JP2002255799A - Pharmaceutical composition containing cyclobutene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition having excellent lipid lowering actions and suppressing effects on arteriosclerosis progression. SOLUTION: This pharmaceutical composition is designed to separately administer an HMG-CoA reductase inhibitor and a cyclobutene derivative having formula (I) [wherein, R<1> and R<2> are each an aryl, or the like; R<3> and R<4> are each hydrogen atom, or the like; A is a group having formula (A-1) (wherein R<5> is hydrogen atom, or the like; R<6> is an amine residue, or the like; X and Y are each oxygen atom, or the like; and Z is a single bond, or the like); G is an alkylene group, or the like; D is carbon atom and E is a group having N-O when the broken line is a double bond; and D is a group having CH, or the like, and E is a group having NH, or the like, when the broken line is a single bond], a pharmacologically acceptable salt thereof, an ester thereof or other derivatives, simultaneously or at a time interval.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 3-hydroxy-
3-Methylglutaryl-CoA (hereinafter abbreviated as HMG-CoA) reductase inhibitor, cyclobutene derivative having ileal-type bile acid transporter inhibitory activity, pharmacologically acceptable salt, ester or other derivative thereof A pharmaceutical composition for simultaneous or separate administration at a time or separately; and It relates to the above pharmaceutical composition.

[0002]

[Prior Art] With the westernization of the diet and the aging of the population, etc.,
Atherosclerosis is on the rise. Atherosclerosis is a major cause of acute coronary syndrome (myocardial infarction, unstable angina, sudden ischemic death), cerebral infarction, intracerebral hemorrhage, etc., and effective prevention and treatment methods are required. I have. Risk factors for atherosclerosis include hyperlipidemia (particularly hypercholesterolemia), hypertension, and abnormal glucose metabolism based on insulin resistance. In addition, these risk factors often develop as complications (syndrome X), and it is considered that their etiologies are intertwined with each other. Diabitis, Vol. 37, No. 1595 (1988) [ Diabetes ,
37 , 1595 (1988)].

[0003] For example, WO 98/40375 discloses that a pharmaceutical composition containing two inhibitors, an HMG-CoA reductase inhibitor and an ileal bile acid transporter inhibitor, is used to administer hyperlipidemia and arterial disease. It is described as being useful as a prophylactic or therapeutic agent for sclerosis.

[0004] However, the invention of this publication discloses HMG-
Despite being a pharmaceutical composition containing two types of a CoA reductase inhibitor and an ileal bile acid transporter inhibitor, the description does not show that only the ileal bile acid transporter inhibitor is administered. Only pharmacological data is described, and no pharmacological data is described at all when two types of HMG-CoA reductase inhibitor and ileal bile acid transporter inhibitor are administered in combination. Therefore, the pharmacological effects of using two agents, an HMG-CoA reductase inhibitor and an ileal bile acid transporter inhibitor, are completely unknown from the description in this publication.

Further, the only pharmacological data described in this publication, and the ileal bile acid transporter inhibitor whose structure is specifically described is a compound having a benzothiazepine skeleton. Ileal bile acid transporter inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, is a cyclobutene derivative having the general formula (I) and is completely different in structure from the benzothiazepine skeleton described in this publication .

Further, in the present invention, a synergistic effect has been confirmed by using two kinds of HMG-CoA reductase inhibitors and cyclobutene derivatives having a specific skeleton.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on a pharmaceutical composition containing an ileal bile acid transporter inhibitor and an HMG-CoA reductase inhibitor. The present invention has been found to be useful as a preventive or therapeutic agent for hyperlipidemia, arteriosclerosis or xanthoma by using a cyclobutene derivative having a porter inhibitory action in combination with an HMG-CoA reductase inhibitor. Was completed.

Accordingly, an object of the present invention is to provide HMG-CoA
Pharmaceutical compositions (preferably hyperlipidemia, arteriosclerosis, or A pharmaceutical composition for the prevention or treatment of tumors.

[0009]

The active ingredient of the pharmaceutical composition of the present invention is a cyclobutene derivative having the following general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, and HMG-CoA. It is a reductase inhibitor.

[0010]

Embedded image

In the above formula, R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1 to 5 groups selected from substituent groups a and b, substituent groups a and an aryl group substituted by 1 to 5 groups with a group selected from b or a heterocyclic group substituted by 1 to 5 groups with a group selected from a substituent group a and b, R ² is a cycloalkyl group, Aryl group, heterocyclic group, cycloalkyl group substituted by 1 to 3 groups selected from substituent group a, aryl group substituted by 1 to 3 groups selected from substituent group a or substituent A heterocyclic group substituted by 1 to 3 groups selected from group a, R ³ and R ⁴ are the same or different and each represent a hydrogen atom or a group selected from substituent group a,
A is the formula (A-1)

[0012]

Embedded image

(Wherein, R ⁵ represents a hydrogen atom, a hydroxy group or a lower alkyl group, R ⁶ represents a hydroxy group, a lower alkoxy group, a lower alkylthio group or an amine residue, and X and Y are the same. or different and each represents an oxygen atom or a sulfur atom, Z is a group having a.) which represents a single bond or a C ₁ -C ₆ alkylene group, G represents a single bond, C ₁ -C ₆
An alkylene group or a substituted C ₁ -C ₆ alkylene group (the substituent is a group selected from a hydroxy group, an oxo group, a cycloalkyl group, an aryl group, a heterocyclic group, and a substituent group a and b; 5-substituted cycloalkyl group, 1 to 5 substituted aryl groups with a group selected from substituent groups a and b, or 1 to 5 substituted with a group selected from substituent groups a and b Is a heterocyclic group which has been obtained).
When the dashed line indicates a double bond, D indicates a carbon atom;
E represents a group having ＮN—O—, and when the broken line represents a single bond, D represents a group having CH or a nitrogen atom;
E is an oxygen atom, a sulfur atom, a group having -NH- or-
Represents a group having CO—, and the substituent group a includes a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono-lower alkylamino group, and a di-lower group. An alkylamino group, a group consisting of a cyano group and a nitro group, and a substituent group b is a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a cycloalkyl group, A group consisting of an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and a cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio group substituted by 1 to 3 groups selected from the substituent group a Is shown.

In the above formula, “cycloalkyl group” in the definition of R ¹ , R ² , G and substituent group b, “cycloalkyl group substituted by 1 to 3 groups selected from substituent group a” And the cycloalkyl moiety of the "cycloalkyl group substituted by 1 to 5 groups selected from substituent groups a and b" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl or indanyl 3 carbon atoms like a group
It is from 10 to 10 saturated carbocyclic groups, and may be condensed with another cyclic group such as a benzene ring. Such cycloalkyl groups, preferably a C ₅ -C ₆ cycloalkyl group, and most preferably a cyclohexyl group.

In the above formula, "aryl group" in the definition of R ¹ , R ² , G and substituent group b, "aryl group substituted by 1 to 3 groups selected from substituent group a", and "aryl group" The aryl part of the “aryl group substituted with 1 to 5 groups selected from the substituent groups a and b” is, for example, 6 to 10 carbon atoms such as a phenyl, indenyl, 1-naphthyl or 2-naphthyl group. And is preferably a phenyl or naphthyl group, and most preferably a phenyl group.

In the above formula, "heterocyclic group", "heterocyclic group substituted by 1 to 3 groups selected from substituent group a", and "substituent group" in the definition of R ¹ , R ² and G The heterocyclic moiety of the "heterocyclic group substituted by 1 to 5 groups selected from a and b" is a group in which a sulfur atom, an oxygen atom and / or a nitrogen atom is 1
And represents a 5- to 7-membered heterocyclic group containing from 3 to 3, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,
Aromatic heterocyclic groups such as triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl or piperazinyl such as piperazinyl A partially or completely reduced heterocyclic group corresponding to the group can be mentioned. Further, the heterocyclic group may be condensed with another cyclic group such as a benzene ring, for example, benzothienyl, benzothiazolyl, benzoxazolyl,
Isobenzofuranyl, chromenil, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl or isoindolinyl groups Can be mentioned. In such a heterocyclic group, a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring is preferable, and a thienyl group, a furyl group, Pyrrolyl group, thiazolyl group, oxazolyl group, imidazolyl group, condensed with a pyridyl group or a benzene ring, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group, more preferably thienyl or pyridyl group, Most preferably, it is a 2-thienyl or 4-pyridyl group.

In the above formula, the “lower alkyl group” in the definition of R ⁵ and the substituent group a is, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
A linear or branched alkyl group having 1 to 6 carbon atoms, such as a 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group; And more preferably a C ₁ -C ₂ alkyl group, and most preferably a methyl group.

In the above formula, the “lower alkoxy group” in the definition of R ⁶ and the substituent group a is the above “lower alkyl group”
Represents a group bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy,
Isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy , 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy, a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably C _1- It is a C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group, and most preferably a methoxy group.

In the above formula, R⁶And the definition of the substituent group a
The “lower alkylthio group” described above is
`` Group '' indicates a group bonded to a sulfur atom, for example, methylthio
E, ethylthio, propylthio, isopropylthio, bu
Tylthio, isobutylthio, s-butylthio, t-butyl
Luthio, pentylthio, isopentylthio, 2-methyl
Butylthio, neopentylthio, hexylthio, 4-methyl
Tylpentylthio, 3-methylpentylthio, 2-methyl
Rupentylthio, 3,3-dimethylbutylthio, 2,2
-Dimethylbutylthio, 1,1-dimethylbutylthio,
1,2-dimethylbutylthio, 1,3-dimethylbutyl
Carbon number such as thio or 2,3-dimethylbutylthio group
1 to 6 linear or branched alkylthio groups, preferably
Suitably, C ₁-C_FourAlkylthio group, more preferably
Is C₁-C_TwoAlkylthio group, most preferably
It is a tylthio group.

In the above formula, the term “amine residue” in the definition of R ⁶ represents an unsubstituted or substituted amino group or a heterocycle containing a nitrogen atom. Group; hydroxyamino group; methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino , 1-ethylpropylamino, hexylamino,
Isohexylamino, 4-methylpentylamino, 3-
Methylpentylamino, 2-methylpentylamino, 1
-Methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3
A "mono-lower alkylamino group" wherein one of the above "lower alkyl groups" such as -dimethylbutylamino, 2,3-dimethylbutylamino or 2-ethylbutylamino group is bonded to an amino group; methoxyamino, ethoxyamino , Propoxyamino, isopropoxyamino, butoxyamino, isobutoxyamino, s-butoxyamino, t-butoxyamino, pentyloxyamino, isopentyloxyamino, 2-methylbutoxyamino, neopentyloxyamino, hexyloxyamino, dimethoxy A "mono or di-lower alkoxyamino group" in which one or two "lower alkoxy groups" such as amino or diethoxyamino are bonded to one or two amino groups; dimethylamino, diethylamino, N-ethyl-N-methylamino, Propylamino, dibutylamido A "di-lower alkylamino group" wherein two such "lower alkyl groups" such as dipentylamino or dihexylamino group are bonded to an amino group; "the above-mentioned groups such as cyclopentylamino, cyclohexylamino, dicyclopentylamino or dicyclohexylamino An amino group in which one or two cycloalkyl groups are substituted; such as sulfomethylamino, 2-sulfoethylamino, 3-sulfopropylamino, 4-sulfobutylamino, 5-sulfopentylamino or 6-sulfohexylamino An amino group substituted by one or two “sulfo lower alkyl groups”; carboxymethylamino, 2-carboxyethylamino, 3-carboxypropylamino, 4-carboxybutylamino, 5-carboxypentylamino, 6-carboxyhexylamino, Methoxy Carboxymethyl methylamino, ethoxy carboxymethylamino, 2-methoxy-carboxyethylamino, 2-ethoxy-carboxyethylamino, 3-methoxy-carboxy propylamino, 3
One or two "lower alkyl groups substituted by carboxy or lower alkoxycarbonyl" such as -ethoxycarboxypropylamino, 4-methoxycarboxybutylamino, 5-methoxycarboxypentylamino or 6-methoxycarboxyhexylamino; An amino group; a saturated cyclic amino residue having a nitrogen atom in the ring such as pyrrolidino, piperidino, piperazino, N-methylpiperazino, morpholino or thiomorpholino; anilino;
An aryl or aralkylamino group in which a nitrogen atom such as benzylamino, N-methylanilino or N-methylbenzylamino may be substituted by a "lower alkyl group"; or, such as pyridylamino, N-methylpyridylamino or N-ethylpyridylamino A nitrogen atom such as a heteroarylamino group which may be substituted with a “lower alkyl group”, preferably an amino group, a hydroxyamino group, a mono-
Lower alkylamino group, di-lower alkylamino group,
The "sulfo lower alkyl group" is an amino group substituted by 1 or 2 or the "lower alkyl group substituted by carboxy or lower alkoxycarbonyl" is an amino group substituted by 1 or 2, more preferably an amino group, It is a hydroxyamino group, a mono-lower alkylamino group or a di-lower alkylamino group, most preferably an amino group or a hydroxyamino group.

In the above formula, “C ₁ ” in the definition of Z and G
-C ₆ C ₁ -C ₆ alkylene moiety of the alkylene group "and" substituted C ₁ -C ₆ alkylene group ", for example, methylene, methylmethylene, ethyl methylene, ethylene, propylene, trimethylene, 1-methylethylene, Dimethylmethylene, tetramethylene, 1-methyltrimethylene,
2-methyltrimethylene, 3-methyltrimethylene, 1
-Methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,
2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2
-Methylpentamethylene, 3-methylpentamethylene,
1 carbon atom such as 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene or 4,4-dimethyltetramethylene
From 6 to 6 linear or branched alkylene groups, and in Z, preferably a C ₁ -C ₄ alkylene group, more preferably a C ₁ -C ₂ alkylene group, most preferably Is
It is a methylene group, and in G, it is preferably a C ₁ -C ₄ alkylene group, more preferably a methylene, methylmethylene or ethylmethylene group, most preferably a methylmethylene group.

In the above formula, the "halogen atom" in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom or a chlorine atom. It is.

In the above formula, the “halogeno lower alkyl group” in the definition of the substituent group “a” represents a group in which the above “lower alkyl group” has been substituted with a halogen atom. Dichloromethyl, dibromomethyl, fluoromethyl, 2,
2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2 ,
A halogeno C ₁ -C ₆ alkyl group such as a 2-dibromoethyl group, preferably a halogeno C ₁ -C ₄ alkyl group, more preferably a halogeno C ₁ -C ₂ alkyl group; Most preferably, it is a trifluoromethyl group.

In the above formula, the “mono-lower alkylamino group” in the definition of the substituent group “a” has the same meaning as described above, and is preferably a mono-C ₁ -C ₄ alkylamino group, More preferably, it is a mono-C ₁ -C ₂ alkylamino group, most preferably a methylamino group.

In the above formula, the “di-lower alkylamino group” in the definition of the substituent group “a” has the same meaning as described above, and is preferably a di-C ₁ -C ₄ alkylamino group, More preferably, it is a di-C ₁ -C ₂ alkylamino group, most preferably a dimethylamino group.

In the above formula, the term "lower alkoxycarbonyl group" in the definition of the substituent group b indicates a group in which the above "lower alkoxy group" is bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl,
Isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2 , 2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,
A straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms such as a 1,3-dimethylbutoxycarbonyl group or a 2,3-dimethylbutoxycarbonyl group, preferably a C ₁ -C ₄ alkoxycarbonyl group; And more preferably a C ₁ -C ₂ alkoxycarbonyl group, and most preferably a methoxycarbonyl group.

In the above formula, the “mono-lower alkylcarbamoyl group” in the definition of the substituent group b represents a group in which one of the above “lower alkyl groups” is bonded to a carbamoyl group, for example, methylcarbamoyl, ethylcarbamoyl, Such as propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, 2-methylbutylcarbamoyl, neopentylcarbamoyl, 1-ethylpropylcarbamoyl or hexylcarbamoyl a a mono- -C ₁ -C ₆ alkylcarbamoyl group, preferably a mono--C ₁ -C ₄ alkylcarbamoyl group, more preferably a mono--C ₁ -C ₂ alkylcarbamoyl group, most Preferably a methylcarbamoyl group.

In the above formula, the “di-lower alkylcarbamoyl group” in the definition of the substituent group b represents a group in which two of the above “lower alkyl groups” are bonded to a carbamoyl group, for example, dimethylcarbamoyl, diethylcarbamoyl, N
Di-C ₁ -C ₆ such as -ethyl-N-methylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl or dihexylcarbamoyl group;
An alkylcarbamoyl group, preferably di-C _1-
It is a C ₄ alkylcarbamoyl group, more preferably a di-C ₁ -C ₂ alkylcarbamoyl group, and most preferably a dimethylcarbamoyl group.

