz, 1H), 12.43 (brs, 1H).
ｂ）化合物24の合成
化合物 23（40.00 g, 222 mmol)をＴＨＦ−水（9:1）混液（400 ml）に懸濁し、10%−パラジウム−炭素（8.00 g, 53%含水品)を加え水素雰囲気下室温で9時間撹拌した。セライトを用いて反応液をろ過し、残渣をＴＨＦ−水（9:1）混液（500 ml）で洗浄した。ろ液、洗液を合わせ96gまで減圧濃縮し、水（100 ml）を加え固体をろ取した。固体を水洗後、乾燥して化合物24（32.20 g, 収率97%)を得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：5.01 (s, 1H), 6.35 (dd, J = 2.0, 8.2Hz, 1H), 6.50 (d, J = 2.0Hz, 1H), 6.74 (d, J = 8.2Hz, 1H), 11.03 (brs, 1H). Reference Example 13 Synthesis of Compound 24

a) Synthesis of Compound 23
2-Amino-5-nitrophenol 22 (22.20 g, 144 mmol) was dissolved in THF (100 ml), and the system was replaced with nitrogen gas and cooled in an ice bath. A THF suspension (100 ml) of 1,1′-carbonyldiimidazole (28.03 g, 173 mmol) was added little by little at 0-5 ° C., and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off under reduced pressure, water (144 ml) was added to the residue, and the mixture was cooled in an ice bath. 2 mol / L hydrochloric acid (144 ml, 288 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with water and dried to give compound 23 (25.81 g, yield 99%).
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 7.28 (d, J = 8.6Hz, 1H), 8.13 (dd, J = 2.0, 8.6Hz, 1H), 8.19 (d, J = 2.0Hz, 1H ), 12.43 (brs, 1H).
b) Synthesis of Compound 24 Compound 23 (40.00 g, 222 mmol) was suspended in a THF-water (9: 1) mixture (400 ml), and 10% -palladium-carbon (8.00 g, 53% water-containing product) was added. The mixture was stirred at room temperature for 9 hours under a hydrogen atmosphere. The reaction solution was filtered using Celite, and the residue was washed with a THF-water (9: 1) mixture (500 ml). The filtrate and washings were combined and concentrated to 96 g under reduced pressure, water (100 ml) was added and the solid was collected by filtration. The solid was washed with water and dried to give compound 24 (32.20 g, yield 97%).
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 5.01 (s, 1H), 6.35 (dd, J = 2.0, 8.2 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.74 (d , J = 8.2Hz, 1H), 11.03 (brs, 1H).

ａ）化合物25の合成
窒素雰囲気下、参考例２で得られた化合物 5（339 mg，1.46 mmol）をＴＨＦ（10 ml）に溶解し、フタルイミド（279 mg, 1.90 mmol)、トリフェニルホスフィン（498 mg, 1.90 mmol)、アゾジカルボン酸ジイソプロピル（0.37 ml, 1.90 mmol)を加え、室温で1時間撹拌した。
溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン−酢酸エチル）により精製して化合物 25（541 mg，収率92%）を得た。
mp 203205℃
^１H-NMR（CDCl₃ / TMS）δppm：1.38-1.55 (m, 3H), 1.68 (q, J = 6.6Hz, 2H), 1.92 (d, J = 9.9Hz, 2H), 2.81 (t, J = 11.4Hz, 2H), 3.74-3.80 (m, 4H), 6.96 (br, 2H), 7.46 (d, J = 9.0Hz, 2H), 7.71-7.74 (m, 2H), 7.84-7.87 (m, 2H).
ｂ）化合物21の合成
化合物 26（537 mg, 1.33 mmol)をエタノール（10 ml）に溶解し、ヒドラジン一水和物（0.16 ml, 3.33 mmol)を加え2時間還流した。放冷後、析出した固体をろ去した。ろ液と固体をクロロホルム−メタノール（9:1混液）で加熱しろ過したろ液を合わせ、溶媒を減圧留去した。残渣に1 mol/L水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を水洗した後、無水硫酸マグネシウムで乾燥後、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（クロロホルム−メタノール）により精製し、化合物 26（280 mg, 収率77%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.27-1.40 (m, 2H), 1.46-1.60 (m, 3H), 1.79 (d, J = 12.9Hz, 2H), 2.13 (br, 5H), 2.74-2.85 (m, 4H), 3.78 (d, J = 12.6 Hz, 2H), 6.91 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H).
ｃ）化合物（Ｉ−２）の合成
化合物 26（276 mg, 1.01 mmol)にＤＭＦ（5 ml）、6−ヒドロキシニコチン酸（155 mg, 1.11 mmol)、ＨＯＢｔ（164 mg, 1.11 mmol)、トリエチルアミン（0.17 ml, 1.21 mmol)、ＤＭＡＰ（6 mg， 0.05 mmol)、ＥＤＣ（232 mg, 1.21 mmol)を加え、室温で2時間撹拌した。溶媒を減圧濃縮し、得られた残渣に水、2 mol/L塩酸を加えクロロホルム−メタノール（9:1混液）で抽出した。有機層を水、飽和重曹水、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−酢酸エチルより再結晶し、化合物（Ｉ−２）（256 mg, 収率65%)を得た。
mp 232−233℃
^１H-NMR（DMSO-d₆ / TMS）δppm：1.14-1.25 (m, 2H), 1.46 (t, J = 6.9Hz, 2H), 1.53 (brs, 1H), 1.77 (d, J = 11.7Hz, 2H), 2.77 (t, J = 11.7Hz, 2H), 3.26 (q, J = 5.7Hz, 2H), 3.85 (d, J = 12.9Hz, 2H), 6.34 (d, J = 9.6Hz, 1H), 7.03 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H), 7.85 (dd, J = 9.6, 2.7Hz, 1H), 7.97 (d, J = 2.4Hz, 1H), 8.19 (t, J = 5.0Hz, 1H), 11.93 (s, 1H). Synthesis of compound (I-2)

a) Synthesis of Compound 25 In a nitrogen atmosphere, Compound 5 (339 mg, 1.46 mmol) obtained in Reference Example 2 was dissolved in THF (10 ml), and phthalimide (279 mg, 1.90 mmol), triphenylphosphine (498 mg, 1.90 mmol) and diisopropyl azodicarboxylate (0.37 ml, 1.90 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (toluene-ethyl acetate) to obtain Compound 25 (541 mg, yield 92%).
mp 203205 ° C
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.38-1.55 (m, 3H), 1.68 (q, J = 6.6Hz, 2H), 1.92 (d, J = 9.9Hz, 2H), 2.81 (t, J = 11.4Hz, 2H), 3.74-3.80 (m, 4H), 6.96 (br, 2H), 7.46 (d, J = 9.0Hz, 2H), 7.71-7.74 (m, 2H), 7.84-7.87 (m, 2H).
b) Synthesis of Compound 21 Compound 26 (537 mg, 1.33 mmol) was dissolved in ethanol (10 ml), hydrazine monohydrate (0.16 ml, 3.33 mmol) was added, and the mixture was refluxed for 2 hours. After allowing to cool, the precipitated solid was removed by filtration. The filtrate and the solid were heated with chloroform-methanol (9: 1 mixed solution) and filtered, and the filtrate was combined. The solvent was distilled off under reduced pressure. To the residue was added 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by alumina column chromatography (chloroform-methanol) to obtain compound 26 (280 mg, yield 77%). Got.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.27-1.40 (m, 2H), 1.46-1.60 (m, 3H), 1.79 (d, J = 12.9Hz, 2H), 2.13 (br, 5H), 2.74 -2.85 (m, 4H), 3.78 (d, J = 12.6 Hz, 2H), 6.91 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H).
c) Synthesis of Compound (I-2) Compound 26 (276 mg, 1.01 mmol) was added to DMF (5 ml), 6-hydroxynicotinic acid (155 mg, 1.11 mmol), HOBt (164 mg, 1.11 mmol), triethylamine ( 0.17 ml, 1.21 mmol), DMAP (6 mg, 0.05 mmol), EDC (232 mg, 1.21 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, water and 2 mol / L hydrochloric acid were added to the resulting residue, and the mixture was extracted with chloroform-methanol (9: 1 mixed solution). The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from methanol-ethyl acetate to obtain Compound (I-2) (256 mg, yield 65%).
mp 232-233 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 1.14-1.25 (m, 2H), 1.46 (t, J = 6.9Hz, 2H), 1.53 (brs, 1H), 1.77 (d, J = 11.7Hz , 2H), 2.77 (t, J = 11.7Hz, 2H), 3.26 (q, J = 5.7Hz, 2H), 3.85 (d, J = 12.9Hz, 2H), 6.34 (d, J = 9.6Hz, 1H ), 7.03 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H), 7.85 (dd, J = 9.6, 2.7Hz, 1H), 7.97 (d, J = 2.4Hz, 1H ), 8.19 (t, J = 5.0Hz, 1H), 11.93 (s, 1H).