In the above formula, the aryloxy moiety of the “aryloxy group” in the definition of the substituent group b and the “aryloxy group substituted by 1 to 3 groups selected from the substituent group a” is the same as the above “ An "aryl group" represents a group bonded to an oxygen atom, for example, phenoxy, 1-indenyloxy, 2-indenyloxy, 1-naphthyloxy, 2-
It is a naphthyloxy group, preferably a phenoxy group.

In the above formula, the aralkyloxy part of the “aralkyloxy group” in the definition of the substituent group b and the “aralkyloxy group substituted by 1 to 3 groups selected from the substituent group a” is benzyl, α-naphthylmethyl, β
-Naphthylmethyl, indenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-
Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl,
-Phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3
-Naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1
-Naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5
A C ₇ -C ₁₆ aralkyl group such as -phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl or 6-naphthylhexyl; And preferably a benzyloxy group.

In the above formula, the group selected from the “arylthio group” and the “substituent group a” in the definition of the substituent group b is 1
The arylthio moiety of the “substituted or three-substituted arylthio group” indicates a group in which the above “aryl group” is bonded to a sulfur atom, for example, phenylthio, 1-indenylthio, 2-
It is an indenylthio, 3-indenylthio, 1-naphthylthio or 2-naphthylthio group, preferably a phenylthio group.

In the above, specific examples of the “cycloalkyl group substituted by 1 to 3 groups selected from the substituent group a” in the definition of R ² include, for example, 2-fluorocyclopropyl, 2-chlorocyclo Propyl, 2- or 3
-Fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2
-, 3- or 4-iodocyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-ethylcyclopentyl, 2-, 3
-Or 4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl, -Methoxycyclopropyl, 2- or 3-methoxycyclopentyl, 2-,
3- or 4-methoxycyclohexyl, 2-, 3-
Or 4-ethoxycyclohexyl, 2-methylthiocyclopropyl, 2- or 3-methylthiocyclopentyl, 2-, 3- or 4-methylthiocyclohexyl, 2-, 3- or 4-ethylthiocyclohexyl, 2-aminocyclopropyl, -Or 3-aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl, 2- or 3-methylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2-dimethylamino Cyclopropyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-dimethoxycyclohexyl , 3,4-dimethoxy-cyclohexyl, 3,5-dimethoxy-cyclohexyl, 3,4,5
Trimethoxycyclohexyl, 2-nitrocyclopropyl, 2- or 3-nitrocyclopentyl or 2-,
A 3- or 4-nitro cyclohexyl, preferably, 1 to 3-substituted C ₅ -C ₆ cycloalkyl group (said substituent is a halogen atom, hydroxy, lower alkyl, halogeno-lower alkyl and lower alkoxy And more preferably a single-substituted cyclohexyl group, wherein said substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group. And most preferably a monosubstituted cyclohexyl group, wherein the substituent is a fluorine, chlorine, hydroxy, methyl, ethyl, trifluoromethyl or methoxy group.

In the above, specific examples of the “aryl group substituted by 1 to 3 groups selected from the substituent group a” in the definition of R ² include, for example, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3
-Or 4-iodophenyl, 2-, 3- or 4
-Hydroxyphenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2
-, 3- or 4-trifluoromethylphenyl, 2
-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-
Propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl,
2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3, 4-dibromophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 2,3,4-
Trifluorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trifluorophenyl, 3,4,5-
Trichlorophenyl, 2,3-dimethylphenyl, 3,
4-dimethylphenyl, 3,5-dimethylphenyl,
2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6 -Fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl,
5-methylinden-3-yl, 5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden- 2-yl, 5-fluoronaphthalen-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-yl, -Chloronaphthalen-1-yl, 5-methylnaphthalen-1-yl, 5-methoxynaphthalen-1-yl, 2-, 3- or 4-nitrophenyl, 5-nitroinden-3-yl, 5-nitroindene -2-yl or 5-nitronaphthalen-1-yl group, preferably 1 to 3 substituted aryl groups (the substituents being a halogen atom, Shi, lower alkyl, a group selected from the group consisting of halogeno lower alkyl and lower alkoxy groups.), And more preferably, one substituted aryl group (the substituent is a halogen atom, hydroxy,
It is a lower alkyl, a halogeno lower alkyl or a lower alkoxy group. ), And more preferably, a single-substituted phenyl or naphthyl group (the substituent is a halogen atom,
A hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group. ), And still more preferably, a single-substituted phenyl group, wherein the substituent is a fluorine atom, a chlorine atom, a hydroxy, methyl, ethyl, trifluoromethyl or methoxy group. Include 4-fluorophenyl, 4-chlorophenyl, 4
-Methylphenyl or 4-methoxyphenyl group.

In the above, specific examples of “heterocyclic group substituted by 1 to 3 groups selected from substituent group a” in the definition of R ² include, for example, 3-, 4- or 5-fluorofuran. -2-yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-methoxyfuran-
2-yl, 2-, 4- or 5-methoxyfuran-3
-Yl, 3-, 4- or 5-methylthiofuran-2
-Yl, 2-, 4- or 5-methylthiofuran-3
-Yl, 3-, 4- or 5-fluorothiophene-
2-yl, 3-, 4- or 5-bromothiophene-
2-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, -, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3-, 4- or 5-methylthiothiophen-2-yl, 2-, 4- or 5-methylthiothiophen-3-yl, 3- or 4-fluorothiazol-5-yl , 3- or 4-hydroxythiazol-5-yl, 3- or 4-methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophene-2- Methylphenol, 2, 4 or 5-fluoro-3-yl, 3-, 4- or 5
-Bromobenzothiophen-2-yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 3-, 4
-Or 5-hydroxybenzothiophen-2-yl, 2-, 4- or 5-hydroxybenzothiophen-3-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 2-, 4- or 5-methylbenzothiophen-3-yl, 3-, 4- or 5-methoxybenzothiophen-2-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-, 5
-, 6- or 7-methylbenzothiazol-2-yl, 2- or 4-fluoropyridin-3-yl, 2
-Or 3-fluoropyridin-4-yl, 2- or 4-hydroxypyridin-3-yl, 2- or 3-hydroxypyridin-4-yl, 2- or 4-
Methylpyridin-3-yl, 2- or 3-methylpyridin-4-yl, 2- or 4-methoxypyridin-4-yl, 2- or 3-methoxypyridin-4-yl
Yl, 2- or 4-methylthiopyridin-3-yl, 2- or 3-methylthiopyridin-4-yl,
3-, 4- or 5-nitrothiophen-2-yl,
2-, 4- or 5-nitrothiophen-3-yl or 1-, 2- or 3-nitropyridin-4-yl group, which is preferably condensed with 1 to 3 substituted benzene rings. And a 5- or 6-membered aromatic heterocyclic group (the substituent is a group selected from the group consisting of a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl and lower alkoxy group), and more preferably. Is a 5- or 6-membered aromatic heterocyclic group which may be condensed with a single-substituted benzene ring (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group). And, more preferably, a thienyl group condensed with one substituted thienyl group, furyl group, pyrrolyl group, thiazolyl group, oxazolyl group, imidazolyl group, pyridyl group, or benzene ring. , Furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group), and still more preferably one-substitution. A thienyl or pyridyl group (the substituent is a halogen atom, a hydroxy, a lower alkyl or a lower alkoxy group), and most preferably a thienyl or a pyridyl group (a substituent) Is a fluorine atom, a chlorine atom,
It is a hydroxy, methyl, ethyl or methoxy group. )
It is.

In the above, specific examples of “cycloalkyl group substituted by 1 to 5 groups selected from substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned “substituted cycloalkyl group” in the definition of R ^2. Cycloalkyl group substituted by 1 to 3 groups selected from group a), 2-carboxycyclopropyl, 2- or 3-carboxycyclopentyl, 2-, 3- or 4-carboxycyclohexyl, 2-methoxycarbonyl Cyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3
-Or 4-methoxycarbonylcyclohexyl, 2
-, 3- or 4-carbamoylcyclohexyl, 2
-, 3- or 4-methylcarbamoylcyclohexyl, 2-, 3- or 4-dimethylcarbamoylcyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexylcyclohexyl, 2-phenylcyclopropyl, 2- Or 3-phenylcyclopentyl, 2-, 3- or 4-
Phenylcyclohexyl, 2-phenoxycyclopropyl, 2- or 3-phenoxycyclopentyl, 2
-, 3- or 4-phenoxycyclohexyl, 2-
Benzyloxycyclopropyl, 2- or 3-benzyloxycyclopentyl, 2-, 3- or 4-benzyloxycyclohexyl, 2-phenylthiocyclopropyl, 2- or 3-phenylthiocyclopentyl or 2-, 3- or 4- A phenylthiocyclohexyl group, preferably 1 to 3 substituted C _5-
C ₆ cycloalkyl group (the substituent is a group selected from the group consisting of a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl and lower alkoxy group)
And more preferably a single-substituted cyclohexyl group (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno-lower alkyl or lower alkoxy group), and most preferably one. A substituted cyclohexyl group (the substituent is a fluorine atom, a chlorine atom, a hydroxy, methyl, ethyl, trifluoromethyl or methoxy group).

In the above, specific examples of the “aryl group substituted by 1 to 5 groups selected from substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned “substituent group” in the definition of R ^2. An aryl group substituted by 1 to 3 groups selected from group a ", 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4- Ethoxycarbonylphenyl, 2-, 3- or 4-carbamoylphenyl, 2-, 3- or 4-methylcarbamoylphenyl, 2-, 3- or 4-dimethylcarbamoylphenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-cyclohexylphenyl,
2-, 3- or 4-phenoxyphenyl, 2-, 3
-Or 4-diphenyl, 2-, 3- or 4-benzyloxyphenyl, 3,4-dibenzyloxyphenyl, 3,5-dibenzyloxyphenyl, 2-, 3-
Or 4-phenylthiophenyl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthioindene- 3-yl, 5-cyclohexylinden-2-yl,
5-phenylinden-2-yl, 5-phenoxyinden-2-yl, 5-benzyloxyinden-2-yl, 5-phenylthioinden-2-yl, 5-nitronaphthalen-2-yl, 5-cyclohexyl Naphthalen-2-yl, 5-phenylnaphthalen-2-yl, 5-
Phenoxynaphthalen-2-yl, 5-benzyloxynaphthalen-2-yl, 5-phenylthionaphthalene-
2-yl, 5-cyclohexylnaphthalen-1-yl,
5-phenylnaphthalen-1-yl, 5-phenoxynaphthalen-1-yl, 5-benzyloxynaphthalene-
A 1-yl or 5-phenylthionaphthalen-1-yl group, preferably an aryl group substituted by 1 to 3 groups selected from substituent groups a and b, more preferably An aryl group substituted by 1 to 3 substituents (the substituent is a group selected from a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and a substituent group a 1 to 3 substituted cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio groups), and more preferably 1 to 3 substituted aryl groups (The substituent is a group selected from the group consisting of a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, and an arylthio group.) Even more preferably, 1 to 3 substituted phenyl or naphthyl groups are selected from the group consisting of halogen atoms, hydroxy groups, lower alkyl groups, halogeno lower alkyl groups, lower alkoxy groups and nitro groups. Is more preferable.), And more preferably,
1 to 3 substituted phenyl groups (the substituents are groups selected from the group consisting of fluorine, chlorine, hydroxy, methyl, ethyl, trifluoromethyl, methoxy and nitro); More preferably, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, -Hydroxyphenyl, 4-hydroxyphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3,4
-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl or 3,4,5-trifluorophenyl group,
Most preferably, it is a 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl or 3,5-dichlorophenyl group.

In the above, specific examples of the “heterocyclic group substituted by 1 to 5 groups selected from the substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned “substituted heterocyclic group” in the definition of R ^2. Heterocyclic group substituted with 1 to 3 groups selected from group a), 3-, 4- or 5-phenylthiophen-2-yl, 2-, 4- or 5-phenylthiophen-3-yl , 1-, 2- or 3-hydroxypyridin-4-yl or 1-, 2- or 3-phenylpyridin-4-yl group, preferably a substituent group a
And b is a heterocyclic group substituted by 1 to 3 groups selected from a group selected from the group consisting of substituents a and b. A 5- or 6-membered aromatic heterocyclic group which may be
A 5- or 6-membered aromatic heterocyclic group which may be condensed with 1 to 3 substituted benzene rings (the substituent is a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, An arylthio group, and a group selected from the group consisting of cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio groups substituted with 1 to 3 groups selected from the substituent group a.)
And even more preferably, a 5- or 6-membered aromatic heterocyclic group which may be condensed with 1 to 3 substituted benzene rings (the substituent is a substituent group a, a cycloalkyl group, an aryl group , An aryloxy group, an aralkyloxy group, and an arylthio group.), And more preferably, one substituted thienyl group, furyl group, pyrrolyl group, thiazolyl group, oxazolyl group. Group, imidazolyl group, pyridyl group, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group condensed with a benzene ring (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group And more preferably a thienyl or pyridyl group which is substituted by 1 (the substituent is a halogen atom) , A hydroxy, a lower alkyl or a lower alkoxy group), and most preferably a thienyl or pyridyl group, which is monosubstituted, wherein the substituent is a fluorine atom, a chlorine atom, a hydroxy, methyl, ethyl or methoxy group. Group).

In the above, specific examples of the “substituted C ₁ -C ₆ alkylene group” in the definition of G include, for example, hydroxymethylene, oxomethylene, cyclopentylmethylene, cyclohexylmethylene, phenylmethylene,
-Naphthylmethylene, 2-naphthylmethylene, 4-fluorophenylmethylene, 4-chlorophenylmethylene,
4-hydroxyphenylmethylene, 4-methylphenylmethylene, 1-naphthylmethylene, 2-naphthylmethylene, 2-thienylmethylene, 4-pyridylmethylene,
-Hydroxyethylene, 1-oxoethylene, 1-cyclopentylethylene, 1-cyclohexylethylene, 1
-Phenylethylene, 1- (1-naphthyl) ethylene,
1- (2-naphthyl) ethylene, 1- (4-fluorophenyl) ethylene, 1- (4-chlorophenyl) ethylene, 1- (4-hydroxyphenyl) ethylene, 1-
(4-methylphenyl) ethylene, 1- (1-naphthyl) ethylene, 1- (2-naphthyl) ethylene, 1-
(2-thienyl) ethylene, 1- (4-pyridyl) ethylene, 2-hydroxyethylene, 2-oxoethylene,
2-cyclopentylethylene, 2-cyclohexylethylene, 2-phenylethylene, 2- (1-naphthyl) ethylene, 2- (2-naphthyl) ethylene, 2- (4-fluorophenyl) ethylene, 2- (4-chlorophenyl) Ethylene, 2- (4-hydroxyphenyl) ethylene, 2- (4-methylphenyl) ethylene, 2- (1-
Naphthyl) ethylene, 2- (2-naphthyl) ethylene,
2- (2-thienyl) ethylene, 2- (4-pyridyl)
Ethylene, 1-hydroxy-2-methylethylene, 2-
Methyl-1-oxoethylene, 1-cyclopentyl-2
-Methylethylene, 1-cyclohexyl-2-methylethylene, 2-methyl-1-phenylethylene, 2-methyl-1- (1-naphthyl) ethylene, 2-methyl-1-
(2-naphthyl) ethylene, 1- (4-fluorophenyl) -2-methylethylene, 1- (4-chlorophenyl) -2-methylethylene, 1- (4-hydroxyphenyl) -2-methylethylene, 1- (4-methylphenyl) -2-methylethylene, 2-methyl-1- (1-naphthyl) ethylene, 2-methyl-1- (2-naphthyl)
Ethylene, 2-methyl-1- (2-thienyl) ethylene, 2-methyl-1- (4-pyridyl) ethylene, 1-
Hydroxytrimethylene, 1-oxotrimethylene, 1
-Cyclopentyl trimethylene, 1-cyclohexyl trimethylene, 1-phenyl trimethylene, 1- (1-naphthyl) trimethylene, 1- (2-naphthyl) trimethylene, 1- (4-fluorophenyl) trimethylene,
-(4-chlorophenyl) trimethylene, 1- (4-hydroxyphenyl) trimethylene, 1- (4-methylphenyl) trimethylene, 1- (1-naphthyl) trimethylene, 1- (2-naphthyl) trimethylene, 1- (2 −
Thienyl) trimethylene, 1- (4-pyridyl) trimethylene, 3-hydroxytrimethylene, 3-oxotrimethylene, 3-cyclopentyltrimethylene, 3-cyclohexyltrimethylene, 3-phenyltrimethylene,
3- (1-naphthyl) trimethylene, 3- (2-naphthyl) trimethylene, 3- (4-fluorophenyl) trimethylene, 3- (4-chlorophenyl) trimethylene,
3- (4-hydroxyphenyl) trimethylene, 3-
(4-methylphenyl) trimethylene, 3- (1-naphthyl) trimethylene, 3- (2-naphthyl) trimethylene, 3- (2-thienyl) trimethylene or 3- (4-
Pyridyl) trimethylene group, preferably C ₁ -C ₆ alkylene group substituted with hydroxy, oxo or aryl, more preferably C ₁ -C ₄ alkylene substituted with hydroxy, oxo or aryl. And more preferably a methylene or ethylene group substituted with hydroxy, oxo or aryl, most preferably
Methylene or ethylene groups substituted with hydroxy, oxo or phenyl.

The "HMG-CoA reductase inhibitor", which is one of the active ingredients of the pharmaceutical composition of the present invention, comprises HMG (3-hydroxy-
It is a drug that specifically and competitively inhibits 3-methylglutaryl) -CoA reductase and lowers serum cholesterol. Therefore, it is originally used as a therapeutic agent for hyperlipidemia. Such HMG-CoA reductase inhibitors include all of natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds, for example,
(+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6 described in JP-A-57-2240 (US Pat. No. 4,346,227).
-Hydroxy-2-methyl-8-[(S) -2-methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoic acid (hereinafter abbreviated as pravastatin). ), JP-A-57-163374 (U.S. Pat.
(SP42319338), (+)-(1S,
3R, 7S, 8S, 8aR) -1,2,3,7,8,8
a-Hexahydro-3,7-dimethyl-8- [2-
[(2R, 4R) -tetrahydro-4-hydroxy-6
-Oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (S) -2-methylbutyrate (hereinafter abbreviated as lovastatin), described in JP-A-56-122375 (USP 4,444,784). , (+)-(1
S, 3R, 7S, 8S, 8aR) -1, 2, 3, 7,
8,8a-Hexahydro-3,7-dimethyl-8- [2
-[(2R, 4R) -tetrahydro-4-hydroxy-
6-oxo-2H-pyran-2-yl] ethyl] -1-
Naphthyl 2,2-dimethylbutyrate (hereinafter abbreviated as simvastatin), (±) (3R) described in JP-T-60-500015 (US Pat. No. 4,739,073).
^* , 5S ^* , 6E) -7- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indole-
2-yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as fluvastatin), JP-A-1-2
No. 16974 (USP5006530),
(3R, 5S, 6E) -7- [4- (4-Fluorophenyl) -2,6-di- (1-methylethyl) -5-methoxymethylpyridin-3-yl] -3,5-dihydroxy- 6-heptenoic acid (hereinafter abbreviated as rivastatin), JP-A-3-58967 (US Pat.
(3R, 5S) -7- [2- (4-
Fluorophenyl) -5- (1-methylethyl) -3-
Phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid (hereinafter abbreviated as atorvastatin);
No. 279866 (US Pat. Nos. 5,854,259 and 58)
(E) -3,5-dihydroxy-7- [4 ′-(4 ″ -fluorophenyl)-described in US Pat.
2'-Cyclopropyl-quinolin-3'-yl] -6
Heptenoic acid (hereinafter abbreviated as pitavastatin) or (+)-(3R, 5S) -7- [4- (4) described in JP-A-5-178841 (US Pat. No. 5,260,440).
-Fluorophenyl) -6-isopropyl-2- (N-
Methyl-N-methanesulfonylamino) pyrimidine-
A statin compound such as 5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid (hereinafter abbreviated as rosuvastatin) may be used. In addition, the HMG-CoA reductase inhibitor which is an active ingredient of the pharmaceutical composition of the present invention is another HMG-CoA reductase inhibitor disclosed in the publication in which the above-mentioned HMG-CoA reductase inhibitor is described. Also contained.

Preferred as such HMG-CoA reductase inhibitors are pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin,
More preferably, pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin, more preferably pravastatin, atorvastatin or pitavastatin, even more preferably pravastatin or atorvastatin, most preferably Is pravastatin.

The planar structural formula of a typical HMG-CoA reductase inhibitor is shown below.

[0042]

Embedded image

[0043]

Embedded image

The cyclobutene derivative having the general formula (I), which is an active ingredient of the pharmaceutical composition of the present invention, and HMG-CoA
When a reductase inhibitor has a basic group such as an amino group, it is reacted with an acid. Indicate the salt so that it can be.

The salt based on a basic group is preferably
Inorganic acid salts such as hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Salts, lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
aryl sulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate,
Organic acid salts such as citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. And most preferably a hydrohalide.

On the other hand, salts based on acidic groups are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and iron salt. Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as methane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates.

In the HMG-CoA reductase inhibitor which is an active ingredient of the pharmaceutical composition of the present invention, pravastatin, lovastatin, simvastatin, fluvastatin,
Rivastatin, atorvastatin or pitavastatin include the closed lactone thereof or a pharmacologically acceptable salt thereof (preferably a sodium salt or a calcium salt).

The cyclobutene derivative having the above general formula (I), its pharmacologically acceptable salt, its ester or other derivative, and H, which are the active ingredients of the pharmaceutical composition of the present invention.
MG-CoA reductase inhibitors have various isomers when an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula. Therefore,
The present invention includes all of these isomers and a mixture of these isomers in any ratio.

[0049] In the compounds having the general formula (I) of the present invention, G in -G-R ¹ group moiety is -CHR ⁰ - is a group, i.e., -G-R ¹ group moiety is represented by the following formula

[0050]

Embedded image

If having a [0051], R ⁰ group and R ¹ groups may have asymmetrically substituted carbon atom, in particular R ⁰ groups are methyl, phenyl R ¹ groups having a phenyl group or a substituted group When it is a group, a compound having an R configuration is preferred.

The cyclobutene derivative having the above general formula (I), its pharmacologically acceptable salt, its ester or other derivative, and the HMG-CoA reductase inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, include: If left in the air or recrystallized, it absorbs water and may absorb water or become hydrated, and such hydrates are also included in the salts of the present invention. You.

The "ester" in the above refers to the ester of the compound (I) of the present invention, since it can be converted to an ester, and such esters include "ester of hydroxy group" and "carboxy group. And an ester in which each ester residue is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.

"General protecting group" means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

As the "general protecting group" for the "ester of hydroxy group", preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, -Methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,
3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-
Dimethyltetradecanoyl, heptadecanoyl, 15-
Alkanoyl groups such as methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, and methoxyacetyl Acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-
A "lower aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl, α- Arylcarbonyl groups such as naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl,
Lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl and 2-nitrobenzoyl Aromatic compounds such as a highly nitrated arylcarbonyl group, a lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, and an arylated arylcarbonyl group such as 4-phenylbenzoyl; Acyl group "; methoxycarbonyl, ethoxycarbonyl,
Lower alkoxycarbonyl groups such as propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl;
An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; tetrahydropyran-2-yl; Bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; like tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl "Tetrahydrofuranyl or tetrahydrothiofuranyl group"; tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenyl Methylsilyl,
A "silyl group" such as a tri-lower alkylsilyl group substituted with one or two aryl groups such as diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-
1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, lower alkoxymethyl groups such as t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2, "Alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl;
"Substituted ethyl group" such as lower alkoxylated ethyl group such as 1-ethoxyethyl and 1- (isopropoxy) ethyl, and halogenated ethyl group such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl , Β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-
Lower alkyl group substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2
1 to 3 wherein the aryl ring is substituted by lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as -nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, and 4-cyanobenzyl. An "aralkyl group" such as a lower alkyl group substituted with two aryl groups; an "alkenyloxycarbonyl group" such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, "Aralkyloxycarbonyl" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Group '', and preferably, Aliphatic acyl group, aromatic acyl group, an alkoxycarbonyl group or an alkoxymethyl group, and more preferably, an aromatic acyl group or an alkoxymethyl group, and most preferably a benzoyl group or a methoxymethyl group.

As the "general protecting group" for the "ester of a carboxy group", the above-mentioned "lower alkyl group"; ethenyl, 1-propenyl, 2-propenyl, 1
-Methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl -2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-
Ethyl-2-butenyl, 3-butenyl, 1-methyl-3
-Butenyl, 2-methyl-3-butenyl, 1-ethyl-
3-butenyl, 1-pentenyl, 2-pentenyl, 1-
Methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2
-Methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl 1-
"Lower alkenyl groups" such as hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2- Ethyl-
2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2
-Methyl-3-butynyl, 1-ethyl-3-butynyl,
2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-
3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-
4-pentynyl, 2-hexynyl, 3-hexynyl, 4
-Lower alkynyl groups such as -hexynyl and 5-hexynyl; the above-mentioned "halogeno lower alkyl"; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl "Hydroxy lower alkyl group" such as;
"Lower aliphatic acyl lower alkyl group" such as acetylmethyl; the "aralkyl group"; the "silyl group"; preferably a lower alkyl group or an aralkyl group, most preferably It is a methyl group, an ethyl group or a benzyl group.

The term "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" means that it is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. It refers to a protecting group, and whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice,
Subsequent examination of the body fluids of the animals allows the determination of the ability to detect the original compound or its pharmacologically acceptable salt, and the determination of the "hydroxyl ester" by "biological such as hydrolysis in vivo". Protecting group that can be cleaved by the method "
As preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-
Isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1
-Valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-
1 such as acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl
-("Lower aliphatic acyl" oxy) "lower alkyl group", cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexyl Carbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-
1- such as cyclohexylcarbonyloxybutyl
1- (acyloxy) "lower alkyl group" such as ("cycloalkyl" carbonyloxy) "lower alkyl group", 1-("aromatic acyl" oxy) "lower alkyl group" such as benzoyloxymethyl; methoxycarbonyl Oxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxy Carbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- ( Pentyloxycarbonyloxy)
Ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy)
Propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl , 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1
-(Propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- ( Hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1-
(Isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy)
(Lower alkoxycarbonyloxy) alkyl groups such as pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl;
(5-phenyl-2-oxo-1,3-dioxolene-
4-yl) methyl, [5- (4-methylphenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
[5- (4-methoxyphenyl) -2-oxo-1,3
-Dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolene-
4-yl] methyl, [5- (4-chlorophenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
(2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,
3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) “Carbonyloxy lower alkyl group” such as methyl, oxodioxorenylmethyl group such as (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; phthalidyl, dimethylphthalidyl,
“Phthalidyl group” such as dimethoxyphthalidyl: the above “lower aliphatic acyl group”: the above “aromatic acyl group”:
"Succinic acid half ester salt residue": "phosphate ester salt residue": "ester forming residue such as amino acid": carbamoyl group: carbamoyl group substituted with one or two lower alkyl groups: Examples thereof include “1- (acyloxy) alkyloxycarbonyl group” such as baroyloxymethyloxycarbonyl, and preferably “carbonyloxyalkyl group”.

On the other hand, as the “protecting group which can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group”, methoxyethyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl ,
Lower alkoxy lower alkyl groups such as isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, 2
Lower alkoxylated lower alkoxy lower alkyl groups such as methoxyethoxymethyl, "aryl" oxy "lower alkyl groups" such as phenoxymethyl, 2,2,2
“Alkoxyalkyl groups” such as halogenated lower alkoxy lower alkyl groups such as trichloroethoxymethyl and bis (2-chloroethoxy) methyl; “lower alkoxy” carbonyl “lower alkyl groups” such as methoxycarbonylmethyl; “Cyano“ lower alkyl ”such as cyanomethyl and 2-cyanoethyl;“ lower alkyl ”thiomethyl such as methylthiomethyl and ethylthiomethyl;“ aryl ”thiomethyl such as phenylthiomethyl and naphthylthiomethyl A "lower alkyl" sulfonyl "lower alkyl group" optionally substituted with halogen "such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; Like "" Le "sulfonyl" lower alkyl group "", the "1- (acyloxy)" lower alkyl group "", the "phthalidyl group"; the "aryl group";
The "lower alkyl group"; the "carboxyalkyl group" such as carboxymethyl; and the "amide-forming residue of amino acid" such as phenylalanine.

The “other derivatives” include, when the compound (I) of the present invention has an amino group and / or a carboxy group, derivatives other than the above “pharmacologically acceptable salts” and the above “esters thereof”. Derivatives are indicated. Examples of such derivatives include amide derivatives other than the above-mentioned mono-lower alkylcarbamoyl group and di-lower alkylcarbamoyl group.

The pharmaceutical composition of the present invention has the general formula (I)
, A pharmacologically acceptable salt thereof, an ester or other derivative thereof, and HMG-CoA
A pharmaceutical composition for administering reductase inhibitors simultaneously or separately at intervals.

In the present invention, "simultaneous administration" is not particularly limited as long as it can be administered at substantially the same time, but administration as a single composition is preferred.

In the present invention, “separately after a time”
The term “administering” is not particularly limited as long as it can be administered separately at different times. For example, first, a cyclobutene derivative having the above general formula (I), a pharmaceutically acceptable salt thereof, An ester or other derivative is administered, and then, after a fixed time, an HMG-CoA reductase inhibitor is administered, or HMG-CoA is first administered.
A means of administering an A reductase inhibitor and then administering a cyclobutene derivative having the above general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof after a predetermined time. . In the pharmaceutical composition of the present invention, (2) the compound having the general formula (I) is preferably a compound represented by the general formula (Ia) or (Ib):

[0063]