ａ）化合物27の合成
窒素雰囲気下、化合物 5（1.37 g，5.0 mmol）を塩化メチレン（15 ml）に溶解し、トリエチルアミン（0.84 ml, 6.0 mmol）を加え氷浴で冷却した。塩化 p-トルエンスルホニル（1.14 g, 6.0 mmol）を加え0℃で45分、室温で3.5時間撹拌した。アンモニア水を加え15分間撹拌した後、水を加えクロロホルムで抽出した。有機層を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（クロロホルム）により精製して化合物 27（1.74 g，収率81%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.22-1.34 (br, 2H), 1.56-1.73 (m, 5H), 2.46 (s, 3H), 2.75 (t, J = 11.7Hz, 2H), 3.74 (d, J = 12.6Hz, 2H), 4.10 (t, J = 6.0Hz, 2H), 6.91 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8.4Hz, 2H), 7.80 (d, J = 8.4Hz, 2H).
ｂ）化合物28の合成
窒素雰囲気下、化合物 22（1.74 g, 4.07 mmol）をＤＭＦ（17 ml）に溶解し、シアン化ナトリウム（299 mg, 6.11 mmol）を加え60℃で5時間撹拌した。溶媒を減圧留去し、得られた残渣に水を加えトルエンで抽出した。有機層を水洗した後、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（トルエン−酢酸エチル）により精製して化合物 28（1.07 g，収率93%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.31-1.42 (m, 2H), 1.64-1.69 (m, 3H), 1.83 (d, J = 13.2Hz, 2H), 2.42 (t, J = 6.9Hz, 2H), 2.78-2.87 (m, 2H), 3.81 (d, J = 13.2Hz, 2H), 6.93 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H).
ｃ）化合物29の合成
化合物 28（1.06 g, 3.75 mmol）をメタノール（10 ml）に溶解し、85%水酸化カリウム（2.31 g, 35.0 mmol)、水（10 ml）を加え20時間還流した。室温まで放冷した後、溶媒を減圧留去し、得られた残渣を5 mol/L塩酸で中和した。析出した固体をろ取し、水洗後乾燥して化合物 29（1.07 g, 収率95%)を得た。
mp 204−206℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：1.10-1.22 (m, 2H), 1.45-1.49 (m, 3H), 1.73 (d, J = 13.5Hz, 2H), 2.25 (t, J = 7.5Hz, 2H), 2.75 (t, J = 10.5Hz, 2H), 3.85 (d, J = 13.5Hz, 2H), 7.03 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
ｄ）化合物（Ｉ−７）の合成
化合物 29（362 mg, 1.2 mmol)にＤＭＦ（5 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（150 mg, 1.0 mmol)、ＨＯＢｔ（162 mg, 1.2 mmol)、トリエチルアミン（0.17 ml, 1.2mmol)、ＤＭＡＰ（6.0 mg， 0.05 mmol)、ＥＤＣ（230 mg, 1.2 mmol)を加え、室温で15時間撹拌した。溶媒を減圧留去し、残渣にクロロホルム−メタノール（9:1混液）、飽和重曹水を加え析出した固体をろ取し、水で洗浄後、乾燥して261 mgの固体を得た。また、ろ液をクロロホルム−メタノール（9:1混液）で抽出し、水洗、無水硫酸マグネシウムで乾燥後、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（クロロホルム−メタノール）により精製し、66 mgの固体を得た。得られた固体を合わせ、シリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、さらにメタノールで再結晶して化合物（Ｉ−７）（244 mg, 収率56%)を得た。
mp 254 256℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：1.16-1.25 (m, 2H), 1.46-1.52 (m, 1H), 1.55 (t, J = 7.2Hz, 2H), 1.76 (d, J = 12.0Hz, 2H), 2.34 (t, J = 6.6Hz, 2H), 2.78 (t, J = 12.6Hz, 2H), 3.87 (d, J = 13.5Hz, 2H), 7.01 (d, J = 8.4Hz, 1H), 7.04 (d, J = 9.0Hz, 2H), 7.21 (dd, J = 8.4, 1.8Hz, 1H), 7.46 (d, J = 9.0Hz, 2H), 7.69 (d, J = 1.5Hz, 1H), 9.95 (s, 1H), 11.51 (s, 1H). Synthesis of Compound (I-7)

a) Synthesis of Compound 27 Under a nitrogen atmosphere, Compound 5 (1.37 g, 5.0 mmol) was dissolved in methylene chloride (15 ml), triethylamine (0.84 ml, 6.0 mmol) was added, and the mixture was cooled in an ice bath. P-Toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added, and the mixture was stirred at 0 ° C. for 45 minutes and at room temperature for 3.5 hours. Aqueous ammonia was added, and the mixture was stirred for 15 minutes. Water was added, and the mixture was extracted with chloroform. The organic layer 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 (chloroform) to obtain Compound 27 (1.74 g, yield 81%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.22-1.34 (br, 2H), 1.56-1.73 (m, 5H), 2.46 (s, 3H), 2.75 (t, J = 11.7Hz, 2H), 3.74 (d, J = 12.6Hz, 2H), 4.10 (t, J = 6.0Hz, 2H), 6.91 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.45 (d , J = 8.4Hz, 2H), 7.80 (d, J = 8.4Hz, 2H).
b) Synthesis of Compound 28 Under a nitrogen atmosphere, Compound 22 (1.74 g, 4.07 mmol) was dissolved in DMF (17 ml), sodium cyanide (299 mg, 6.11 mmol) was added, and the mixture was stirred at 60 ° C. for 5 hours. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give compound 28 (1.07 g, yield 93%). Got.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.31-1.42 (m, 2H), 1.64-1.69 (m, 3H), 1.83 (d, J = 13.2Hz, 2H), 2.42 (t, J = 6.9Hz , 2H), 2.78-2.87 (m, 2H), 3.81 (d, J = 13.2Hz, 2H), 6.93 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H).
c) Synthesis of Compound 29 Compound 28 (1.06 g, 3.75 mmol) was dissolved in methanol (10 ml), 85% potassium hydroxide (2.31 g, 35.0 mmol) and water (10 ml) were added, and the mixture was refluxed for 20 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was neutralized with 5 mol / L hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to obtain Compound 29 (1.07 g, yield 95%).
mp 204−206 ℃ (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.10-1.22 (m, 2H), 1.45-1.49 (m, 3H), 1.73 (d, J = 13.5 Hz, 2H), 2.25 (t, J = 7.5Hz, 2H), 2.75 (t, J = 10.5Hz, 2H), 3.85 (d, J = 13.5Hz, 2H), 7.03 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz , 2H).
d) Synthesis of Compound (I-7) Compound 29 (362 mg, 1.2 mmol) was added to DMF (5 ml), 6-amino-3H-benzoxazol-2-one (150 mg, 1.0 mmol), HOBt (162 mg). , 1.2 mmol), triethylamine (0.17 ml, 1.2 mmol), DMAP (6.0 mg, 0.05 mmol) and EDC (230 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, chloroform-methanol (9: 1 mixed solution) and saturated aqueous sodium hydrogen carbonate were added to the residue, the precipitated solid was collected by filtration, washed with water, and dried to obtain 261 mg of a solid. The filtrate was extracted with chloroform-methanol (9: 1 mixed solution), washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol). 66 mg of solid was obtained. The obtained solids were combined, purified by silica gel column chromatography (chloroform-methanol), and further recrystallized from methanol to obtain compound (I-7) (244 mg, yield 56%).
mp 254 256 ℃ (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 1.16-1.25 (m, 2H), 1.46-1.52 (m, 1H), 1.55 (t, J = 7.2Hz, 2H), 1.76 (d, J = 12.0Hz, 2H), 2.34 (t, J = 6.6Hz, 2H), 2.78 (t, J = 12.6Hz, 2H), 3.87 (d, J = 13.5Hz, 2H), 7.01 (d, J = 8.4Hz , 1H), 7.04 (d, J = 9.0Hz, 2H), 7.21 (dd, J = 8.4, 1.8Hz, 1H), 7.46 (d, J = 9.0Hz, 2H), 7.69 (d, J = 1.5Hz , 1H), 9.95 (s, 1H), 11.51 (s, 1H).

ａ）化合物30の合成
窒素雰囲気下、参考例８で得られた化合物 15（1.34 g，5.51 mmol）をＴＨＦ（20 ml）に溶解し、ジエチルホスホノ酢酸エチル（1.36 g, 6.06 mmol）、水酸化リチウム（435 mg, 18.2 mmol）を加え2時間還流した。氷浴で冷却した後、2 mol/L塩酸 7 mlを加え、ジエチルエーテルで抽出した。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、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム）により精製した。ジエチルエーテル−ヘキサンで再結晶し、化合物 30（1.22 g，収率71%）を得た。
mp 71 74℃
^１H-NMR（CDCl₃ / TMS）δppm：1.29 (t, J = 7.2Hz, 3H), 2.46 (t, J = 5.7Hz, 2H), 3.11 (t, J = 5.7Hz, 2H), 3.45 (q, J = 6.0Hz, 4H), 4.17 (q, J = 7.2Hz, 2H), 5.75 (s, 1H), 6.94 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
ｂ）化合物31の合成
化合物 30（500 mg, 1.60 mmol）をエタノール（15 ml）に溶解し、10％パラジウム−炭素（50 mg）を加え系内を水素ガスで置換し、室温で1.5時間撹拌した。反応液をろ過して不溶物を除去し、ろ液を減圧留去した。得られた残渣にジエチルエーテルを加え、セライトを用いてろ過し、ジエチルエーテルで洗浄した。ろ液、洗液を合わせ溶媒を減圧留去して、化合物 31（488 mg, 収率97%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.27 (t, J = 7.2Hz, 3H), 1.38-1.46 (m, 2H), 1.84 (d, J = 12.9Hz, 2H), 1.95-2.04 (m, 1H), 2.28 (d, J = 12.9Hz, 2H), 2.84 (dt, J = 2.1, 12.6Hz, 2H), 4.15 (q, J = 7.2Hz, 2H), 6.93 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
ｃ）化合物32の合成
化合物 31（485 mg, 1.54 mmol）をメタノール（10 ml）に溶解し、2 mol/L水酸化ナトリウム（2 ml, 4.0 mmol）を加え65℃で45分間撹拌した。溶媒を減圧留去し、残渣に2 mol/L塩酸を加え酸性とし、析出した結晶をろ取した。水洗後、乾燥して化合物 32（399 mg, 収率96%）を得た。
mp 103 104℃
^１H-NMR（CDCl₃ / TMS）δppm：1.36-1.49 (m, 2H), 1.88 (d, J = 12.3Hz, 2H), 1.97-2.05 (m, 1H), 2.35 (d, J = 6.9Hz, 2H), 2.84 (dt, J = 2.4, 12.6Hz, 2H), 3.79 (d, J = 12.6Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 7.46 (d, J = 9.0Hz, 2H).
ｄ）化合物（Ｉ−７）の合成
化合物 32（388 mg, 1.35 mmol)に塩化メチレン（10 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（203 mg, 1.35 mmol)、ＨＯＢｔ（219 mg, 1.62 mmol)、トリエチルアミン（0.23 ml, 1.62mmol)、ＤＭＡＰ（8.0 mg， 0.07 mmol)、ＥＤＣ（311 mg, 1.62 mmol)を加え、室温で19時間撹拌した。飽和重曹水を加え析出した固体をろ取し、水で洗浄後、乾燥して105 mgの固体を得た。また、ろ液をクロロホルムで抽出し、無水硫酸マグネシウムで乾燥後、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（アセトニトリル−クロロホルム）により精製し、さらにアセトン−イソプロパノールで再結晶して121 mgの固体を得た。得られた固体を合わせ、シリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、さらに酢酸エチル−メタノール−イソプロパノールで再結晶して化合物（Ｉ−７）（153 mg, 収率27%)を得た。
mp 245 246℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：1.23-1.34 (m, 2H), 1.75 (d, J = 12.0Hz, 2H), 1.96-2.06 (m, 1H), 2.25 (d, J = 7.2Hz, 2H), 2.83 (t, J = 12.3Hz, 2H), 3.86 (d, J = 12.0Hz, 2H), 7.02 (t, J = 9.9Hz, 3H), 7.22 (dd, J = 8.7, 1.8Hz, 1H), 7.47 (d, J = 8.7Hz, 2H), 7.70 (d, J = 1.8Hz, 1H), 9.95 (s, 1H), 11.51 (s, 1H). Synthesis of Compound (I-8)

a) Synthesis of Compound 30 In a nitrogen atmosphere, Compound 15 (1.34 g, 5.51 mmol) obtained in Reference Example 8 was dissolved in THF (20 ml), and ethyl diethylphosphonoacetate (1.36 g, 6.06 mmol), water Lithium oxide (435 mg, 18.2 mmol) was added and refluxed for 2 hours. After cooling in an ice bath, 7 ml of 2 mol / L hydrochloric acid was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform). Recrystallization from diethyl ether-hexane gave Compound 30 (1.22 g, yield 71%).
mp 71 74 ° C
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.29 (t, J = 7.2Hz, 3H), 2.46 (t, J = 5.7Hz, 2H), 3.11 (t, J = 5.7Hz, 2H), 3.45 ( q, J = 6.0Hz, 4H), 4.17 (q, J = 7.2Hz, 2H), 5.75 (s, 1H), 6.94 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
b) Synthesis of Compound 31 Compound 30 (500 mg, 1.60 mmol) was dissolved in ethanol (15 ml), 10% palladium-carbon (50 mg) was added, the system was replaced with hydrogen gas, and the mixture was stirred at room temperature for 1.5 hours. did. The reaction solution was filtered to remove insoluble matters, and the filtrate was distilled off under reduced pressure. Diethyl ether was added to the resulting residue, filtered through celite, and washed with diethyl ether. The filtrate and washing solution were combined and the solvent was distilled off under reduced pressure to obtain Compound 31 (488 mg, yield 97%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.27 (t, J = 7.2Hz, 3H), 1.38-1.46 (m, 2H), 1.84 (d, J = 12.9Hz, 2H), 1.95-2.04 (m , 1H), 2.28 (d, J = 12.9Hz, 2H), 2.84 (dt, J = 2.1, 12.6Hz, 2H), 4.15 (q, J = 7.2Hz, 2H), 6.93 (d, J = 8.7Hz , 2H), 7.46 (d, J = 8.7Hz, 2H).
c) Synthesis of Compound 32 Compound 31 (485 mg, 1.54 mmol) was dissolved in methanol (10 ml), 2 mol / L sodium hydroxide (2 ml, 4.0 mmol) was added, and the mixture was stirred at 65 ° C. for 45 minutes. The solvent was distilled off under reduced pressure, 2 mol / L hydrochloric acid was added to the residue to make it acidic, and the precipitated crystals were collected by filtration. After washing with water and drying, compound 32 (399 mg, yield 96%) was obtained.
mp 103 104 ° C
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.36-1.49 (m, 2H), 1.88 (d, J = 12.3Hz, 2H), 1.97-2.05 (m, 1H), 2.35 (d, J = 6.9Hz , 2H), 2.84 (dt, J = 2.4, 12.6Hz, 2H), 3.79 (d, J = 12.6Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 7.46 (d, J = 9.0Hz , 2H).
d) Synthesis of Compound (I-7) Compound 32 (388 mg, 1.35 mmol) was added to methylene chloride (10 ml), 6-amino-3H-benzoxazol-2-one (203 mg, 1.35 mmol), HOBt (219 mg, 1.62 mmol), triethylamine (0.23 ml, 1.62 mmol), DMAP (8.0 mg, 0.07 mmol), EDC (311 mg, 1.62 mmol) were added, and the mixture was stirred at room temperature for 19 hours. Saturated aqueous sodium hydrogen carbonate was added, and the precipitated solid was collected by filtration, washed with water, and dried to obtain 105 mg of a solid. The filtrate was extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetonitrile-chloroform) and recrystallized from acetone-isopropanol. 121 mg of solid was obtained. The obtained solids were combined, purified by silica gel column chromatography (chloroform-methanol), and further recrystallized from ethyl acetate-methanol-isopropanol to obtain compound (I-7) (153 mg, 27% yield). .
mp 245 246 ℃ (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.23-1.34 (m, 2H), 1.75 (d, J = 12.0Hz, 2H), 1.96-2.06 (m, 1H), 2.25 (d, J = 7.2Hz, 2H), 2.83 (t, J = 12.3Hz, 2H), 3.86 (d, J = 12.0Hz, 2H), 7.02 (t, J = 9.9Hz, 3H), 7.22 (dd, J = 8.7, 1.8Hz, 1H), 7.47 (d, J = 8.7Hz, 2H), 7.70 (d, J = 1.8Hz, 1H), 9.95 (s, 1H), 11.51 (s, 1H).

ａ）化合物33の合成
化合物 30（376 mg, 1.2 mmol）をメタノール（10 ml）に溶解し、水酸化リチウム（252 mg, 6.0 mmol）、水（1 ml）を加え室温で85分間、65℃で45分間撹拌した。溶媒を減圧留去し、残渣に水、2 mol/L塩酸を加え酸性とし、析出した結晶をろ取した。水洗後、乾燥して得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物 33（286 mg, 収率84%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：2.36 (br, 1H), 3.14 (s, 2H), 3.49 (t, J = 5.7Hz, 2H), 3.86 (br, 1H), 5.73 and 5.79 (s, 1H), 6.90 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
ｂ）化合物（Ｉ−１６）の合成
化合物 33（280 mg, 0.98 mmol)に塩化メチレン（10 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（147 mg, 0.98 mmol)、ＨＯＢｔ（159 mg, 1.18 mmol)、トリエチルアミン（0.16 ml, 1.18mmol)、ＤＭＡＰ（6.0 mg， 0.05 mmol)、ＥＤＣ（226 mg, 1.18 mmol)を加え、室温で4日間撹拌した。析出した固体をろ取し、塩化メチレンで洗浄後、乾燥して338 mgの固体を得た。また、ろ液を減圧濃縮し、残渣に飽和重曹水、ジエチルエーテルを加え、固体をろ取した。水、ジエチルエーテルで洗浄後、乾燥して35 mgの固体を得た。得られた固体を合わせ、シリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、さらに酢酸エチル−メタノールで再結晶して化合物（Ｉ−１６）（225 mg, 収率55%)を得た。
mp 203 205℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：2.26 (br, 2H), 3.09 (s, 2H), 3.47 (t, J = 5.7Hz, 2H), 3.78 (br, 2H), 5.69 (s, 1H), 7.02 (d, J = 8.1Hz, 1H), 7.03 (d, J = 8.7Hz, 2H), 7.23 (dd, J = 8.4, 1.8Hz, 1H), 7.49 (d, J = 8.7Hz, 2H), 7.69 (d, J = 1.5Hz, 1H), 10.06 (s, 1H), 11.53 (s, 1H). Synthesis of Compound (I-16)

a) Synthesis of Compound 33 Compound 30 (376 mg, 1.2 mmol) was dissolved in methanol (10 ml), and lithium hydroxide (252 mg, 6.0 mmol) and water (1 ml) were added. For 45 minutes. The solvent was distilled off under reduced pressure, water and 2 mol / L hydrochloric acid were added to the residue to make it acidic, and the precipitated crystals were collected by filtration. The solid obtained by washing with water and drying was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 33 (286 mg, 84% yield).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 2.36 (br, 1H), 3.14 (s, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.86 (br, 1H), 5.73 and 5.79 (s , 1H), 6.90 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
b) Synthesis of Compound (I-16) Compound 33 (280 mg, 0.98 mmol) was added to methylene chloride (10 ml), 6-amino-3H-benzoxazol-2-one (147 mg, 0.98 mmol), HOBt (159 mg, 1.18 mmol), triethylamine (0.16 ml, 1.18 mmol), DMAP (6.0 mg, 0.05 mmol), EDC (226 mg, 1.18 mmol) were added, and the mixture was stirred at room temperature for 4 days. The precipitated solid was collected by filtration, washed with methylene chloride, and dried to obtain 338 mg of a solid. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and diethyl ether were added to the residue, and the solid was collected by filtration. After washing with water and diethyl ether, it was dried to obtain 35 mg of a solid. The obtained solids were combined, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from ethyl acetate-methanol to obtain compound (I-16) (225 mg, yield 55%).
mp 203 205 ℃ (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.26 (br, 2H), 3.09 (s, 2H), 3.47 (t, J = 5.7Hz, 2H), 3.78 (br, 2H), 5.69 (s , 1H), 7.02 (d, J = 8.1Hz, 1H), 7.03 (d, J = 8.7Hz, 2H), 7.23 (dd, J = 8.4, 1.8Hz, 1H), 7.49 (d, J = 8.7Hz , 2H), 7.69 (d, J = 1.5Hz, 1H), 10.06 (s, 1H), 11.53 (s, 1H).