Embedded image

A pharmaceutical composition which is a compound having the formula:
In (2), more preferably, (3) the general formula (I)
Is a compound having the general formula (Ia), and in any one selected from (1) to (3), more preferably (4) Z is
A pharmaceutical composition which is a single bond or a C ₁ -C ₂ alkylene group,
(5) a pharmaceutical composition wherein Z is a single bond or a methylene group; (6) a pharmaceutical composition wherein Z is a single bond;
In any one selected from (1) to (6), still more preferably, (7) a pharmaceutical composition wherein R ⁵ is a hydrogen atom or a lower alkyl group, and (8) R ⁵ is hydrogen A pharmaceutical composition which is an atom or a methyl group, (9) R
⁵ is a pharmaceutical composition wherein hydrogen is a hydrogen atom, and in any one selected from (1) to (9), more preferably (10) R ⁶ is a hydroxy group or an amine residue A pharmaceutical composition, (11) wherein R ⁶ is a hydroxy group,
A pharmaceutical composition which is a hydroxyamino group or an amino group,
(12) A pharmaceutical composition wherein R ⁶ is a hydroxy group, and in any one selected from (1) to (12), more preferably (13) X and Y are oxygen atoms A pharmaceutical composition, in any one selected from (1) to (13), still more preferably,
(14) A pharmaceutical composition wherein D is a group having a CH or a nitrogen atom, (15) a pharmaceutical composition wherein D is a group having a CH and any one selected from (1) to (15) In one paragraph, more preferably, (16) a pharmaceutical composition wherein E is a group having an oxygen atom, a sulfur atom or -NH-, and (17) a pharmaceutical composition wherein E is a group having -NH-. In any one selected from (1) to (17), more preferably (18) G is C
₁ -C ₆ pharmaceutical composition is an alkylene group or substituted C ₁ -C ₆ alkylene group, (19) G is, C ₁ -C ₆ alkylene group or substituted C ₁ -C ₆ alkylene group (said substituent Wherein the group is a hydroxy group, an oxo group, an aryl group or an aryl group substituted by 1 to 3 groups selected from the group of substituents a)), wherein (20) G is C _1-
(21) G is a pharmaceutical composition which is a C ₆ alkylene group,
C ₁ -C ₄ pharmaceutical composition is an alkylene group, (22) G
Is a methylene, methylmethylene or ethylmethylene group, (23) a pharmaceutical composition wherein G is a methylmethylene group, and in any one selected from (1) to (23), Even more preferably, (2)
4) R ¹ is selected from a cycloalkyl group, an aryl group, a heterocyclic group, an aryl group substituted with 1 to 3 groups selected from substituent groups a and b, or a substituent group a and b (25) a 5- to 6-membered aromatic heterocyclic group which may be condensed with an aryl group or a benzene ring, wherein R ¹ is a heterocyclic group substituted with 1 to 3 heterocyclic groups, aryl groups substituted with 1 to 3 groups selected from a and b, or 5 to 3 groups substituted with 1 to 3 groups substituted with a group selected from substituent groups a and b which may be condensed with a benzene ring; A pharmaceutical composition which is a 6-membered aromatic heterocyclic group, (26) wherein R ¹ is
A 5- or 6-membered aromatic heterocyclic group which may be condensed with an aryl group or a benzene ring, or a 5- or 6-membered aromatic heterocyclic group which may be condensed with 1 to 3 substituted aryl groups or a benzene ring ( The substituent is a substituent group a, a cycloalkyl group,
Aryl group, aryloxy group, aralkyloxy group,
Cycloalkyl, aryl substituted with 1 to 3 arylthio groups and a group selected from substituent group a, aryl,
It is a group selected from the group consisting of aryloxy, aralkyloxy and arylthio groups. Wherein R ¹ is fused with an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or a substituted or unsubstituted aryl group or a benzene ring with 1 to 3 groups; 5- or 6-membered aromatic heterocyclic group which may be a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a nitro group, a cycloalkyl group, an aryl group, an aryloxy group and is a group selected from the group consisting of an arylthio group.) the pharmaceutical composition is, that (28) R ^1, a phenyl group, a naphthyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl Group, pyridyl group, condensed with benzene ring, thienyl, furyl, pyrrolyl, thiazolyl,
An oxazolyl, imidazolyl or pyridyl group, or a 1 to 3 substituted phenyl or naphthyl group (the substituent is a group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group) Wherein R ¹ is phenyl, 1-naphthyl, 2-naphthyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methylphenyl, 4-methylphenyl,
3,4-dimethylphenyl, 3-methoxyphenyl, 4
-Methoxyphenyl, 3,4-dimethoxyphenyl,
A pharmaceutical composition which is 3,4,5-trimethoxyphenyl, 3,4,5-trifluorophenyl, thienyl or pyridyl group, (30) wherein R ¹ is phenyl, 3-fluorophenyl, 3-chlorophenyl, A pharmaceutical composition which is a 4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-thienyl or 4-pyridyl group, and is selected from (1) to (30). In any one of the above, (31) an aryl group in which R ² is substituted with 1 to 3 groups selected from a cycloalkyl group, an aryl group, a heterocyclic group, and a group selected from a substituent group a, or, the pharmaceutical composition is a 1 to 3-substituted heterocyclic group with a group selected from substituent group a, (32) R ² is an aryl group, 5- or 6-membered may be condensed with the benzene ring An aromatic heterocyclic group, or a 5- to 6-membered aromatic heterocyclic group which may be condensed with an aryl group or a benzene ring substituted with 1 to 3 substituents (the substituent may be a halogen atom, a hydroxy group, A group selected from the group consisting of a halogeno lower alkyl group and a lower alkoxy group.)
² , aryl group, thienyl group, furyl group, pyrrolyl group, thiazolyl group, oxazolyl group, imidazolyl group,
A thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group condensed with a pyridyl group or a benzene ring, or a single-substituted aryl group (the substituent may be a halogen atom, a hydroxy group, a lower alkyl group, a halogeno group, (34) a pharmaceutical composition, wherein R ² is a phenyl group, a naphthyl group, a 2-thienyl group, a 4-pyridyl group, or a single-substituted phenyl or naphthyl group; group (said substituent is a halogen atom, hydroxy group, lower alkyl group, a halogeno-lower alkyl group or a lower alkoxy group.) the pharmaceutical composition is, that (35) R ^2, phenyl group, or, one substituent Phenyl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or It is a Grade alkoxy group.)
Pharmaceutical compositions is, the (36) R ^2, phenyl, 4-
A pharmaceutical composition which is a fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 4-methoxyphenyl group, and in any one selected from (1) to (36), more preferably (37) A pharmaceutical composition wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkoxy group, an amino group or a di-lower alkylamino group; (38) R ³ and R ⁴ are
A pharmaceutical composition which is the same or different and is a hydrogen atom, a hydroxy group or a lower alkoxy group, (39) R ³ and R
(40) The pharmaceutical composition, wherein ⁴ is a hydrogen atom, wherein the cyclobutene derivative having the general formula (I) is 4- {3-
[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, 4- {3-[(1 -(3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione and 3- {3-[(4-fluorophenyl) )-(1- (3-Fluorophenyl) ethylamino) methyl] phenylamino} -4-hydroxy-3
-A pharmaceutical composition which is any one compound selected from cyclobutene-1,2-dione or a pharmacologically acceptable salt thereof, in any one selected from (1) to (40), Even more preferably, (41) HM
A pharmaceutical composition wherein the G-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin or rosuvastatin, (42) the HMG-CoA reductase inhibitor is pravastatin, atorvastatin or pitavastatin Pharmaceutical composition, (43) HMG-
(44) a pharmaceutical composition wherein the CoA reductase inhibitor is pravastatin or atorvastatin;
The pharmaceutical composition wherein the reductase inhibitor is pravastatin.

Further, in the pharmaceutical composition of the present invention,
(2) and (3), (4) to (6), (7) to (9), (10) to (12), (13), (14) and (15), (16) and (17) ), (18) to (2)
3), (24) to (30), (31) to (36), and a pharmaceutical composition obtained by arbitrarily combining any one selected from the group consisting of (37) to (39) are also preferable. In addition, any one of the above combinations or (40)
Pharmaceutical compositions obtained by optionally combining (41) to (44) are also suitable.

Specific examples of the cyclobutene derivative having the general formula (I) which is an active ingredient of the pharmaceutical composition of the present invention include, for example, the compounds shown in Tables 1 to 4 below. Is not limited to these compounds. The compounds in Tables 1 to 4 have the structural formulas (I-1) to (I-4), respectively.

In Tables 1 to 4, the substituents of R ¹ , R ² and A are as follows.

[0068]

Embedded image

[0069]

Embedded image

[0070]

Embedded image

[0071]

Embedded image

[0072]

Embedded image

[0073]

Embedded image

[0074]

Embedded image

The abbreviations of the above-mentioned substituents in the table are as follows. Ac: acetyl group Bz: benzyl group Et: ethyl group cHx: cyclohexyl group Me: methyl group Ph: phenyl group Pr: propyl group iPr: isopropyl group Ph: phenyl group single bond: single bond.

[0076]

[Table 1]

[0077]

Embedded image

[0078] Compd. R ¹ R ² R ³ R ⁴ ADEG No. Substituent No. Substituent No. Substituent No. 1-1 (b-7) (b-7) HH (a-1) -CH- -NH- -CH (Me)-1-2 (b-7) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-3 (b-11) (b-7) HH (a-1) -CH- -NH- -CH (Me)-1-4 (b-11 ) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-5 (b-12) (b-35) HH (a-1) -CH- -NH-- CH (Me)-1-6 (b-15) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-7 (b-18) (b-7) HH (a-1) -CH- -NH- -CH (Me)-1-8 (b-18) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1- 9 (b-19) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-10 (b-20) (b-7) HH (a-1) -CH --NH- -CH (Me)-1-11 (b-20) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-12 (b-21) ( b-35) HH (a-1) -CH- -NH- -CH (Me)-1-13 (b-24) (b-35) HH (a-1) -CH- -NH- -CH ( Me)-1-14 (b-25) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-15 (b-72) (b-35) HH (a -1) -CH- -NH- -CH (Me)-1-16 (b-73) (b-7) HH (a-1) -CH- -NH- -CH (Me)-1-17 ( b-73) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-18 (b-74) (b-35) HH (a-1) -CH-- NH- -CH (Me)-1-19 (b-76) (b-35) HH (a-1) -CH- -NH- -CH (Me)-1-20 (b-77) (b- 7) HH (a-1) -CH- -NH- -CH (Me)-1-21 (b-77) (b-35) HH (a-1) -CH- -NH- -CH (Me) -1-22 (b-11) (b-35) HH (a-2) -C H- -NH- -CH (Me)-1-23 (b-18) (b-35) HH (a-2) -CH- -NH- -CH (Me)-1-24 (b-20) (b-35) HH (a-2) -CH- -NH- -CH (Me)-1-25 (b-7) (b-35) HH (a-3) -CH- -NH- -CH (Me)-1-26 (b-11) (b-35) HH (a-3) -CH- -NH- -CH (Me)-1-27 (b-18) (b-35) HH ( a-3) -CH- -NH- -CH (Me)-1-28 (b-20) (b-35) HH (a-3) -CH- -NH- -CH (Me)-1-29 (b-73) (b-35) HH (a-3) -CH- -NH- -CH (Me)-1-30 (b-77) (b-35) HH (a-3) -CH- -NH- -CH (Me)-1-31 (b-11) (b-35) HH (a-4) -CH- -NH- -CH (Me)-1-32 (b-18) (b -35) HH (a-4) -CH- -NH- -CH (Me)-1-33 (b-20) (b-35) HH (a-4) -CH- -NH- -CH (Me )-1-34 (b-7) (b-7) HH (a-5) -CH- -NH- -CH (Me)-1-35 (b-7) (b-35) HH (a- 5) -CH- -NH- -CH (Me)-1-36 (b-11) (b-7) HH (a-5) -CH- -NH- -CH (Me)-1-37 (b -11) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-38 (b-12) (b-35) HH (a-5) -CH- -NH --CH (Me)-1-39 (b-15) (b-35) HH (a-5) -CH- -NH- -CH (Me) -1-40 (b-18) (b-7 ) HH (a-5) -CH- -NH- -CH (Me)-1-41 (b-18) (b-35) HH (a-5) -CH- -NH- -CH (Me)- 1-42 (b-19) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-43 (b-20) (b-7) HH (a-5) -CH- -NH- -CH (Me)-1-4 4 (b-20) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-45 (b-21) (b-35) HH (a-5) -CH --NH- -CH (Me)-1-46 (b-24) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-47 (b-25) ( b-35) HH (a-5) -CH- -NH- -CH (Me)-1-48 (b-72) (b-35) HH (a-5) -CH- -NH- -CH ( Me)-1-49 (b-73) (b-7) HH (a-5) -CH- -NH- -CH (Me) -1-50 (b-73) (b-35) HH (a -5) -CH- -NH- -CH (Me)-1-51 (b-74) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-52 ( b-76) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-53 (b-77) (b-7) HH (a-5) -CH-- NH- -CH (Me)-1-54 (b-77) (b-35) HH (a-5) -CH- -NH- -CH (Me)-1-55 (b-11) (b- 35) HH (a-6) -CH- -NH- -CH (Me)-1-56 (b-18) (b-35) HH (a-6) -CH- -NH- -CH (Me) -1-57 (b-20) (b-35) HH (a-6) -CH- -NH- -CH (Me)-1-58 (b-7) (b-35) HH (a-7 ) -CH- -NH- -CH (Me)-1-59 (b-11) (b-35) HH (a-7) -CH- -NH- -CH (Me)-1-60 (b- 18) (b-35) HH (a-7) -CH- -NH- -CH (Me)-1-61 (b-20) (b-35) HH (a-7) -CH- -NH- -CH (Me)-1-62 (b-73) (b-35) HH (a-7) -CH- -NH- -CH (Me)-1-63 (b-77) (b-35) HH (a-7) -CH- -NH- -CH (Me)-1-64 (b-11) (b-35) HH (a-8) -CH- -NH- -CH (Me) -1 -65 (b-18) (b-35) HH (a-8) -CH- -NH- -CH (Me)-1-66 (b-20) (b-35) HH (a-8) -CH- -NH- -CH (Me) -1 -67 (b-11) (b-35) HH (a-11) -CH- -NH- -CH (Me)-1-68 (b-18) (b-35) HH (a-11)- CH- -NH- -CH (Me)-1-69 (b-20) (b-35) HH (a-11) -CH- -NH- -CH (Me)-1-70 (b-2) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-71 (b-7) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-72 (b-7) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-1-73 (b-7) (b-35) HH ( a-14) -CH- -NH- -CH (Me)-1-74 (b-7) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-1-75 (b-8) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-76 (b-11) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-77 (b-11) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-1-78 (b-11) (b -35) HH (a-14) -CH- -NH- -CH (Me)-1-79 (b-11) (b-35) HH (a-14) -CH- -NH- -COCH (Me )-1-80 (b-12) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-81 (b-12) (b-35) HH (a- 14) -CH- -NH- -CH (Me)-1-82 (b-15) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-83 (b -15) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-84 (b-18) (b-7) HH (a-14) -CH- -NH --CH (Me)-1-85 (b-18) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-1-86 (b-18) (b-35 ) HH (a-14) -CH- -NH- -CH (Me)-1-87 (b-18) (b-35) HH (a-14) -CH- -NH- -COCH (Me)- 1-88 (b-19) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-89 (b-19) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-90 (b-20) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-91 (b-20 ) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-1-92 (b-20) (b-35) HH (a-14) -CH- -NH-- CH (Me)-1-93 (b-20) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-1-94 (b-21) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-95 (b-21) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1- 96 (b-24) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-97 (b-24) (b-35) HH (a-14) -CH --NH- -CH (Me)-1-98 (b-25) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1-99 (b-25) ( b-35) HH (a-14) -CH- -NH- -CH (Me)-1-100 (b-72) (b-7) HH (a-14) -CH- -NH- -CH ( (Me)-1-101 (b-72) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-102 (b-73) (b-7) HH (a -14) -CH- -NH- -CH (Me)-1-103 (b-73) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-1-104 ( b-73) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-105 (b-73) (b-35) HH (a-14) -CH-- NH- -COCH (Me)-1-106 (b-74) (b-7) HH (a-14) -CH- -NH- -CH (Me)-1- 107 (b-74) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-108 (b-76) (b-7) HH (a-14) -CH --NH- -CH (Me)-1-109 (b-76) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-110 (b-77) ( b-7) HH (a-14) -CH- -NH- -CH (Me)-1-111 (b-77) (b-7) HH (a-14) -CH- -NH- -COCH ( (Me)-1-112 (b-77) (b-35) HH (a-14) -CH- -NH- -CH (Me)-1-113 (b-77) (b-35) HH (a -14) -CH- -NH- -COCH (Me)-1-114 (b-7) (b-7) HH (a-15) -CH- -NH- -CH (Me)-1-115 ( b-7) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-116 (b-11) (b-7) HH (a-15) -CH-- NH- -CH (Me)-1-117 (b-11) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-118 (b-12) (b- 35) HH (a-15) -CH- -NH- -CH (Me)-1-119 (b-15) (b-35) HH (a-15) -CH- -NH- -CH (Me) -1-120 (b-18) (b-7) HH (a-15) -CH- -NH- -CH (Me)-1-121 (b-18) (b-35) HH (a-15 ) -CH- -NH- -CH (Me)-1-122 (b-19) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-123 (b- 20) (b-7) HH (a-15) -CH- -NH- -CH (Me)-1-124 (b-20) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-125 (b-21) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-126 (b-24) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-127 (b-25) (b-35) HH (a-1 5) -CH- -NH- -CH (Me)-1-128 (b-72) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-129 (b -73) (b-7) HH (a-15) -CH- -NH- -CH (Me)-1-130 (b-73) (b-35) HH (a-15) -CH- -NH --CH (Me)-1-131 (b-74) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-132 (b-76) (b-35 ) HH (a-15) -CH- -NH- -CH (Me)-1-133 (b-77) (b-7) HH (a-15) -CH- -NH- -CH (Me)- 1-134 (b-77) (b-35) HH (a-15) -CH- -NH- -CH (Me)-1-135 (b-7) (b-7) HH (a-18) -CH- -NH- -CH (Me)-1-136 (b-7) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-137 (b-11 ) (b-7) HH (a-18) -CH- -NH- -CH (Me)-1-138 (b-11) (b-35) HH (a-18) -CH- -NH-- CH (Me)-1-139 (b-12) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-140 (b-15) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-141 (b-18) (b-7) HH (a-18) -CH- -NH- -CH (Me)-1- 142 (b-18) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-143 (b-19) (b-35) HH (a-18) -CH --NH- -CH (Me)-1-144 (b-20) (b-7) HH (a-18) -CH- -NH- -CH (Me)-1-145 (b-20) ( b-35) HH (a-18) -CH- -NH- -CH (Me)-1-146 (b-21) (b-35) HH (a-18) -CH- -NH- -CH ( Me)-1-147 (b-24) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-148 (b-25) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-149 (b-72) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-150 (b-73) (b-7) HH (a-18) -CH- -NH- -CH (Me)-1-151 (b-73) (b -35) HH (a-18) -CH- -NH- -CH (Me)-1-152 (b-74) (b-35) HH (a-18) -CH- -NH- -CH (Me )-1-153 (b-76) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-154 (b-77) (b-7) HH (a- 18) -CH- -NH- -CH (Me)-1-155 (b-77) (b-35) HH (a-18) -CH- -NH- -CH (Me)-1-156 (b -7) (b-35) HH (a-19) -CH- -NH- -CH (Me)-1-157 (b-11) (b-35) HH (a-19) -CH- -NH --CH (Me)-1-158 (b-18) (b-35) HH (a-19) -CH- -NH- -CH (Me)-1-159 (b-20) (b-35 ) HH (a-19) -CH- -NH- -CH (Me)-1-160 (b-73) (b-35) HH (a-19) -CH- -NH- -CH (Me)- 1-161 (b-77) (b-35) HH (a-19) -CH- -NH- -CH (Me)-1-162 (b-7) (b-7) HH (a-20) -CH- -NH- -CH (Me)-1-163 (b-7) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-164 (b-11 ) (b-7) HH (a-20) -CH- -NH- -CH (Me)-1-165 (b-11) (b-35) HH (a-20) -CH- -NH-- CH (Me)-1-166 (b-12) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-167 (b-15) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-168 (b-18) (b-7) HH (a-20) -CH- -NH- -CH (Me)-1-169 (b-18) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-170 (b-19) (b -35) HH (a-20) -CH- -NH- -CH (Me)-1-171 (b-20) (b-7) HH (a-20) -CH- -NH- -CH (Me )-1-172 (b-20) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-173 (b-21) (b-35) HH (a- 20) -CH- -NH- -CH (Me)-1-174 (b-24) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-175 (b -25) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-176 (b-72) (b-35) HH (a-20) -CH- -NH --CH (Me)-1-177 (b-73) (b-7) HH (a-20) -CH- -NH- -CH (Me)-1-178 (b-73) (b-35 ) HH (a-20) -CH- -NH- -CH (Me)-1-179 (b-74) (b-35) HH (a-20) -CH- -NH- -CH (Me)- 1-180 (b-76) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-181 (b-77) (b-7) HH (a-20) -CH- -NH- -CH (Me)-1-182 (b-77) (b-35) HH (a-20) -CH- -NH- -CH (Me)-1-183 (b-11 ) (b-35) HH (a-21) -CH- -NH- -CH (Me)-1-184 (b-18) (b-35) HH (a-21) -CH- -NH-- CH (Me)-1-185 (b-20) (b-35) HH (a-21) -CH- -NH- -CH (Me)-1-186 (b-7) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1-187 (b-11) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1- 188 (b-18) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1-189 (b- 20) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1-190 (b-73) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1-191 (b-77) (b-35) HH (a-24) -CH- -NH- -CH (Me)-1-192 (b-7) (b-7) HH (a-26) -CH- -NH- -CH (Me)-1-193 (b-7) (b-35) HH (a-26) -CH- -NH- -CH (Me) -1 -194 (b-11) (b-7) HH (a-26) -CH- -NH- -CH (Me)-1-195 (b-11) (b-35) HH (a-26)- CH- -NH- -CH (Me)-1-196 (b-12) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-197 (b-15) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-198 (b-18) (b-7) HH (a-26) -CH- -NH- -CH (Me)-1-199 (b-18) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-200 (b-19) (b-35) HH ( a-26) -CH- -NH- -CH (Me)-1-201 (b-20) (b-7) HH (a-26) -CH- -NH- -CH (Me)-1-202 (b-20) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-203 (b-21) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-204 (b-24) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-205 (b-25) (b -35) HH (a-26) -CH- -NH- -CH (Me)-1-206 (b-72) (b-35) HH (a-26) -CH- -NH- -CH (Me )-1-207 (b-73) (b-7) HH (a-26) -CH- -NH- -CH (Me)-1-208 (b-73) (b-35) HH (a- 26) -CH- -NH- -CH (Me)-1-209 (b-74) (b-35) HH (a-26) -CH-- NH- -CH (Me)-1-210 (b-76) (b-35) HH (a-26) -CH- -NH- -CH (Me)-1-211 (b-77) (b- 7) HH (a-26) -CH- -NH- -CH (Me)-1-212 (b-77) (b-35) HH (a-26) -CH- -NH- -CH (Me) -1-213 (b-11) (b-35) HH (a-27) -CH- -NH- -CH (Me)-1-214 (b-18) (b-35) HH (a-27 ) -CH- -NH- -CH (Me)-1-215 (b-20) (b-35) HH (a-27) -CH- -NH- -CH (Me)-1-216 (b- 7) (b-35) HH (a-28) -CH- -NH- -CH (Me)-1-217 (b-11) (b-35) HH (a-28) -CH- -NH- -CH (Me)-1-218 (b-18) (b-35) HH (a-28) -CH- -NH- -CH (Me)-1-219 (b-20) (b-35) HH (a-28) -CH- -NH- -CH (Me)-1-220 (b-73) (b-35) HH (a-28) -CH- -NH- -CH (Me) -1 -221 (b-77) (b-35) HH (a-28) -CH- -NH- -CH (Me)-1-222 (b-11) (b-35) HH (a-29)- CH- -NH- -CH (Me)-1-223 (b-18) (b-35) HH (a-29) -CH- -NH- -CH (Me)-1-224 (b-20) (b-35) HH (a-29) -CH- -NH- -CH (Me)-1-225 (b-7) (b-7) HH (a-31) -CH- -NH- -CH (Me)-1-226 (b-7) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-227 (b-11) (b-7) HH ( a-31) -CH- -NH- -CH (Me)-1-228 (b-11) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-229 (b-12) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-230 (b-15) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-231 (b-18) (b-7) HH (a-31) -CH- -NH- -CH (Me)-1-232 (b-18) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-233 (b-19) (b-35) HH ( a-31) -CH- -NH- -CH (Me)-1-234 (b-20) (b-7) HH (a-31) -CH- -NH- -CH (Me)-1-235 (b-20) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-236 (b-21) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-237 (b-24) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-238 (b-25) (b -35) HH (a-31) -CH- -NH- -CH (Me)-1-239 (b-72) (b-35) HH (a-31) -CH- -NH- -CH (Me )-1-240 (b-73) (b-7) HH (a-31) -CH- -NH- -CH (Me)-1-241 (b-73) (b-35) HH (a- 31) -CH- -NH- -CH (Me)-1-242 (b-74) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-243 (b -76) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-244 (b-77) (b-7) HH (a-31) -CH- -NH --CH (Me)-1-245 (b-77) (b-35) HH (a-31) -CH- -NH- -CH (Me)-1-246 (b-11) (b-35 ) HH (a-32) -CH- -NH- -CH (Me)-1-247 (b-18) (b-35) HH (a-32) -CH- -NH- -CH (Me)- 1-248 (b-20) (b-35) HH (a-32) -CH- -NH- -CH (Me)-1-249 (b-7) (b-35) HH (a-33) -CH- -NH- -CH (Me)-1-250 (b-11) (b-35) HH (a-33) -CH- -NH --CH (Me)-1-251 (b-18) (b-35) HH (a-33) -CH- -NH- -CH (Me)-1-252 (b-20) (b-35 ) HH (a-33) -CH- -NH- -CH (Me)-1-253 (b-73) (b-35) HH (a-33) -CH- -NH- -CH (Me)- 1-254 (b-77) (b-35) HH (a-33) -CH- -NH- -CH (Me)-1-255 (b-11) (b-35) HH (a-34) -CH- -NH- -CH (Me)-1-256 (b-18) (b-35) HH (a-34) -CH- -NH- -CH (Me)-1-257 (b-20 ) (b-35) HH (a-34) -CH- -NH- -CH (Me)-1-258 (b-11) (b-35) HH (a-36) -CH- -NH-- CH (Me)-1-259 (b-18) (b-35) HH (a-36) -CH- -NH- -CH (Me)-1-260 (b-20) (b-35) HH (a-36) -CH- -NH- -CH (Me)-1-261 (b-11) (b-35) HH (a-39) -CH- -NH- -CH (Me)-1- 262 (b-18) (b-35) HH (a-39) -CH- -NH- -CH (Me)-1-263 (b-20) (b-35) HH (a-39) -CH --NH- -CH (Me)-1-264 (b-7) (b-7) HH (a-43) -CH- -NH- -CH (Me)-1-265 (b-7) ( b-35) HH (a-43) -CH- -NH- -CH (Me)-1-266 (b-11) (b-7) HH (a-43) -CH- -NH- -CH ( Me)-1-267 (b-11) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-268 (b-12) (b-35) HH (a -43) -CH- -NH- -CH (Me)-1-269 (b-15) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-270 ( b-18) (b-7) HH (a-43) -CH- -NH- -CH (Me)-1-271 (b-18) ( b-35) HH (a-43) -CH- -NH- -CH (Me)-1-272 (b-19) (b-35) HH (a-43) -CH- -NH- -CH ( Me)-1-273 (b-20) (b-7) HH (a-43) -CH- -NH- -CH (Me)-1-274 (b-20) (b-35) HH (a -43) -CH- -NH- -CH (Me)-1-275 (b-21) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-276 ( b-24) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-277 (b-25) (b-35) HH (a-43) -CH-- NH- -CH (Me)-1-278 (b-72) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-279 (b-73) (b- 7) HH (a-43) -CH- -NH- -CH (Me)-1-280 (b-73) (b-35) HH (a-43) -CH- -NH- -CH (Me) -1-281 (b-74) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-282 (b-76) (b-35) HH (a-43 ) -CH- -NH- -CH (Me)-1-283 (b-77) (b-7) HH (a-43) -CH- -NH- -CH (Me)-1-284 (b- 77) (b-35) HH (a-43) -CH- -NH- -CH (Me)-1-285 (b-11) (b-35) HH (a-44) -CH- -NH- -CH (Me)-1-286 (b-18) (b-35) HH (a-44) -CH- -NH- -CH (Me)-1-287 (b-20) (b-35) HH (a-44) -CH- -NH- -CH (Me)-1-288 (b-7) (b-35) HH (a-45) -CH- -NH- -CH (Me) -1 -289 (b-11) (b-35) HH (a-45) -CH- -NH- -CH (Me)-1-290 (b-18) (b-35) HH (a-45)- CH- -NH- -CH (Me)-1-291 (b-20) (b-35) HH (a-45) -CH- -NH --CH (Me)-1-292 (b-73) (b-35) HH (a-45) -CH- -NH- -CH (Me)-1-293 (b-77) (b-35 ) HH (a-45) -CH- -NH- -CH (Me)-1-294 (b-11) (b-35) HH (a-46) -CH- -NH- -CH (Me)- 1-295 (b-18) (b-35) HH (a-46) -CH- -NH- -CH (Me)-1-296 (b-20) (b-35) HH (a-46) -CH- -NH- -CH (Me)- .