ａ）化合物34の合成
参考例１１で得られた化合物 19（2.35 g, 7.80 mmol）をメタノール（24 ml）に溶解し、2 mol/L水酸化ナトリウム水溶液（7.8 ml, 15.6 mmol）を加え30分間還流した。溶媒を減圧留去し、残渣に2 mol/L塩酸を加え酸性とし、析出した結晶をろ取した。水洗後、乾燥して化合物 34（2.06 g, 収率97%）を得た。
mp 206 208℃ (decompose)
ｂ）化合物（Ｉ−１８）の合成
化合物 34（273 mg, 1.0 mmol)にＤＭＦ（5 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（150 mg, 1.0 mmol)、ＨＯＢｔ（162 mg, 1.2 mmol)、トリエチルアミン（0.17 ml, 1.2mmol)、ＤＭＡＰ（12.0 mg， 0.1 mmol)、ＥＤＣ（230 mg, 1.2 mmol)を加え、室温で41時間撹拌した。溶媒を減圧留去し、残渣に飽和重曹水、水を加え固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム−アセトン）により精製し、さらにアセトン−メタノールで再結晶して化合物（Ｉ−１８）（341 mg, 収率84%)を得た。
mp 302 304℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：1.63-1.77 (m, 2H), 1.87 (d, J = 10.2Hz, 2H), 2.53-2.61 (m, 1H), 2.87 (t, J = 9.9Hz, 2H), 3.95 (d, J = 13.2Hz, 2H), 7.01 (d, J = 8.4Hz, 1H), 7.08 (d, J = 8.7Hz, 2H), 7.25 (dd, J = 8.7, 2.1Hz, 1H), 7.49 (d, J = 8.7Hz, 2H), 7.70 (d, J = 2.1Hz, 1H), 9.99 (s, 1H), 11.50 (s, 1H). Synthesis of Compound (I-18)

a) Synthesis of Compound 34 Compound 19 (2.35 g, 7.80 mmol) obtained in Reference Example 11 was dissolved in methanol (24 ml), and 2 mol / L aqueous sodium hydroxide solution (7.8 ml, 15.6 mmol) was added. Refluxed for minutes. The solvent was distilled off under reduced pressure, 2 mol / L hydrochloric acid was added to the residue to make it acidic, and the precipitated crystals were collected by filtration. After washing with water and drying, compound 34 (2.06 g, yield 97%) was obtained.
mp 206 208 ℃ (decompose)
b) Synthesis of Compound (I-18) Compound 34 (273 mg, 1.0 mmol) was added to DMF (5 ml), 6-amino-3H-benzoxazol-2-one (150 mg, 1.0 mmol), HOBt (162 mg). , 1.2 mmol), triethylamine (0.17 ml, 1.2 mmol), DMAP (12.0 mg, 0.1 mmol), EDC (230 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 41 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate and water were added to the residue, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform-acetone), and recrystallized from acetone-methanol to obtain compound (I-18) (341 mg, yield 84%).
mp 302 304 ° C (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 1.63-1.77 (m, 2H), 1.87 (d, J = 10.2Hz, 2H), 2.53-2.61 (m, 1H), 2.87 (t, J = 9.9Hz, 2H), 3.95 (d, J = 13.2Hz, 2H), 7.01 (d, J = 8.4Hz, 1H), 7.08 (d, J = 8.7Hz, 2H), 7.25 (dd, J = 8.7, 2.1Hz, 1H), 7.49 (d, J = 8.7Hz, 2H), 7.70 (d, J = 2.1Hz, 1H), 9.99 (s, 1H), 11.50 (s, 1H).

ａ）化合物35の合成
参考例４で得られた化合物 10（981 mg，4.0 mmol）をＴＨＦ（40 ml）に溶解し、フタルイミド（765 mg, 5.2 mmol)、トリフェニルホスフィン（1.36 g, 5.2 mmol)、アゾジカルボン酸ジイソプロピル（1.08 ml, 5.2 mmol)を加え、室温で16時間撹拌した。溶媒を減圧濃縮し、得られた残渣に飽和重曹水、水を加えクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、得られた残渣をメタノールで洗浄して化合物 35（1.08 g，収率72%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.77-1.86 (m, 2H), 2.55-2.72 (m, 2H), 2.86-2.99 (m, 2H), 3.89-3.99 (m, 2H), 4.27-4.40 (m, 1H), 6.96(d, J = 8.7Hz, 2H), 7.49 (d, J = 8.7Hz, 2H), 7.72 (dd, J = 3.0, 5.6Hz, 2H), 7.84 (dd, J = 3.0, 5.6 Hz, 2H).
ｂ）化合物36の合成
化合物 30（262 mg, 0.7 mmol)をエタノール（7 ml）に溶解し、ヒドラジン一水和物（0.087 ml, 1.75 mmol)を加え2時間還流した。放冷後、析出した固体をろ去し、ろ液を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（アミノカラム、クロロホルム−メタノール）により精製し、化合物 36（125 mg, 収率73%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.30 (brs, 2H), 1.38-1.53 (m, 2H), 1.87-1.98 (m, 2H), 2.82-2.94 (m, 3H), 3.71-3.81 (m, 2H), 6.92 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H).
ｃ）化合物（Ｉ−２３）の合成
化合物 37（60 mg, 0.22 mmol)をアセトニトリル（2 ml）に溶解し、トリエチルアミン（0.034 ml, 0.24 mmol)を加えた。化合物 36（49 mg, 0.20 mmol)のアセトニトリル（1 ml）溶液を加え6時間還流した。析出した結晶をろ去し、水、酢酸エチルで洗浄後、乾燥し（Ｉ−２３）（50 mg, 収率59%)を得た。
mp 294 296℃
^１H-NMR（DMSO-d₆ / TMS）δppm：1.31-1.55 (m, 2H), 1.80-2.00 (m, 2H), 2.88-3.10 (m, 2H), 3.60-3.85 (m, 3H), 6.17 (s, 1H), 6.95 (s, 2H), 7.06 (d, J = 5.4Hz, 2H), 7.48 (d, J = 6.0Hz, 2H), 7.54 (s, 1H), 8.35 (s, 1H), 11.35 (brs, 1H). Synthesis of compound (I-23)

a) Synthesis of Compound 35 Compound 10 (981 mg, 4.0 mmol) obtained in Reference Example 4 was dissolved in THF (40 ml), phthalimide (765 mg, 5.2 mmol), triphenylphosphine (1.36 g, 5.2 mmol). ) And diisopropyl azodicarboxylate (1.08 ml, 5.2 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and water were added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with methanol to obtain Compound 35 (1.08 g, yield 72%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.77-1.86 (m, 2H), 2.55-2.72 (m, 2H), 2.86-2.99 (m, 2H), 3.89-3.99 (m, 2H), 4.27- 4.40 (m, 1H), 6.96 (d, J = 8.7Hz, 2H), 7.49 (d, J = 8.7Hz, 2H), 7.72 (dd, J = 3.0, 5.6Hz, 2H), 7.84 (dd, J = 3.0, 5.6 Hz, 2H).
b) Synthesis of Compound 36 Compound 30 (262 mg, 0.7 mmol) was dissolved in ethanol (7 ml), hydrazine monohydrate (0.087 ml, 1.75 mmol) was added, and the mixture was refluxed for 2 hours. After allowing to cool, the precipitated solid was removed by filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (amino column, chloroform-methanol) to obtain Compound 36 (125 mg, yield 73%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.30 (brs, 2H), 1.38-1.53 (m, 2H), 1.87-1.98 (m, 2H), 2.82-2.94 (m, 3H), 3.71-3.81 ( m, 2H), 6.92 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H).
c) Synthesis of Compound (I-23) Compound 37 (60 mg, 0.22 mmol) was dissolved in acetonitrile (2 ml), and triethylamine (0.034 ml, 0.24 mmol) was added. A solution of compound 36 (49 mg, 0.20 mmol) in acetonitrile (1 ml) was added and refluxed for 6 hours. The precipitated crystals were filtered off, washed with water and ethyl acetate, and dried to give (I-23) (50 mg, yield 59%).
mp 294 296 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.31-1.55 (m, 2H), 1.80-2.00 (m, 2H), 2.88-3.10 (m, 2H), 3.60-3.85 (m, 3H), 6.17 (s, 1H), 6.95 (s, 2H), 7.06 (d, J = 5.4Hz, 2H), 7.48 (d, J = 6.0Hz, 2H), 7.54 (s, 1H), 8.35 (s, 1H ), 11.35 (brs, 1H).

ａ）化合物39の合成
窒素雰囲気下、化合物 15（1.18 g，4.85 mmol）、化合物 38（1.45 g, 5.09 mmol）、ＤＭＰＯ（1.80 g, 14.1 mmol）のＴＨＦ（10 ml）溶液を氷浴で冷却し、水素化ナトリウム（60% 油性, 204 mg, 5.09 mmol）のＴＨＦ（10 ml）懸濁液を滴下した。室温で3時間撹拌した後、氷水を加えジエチルエーテルで抽出した。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（クロロホルム）により精製して化合物 39（1.43 g，収率79%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.35 (t, J = 6.9Hz, 3H), 2.73 (t, J = 6.0Hz, 2H), 2.79 (t, J = 6.0Hz, 2H), 3.40-3.45 (m, 4H), 3.51 (s, 3H), 4.27 (q, J = 6.9Hz, 2H), 4.85 (s, 2H), 6.93 (d, J = 8.7Hz, 2H), 7.49 (d, J = 8.7Hz, 2H).
ｂ）化合物40の合成
化合物 39（1.43 g, 3.83 mmol）をエタノール（30 ml）に溶解し、p-トルエンスルホン酸一水和物（73 mg, 0.38 mmol)を加え15時間還流した。室温まで放冷した後、溶媒を減圧留去し、残渣に水、飽和重曹水を加えクロロホルムで抽出した。有機層を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（クロロホルム−アセトニトリル）により精製し、化合物 40（1.19 g，収率95%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.39 (t, J = 7.2Hz, 3H), 1.73-1.87 (m, 2H), 2.06 (d, J = 11.4Hz, 2H), 2.93-3.02 (m, 2H), 3.22-3.32 (m, 1H), 3.77-3.84 (m, 2H), 4.35 (q, J = 7.2Hz, 2H), 6.97 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
ｃ）化合物41の合成
化合物 40（329 mg, 1.0 mmol）をエタノール（10 ml）に溶解し、85％水酸化カリウム（99 mg, 1.5 mmol）、水（1 ml）を加え室温で75分間撹拌した。溶媒を減圧留去し、残渣に氷、2 mol/L塩酸（0.8 ml, 1.6 mmol）を加え酸性とし、析出した固体をろ取した。固体を水洗後、乾燥して粗製の化合物 41（261 mg, 粗収率87%）を得た。
ｄ） 化合物（Ｉ−２６）の合成
化合物 41（261 mg, 0.87 mmol)にＤＭＦ（5 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（156 mg, 1.04 mmol)、ＨＯＢｔ（140 mg, 1.04 mmol)、トリエチルアミン（0.15 ml, 1.04 mmol)、ＤＭＡＰ（11.0 mg， 0.09 mmol)、ＥＤＣ（199 mg, 1.04 mmol)を加え、室温で64時間撹拌した。溶媒を減圧留去し、残渣に飽和重曹水、水を加え固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、さらにアセトン−酢酸エチルで再結晶して化合物（Ｉ−２６）（179 mg, 収率48%)を得た。
mp 230 232℃
^１H-NMR（DMSO-d₆ / TMS）δppm：1.48-1.62 (m, 2H), 1.95 (d, J = 11.7Hz, 2H), 2.99 (t, J = 11.7Hz, 2H), 3.53-3.60 (m, 1H), 3.92 (d, J = 12.9Hz, 2H), 7.08 (d, J = 8.7Hz, 3H), 7.49 (d, J = 8.7Hz, 2H), 7.57 (dd, J = 8.7, 1.8Hz, 1H), 7.82 (d, J = 1.8Hz, 1H), 10.63 (s, 1H), 11.64 (s, 1H). Synthesis of Compound (I-26)

a) Synthesis of Compound 39 In a nitrogen atmosphere, a solution of Compound 15 (1.18 g, 4.85 mmol), Compound 38 (1.45 g, 5.09 mmol) and DMPO (1.80 g, 14.1 mmol) in THF (10 ml) was cooled in an ice bath. A suspension of sodium hydride (60% oily, 204 mg, 5.09 mmol) in THF (10 ml) was added dropwise. After stirring at room temperature for 3 hours, ice water was added and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to give compound 39 (1.43 g, yield 79% )
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.35 (t, J = 6.9Hz, 3H), 2.73 (t, J = 6.0Hz, 2H), 2.79 (t, J = 6.0Hz, 2H), 3.40- 3.45 (m, 4H), 3.51 (s, 3H), 4.27 (q, J = 6.9Hz, 2H), 4.85 (s, 2H), 6.93 (d, J = 8.7Hz, 2H), 7.49 (d, J = 8.7Hz, 2H).
b) Synthesis of Compound 40 Compound 39 (1.43 g, 3.83 mmol) was dissolved in ethanol (30 ml), p-toluenesulfonic acid monohydrate (73 mg, 0.38 mmol) was added, and the mixture was refluxed for 15 hours. After allowing to cool to room temperature, the solvent was evaporated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with chloroform. The organic layer 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 (chloroform-acetonitrile) to obtain Compound 40 (1.19 g, yield 95%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.39 (t, J = 7.2Hz, 3H), 1.73-1.87 (m, 2H), 2.06 (d, J = 11.4Hz, 2H), 2.93-3.02 (m , 2H), 3.22-3.32 (m, 1H), 3.77-3.84 (m, 2H), 4.35 (q, J = 7.2Hz, 2H), 6.97 (d, J = 8.7Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).
c) Synthesis of Compound 41 Compound 40 (329 mg, 1.0 mmol) was dissolved in ethanol (10 ml), 85% potassium hydroxide (99 mg, 1.5 mmol) and water (1 ml) were added, and the mixture was stirred at room temperature for 75 minutes. did. The solvent was distilled off under reduced pressure, and the residue was acidified with ice and 2 mol / L hydrochloric acid (0.8 ml, 1.6 mmol), and the precipitated solid was collected by filtration. The solid was washed with water and dried to give crude compound 41 (261 mg, crude yield 87%).
d) Synthesis of Compound (I-26) Compound 41 (261 mg, 0.87 mmol) was added to DMF (5 ml), 6-amino-3H-benzoxazol-2-one (156 mg, 1.04 mmol), HOBt (140 mg). , 1.04 mmol), triethylamine (0.15 ml, 1.04 mmol), DMAP (11.0 mg, 0.09 mmol) and EDC (199 mg, 1.04 mmol) were added, and the mixture was stirred at room temperature for 64 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate and water were added to the residue, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform-methanol), and further recrystallized from acetone-ethyl acetate to obtain compound (I-26) (179 mg, yield 48%).
mp 230 232 ℃
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.48-1.62 (m, 2H), 1.95 (d, J = 11.7Hz, 2H), 2.99 (t, J = 11.7Hz, 2H), 3.53-3.60 (m, 1H), 3.92 (d, J = 12.9Hz, 2H), 7.08 (d, J = 8.7Hz, 3H), 7.49 (d, J = 8.7Hz, 2H), 7.57 (dd, J = 8.7, 1.8Hz, 1H), 7.82 (d, J = 1.8Hz, 1H), 10.63 (s, 1H), 11.64 (s, 1H).

ａ）化合物42の合成
窒素雰囲気下、ジイソプロピルアミン（0.50 ml, 3.57 mmol)のＴＨＦ（5 ml）溶液をドライアイス−アセトン浴で-78℃に冷却し、これに2.67Ｍ n-ブチルリチウム−ヘキサン溶液（1.20 ml, 3.09 mmol）を滴下し、-78℃で15分間撹拌した。酢酸エチル（0.30 ml, 3.09 mmol)のＴＨＦ（2 ml）溶液を滴下し-78℃で30分間撹拌した後、参考例９で得られた化合物 16（500 mg, 2.38 mmol)のＴＨＦ（5 ml）溶液を加え、-78℃で50分間撹拌した。塩化アンモニウム（330 mg, 6.18 mmol)の水（2 ml）溶液を加え室温に昇温した後、水を加えジエチルエーテルで抽出した。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（クロロホルム−アセトニトリル）により精製して化合物 42（703 mg, 収率99%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.30 (t, J = 7.2Hz, 3H), 1.73-1.84 (m, 4H), 2.51 (s, 2H), 3.20 (t, J = 9.9Hz, 2H), 3.36 (q, J = 7.2Hz, 2H), 3.61 (s, 1H), 6.88 (d, J = 8.7Hz, 2H), 7.20 (d, J = 8.7Hz, 2H).
ｂ）化合物43の合成
化合物 42（703 mg, 2.36 mmol）をメタノール（10 ml）に溶解し、2 mol/L水酸化ナトリウム水溶液（2.4 ml, 4.8 mmol）を加え20分間還流した。酢酸（0.55 ml, 9.6 mmol）を加えた後、溶媒を減圧留去し残渣に水を加え析出した結晶をろ取した。水洗後、乾燥して化合物 43（526 mg, 収率83%）を得た。
mp 130 133℃
^１H-NMR（CDCl₃ / TMS）δppm：1.86-1.98 (m, 4H), 2.61 (s, 2H), 3.27-3.40 (m, 4H), 7.09 (d, J = 8.7Hz, 2H), 7.26 (d, J = 8.7Hz, 2H).
ｃ） 化合物（Ｉ−３４）の合成
化合物 43（270 mg, 1.0 mmol)にＤＭＦ（5 ml）、6−アミノ-3H-ベンズオキサゾール-2-オン（150 mg, 1.0 mmol)、ＨＯＢｔ（162 mg, 1.2 mmol)、ＤＭＡＰ（12.0 mg， 0.1 mmol)、ＥＤＣ（230 mg, 1.2 mmol)を加え、室温で63時間撹拌した。溶媒を減圧留去し、残渣に飽和重曹水、水を加え固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、さらにＴＨＦ−酢酸エチルで再結晶して化合物（Ｉ−３４）（314 mg, 収率78%)を得た。
mp 255 257℃ (decompose)
^１H-NMR（DMSO-d₆ / TMS）δppm：1.63-1.80 (m, 4H), 2.46 (s, 2H), 3.04-3.13 (m, 2H), 3.34-3.40 (m, 2H), 4.75 (s, 1H), 6.94 (d, J = 8.7Hz, 2H), 7.01 (d, J = 8.7Hz, 1H), 7.19 (d, J = 8.7Hz, 2H), 7.13 (dd, J = 8.7, 1.8Hz, 1H), 7.70 (d, J = 1.8Hz, 1H), 9.94 (s, 1H), 11.53 (brs, 1H). Synthesis of Compound (I-34)

a) Synthesis of Compound 42 Under a nitrogen atmosphere, a solution of diisopropylamine (0.50 ml, 3.57 mmol) in THF (5 ml) was cooled to −78 ° C. in a dry ice-acetone bath, and 2.67M n-butyllithium-hexane was added thereto. A solution (1.20 ml, 3.09 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 15 minutes. A solution of ethyl acetate (0.30 ml, 3.09 mmol) in THF (2 ml) was added dropwise and stirred at −78 ° C. for 30 minutes, and then the compound 16 (500 mg, 2.38 mmol) obtained in Reference Example 9 in THF (5 ml) was stirred. ) The solution was added and stirred at -78 ° C for 50 minutes. A solution of ammonium chloride (330 mg, 6.18 mmol) in water (2 ml) was added, the temperature was raised to room temperature, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetonitrile) to give compound 42 (703 mg, yield). 99%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 1.30 (t, J = 7.2Hz, 3H), 1.73-1.84 (m, 4H), 2.51 (s, 2H), 3.20 (t, J = 9.9Hz, 2H ), 3.36 (q, J = 7.2Hz, 2H), 3.61 (s, 1H), 6.88 (d, J = 8.7Hz, 2H), 7.20 (d, J = 8.7Hz, 2H).
b) Synthesis of Compound 43 Compound 42 (703 mg, 2.36 mmol) was dissolved in methanol (10 ml), 2 mol / L aqueous sodium hydroxide solution (2.4 ml, 4.8 mmol) was added, and the mixture was refluxed for 20 minutes. Acetic acid (0.55 ml, 9.6 mmol) was added, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration. After washing with water and drying, Compound 43 (526 mg, yield 83%) was obtained.
mp 130 133 ℃
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.86-1.98 (m, 4H), 2.61 (s, 2H), 3.27-3.40 (m, 4H), 7.09 (d, J = 8.7Hz, 2H), 7.26 (d, J = 8.7Hz, 2H).
c) Synthesis of Compound (I-34) Compound 43 (270 mg, 1.0 mmol) was added to DMF (5 ml), 6-amino-3H-benzoxazol-2-one (150 mg, 1.0 mmol), HOBt (162 mg). , 1.2 mmol), DMAP (12.0 mg, 0.1 mmol), EDC (230 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 63 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate and water were added to the residue, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (chloroform-methanol), and further recrystallized from THF-ethyl acetate to obtain compound (I-34) (314 mg, yield 78%).
mp 255 257 ℃ (decompose)
¹ H-NMR (DMSO-d ₆ / TMS) δppm: 1.63-1.80 (m, 4H), 2.46 (s, 2H), 3.04-3.13 (m, 2H), 3.34-3.40 (m, 2H), 4.75 ( s, 1H), 6.94 (d, J = 8.7Hz, 2H), 7.01 (d, J = 8.7Hz, 1H), 7.19 (d, J = 8.7Hz, 2H), 7.13 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J = 1.8Hz, 1H), 9.94 (s, 1H), 11.53 (brs, 1H).

ａ）化合物45の合成
窒素雰囲気下、化合物 44（7.52 g，16.4 mmol）をＴＨＦ（30 ml）に溶解し、カリウムヘキサメチルジシラジド（6.90 g, 32.9 mmol）を加え室温で30分間撹拌した。化合物 15（1.00 g，4.11 mmol）のＴＨＦ（10 ml）溶液を加え、室温で3時間撹拌した。水、2 mol/L塩酸を加え、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（ヘキサン−酢酸エチル）により精製して化合物 45（0.48 g，収率34%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.26 (t, J = 7.1Hz, 3H), 2.26-2.32 (m, 2H), 2.34-2.42 (m, 6H), 3.29-3.36 (m, 4H), 4.13 (q, J = 7.1Hz, 2H), 5.20-5.26 (m, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
ｂ）化合物46の合成
化合物 45（470 mg, 1.38 mmol）をメタノール（10 ml）に溶解し、1 mol/L水酸化ナトリウム水溶液（2.1 ml, 2.1 mmol）を加え室温で4時間撹拌した。2 mol/L塩酸を加え酸性とした後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、化合物 46（426 mg，収率99%）を得た。
^１H-NMR（DMSO-d₆ / TMS）δppm：2.12-2.32 (m, 8H), 3.23-3.40 (m, 4H), 5.18-5.27 (m, 1H), 7.05 (d, J = 6.3Hz, 2H), 7.48 (d, J = 6.3Hz, 2H), 12.03 (s, 1H).
ｃ）化合物47の合成
化合物 46（420 mg, 1.34 mmol）、Ｎ−メチルモルホリン（0.15 ml, 1.34 mmol）をＴＨＦ（8 ml）に溶解し氷浴で冷却した。クロロ炭酸イソブチル（0.17 ml, 1.34 mmol）、トリエチルアミン（0.21 ml, 1.47 mmol）、Ｎ，Ｏ−ジメトキシアミン塩酸塩（131 mg, 1.34 mmol）のＤＭＦ（3 ml）溶液を順に加え0℃で30分間、室温で5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）により精製して化合物 47（427 mg，収率89%）を得た。
^１H-NMR（CDCl₃ / TMS）δppm：2.26-2.53 (m, 8H), 3.18 (s, 3H), 3.30-3.36 (m, 4H), 3.68 (s, 3H), 5.25-5.30 (m, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
ｄ）化合物48の合成
窒素雰囲気下、5-ブロモ-2-tert-ブトキシピリジン（400 mg, 1.74 mmol)をＴＨＦ（8 ml）に溶解し、ドライアイス−アセトン浴で-78℃に冷却した。2.6Ｍ n-ブチルリチウム−ヘキサン溶液（0.72 ml, 1.86 mmol）を滴下し-78℃で30分間撹拌した後、化合物 42（415 mg, 1.16 mmol）のＴＨＦ（4 ml）溶液を加え-78℃で1時間、-40℃で5時間撹拌した。飽和塩化アンモニウム水溶液、水を加え室温に昇温した後、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（クロロホルム−アセトニトリル）により精製して化合物 48（275 mg, 収率53%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.61 (s, 9H), 2.25-2.32 (m, 2H), 2.35-2.42 (m, 2H), 2.43-2.52 (m, 2H), 2.90-2.99 (m, 2H), 3.29-3.34 (m, 4H), 5.26-5.32 (m, 1H), 6.66 (d, J = 8.7Hz, 1H), 6.90 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H), 8.07 (dd, J = 2.6, 8.7Hz, 1H), 8.74 (d, J = 2.6 Hz, 1H).
ｅ）化合物（Ｉ−１９）の合成
化合物 48（120 mg, 0.27 mmol）をクロロホルム（3 ml）に溶解し、氷浴で冷却した。トリフルオロ酢酸（2 ml）を加え0℃で1.5時間撹拌した後、飽和重曹水を加えクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、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（クロロホルム−メタノール）により精製した。得られた固体をメタノール−水より再結晶して化合物（Ｉ−１９）（77 mg, 収率73%)を得た。
mp 137 139℃
^１H-NMR（DMSO-d₆ / TMS）δppm：2.19-2.22 (m, 2H), 2.22-2.39 (m, 4H), 2.78-2.92 (m, 2H), 3.20-3.47 (m, 4H), 5.18-5.30 (m, 1H), 6.36 (d, J = 9.6Hz, 1H), 7.04 (d, J = 8.8Hz, 2H), 7.47 (d, J = 8.8Hz, 2H), 7.87 (dd, J = 2.4, 9.6Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 12.12 (brs, 1H). Synthesis of Compound (I-19)

a) Synthesis of Compound 45 In a nitrogen atmosphere, Compound 44 (7.52 g, 16.4 mmol) was dissolved in THF (30 ml), potassium hexamethyldisilazide (6.90 g, 32.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. . A solution of compound 15 (1.00 g, 4.11 mmol) in THF (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water and 2 mol / L hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 45 (0.48 g, yield). 34%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.26 (t, J = 7.1 Hz, 3H), 2.26-2.32 (m, 2H), 2.34-2.42 (m, 6H), 3.29-3.36 (m, 4H) , 4.13 (q, J = 7.1Hz, 2H), 5.20-5.26 (m, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
b) Synthesis of Compound 46 Compound 45 (470 mg, 1.38 mmol) was dissolved in methanol (10 ml), 1 mol / L aqueous sodium hydroxide solution (2.1 ml, 2.1 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was acidified with 2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 46 (426 mg, yield 99%).
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.12-2.32 (m, 8H), 3.23-3.40 (m, 4H), 5.18-5.27 (m, 1H), 7.05 (d, J = 6.3 Hz, 2H), 7.48 (d, J = 6.3Hz, 2H), 12.03 (s, 1H).
c) Synthesis of Compound 47 Compound 46 (420 mg, 1.34 mmol) and N-methylmorpholine (0.15 ml, 1.34 mmol) were dissolved in THF (8 ml) and cooled in an ice bath. Add a solution of isobutyl chlorocarbonate (0.17 ml, 1.34 mmol), triethylamine (0.21 ml, 1.47 mmol), N, O-dimethoxyamine hydrochloride (131 mg, 1.34 mmol) in DMF (3 ml) in that order at 0 ° C for 30 minutes. And stirred at room temperature for 5 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 magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 47 (427 mg, yield 89 %).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 2.26-2.53 (m, 8H), 3.18 (s, 3H), 3.30-3.36 (m, 4H), 3.68 (s, 3H), 5.25-5.30 (m, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.46 (d, J = 8.7Hz, 2H).
d) Synthesis of Compound 48 5-Bromo-2-tert-butoxypyridine (400 mg, 1.74 mmol) was dissolved in THF (8 ml) under a nitrogen atmosphere and cooled to -78 ° C in a dry ice-acetone bath. A 2.6M n-butyllithium-hexane solution (0.72 ml, 1.86 mmol) was added dropwise and stirred at -78 ° C for 30 minutes, and then a solution of compound 42 (415 mg, 1.16 mmol) in THF (4 ml) was added to -78 ° C. And stirred at -40 ° C for 5 hours. A saturated aqueous ammonium chloride solution and water were added and the temperature was raised to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetonitrile) to give compound 48 (275 mg, yield). 53%).
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.61 (s, 9H), 2.25-2.32 (m, 2H), 2.35-2.42 (m, 2H), 2.43-2.52 (m, 2H), 2.90-2.99 ( m, 2H), 3.29-3.34 (m, 4H), 5.26-5.32 (m, 1H), 6.66 (d, J = 8.7Hz, 1H), 6.90 (d, J = 8.7Hz, 2H), 7.46 (d , J = 8.7Hz, 2H), 8.07 (dd, J = 2.6, 8.7Hz, 1H), 8.74 (d, J = 2.6 Hz, 1H).
e) Synthesis of Compound (I-19) Compound 48 (120 mg, 0.27 mmol) was dissolved in chloroform (3 ml) and cooled in an ice bath. Trifluoroacetic acid (2 ml) was added, and the mixture was stirred at 0 ° C. for 1.5 hr, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer 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 (chloroform-methanol). The obtained solid was recrystallized from methanol-water to obtain compound (I-19) (77 mg, yield 73%).
mp 137 139 ℃
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 2.19-2.22 (m, 2H), 2.22-2.39 (m, 4H), 2.78-2.92 (m, 2H), 3.20-3.47 (m, 4H), 5.18-5.30 (m, 1H), 6.36 (d, J = 9.6Hz, 1H), 7.04 (d, J = 8.8Hz, 2H), 7.47 (d, J = 8.8Hz, 2H), 7.87 (dd, J = 2.4, 9.6Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 12.12 (brs, 1H).

ａ）化合物50の合成
化合物 49（144 mg, 0.32 mmol）を酢酸エチル（5 ml）に溶解し、10％パラジウム−炭素（15 mg）を加え系内を水素ガスで置換し、室温で16時間撹拌した。反応液をセライトを用いてろ過し、ろ液を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物 50（88 mg, 収率61%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：1.23-1.53 (m, 5H), 1.62 (s, 9H), 1.73-1.85 (m, 4H), 2.72-2.84 (m, 2H), 2.48-2.94 (m, 2H), 3.76-3.81 (m, 2H), 6.67 (d, J = 8.7Hz, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H), 8.08 (dd, J = 2.4, 8.7Hz, 1H), 8.75 (d, J = 2.4Hz, 1H).
ｂ）化合物（Ｉ−２０）の合成
化合物 50（85 mg, 0.19 mmol）をクロロホルム（2 ml）に溶解し、氷浴で冷却した。トリフルオロ酢酸（1 ml）を加え0℃で1.5時間撹拌した後、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（クロロホルム−メタノール）により精製した。得られた固体をメタノール−水より再結晶して化合物（Ｉ−２０）（61 mg, 収率82%)を得た。
mp 171 173℃
^１H-NMR（DMSO-d₆ / TMS）δppm：1.08-1.31 (m, 4H), 1.38-1.51 (m, 1H), 1.52-1.65 (m, 2H), 1.65-1.80 (m, 2H), 2.68-2.87 (m, 4H), 3.72-3.90 (m, 2H), 6.37 (d, J = 7.2Hz, 1H), 7.02 (d, J = 6.6Hz, 2H), 7.46 (d, J = 6.6Hz, 2H), 7.87 (dd, J = 1.8, 7.2Hz, 1H), 8.25 (d, J = 1.8Hz, 1H), 12.11 (brs, 1H). Synthesis of Compound (I-20)

a) Synthesis of Compound 50 Compound 49 (144 mg, 0.32 mmol) was dissolved in ethyl acetate (5 ml), 10% palladium-carbon (15 mg) was added, the inside of the system was replaced with hydrogen gas, and 16 hours at room temperature. Stir. The reaction solution was filtered using Celite, and the residue obtained by distilling the filtrate under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 50 (88 mg, 61% yield). It was.
¹ H-NMR (CDCl ₃ / TMS) δ ppm: 1.23-1.53 (m, 5H), 1.62 (s, 9H), 1.73-1.85 (m, 4H), 2.72-2.84 (m, 2H), 2.48-2.94 ( m, 2H), 3.76-3.81 (m, 2H), 6.67 (d, J = 8.7Hz, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8.7Hz, 2H), 8.08 (dd, J = 2.4, 8.7Hz, 1H), 8.75 (d, J = 2.4Hz, 1H).
b) Synthesis of Compound (I-20) Compound 50 (85 mg, 0.19 mmol) was dissolved in chloroform (2 ml) and cooled in an ice bath. Trifluoroacetic acid (1 ml) was added, and the mixture was stirred at 0 ° C. for 1.5 hr, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol). The obtained solid was recrystallized from methanol-water to obtain compound (I-20) (61 mg, yield 82%).
mp 171 173 ° C
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 1.08-1.31 (m, 4H), 1.38-1.51 (m, 1H), 1.52-1.65 (m, 2H), 1.65-1.80 (m, 2H), 2.68-2.87 (m, 4H), 3.72-3.90 (m, 2H), 6.37 (d, J = 7.2Hz, 1H), 7.02 (d, J = 6.6Hz, 2H), 7.46 (d, J = 6.6Hz , 2H), 7.87 (dd, J = 1.8, 7.2Hz, 1H), 8.25 (d, J = 1.8Hz, 1H), 12.11 (brs, 1H).

ａ）化合物52の合成
1-(4-クロロフェニル)ピペラジン塩酸塩 51（2.33 g, 10.0 mmol)を塩化メチレン（20 ml）に溶解し、2 mol/L水酸化ナトリウム水溶液（13.0 ml, 26.0 mmol）を加え氷浴で冷却した。塩化クロロアセチル（1.47 g, 13.0 mmol）の塩化メチレン（5 ml）溶液を加え、0℃で1時間撹拌した後、2 mol/L塩酸（7.0 ml, 14.0 mmol）を加え酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣を酢酸エチル−ヘキサンより再結晶して化合物 52（2.26 g, 収率83%)を得た。
^１H-NMR（CDCl₃ / TMS）δppm：3.15 (t, J = 5.2Hz, 2H), 3.20 (t, J = 5.2Hz, 2H), 3.68 (t, J = 5.2Hz, 2H), 3.78 (t, J = 5.2Hz, 2H), 4.11 (s, 2H), 6.85 (d, J = 9.1Hz, 2H), 7.23 (d, J = 9.1Hz, 2H).
ｂ）化合物（I-２４４）の合成
化合物 52（546 mg, 2.0 mmol)、6−アミノ-3H-ベンズオキサゾール-2-オン（300 mg, 2.0 mmol)をＤＭＦ（10 ml）に溶解し、80℃で1時間、100℃で4時間撹拌した。溶媒を減圧留去し、残渣に飽和重曹水を加え酢酸エチル−ＴＨＦ（1:1）混液で抽出した。有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製した。アモルファス状物質をメタノールを用いて結晶化させ、ろ取、ジエチルエーテルで洗浄、乾燥して化合物 （I-２４４）（135 mg, 収率17%)を得た。
mp 211 213℃
^１H-NMR（DMSO-d₆ / TMS）δppm：3.11-3.23 (m, 4H), 3.58-3.68 (m, 4H), 3.93 (d, J = 5.1Hz, 2H), 5.56 (t, J = 5.1Hz, 1H), 6.48 (dd, J = 2.0, 8.6Hz, 1H), 6.70 (d, J = 2.0Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 6.98 (d, J = 9.1Hz, 2H), 7.26 (d, J = 9.1Hz, 2H), 11.12 (brs, 1H).
以下、同様にしてその他の化合物（Ｉ）を合成した。以下に構造式および物理恒数を示す。 Synthesis of Compound (I-21)

a) Synthesis of Compound 52
Dissolve 1- (4-chlorophenyl) piperazine hydrochloride 51 (2.33 g, 10.0 mmol) in methylene chloride (20 ml), add 2 mol / L aqueous sodium hydroxide solution (13.0 ml, 26.0 mmol), and cool in an ice bath. did. A solution of chloroacetyl chloride (1.47 g, 13.0 mmol) in methylene chloride (5 ml) was added and stirred at 0 ° C. for 1 hour, 2 mol / L hydrochloric acid (7.0 ml, 14.0 mmol) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain Compound 52 (2.26 g, yield 83%).
¹ H-NMR (CDCl ₃ / TMS) δppm: 3.15 (t, J = 5.2Hz, 2H), 3.20 (t, J = 5.2Hz, 2H), 3.68 (t, J = 5.2Hz, 2H), 3.78 ( t, J = 5.2Hz, 2H), 4.11 (s, 2H), 6.85 (d, J = 9.1Hz, 2H), 7.23 (d, J = 9.1Hz, 2H).
b) Synthesis of Compound (I-244) Compound 52 (546 mg, 2.0 mmol), 6-amino-3H-benzoxazol-2-one (300 mg, 2.0 mmol) was dissolved in DMF (10 ml), and 80 The mixture was stirred at ° C for 1 hour and at 100 ° C for 4 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with a mixed solution of ethyl acetate-THF (1: 1). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol). The amorphous substance was crystallized from methanol, collected by filtration, washed with diethyl ether, and dried to obtain Compound (I-244) (135 mg, yield 17%).
mp 211 213 ℃
¹ H-NMR (DMSO-d ₆ / TMS) δ ppm: 3.11-3.23 (m, 4H), 3.58-3.68 (m, 4H), 3.93 (d, J = 5.1 Hz, 2H), 5.56 (t, J = 5.1Hz, 1H), 6.48 (dd, J = 2.0, 8.6Hz, 1H), 6.70 (d, J = 2.0Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 6.98 (d, J = 9.1Hz, 2H), 7.26 (d, J = 9.1Hz, 2H), 11.12 (brs, 1H).
Thereafter, other compounds (I) were synthesized in the same manner. The structural formula and physical constant are shown below.

Test Example 1 Analgesic Action by Mouse Formalin Test Pain behavior of mice by formalin is divided into two phases over time, and mice exhibit pain behaviors called licking and biting behavior. In the first phase, acute pain develops in 5 minutes immediately after formalin administration, and in the second phase, inflammatory pain develops in 20 minutes from 10 to 30 minutes after administration. In the experiment, ddY male mice (5 weeks old) were used. Formalin (2%) solution was administered subcutaneously to the right hind limb of mice. A test compound having an NMDA receptor antagonistic activity (Compound No.) was dissolved in a 0.5% methylcellulose solution, and was orally administered at a different concentration (50 mg / kg or 30 mg / kg) 60 minutes before formalin administration. Pain behavior time was measured for 30 minutes after formalin administration. When the test compound shows an analgesic effect, pain behavior time is shortened. The analgesic rate (%) was calculated by substituting the measurement time into the following equation. The analgesic rate (%) in the first phase and the second phase of the test compound is shown in Table (No.).
Analgesic rate (%) = (1-pain behavior time in the presence of test compound / pain behavior time in the absence of test compound) × 100

(50)は、50mg/kgを示す。
以上の結果から、本発明に使用する化合物は第１相において２５％以上の鎮痛率、第2相において４５％以上の鎮痛率を示たため、本発明に使用する化合物は鎮痛効果を示すことが明らかとなった。
なお、被検化合物ＮＭＤＡ受容体（ＮＲ１／ＮＲ２Ｂ受容体）に対する拮抗作用は以下の方法で測定した。
リガンドにＮＲ１／ＮＲ２Ｂサブタイプ受容体特異的な拮抗薬であるIfenprodilを用いて被検化合物との受容体競合実験を実施した。
動物は雄性、Slc:Wistarラットを用い、断頭後脳を摘出し大脳皮質を分画した。
大脳皮質を２０倍量の氷冷50ｍM Tris・HCl緩衝液(pH 7.4)でホモジナイズし、４℃、27,500×gで１０分間遠心分離した。得られた沈殿を同緩衝液で懸濁後、再度遠心分離した。この操作を3回繰り返し、得られた沈殿を緩衝液で懸濁後、−８０℃で保存した。実験直前に、室温で融解後４℃、27,500×gで１０分間遠心分離し、得られた沈殿を緩衝液で懸濁した。さらに緩衝液で10倍に希釈し、これを膜標品として実験に用いた。
結合実験は、470μlの上記膜標品に10μlの異なる濃度の被検化合物、10μlの標識リガンド[³H]-Ifenprodilおよび10μlのGBR-12909を加え、氷温で120分間インキュベーションした。標識リガンドの[³H]-Ifenprodilの濃度は最終５nMとし、GBR-12909の濃度は最終3μMとした。全結合量の測定には溶媒であるDMSOを用い、非特異的結合量の測定には100μMのIfenprodilを使用した。なお、GBR-12909は、[³H]-Ifenprodilの non-polyamine-sensitive siteに対する結合をブロックする為に添加した。インキュベーション後、Whatman GF/C濾紙（Whatman社製）を用いて結合体とフリー体を分離し、2.5mlの氷冷緩衝液で濾紙を４回洗浄した。濾紙をバイアル瓶中で液体シンチレーション（クリアゾルI、ナカライテスク社製）に浸し、液体シンチレーションカウンターで放射活性（dpm）を測定した。測定値より結合阻害率(%)を下式によって求め、結合を５０％抑制する用量（IC₅₀）を算出した。 GBR-12909（バノキセリン）の式を以下に示す。

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

(50) indicates 50 mg / kg.
From the above results, the compound used in the present invention showed an analgesic rate of 25% or more in the first phase and an analgesic rate of 45% or more in the second phase. Therefore, the compound used in the present invention shows an analgesic effect. It became clear.
In addition, the antagonistic action with respect to the test compound NMDA receptor (NR1 / NR2B receptor) was measured by the following method.
A receptor competition experiment with a test compound was conducted using Ifenprodil, which is an NR1 / NR2B subtype receptor-specific antagonist, as a ligand.
The animals were male, Slc: Wistar rats. After decapitation, the brain was 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, centrifuged at 27,500 × g for 10 minutes at 4 ° C., 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. 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

  The compound contained in the analgesic of the present invention exhibits strong binding to the NR1 / NR2B subtype receptor, and is useful as an analgesic with few side effects on motor function (sensory abnormality), psychiatric symptoms (schizophrenia) and the like.

Claims (11)

Formula (I):

(Where
Z is N or CR ¹
A ¹ is a nitrogen-containing aromatic monocyclic group which may have a substituent or a nitrogen-containing aromatic condensed cyclic group which may have a substituent,
The nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group has the following conditions:
i) having at least one group selected from optionally protected hydroxy, optionally protected amino and optionally substituted aminooxy, or
ii) satisfying at least one of -NH- in the ring,
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 and R ² are each independently hydrogen, hydroxy or lower alkyl, and R ¹ and R ² may be combined to form a single bond;
R ^a , R ^b , R ^c and R ^d are each independently hydrogen or lower alkyl, and when a plurality of R ^a , a plurality of R ^b , a plurality of R ^c or a plurality of R ^d are present, May be different,
w is 2 or 3, t is 1 or 2,
X is ^{- (CR 3 R 4) m-} ,
^{-CONR 5 (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) 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-,
^{- (CR 3 R 4) mC} (= N-OR 7) -,
^{-CH (OR 8) (CR 3} R 4) n-,
^{- (CR 3 R 4) mCH} (OR 8) -,
^{-NR 5 COCO (CR 3 R 4} ) n-,
^{- (CR 3 R 4) mNR} 5 COCO-,
^{-COCONR 5 (CR 3 R 4)} n-,
^{-NR 5 COCH (OR 8) (} CR 3 R 4) n-,
^{-CH (OR 8) (CR 3} R 4) nNR 5 CO-,
^{-NR 5 (CR 3 R 4)} mCO-,
^{-A 3 - (CR 3 R 4} ) n-,
^{- (CR 3 R 4) m} -A 3 -,
^{-A 3 -CR 10 = CR 11 (} CR 3 R 4) n-,
^{-CR 10 = CR 11 (CR 3} R 4) n-A 3 -,
^{-A 3 -NR 6 (CR 3 R} 4) n-,
^{- (CR 3 R 4) nNR} 6 -A 3 - or ^{-NR 6 (CR 3 R 4)} m-A 3 - and is,
When Z is CR ¹ -CONR ⁵ (CR ³ R ⁴ ) m -NR ^6- ,
-(CR ³ R ⁴ ) mCONR ^5- ,
^{- (CR 3 R 4) mNR} 5 CONR 6 -,
^{-CO (CR 3 R 4) mNR} 5 -,
-A ^3- (CR ³ R ⁴ ) mNR ^6-
m is an integer of 1 to 4, n and r are integers of 0 to 4,
A ³ is an aromatic hydrocarbon cyclic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent A formula group,
R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl or optionally substituted lower alkoxy, and each of R ³ and R ⁴ is a plurality of If there are any, they may be different,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen or lower alkyl;
When m or n is 1 or more, R ¹ may form a single bond together with R ³ on CR ³ R ⁴ adjacent to the carbon atom to which R ¹ is bonded.
Or a pharmaceutically acceptable salt thereof or a solvate thereof. The analgesic according to claim 1, wherein w is 2 or 3, and t is 1. X is ^{- (CR 3 R 4) m} -, - CONR 5 (CR 3 R 4) n -, - (CR 3 R 4) mCONR 5 -, - NR 5 CONR 6 (CR 3 R 4) n -, - ^{C (= n-OR 7)} (CR 3 R 4) n -, - CH (OR 8) (CR 3 R 4) n -, - NR 5 COCO (CR 3 R 4) n -, - NR 5 COCH ( ^{OR 8) (CR 3 R 4} ) n -, - A 3 - (CR 3 R 4) n -, - A 3 -CR 10 = CR 11 (CR 3 R 4) n -, - NR 5 (CR 3 R ⁴⁾ MCO-or ^{-A 3 - (CR 3 R 4} ) nNR 6 - a is, claim 1 or 2 analgesics according. 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 atom other than -NH- may be substituted. The analgesic according to any one of claims 1 to 3, which is an indolyl which may be used. A ¹ is

The analgesic in any one of Claims 1-3 which is group shown by these. X is ^{-CONH (CHR 3) n -,} - NHCONH (CHR 3) n- or -NHCOCO ^(CHR 3) is a n-, analgesic agent according to any one of claims 1 to 5. X is —CO (CHR ³ ) ₂ —, —CONHCHR ³ —, —CONH (CHR ³ ) ₂ —, —NHCOCHR ³ —, —NHCO (CHR ³ ) ₂ —, —NHCONH—, —NHCOCO— or —NHCH ₂ The analgesic according to any one of claims 1 to 5, which is CO-. When Z is CR ¹ and R ¹ and R ² are each independently hydrogen or hydroxy, R ¹ and R ² together form a single bond, or m or n is 1 or more, R ¹ forms a single bond together with R ³ on CR ³ R ⁴ and the adjacent carbon atom to which R ¹ is attached, analgesic agent according to any one of claims 1 to 7. The analgesic according to any one of claims 1 to 7, wherein Z is N. A ² are each halogen, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy and one or more phenyl or pyridyl optionally substituted by a group selected from halogeno-lower alkoxy, any of claims 1 to 9 The analgesic according to crab. The analgesic according to any one of claims 1 to 10, wherein A ² is para-substituted phenyl, meta, para-disubstituted phenyl or meta-, para-tri-substituted phenyl.