[0079]

[Table 2]

[0080]

Embedded image

[0081]  Compd. R¹ R^Two R^Three R^Four A D E G No. Substituent No. Substituent No. Substituent No.  2-1 (b-2) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-2 (b-2) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3 (b-7) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-4 (b-7 ) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-5 (b-7) (b-12) HH (a-1) -CH- -NH-- CH (Me)-2-6 (b-7) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-7 (b-7) (b-34) HH (a-1) -CH- -NH- -CH (Me)-2-8 (b-7) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2- 9 (b-7) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-10 (b-7) (b-37) HH (a-1) -CH --NH- -CH (Me)-2-11 (b-7) (b-73) HH (a-1) -CH- -NH- -CH (Me)-2-12 (b-7) ( b-77) HH (a-1) -CH- -NH- -CH (Me)-2-13 (b-8) (b-35) HH (a-1) -CH- -NH- -CH ( Me)-2-14 (b-9) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-15 (b-10) (b-35) HH (a -1) -CH- -NH- -CH (Me)-2-16 (b-11) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-17 ( b-11) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-18 (b-11) (b-12) HH (a-1) -CH-- NH- -CH (Me)-2-19 (b-11) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-20 (b-11) (b- 34) HH (a-1) -CH- -NH- -CH (Me)-2-21 (b-11) (b-35) HH (a-1) -CH- -NH- -CH (Me) -2-22 (b-11) (b -35) HH (a-1) -CH- -NH- -COCH (Me)-2-23 (b-11) (b-37) HH (a-1) -CH- -NH- -CH (Me )-2-24 (b-11) (b-73) HH (a-1) -CH- -NH- -CH (Me)-2-25 (b-11) (b-77) HH (a- 1) -CH- -NH- -CH (Me)-2-26 (b-12) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-27 (b -12) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-28 (b-12) (b-35) HH (a-1) -CH- -NH --CH (Me)-2-29 (b-12) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-30 (b-13) (b-35 ) HH (a-1) -CH- -NH- -CH (Me)-2-31 (b-14) (b-35) HH (a-1) -CH- -NH- -CH (Me)- 2-32 (b-15) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-33 (b-15) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-34 (b-15) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-35 (b-15 ) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-36 (b-17) (b-35) HH (a-1) -CH- -NH-- CH (Me)-2-37 (b-18) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-38 (b-18) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-39 (b-18) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2- 40 (b-18) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-41 (b-18) (b-34) HH (a-1) -CH --NH- -CH (Me)-2-42 (b-18) (b-35) HH (a-1) -CH- -NH- -CH (Me)- 2-43 (b-18) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-44 (b-18) (b-37) HH (a-1) -CH- -NH- -CH (Me)-2-45 (b-18) (b-73) HH (a-1) -CH- -NH- -CH (Me)-2-46 (b-18 ) (b-77) HH (a-1) -CH- -NH- -CH (Me)-2-47 (b-19) (b-7) HH (a-1) -CH- -NH-- CH (Me)-2-48 (b-19) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-49 (b-19) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-50 (b-19) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2- 51 (b-20) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-52 (b-20) (b-7) HH (a-1) -CH --NH- -COCH (Me)-2-53 (b-20) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-54 (b-20) ( b-15) HH (a-1) -CH- -NH- -CH (Me)-2-55 (b-20) (b-34) HH (a-1) -CH- -NH- -CH ( Me)-2-56 (b-20) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-57 (b-20) (b-35) HH (a -1) -CH- -NH- -COCH (Me)-2-58 (b-20) (b-37) HH (a-1) -CH- -NH- -CH (Me)-2-59 ( b-20) (b-73) HH (a-1) -CH- -NH- -CH (Me)-2-60 (b-20) (b-77) HH (a-1) -CH-- NH- -CH (Me)-2-61 (b-21) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-62 (b-21) (b- 7) HH (a-1) -CH- -NH- -COCH (Me)-2-63 (b-21) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-64 (b-21) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-65 (b-23) (b -35) HH (a-1) -CH- -NH- -CH (Me)-2-66 (b-24) (b-7) HH (a-1) -CH- -NH- -CH (Me )-2-67 (b-24) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-68 (b-24) (b-35) HH (a- 1) -CH- -NH- -CH (Me)-2-69 (b-24) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-70 (b -25) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-71 (b-25) (b-7) HH (a-1) -CH- -NH --COCH (Me)-2-72 (b-25) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-73 (b-25) (b-35 ) HH (a-1) -CH- -NH- -COCH (Me)-2-74 (b-35) (b-35) HH (a-1) -CH- -NH- -CH (Me)- 2-75 (b-72) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-76 (b-72) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-77 (b-72) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-78 (b-72 ) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-79 (b-73) (b-7) HH (a-1) -CH- -NH-- CH (Me)-2-80 (b-73) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-81 (b-73) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-82 (b-73) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2- 83 (b-73) (b-34) HH (a-1) -CH- -NH- -CH (Me)-2-84 (b-73) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-85 (b-73) (b-35) HH (a-1) -CH- -NH- -COCH (Me) -2 -86 (b-73) (b-37) HH (a-1) -CH- -NH- -CH (Me)-2-87 (b-73) (b-73) HH (a-1)- CH- -NH- -CH (Me)-2-88 (b-73) (b-77) HH (a-1) -CH- -NH- -CH (Me)-2-89 (b-74) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-90 (b-74) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-91 (b-74) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-92 (b-74) (b-35) HH ( a-1) -CH- -NH- -COCH (Me)-2-93 (b-75) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-94 (b-76) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-95 (b-76) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-96 (b-76) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-97 (b-76) (b -35) HH (a-1) -CH- -NH- -COCH (Me)-2-98 (b-77) (b-7) HH (a-1) -CH- -NH- -CH (Me )-2-99 (b-77) (b-7) HH (a-1) -CH- -NH- -COCH (Me) -2-100 (b-77) (b-12) HH (a- 1) -CH- -NH- -CH (Me)-2-101 (b-77) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-102 (b -77) (b-34) HH (a-1) -CH- -NH- -CH (Me)-2-103 (b-77) (b-35) HH (a-1) -CH- -NH --CH (Me)-2-104 (b-77) (b-35) HH (a-1) -CH- -NH- -COCH (Me )-2-105 (b-77) (b-37) HH (a-1) -CH- -NH- -CH (Me)-2-106 (b-77) (b-73) HH (a- 1) -CH- -NH- -CH (Me)-2-107 (b-77) (b-77) HH (a-1) -CH- -NH- -CH (Me)-2-108 (b -78) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-109 (b-79) (b-35) HH (a-1) -CH- -NH --CH (Me)-2-110 (b-7) (b-7) HH (a-2) -CH- -NH- -CH (Me)-2-111 (b-7) (b-35 ) HH (a-2) -CH- -NH- -CH (Me)-2-112 (b-11) (b-7) HH (a-2) -CH- -NH- -CH (Me)- 2-113 (b-11) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-114 (b-12) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-115 (b-15) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-116 (b-18 ) (b-7) HH (a-2) -CH- -NH- -CH (Me)-2-117 (b-18) (b-35) HH (a-2) -CH- -NH-- CH (Me)-2-118 (b-19) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-119 (b-20) (b-7) HH (a-2) -CH- -NH- -CH (Me)-2-120 (b-20) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2- 121 (b-21) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-122 (b-24) (b-35) HH (a-2) -CH --NH- -CH (Me)-2-123 (b-25) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-124 (b-72) ( b-35) HH (a-2) -CH- -NH- -CH (Me)-2-125 (b-73) (b-7) HH (a-2) -CH- -NH- -CH (Me)-2-126 (b-73) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2- 127 (b-74) (b-35) HH (a-2) -CH- -NH- -CH (Me)-2-128 (b-76) (b-35) HH (a-2) -CH --NH- -CH (Me)-2-129 (b-77) (b-7) HH (a-2) -CH- -NH- -CH (Me)-2-130 (b-77) ( b-35) HH (a-2) -CH- -NH- -CH (Me)-2-131 (b-2) (b-35) HH (a-3) -CH- -NH- -CH ( Me)-2-132 (b-7) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-133 (b-7) (b-7) HH (a -3) -CH- -NH- -COCH (Me)-2-134 (b-7) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-135 ( b-7) (b-35) HH (a-3) -CH- -NH- -COCH (Me)-2-136 (b-8) (b-35) HH (a-3) -CH-- NH- -CH (Me)-2-137 (b-11) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-138 (b-11) (b- 7) HH (a-3) -CH- -NH- -COCH (Me)-2-139 (b-11) (b-35) HH (a-3) -CH- -NH- -CH (Me) -2-140 (b-11) (b-35) HH (a-3) -CH- -NH- -COCH (Me)-2-141 (b-12) (b-7) HH (a-3 ) -CH- -NH- -CH (Me)-2-142 (b-12) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-143 (b- 15) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-144 (b-15) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-145 (b-18) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2 -146 (b-18) (b-7) HH (a-3) -CH- -NH- -COCH (Me)-2-147 (b-18) (b-35) HH (a-3)- CH- -NH- -CH (Me)-2-148 (b-18) (b-35) HH (a-3) -CH- -NH- -COCH (Me)-2-149 (b-19) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-150 (b-19) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-151 (b-20) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-152 (b-20) (b-7) HH ( a-3) -CH- -NH- -COCH (Me)-2-153 (b-20) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-154 (b-20) (b-35) HH (a-3) -CH- -NH- -COCH (Me)-2-155 (b-21) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-156 (b-21) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-157 (b-24) (b -7) HH (a-3) -CH- -NH- -CH (Me)-2-158 (b-24) (b-35) HH (a-3) -CH- -NH- -CH (Me )-2-159 (b-25) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-160 (b-25) (b-35) HH (a- 3) -CH- -NH- -CH (Me)-2-161 (b-72) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-162 (b -72) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-163 (b-73) (b-7) HH (a-3) -CH- -NH --CH (Me)-2-164 (b-73) (b-7) HH (a-3) -CH- -NH- -COCH (Me)-2-165 (b-73) (b-35 ) HH (a-3) -CH- -NH- -CH (Me)-2-166 (b-73) (b-35) H H (a-3) -CH- -NH- -COCH (Me)-2-167 (b-74) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2 -168 (b-74) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-169 (b-76) (b-7) HH (a-3)- CH- -NH- -CH (Me)-2-170 (b-76) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-171 (b-77) (b-7) HH (a-3) -CH- -NH- -CH (Me)-2-172 (b-77) (b-7) HH (a-3) -CH- -NH- -COCH (Me)-2-173 (b-77) (b-35) HH (a-3) -CH- -NH- -CH (Me)-2-174 (b-77) (b-35) HH ( a-3) -CH- -NH- -COCH (Me)-2-175 (b-7) (b-7) HH (a-4) -CH- -NH- -CH (Me)-2-176 (b-7) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-177 (b-11) (b-7) HH (a-4) -CH- -NH- -CH (Me)-2-178 (b-11) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-179 (b-12) (b -35) HH (a-4) -CH- -NH- -CH (Me)-2-180 (b-15) (b-35) HH (a-4) -CH- -NH- -CH (Me )-2-181 (b-18) (b-7) HH (a-4) -CH- -NH- -CH (Me)-2-182 (b-18) (b-35) HH (a- 4) -CH- -NH- -CH (Me)-2-183 (b-19) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-184 (b -20) (b-7) HH (a-4) -CH- -NH- -CH (Me)-2-185 (b-20) (b-35) HH (a-4) -CH- -NH --CH (Me)-2-186 (b-21) (b-35) HH (a-4) -CH- -NH- -CH (M e)-2-187 (b-24) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-188 (b-25) (b-35) HH (a -4) -CH- -NH- -CH (Me)-2-189 (b-72) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-190 ( b-73) (b-7) HH (a-4) -CH- -NH- -CH (Me)-2-191 (b-73) (b-35) HH (a-4) -CH-- NH- -CH (Me)-2-192 (b-74) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-193 (b-76) (b- 35) HH (a-4) -CH- -NH- -CH (Me)-2-194 (b-77) (b-7) HH (a-4) -CH- -NH- -CH (Me) -2-195 (b-77) (b-35) HH (a-4) -CH- -NH- -CH (Me)-2-196 (b-2) (b-7) HH (a-5 ) -CH- -NH- -CH (Me)-2-197 (b-2) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-198 (b- 7) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-199 (b-7) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-200 (b-7) (b-12) HH (a-5) -CH- -NH- -CH (Me)-2-201 (b-7) (b-15) HH (a-5) -CH- -NH- -CH (Me)-2-202 (b-7) (b-34) HH (a-5) -CH- -NH- -CH (Me)-2 -203 (b-7) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-204 (b-7) (b-35) HH (a-5)- CH- -NH- -COCH (Me)-2-205 (b-7) (b-37) HH (a-5) -CH- -NH- -CH (Me)-2-206 (b-7) (b-73) HH (a-5) -CH- -NH- -CH (Me)-2-207 (b-7) (b-77) HH (a-5) -CH- -NH- -CH (Me)-2-208 (b-8) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-209 (b-9 ) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-210 (b-10) (b-35) HH (a-5) -CH- -NH-- CH (Me)-2-211 (b-11) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-212 (b-11) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-213 (b-11) (b-12) HH (a-5) -CH- -NH- -CH (Me)-2- 214 (b-11) (b-15) HH (a-5) -CH- -NH- -CH (Me)-2-215 (b-11) (b-34) HH (a-5) -CH --NH- -CH (Me)-2-216 (b-11) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-217 (b-11) ( b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-218 (b-11) (b-37) HH (a-5) -CH- -NH- -CH ( Me)-2-219 (b-11) (b-73) HH (a-5) -CH- -NH- -CH (Me) -2- 220 (b-11) (b-77) HH (a -5) -CH- -NH- -CH (Me)-2-221 (b-12) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-222 ( b-12) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-223 (b-12) (b-35) HH (a-5) -CH-- NH- -CH (Me)-2-224 (b-12) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-225 (b-13) (b- 35) HH (a-5) -CH- -NH- -CH (Me)-2-226 (b-14) (b-35) HH (a-5) -CH- -NH- -CH (Me) -2-227 (b-15) (b-7) HH (a-5) -CH- -NH- -CH (Me)- 2-228 (b-15) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-229 (b-15) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-230 (b-15) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-231 (b-17 ) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-232 (b-18) (b-7) HH (a-5) -CH- -NH-- CH (Me)-2-233 (b-18) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-234 (b-18) (b-12) HH (a-5) -CH- -NH- -CH (Me)-2-235 (b-18) (b-15) HH (a-5) -CH- -NH- -CH (Me)-2- 236 (b-18) (b-34) HH (a-5) -CH- -NH- -CH (Me)-2-237 (b-18) (b-35) HH (a-5) -CH --NH- -CH (Me)-2-238 (b-18) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-239 (b-18) ( b-37) HH (a-5) -CH- -NH- -CH (Me)-2-240 (b-18) (b-73) HH (a-5) -CH- -NH- -CH ( Me)-2-241 (b-18) (b-77) HH (a-5) -CH- -NH- -CH (Me)-2-242 (b-19) (b-7) HH (a -5) -CH- -NH- -CH (Me)-2-243 (b-19) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-244 ( b-19) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-245 (b-19) (b-35) HH (a-5) -CH-- NH- -COCH (Me)-2-246 (b-20) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-247 (b-20) (b- 7) HH (a-5) -CH- -NH- -COCH (Me)-2-248 (b-20) (b-12) HH (a-5) -CH- -NH- -CH (Me)-2-249 (b-20) (b-15) HH (a-5) -CH- -NH- -CH (Me)-2-250 (b-20) (b-34) HH (a-5) -CH- -NH- -CH (Me)-2-251 (b-20) (b-35) HH ( a-5) -CH- -NH- -CH (Me)-2-252 (b-20) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-253 (b-20) (b-37) HH (a-5) -CH- -NH- -CH (Me)-2-254 (b-20) (b-73) HH (a-5) -CH- -NH- -CH (Me)-2-255 (b-20) (b-77) HH (a-5) -CH- -NH- -CH (Me)-2-256 (b-21) (b -7) HH (a-5) -CH- -NH- -CH (Me)-2-257 (b-21) (b-7) HH (a-5) -CH- -NH- -COCH (Me )-2-258 (b-21) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-259 (b-21) (b-35) HH (a- 5) -CH- -NH- -COCH (Me)-2-260 (b-23) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-261 (b -24) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-262 (b-24) (b-7) HH (a-5) -CH- -NH --COCH (Me)-2-263 (b-24) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-264 (b-24) (b-35 ) HH (a-5) -CH- -NH- -COCH (Me)-2-265 (b-25) (b-7) HH (a-5) -CH- -NH- -CH (Me)- 2-266 (b-25) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-267 (b-25) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-268 (b-25) (b-35) HH (a -5) -CH- -NH- -COCH (Me)-2-269 (b-35) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-270 ( b-72) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-271 (b-72) (b-7) HH (a-5) -CH-- NH- -COCH (Me)-2-272 (b-72) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-273 (b-72) (b- 35) HH (a-5) -CH- -NH- -COCH (Me)-2-274 (b-73) (b-7) HH (a-5) -CH- -NH- -CH (Me) -2-275 (b-73) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-276 (b-73) (b-12) HH (a-5 ) -CH- -NH- -CH (Me)-2-277 (b-73) (b-15) HH (a-5) -CH- -NH- -CH (Me)-2-278 (b- 73) (b-34) HH (a-5) -CH- -NH- -CH (Me)-2-279 (b-73) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-280 (b-73) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-281 (b-73) (b-37) HH (a-5) -CH- -NH- -CH (Me)-2-282 (b-73) (b-73) HH (a-5) -CH- -NH- -CH (Me) -2 -283 (b-73) (b-77) HH (a-5) -CH- -NH- -CH (Me)-2-284 (b-74) (b-7) HH (a-5)- CH- -NH- -CH (Me)-2-285 (b-74) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-286 (b-74) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-287 (b-74) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-288 (b-75) (b-35) HH (a-5) -CH- -NH --CH (Me)-2-289 (b-76) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-290 (b-76) (b-7 ) HH (a-5) -CH- -NH- -COCH (Me)-2-291 (b-76) (b-35) HH (a-5) -CH- -NH- -CH (Me)- 2-292 (b-76) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2-293 (b-77) (b-7) HH (a-5) -CH- -NH- -CH (Me)-2-294 (b-77) (b-7) HH (a-5) -CH- -NH- -COCH (Me)-2-295 (b-77 ) (b-12) HH (a-5) -CH- -NH- -CH (Me)-2-296 (b-77) (b-15) HH (a-5) -CH- -NH-- CH (Me)-2-297 (b-77) (b-34) HH (a-5) -CH- -NH- -CH (Me)-2-298 (b-77) (b-35) HH (a-5) -CH- -NH- -CH (Me)-2-299 (b-77) (b-35) HH (a-5) -CH- -NH- -COCH (Me)-2- 300 (b-77) (b-37) HH (a-5) -CH- -NH- -CH (Me)-2-301 (b-77) (b-73) HH (a-5) -CH --NH- -CH (Me)-2-302 (b-77) (b-77) HH (a-5) -CH- -NH- -CH (Me)-2-303 (b-78) ( b-35) HH (a-5) -CH- -NH- -CH (Me)-2-304 (b-79) (b-35) HH (a-5) -CH- -NH- -CH ( Me)-2-305 (b-7) (b-7) HH (a-6) -CH- -NH- -CH (Me)-2-306 (b-7) (b-35) HH (a -6) -CH- -NH- -CH (Me)-2-307 (b-11) (b-7) HH (a-6) -CH- -NH- -CH (Me)-2-308 ( b-11) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-309 (b- 12) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-310 (b-15) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-311 (b-18) (b-7) HH (a-6) -CH- -NH- -CH (Me)-2-312 (b-18) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-313 (b-19) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2 -314 (b-20) (b-7) HH (a-6) -CH- -NH- -CH (Me)-2-315 (b-20) (b-35) HH (a-6)- CH- -NH- -CH (Me)-2-316 (b-21) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-317 (b-24) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-318 (b-25) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-319 (b-72) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-320 (b-73) (b-7) HH ( a-6) -CH- -NH- -CH (Me)-2-321 (b-73) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-322 (b-74) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-323 (b-76) (b-35) HH (a-6) -CH- -NH- -CH (Me)-2-324 (b-77) (b-7) HH (a-6) -CH- -NH- -CH (Me)-2-325 (b-77) (b -35) HH (a-6) -CH- -NH- -CH (Me)-2-326 (b-2) (b-35) HH (a-7) -CH- -NH- -CH (Me )-2-327 (b-7) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-328 (b-7) (b-7) HH (a- 7) -CH- -NH- -COCH (Me)-2-329 (b-7) (b-35) HH (a-7) -CH- -N H- -CH (Me)-2-330 (b-7) (b-35) HH (a-7) -CH- -NH- -COCH (Me)-2-331 (b-8) (b- 35) HH (a-7) -CH- -NH- -CH (Me)-2-332 (b-11) (b-7) HH (a-7) -CH- -NH- -CH (Me) -2-333 (b-11) (b-7) HH (a-7) -CH- -NH- -COCH (Me)-2-334 (b-11) (b-35) HH (a-7 ) -CH- -NH- -CH (Me)-2-335 (b-11) (b-35) HH (a-7) -CH- -NH- -COCH (Me)-2-336 (b- 12) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-337 (b-12) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-338 (b-15) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-339 (b-15) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-340 (b-18) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2 -341 (b-18) (b-7) HH (a-7) -CH- -NH- -COCH (Me)-2-342 (b-18) (b-35) HH (a-7)- CH- -NH- -CH (Me)-2-343 (b-18) (b-35) HH (a-7) -CH- -NH- -COCH (Me)-2-344 (b-19) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-345 (b-19) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-346 (b-20) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-347 (b-20) (b-7) HH ( a-7) -CH- -NH- -COCH (Me)-2-348 (b-20) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-349 (b-20) (b-35) HH (a-7) -CH- -NH- -COCH (Me)-2-350 (b-21) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-351 (b-21) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-352 (b-24) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-353 (b-24) (b -35) HH (a-7) -CH- -NH- -CH (Me)-2-354 (b-25) (b-7) HH (a-7) -CH- -NH- -CH (Me )-2-355 (b-25) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-356 (b-72) (b-7) HH (a- 7) -CH- -NH- -CH (Me)-2-357 (b-72) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-358 (b -73) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-359 (b-73) (b-7) HH (a-7) -CH- -NH --COCH (Me)-2-360 (b-73) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-361 (b-73) (b-35 ) HH (a-7) -CH- -NH- -COCH (Me)-2-362 (b-74) (b-7) HH (a-7) -CH- -NH- -CH (Me)- 2-363 (b-74) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-364 (b-76) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-365 (b-76) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-366 (b-77 ) (b-7) HH (a-7) -CH- -NH- -CH (Me)-2-367 (b-77) (b-7) HH (a-7) -CH- -NH-- COCH (Me)-2-368 (b-77) (b-35) HH (a-7) -CH- -NH- -CH (Me)-2-369 (b-77) (b-35) HH (a-7) -CH- -NH- -COCH (Me)-2-370 (b-7) (b-7) HH (a-8) -CH- -NH- -CH (Me)-2-371 (b-7) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-372 (b-11 ) (b-7) HH (a-8) -CH- -NH- -CH (Me)-2-373 (b-11) (b-35) HH (a-8) -CH- -NH-- CH (Me)-2-374 (b-12) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-375 (b-15) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-376 (b-18) (b-7) HH (a-8) -CH- -NH- -CH (Me)-2- 377 (b-18) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-378 (b-19) (b-35) HH (a-8) -CH --NH- -CH (Me)-2-379 (b-20) (b-7) HH (a-8) -CH- -NH- -CH (Me)-2-380 (b-20) ( b-35) HH (a-8) -CH- -NH- -CH (Me)-2-381 (b-21) (b-35) HH (a-8) -CH- -NH- -CH ( Me)-2-382 (b-24) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-383 (b-25) (b-35) HH (a -8) -CH- -NH- -CH (Me)-2-384 (b-72) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-385 ( b-73) (b-7) HH (a-8) -CH- -NH- -CH (Me)-2-386 (b-73) (b-35) HH (a-8) -CH-- NH- -CH (Me)-2-387 (b-74) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-388 (b-76) (b- 35) HH (a-8) -CH- -NH- -CH (Me)-2-389 (b-77) (b-7) HH (a-8) -CH- -NH- -CH (Me) -2-390 (b-77) (b-35) HH (a-8) -CH- -NH- -CH (Me)-2-391 (b-7) (b-35) HH (a-9) -CH- -NH- -CH (Me)-2-392 (b-11) (b-35) HH (a-9) -CH- -NH- -CH (Me)-2-393 (b-18) (b-35) HH (a-9) -CH- -NH- -CH (Me)-2-394 (b-7) (b -35) HH (a-10) -CH- -NH- -CH (Me)-2-395 (b-11) (b-35) HH (a-10) -CH- -NH- -CH (Me )-2-396 (b-18) (b-35) HH (a-10) -CH- -NH- -CH (Me)-2-397 (b-20) (b-35) HH (a- 10) -CH- -NH- -CH (Me)-2-398 (b-73) (b-35) HH (a-10) -CH- -NH- -CH (Me)-2-399 (b -77) (b-35) HH (a-10) -CH- -NH- -CH (Me)-2-400 (b-7) (b-7) HH (a-11) -CH- -NH --CH (Me)-2-401 (b-7) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-402 (b-11) (b-7 ) HH (a-11) -CH- -NH- -CH (Me)-2-403 (b-11) (b-35) HH (a-11) -CH- -NH- -CH (Me)- 2-404 (b-12) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-405 (b-15) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-406 (b-18) (b-7) HH (a-11) -CH- -NH- -CH (Me)-2-407 (b-18 ) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-408 (b-19) (b-35) HH (a-11) -CH- -NH-- CH (Me)-2-409 (b-20) (b-7) HH (a-11) -CH- -NH- -CH (Me)-2-410 (b-20) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-411 (b-21) (b-3 5) HH (a-11) -CH- -NH- -CH (Me)-2-412 (b-24) (b-35) HH (a-11) -CH- -NH- -CH (Me) -2-413 (b-25) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-414 (b-72) (b-35) HH (a-11 ) -CH- -NH- -CH (Me)-2-415 (b-73) (b-7) HH (a-11) -CH- -NH- -CH (Me)-2-416 (b- 73) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-417 (b-74) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-418 (b-76) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2-419 (b-77) (b-7) HH (a-11) -CH- -NH- -CH (Me)-2-420 (b-77) (b-35) HH (a-11) -CH- -NH- -CH (Me)-2 -421 (b-7) (b-35) HH (a-12) -CH- -NH- -CH (Me)-2-422 (b-11) (b-35) HH (a-12)- CH- -NH- -CH (Me)-2-423 (b-18) (b-35) HH (a-12) -CH- -NH- -CH (Me)-2-424 (b-20) (b-35) HH (a-12) -CH- -NH- -CH (Me)-2-425 (b-73) (b-35) HH (a-12) -CH- -NH- -CH (Me)-2-426 (b-77) (b-35) HH (a-12) -CH- -NH- -CH (Me)-2-427 (b-7) (b-35) HH ( a-13) -CH- -NH- -CH (Me)-2-428 (b-11) (b-35) HH (a-13) -CH- -NH- -CH (Me)-2-429 (b-18) (b-35) HH (a-13) -CH- -NH- -CH (Me)-2-430 (b-1) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-431 (b-2) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-432 (b-2) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2- 433 (b-2) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-434 (b-2) (b-15) HH (a-14) -CH --NH- -CH (Me)-2-435 (b-2) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-436 (b-2) ( b-35) HH (a-14) -CH- -NH- -CH (Me)-2-437 (b-2) (b-35) HH (a-14) -CH- -NH--(CH_Two)_Two-2-438 (b-2) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-439 (b-2) (b-73) HH (a-14 ) -CH- -NH- -CH (Me)-2-440 (b-2) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-441 (b- 3) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-442 (b-4) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-443 (b-5) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-444 (b-6) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-445 (b-7) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2 -446 (b-7) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2-447 (b-7) (b-7) HH (a-14)- CH- -NH- single bond 2-448 (b-7) (b-7) HH (a-14) -CH- -NH- -CH_Two-2-449 (b-7) (b-7) H H (a-14) -CH- -NH--(CH_Two)_Two-2-450 (b-7) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-451 (b-7) (b-7) HH (a-14 ) -CH- -NH- -CH (Et)-2-452 (b-7) (b-7) HH (a-14) -CH- -NH--(CH_Two)_Three-2-453 (b-7) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-454 (b-7) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-455 (b-7) (b-7) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-456 (b-7) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-457 (b-7) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-458 (b-7) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-459 (b-7) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-460 (b-7) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-461 (b-7) (b-7) HH (a-14) -CH- -NH- -CO- 2-462 (b-7) (b-7) HH (a- 14) -CH- -NH- -COCH_Two-2-463 (b-7) (b-7) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-464 (b-7) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-465 (b-7) (b-7) HH (a-14 ) -CH- -NH- -COCH (Et)-2-466 (b-7) (b-7) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-467 (b-7) (b-7) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-468 (b-7) (b-7) H H (a-14) -CH- -O- -CH_Two-2-469 (b-7) (b-7) H H (a-14) -CH- -O--(CH_Two)_Two-2-470 (b-7) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-471 (b-7) (b-7) HH (a-14 ) -CH- -S- -CH_Two-2-472 (b-7) (b-7) H H (a-14) -CH- -S--(CH_Two)_Two-2-473 (b-7) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-474 (b-7) (b-7) 4-FH (a -14) -CH- -NH- -CH (Me)-2-475 (b-7) (b-7) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 476 (b-7) (b-7) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-477 (b-7) (b-7) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-478 (b-7) (b-7) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-479 (b-7) (b-7) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-480 (b-7) (b-7) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-481 (b-7) (b-7) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-482 (b-7) (b-7) HH (a-14) N -CO- -CH_Two-2-483 (b-7) (b-7) H H (a-14) N -CO--(CH_Two)_Two-2-484 (b-7) (b-7) HH (a-14) N -CO- -CH (Me)-2-485 (b-7) (b-8) HH (a-14)- CH- -NH- -CH (Me)-2-486 (b-7) (b-10) HH (a-14) -CH- -NH- -CH (Me)-2-487 (b-7) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-488 (b-7) (b-11) HH (a-14) -CH- -NH- -COCH (Me)-2-489 (b-7) (b-11) HH (a-14) -CH- -O- -CH (Me)-2-490 (b-7) (b-11) HH ( a-14) -CH- -S- -CH (Me)-2-491 (b-7) (b-12) HH (a-14) -CH- -NH--(CH_Two)_Two-2-492 (b-7) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-493 (b-7) (b-12) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-494 (b-7) (b-12) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-495 (b-7) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-496 (b-7) (b-12) HH (a-14 ) -CH- -O- -CH (Me)-2-497 (b-7) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-498 (b- 7) (b-12) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-499 (b-7) (b-12) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-500 (b-7) (b-12) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-501 ( b-7) (b-12) 4-MeO H (a-14) -CH- -NH- -CH (Me)-2-502 (b-7) (b-12) 4-MeO 5-MeO ( a-14) -CH- -NH- -CH (Me)-2-503 (b-7) (b-12) HH (a-14) N -CO- -CH (Me)-2-504 (b -7) (b-13) HH (a-14) -CH- -NH- -CH (Me)-2-505 (b-7) (b-14) HH (a-14) -CH- -NH --CH (Me)-2-506 (b-7) (b-14) HH (a-14) -CH- -NH- -COCH (Me)-2-507 (b-7) (b-14 ) HH (a-14) -CH- -O- -CH (Me)-2-508 (b-7) (b-14) HH (a-14) -CH- -S- -CH (Me)- 2-509 (b-7) (b-15) HH (a-14) -CH- -NH--(CH_Two)_Two-2-510 (b-7) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-511 (b-7) (b-15) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-512 (b-7) (b-15) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-513 (b-7) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-514 (b-7) (b-15) HH (a-14 ) -CH- -O- -CH (Me)-2-515 (b-7) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-516 (b- 7) (b-15) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-517 (b-7) (b-15) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-518 (b-7) (b-15) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-519 ( b-7) (b-15) HH (a-14) N -CO- -CH (Me)-2-520 (b-7) (b-16) HH (a-14) -CH- -NH- -CH (Me)-2-521 (b-7) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-522 (b-7) (b-17) HH (a-14) -CH- -NH- -COCH (Me)-2-523 (b-7) (b-17) HH (a-14) -CH- -O- -CH (Me)-2 -524 (b-7) (b-17) HH (a-14) -CH- -S- -CH (Me)-2-525 (b-7) (b-23) HH (a-14)- CH- -NH- -CH (Me)-2-526 (b-7) (b-24) HH (a-14) -CH- -NH- -CH (Me)-2-527 (b-7) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-528 (b-7) (b-25) HH (a-14) -CH- -NH- -COCH (Me)-2-529 (b-7) (b-25) HH (a-14) -CH- -O- -CH (Me)-2-530 (b-7) (b-25) HH ( a-14) -CH- -S- -CH (Me)-2-531 (b-7) (b-27) HH (a-14) -CH- -NH- -CH (Me)-2-532 (b-7) (b-28) HH (a-14) -CH- -NH- -CH (Me)-2-533 (b-7) (b-30) HH (a-14) -CH- -NH- -CH (Me)-2-534 (b-7) (b-31) HH (a-14) -CH- -NH- -CH (Me)-2-535 (b-7) (b-32) HH (a-14) -CH- -NH- -CH (Me)-2-536 (b-7) (b-33) HH ( a-14) -CH- -NH- -CH (Me)-2-537 (b-7) (b-33) HH (a-14) -CH- -NH- -COCH (Me)-2-538 (b-7) (b-33) HH (a-14) -CH- -O- -CH (Me)-2-539 (b-7) (b-33) HH (a-14) -CH- -S- -CH (Me)-2-540 (b-7) (b-34) HH (a-14) -CH- -NH--(CH_Two)_Two-2-541 (b-7) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-542 (b-7) (b-34) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-543 (b-7) (b-34) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-544 (b-7) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-545 (b-7) (b-34) HH (a-14 ) -CH- -O- -CH (Me)-2-546 (b-7) (b-34) HH (a-14) -CH- -S- -CH (Me)-2-547 (b- 7) (b-34) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-548 (b-7) (b-34) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-549 (b-7) (b-34) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-550 ( b-7) (b-34) HH (a-14) N -CO- -CH (Me)-2-551 (b-7) (b-35) HH (a-14) -CH- -NH- single bond 2-552 (b-7) (b-35) HH (a-14) -CH- -NH- -CH_Two-2-553 (b-7) (b-35) H H (a-14) -CH- -NH--(CH_Two)_Two-2-554 (b-7) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-555 (b-7) (b-35) HH (a-14 ) -CH- -NH- -CH (Et)-2-556 (b-7) (b-35) HH (a-14) -CH- -NH--(CH_Two)_Three-2-557 (b-7) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-558 (b-7) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-559 (b-7) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-560 (b-7) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-561 (b-7) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-562 (b-7) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-563 (b-7) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-564 (b-7) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-565 (b-7) (b-35) HH (a-14) -CH- -NH- -CO- 2-566 (b-7) (b-35) HH (a- 14) -CH- -NH- -COCH_Two-2-567 (b-7) (b-35) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-568 (b-7) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-569 (b-7) (b-35) HH (a-14 ) -CH- -NH- -COCH (Et)-2-570 (b-7) (b-35) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-571 (b-7) (b-35) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-572 (b-7) (b-35) H H (a-14) -CH- -O- -CH_Two-2-573 (b-7) (b-35) H H (a-14) -CH- -O--(CH_Two)_Two-2-574 (b-7) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-575 (b-7) (b-35) HH (a-14 ) -CH- -S- -CH_Two-2-576 (b-7) (b-35) H H (a-14) -CH- -S--(CH_Two)_Two-2-577 (b-7) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-578 (b-7) (b-35) 4-FH (a -14) -CH- -NH- -CH (Me)-2-579 (b-7) (b-35) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 580 (b-7) (b-35) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-581 (b-7) (b-35) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-582 (b-7) (b-35) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-583 (b-7) (b-35) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-584 (b-7) (b-35) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-585 (b-7) (b-35) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-586 (b-7) (b-35) HH (a-14) N -CO- -CH_Two-2-587 (b-7) (b-35) H H (a-14) N -CO--(CH_Two)_Two-2-588 (b-7) (b-35) HH (a-14) N -CO- -CH (Me)-2-589 (b-7) (b-37) HH (a-14)- CH- -NH- single bond 2-590 (b-7) (b-37) HH (a-14) -CH- -NH- -CH_Two-2-591 (b-7) (b-37) H H (a-14) -CH- -NH--(CH_Two)_Two-2-592 (b-7) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-593 (b-7) (b-37) HH (a-14 ) -CH- -NH- -CH (Et)-2-594 (b-7) (b-37) HH (a-14) -CH- -NH--(CH_Two)_Three-2-595 (b-7) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-596 (b-7) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-597 (b-7) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-598 (b-7) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (Ph)-2-599 (b-7) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-600 (b-7) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-601 (b-7) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-602 (b-7) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-603 (b-7) (b-37) HH (a-14) -CH- -NH- -CO- 2-604 (b-7) (b-37) HH (a- 14) -CH- -NH- -COCH_Two-2-605 (b-7) (b-37) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-606 (b-7) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-607 (b-7) (b-37) HH (a-14 ) -CH- -NH- -COCH (Et)-2-608 (b-7) (b-37) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-609 (b-7) (b-37) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-610 (b-7) (b-37) H H (a-14) -CH- -O- -CH_Two-2-611 (b-7) (b-37) H H (a-14) -CH- -O--(CH_Two)_Two-2-612 (b-7) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-613 (b-7) (b-37) HH (a-14 ) -CH- -S- -CH_Two-2-614 (b-7) (b-37) H H (a-14) -CH- -S--(CH_Two)_Two-2-615 (b-7) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-616 (b-7) (b-37) 4-FH (a -14) -CH- -NH- -CH (Me)-2-617 (b-7) (b-37) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 618 (b-7) (b-37) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-619 (b-7) (b-37) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-620 (b-7) (b-37) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-621 (b-7) (b-37) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-622 (b-7) (b-37) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-623 (b-7) (b-37) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-624 (b-7) (b-37) HH (a-14) N -CO- -CH_Two-2-625 (b-7) (b-37) H H (a-14) N -CO--(CH_Two)_Two-2-626 (b-7) (b-37) HH (a-14) N -CO- -CH (Me)-2-627 (b-7) (b-38) HH (a-14)- CH- -NH- -CH (Me)-2-628 (b-7) (b-41) HH (a-14) -CH- -NH- -CH (Me)-2-629 (b-7) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-630 (b-7) (b-42) HH (a-14) -CH- -NH- -COCH (Me)-2-631 (b-7) (b-42) HH (a-14) -CH- -O- -CH (Me)-2-632 (b-7) (b-42) HH ( a-14) -CH- -S- -CH (Me)-2-633 (b-7) (b-43) HH (a-14) -CH- -NH- -CH (Me)-2-634 (b-7) (b-72) HH (a-14) -CH- -NH--(CH_Two)_Two-2-635 (b-7) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-636 (b-7) (b-72) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-637 (b-7) (b-72) HH (a-14) -CH- -NH- -COCH (Me)-2-638 (b-7) (b-72) HH (a-14) -CH- -O- -CH (Me)-2-639 (b-7) (b-72) HH (a-14) -CH- -S- -CH (Me)-2- 640 (b-7) (b-72) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-641 (b-7) (b-72) 4-OH H ( a-14) -CH- -NH- -CH (Me)-2-642 (b-7) (b-72) 6-OH H (a-14) -CH- -NH- -CH (Me)- 2-643 (b-7) (b-73) HH (a-14) -CH- -NH- single bond 2-644 (b-7) (b-73) HH (a-14) -CH-- NH- -CH_Two-2-645 (b-7) (b-73) H H (a-14) -CH- -NH--(CH_Two)_Two-2-646 (b-7) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-647 (b-7) (b-73) HH (a-14 ) -CH- -NH- -CH (Et)-2-648 (b-7) (b-73) HH (a-14) -CH- -NH--(CH_Two)_Three-2-649 (b-7) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-650 (b-7) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-651 (b-7) (b-73) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-652 (b-7) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-653 (b-7) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-654 (b-7) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-655 (b-7) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-656 (b-7) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-657 (b-7) (b-73) HH (a-14) -CH- -NH- -CO- 2-658 (b-7) (b-73) HH (a- 14) -CH- -NH- -COCH_Two-2-659 (b-7) (b-73) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-660 (b-7) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-661 (b-7) (b-73) HH (a-14 ) -CH- -NH- -COCH (Et)-2-662 (b-7) (b-73) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-663 (b-7) (b-73) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-664 (b-7) (b-73) H H (a-14) -CH- -O- -CH_Two-2-665 (b-7) (b-73) H H (a-14) -CH- -O--(CH_Two)_Two-2-666 (b-7) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-667 (b-7) (b-73) HH (a-14 ) -CH- -S- -CH_Two-2-668 (b-7) (b-73) H H (a-14) -CH- -S--(CH_Two)_Two-2-669 (b-7) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-670 (b-7) (b-73) 4-FH (a -14) -CH- -NH- -CH (Me)-2-671 (b-7) (b-73) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 672 (b-7) (b-73) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-673 (b-7) (b-73) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-674 (b-7) (b-73) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-675 (b-7) (b-73) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-676 (b-7) (b-73) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-677 (b-7) (b-73) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-678 (b-7) (b-73) HH (a-14) N -CO- -CH_Two-2-679 (b-7) (b-73) H H (a-14) N -CO--(CH_Two)_Two-2-680 (b-7) (b-73) HH (a-14) N -CO- -CH (Me)-2-681 (b-7) (b-74) HH (a-14)- CH- -NH- -CH (Me)-2-682 (b-7) (b-74) HH (a-14) -CH- -NH- -COCH (Me)-2-683 (b-7) (b-74) HH (a-14) -CH- -O- -CH (Me)-2-684 (b-7) (b-74) HH (a-14) -CH- -S- -CH (Me)-2-685 (b-7) (b-75) HH (a-14) -CH- -NH- -CH (Me)-2-686 (b-7) (b-76) HH ( a-14) -CH- -NH- -CH (Me)-2-687 (b-7) (b-76) HH (a-14) -CH- -NH- -COCH (Me) -2-688 (b-7) (b-76) HH (a-14) -CH- -O- -CH (Me)-2-689 (b-7) (b-76) HH (a-14) -CH- -S- -CH (Me)-2-690 (b-7) (b-77) HH (a-14) -CH- -NH--(CH_Two)_Two-2-691 (b-7) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-692 (b-7) (b-77) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-693 (b-7) (b-77) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-694 (b-7) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-695 (b-7) (b-77) HH (a-14 ) -CH- -O- -CH (Me)-2-696 (b-7) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-697 (b- 7) (b-77) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-698 (b-7) (b-77) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-699 (b-7) (b-77) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-700 ( b-7) (b-77) HH (a-14) N -CO- -CH (Me)-2-701 (b-7) (b-78) HH (a-14) -CH- -NH- -CH (Me)-2-702 (b-8) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-703 (b-8) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-704 (b-9) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2 -705 (b-9) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-706 (b-10) (b-7) HH (a-14)- CH- -NH- -CH (Me)-2-707 (b-10) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-708 (b-11) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-709 (b-11) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2-710 (b-11) (b-7) HH (a-14) -CH- -NH- single bond 2-711 (b-11) (b-7) HH (a-14) -CH- -NH- -CH_Two-2-712 (b-11) (b-7) H H (a-14) -CH- -NH--(CH_Two)_Two-2-713 (b-11) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-714 (b-11) (b-7) HH (a-14 ) -CH- -NH- -CH (Et)-2-715 (b-11) (b-7) HH (a-14) -CH- -NH--(CH_Two)_Three-2-716 (b-11) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-717 (b-11) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-718 (b-11) (b-7) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-719 (b-11) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-720 (b-11) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-721 (b-11) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-722 (b-11) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-723 (b-11) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-724 (b-11) (b-7) HH (a-14) -CH- -NH- -CO- 2-725 (b-11) (b-7) HH (a- 14) -CH- -NH- -COCH_Two-2-726 (b-11) (b-7) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-727 (b-11) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-728 (b-11) (b-7) HH (a-14 ) -CH- -NH- -COCH (Et)-2-729 (b-11) (b-7) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-730 (b-11) (b-7) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-731 (b-11) (b-7) H H (a-14) -CH- -O- -CH_Two-2-732 (b-11) (b-7) H H (a-14) -CH- -O--(CH_Two)_Two-2-733 (b-11) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-734 (b-11) (b-7) HH (a-14 ) -CH- -S- -CH_Two-2-735 (b-11) (b-7) H H (a-14) -CH- -S--(CH_Two)_Two-2-736 (b-11) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-737 (b-11) (b-7) 4-FH (a -14) -CH- -NH- -CH (Me)-2-738 (b-11) (b-7) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 739 (b-11) (b-7) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-740 (b-11) (b-7) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-741 (b-11) (b-7) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-742 (b-11) (b-7) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-743 (b-11) (b-7) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-744 (b-11) (b-7) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-745 (b-11) (b-7) HH (a-14) N -CO- -CH_Two-2-746 (b-11) (b-7) H H (a-14) N -CO--(CH_Two)_Two-2-747 (b-11) (b-7) HH (a-14) N -CO- -CH (Me)-2-748 (b-11) (b-8) HH (a-14)- CH- -NH- -CH (Me)-2-749 (b-11) (b-10) HH (a-14) -CH- -NH- -CH (Me)-2-750 (b-11) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-751 (b-11) (b-11) HH (a-14) -CH- -NH- -COCH (Me)-2-752 (b-11) (b-11) HH (a-14) -CH- -O- -CH (Me)-2-753 (b-11) (b-11) HH ( a-14) -CH- -S- -CH (Me)-2-754 (b-11) (b-12) HH (a-14) -CH- -NH--(CH_Two)_Two-2-755 (b-11) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-756 (b-11) (b-12) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-757 (b-11) (b-12) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-758 (b-11) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-759 (b-11) (b-12) HH (a-14 ) -CH- -O- -CH (Me)-2-760 (b-11) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-761 (b- 11) (b-12) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-762 (b-11) (b-12) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-763 (b-11) (b-12) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-764 ( b-11) (b-12) HH (a-14) N -CO- -CH (Me)-2-765 (b-11) (b-13) HH (a-14) -CH- -NH- -CH (Me)-2-766 (b-11) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-767 (b-11) (b-14) HH (a-14) -CH- -NH- -COCH (Me)-2-768 (b-11) (b-14) HH (a-14) -CH- -O- -CH (Me)-2 -769 (b-11) (b-14) HH (a-14) -CH- -S- -CH (Me)-2-770 (b-11) (b-15) HH (a-14)- CH- -NH--(CH_Two)_Two-2-771 (b-11) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-772 (b-11) (b-15) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-773 (b-11) (b-15) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-774 (b-11) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-775 (b-11) (b-15) HH (a-14 ) -CH- -O- -CH (Me)-2-776 (b-11) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-777 (b- 11) (b-15) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-778 (b-11) (b-15) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-779 (b-11) (b-15) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-780 ( b-11) (b-15) HH (a-14) N -CO- -CH (Me)-2-781 (b-11) (b-16) HH (a-14) -CH- -NH- -CH (Me)-2-782 (b-11) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-783 (b-11) (b-17) HH (a-14) -CH- -NH- -COCH (Me)-2-784 (b-11) (b-17) HH (a-14) -CH- -O- -CH (Me)-2 -785 (b-11) (b-17) HH (a-14) -CH- -S- -CH (Me)-2-786 (b-11) (b-23) HH (a-14)- CH- -NH- -CH (Me)-2-787 (b-11) (b-24) HH (a-14) -CH- -NH- -CH (Me)-2-788 (b-11) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-789 (b-11) (b-25) HH (a-14) -CH- -NH- -COCH (Me)-2-790 (b-11) (b-25) HH (a-14) -CH- -O- -CH (Me)-2-791 (b-11) (b-25) HH ( a-14) -CH- -S- -CH (Me)-2-792 (b-11) (b-27) HH (a-14) -CH- -NH- -CH (Me)-2-793 (b-11) (b-28) HH (a-14) -CH- -NH-- CH (Me)-2-794 (b-11) (b-30) HH (a-14) -CH- -NH- -CH (Me)-2-795 (b-11) (b-31) HH (a-14) -CH- -NH- -CH (Me)-2-796 (b-11) (b-32) HH (a-14) -CH- -NH- -CH (Me)-2- 797 (b-11) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-798 (b-11) (b-33) HH (a-14) -CH --NH- -COCH (Me)-2-799 (b-11) (b-33) HH (a-14) -CH- -O- -CH (Me)-2-800 (b-11) ( b-33) HH (a-14) -CH- -S- -CH (Me)-2-801 (b-11) (b-34) HH (a-14) -CH- -NH--(CH_Two)_Two-2-802 (b-11) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-803 (b-11) (b-34) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-804 (b-11) (b-34) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-805 (b-11) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-806 (b-11) (b-34) HH (a-14 ) -CH- -O- -CH (Me)-2-807 (b-11) (b-34) HH (a-14) -CH- -S- -CH (Me)-2-808 (b- 11) (b-34) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-809 (b-11) (b-34) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-810 (b-11) (b-34) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-811 ( b-11) (b-34) HH (a-14) N -CO- -CH (Me)-2-812 (b-11) (b-35) HH (a-14) -CH- -NH- single bond 2-813 (b-11) (b-35) HH (a-14) -CH- -NH- -CH_Two-2-814 (b-11) (b-35) H H (a-14) -CH- -NH--(CH_Two)_Two-2-815 (b-11) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-816 (b-11) (b-35) HH (a-14 ) -CH- -NH- -CH (Et)-2-817 (b-11) (b-35) HH (a-14) -CH- -NH--(CH_Two)_Three-2-818 (b-11) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-819 (b-11) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-820 (b-11) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-821 (b-11) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-822 (b-11) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-823 (b-11) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-824 (b-11) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-825 (b-11) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-826 (b-11) (b-35) HH (a-14) -CH- -NH- -CO- 2-827 (b-11) (b-35) HH (a- 14) -CH- -NH- -COCH_Two-2-828 (b-11) (b-35) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-829 (b-11) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-830 (b-11) (b-35) HH (a-14 ) -CH- -NH- -COCH (Et)-2-831 (b-11) (b-35) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-832 (b-11) (b-35) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-833 (b-11) (b-35) H H (a-14) -CH- -O- -CH_Two-2-834 (b-11) (b-35) H H (a-14) -CH- -O--(CH_Two)_Two-2-835 (b-11) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-836 (b-11) (b-35) HH (a-14 ) -CH- -S- -CH_Two-2-837 (b-11) (b-35) H H (a-14) -CH- -S--(CH_Two)_Two-2-838 (b-11) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-839 (b-11) (b-35) 4-FH (a -14) -CH- -NH- -CH (Me)-2-840 (b-11) (b-35) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 841 (b-11) (b-35) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-842 (b-11) (b-35) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-843 (b-11) (b-35) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-844 (b-11) (b-35) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-845 (b-11) (b-35) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-846 (b-11) (b-35) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-847 (b-11) (b-35) HH (a-14) N -CO- -CH_Two-2-848 (b-11) (b-35) H H (a-14) N -CO--(CH_Two)_Two-2-849 (b-11) (b-35) HH (a-14) N -CO- -CH (Me)-2-850 (b-11) (b-37) HH (a-14)- CH- -NH- single bond 2-851 (b-11) (b-37) HH (a-14) -CH- -NH- -CH_Two-2-852 (b-11) (b-37) H H (a-14) -CH- -NH--(CH_Two)_Two-2-853 (b-11) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-854 (b-11) (b-37) HH (a-14 ) -CH- -NH- -CH (Et)-2-855 (b-11) (b-37) HH (a-14) -CH- -NH--(CH_Two)_Three-2-856 (b-11) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-857 (b-11) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-858 (b-11) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-859 (b-11) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-860 (b-11) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-861 (b-11) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-862 (b-11) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-863 (b-11) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-864 (b-11) (b-37) HH (a-14) -CH- -NH- -CO- 2-865 (b-11) (b-37) HH (a- 14) -CH- -NH- -COCH_Two-2-866 (b-11) (b-37) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-867 (b-11) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-868 (b-11) (b-37) HH (a-14 ) -CH- -NH- -COCH (Et)-2-869 (b-11) (b-37) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-870 (b-11) (b-37) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-871 (b-11) (b-37) H H (a-14) -CH- -O- -CH_Two-2-872 (b-11) (b-37) H H (a-14) -CH- -O--(CH_Two)_Two-2-873 (b-11) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-874 (b-11) (b-37) HH (a-14 ) -CH- -S- -CH_Two-2-875 (b-11) (b-37) H H (a-14) -CH- -S--(CH_Two)_Two-2-876 (b-11) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-877 (b-11) (b-37) 4-FH (a -14) -CH- -NH- -CH (Me)-2-878 (b-11) (b-37) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 879 (b-11) (b-37) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-880 (b-11) (b-37) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-881 (b-11) (b-37) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-882 (b-11) (b-37) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-883 (b-11) (b-37) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-884 (b-11) (b-37) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-885 (b-11) (b-37) HH (a-14) N -CO- -CH_Two-2-886 (b-11) (b-37) H H (a-14) N -CO--(CH_Two)_Two-2-887 (b-11) (b-37) HH (a-14) N -CO- -CH (Me)-2-888 (b-11) (b-38) HH (a-14)- CH- -NH- -CH (Me)-2-889 (b-11) (b-41) HH (a-14) -CH- -NH- -CH (Me)-2-890 (b-11) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-891 (b-11) (b-42) HH (a-14) -CH- -NH- -COCH (Me)-2-892 (b-11) (b-42) HH (a-14) -CH- -O- -CH (Me)-2-893 (b-11) (b-42) HH ( a-14) -CH- -S- -CH (Me)-2-894 (b-11) (b-43) HH (a-14) -CH- -NH- -CH (Me)-2-895 (b-11) (b-72) HH (a-14) -CH- -NH--(CH_Two)_Two-2-896 (b-11) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-897 (b-11) (b-72) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-898 (b-11) (b-72) HH (a-14) -CH- -NH- -COCH (Me)-2-899 (b-11) (b-72) HH (a-14) -CH- -O- -CH (Me)-2-900 (b-11) (b-72) HH (a-14) -CH- -S- -CH (Me)-2- 901 (b-11) (b-72) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-902 (b-11) (b-72) 4-OH H ( a-14) -CH- -NH- -CH (Me)-2-903 (b-11) (b-72) 6-OH H (a-14) -CH- -NH- -CH (Me)- 2-904 (b-11) (b-73) HH (a-14) -CH- -NH- single bond 2-905 (b-11) (b-73) HH (a-14) -CH-- NH- -CH_Two-2-906 (b-11) (b-73) H H (a-14) -CH- -NH--(CH_Two)_Two-2-907 (b-11) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-908 (b-11) (b-73) HH (a-14 ) -CH- -NH- -CH (Et)-2-909 (b-11) (b-73) HH (a-14) -CH- -NH--(CH_Two)_Three-2-910 (b-11) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-911 (b-11) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-912 (b-11) (b-73) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-913 (b-11) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-914 (b-11) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-915 (b-11) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-916 (b-11) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-917 (b-11) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-918 (b-11) (b-73) HH (a-14) -CH- -NH- -CO- 2-919 (b-11) (b-73) HH (a- 14) -CH- -NH- -COCH_Two-2-920 (b-11) (b-73) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-921 (b-11) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-922 (b-11) (b-73) HH (a-14 ) -CH- -NH- -COCH (Et)-2-923 (b-11) (b-73) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-924 (b-11) (b-73) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-925 (b-11) (b-73) H H (a-14) -CH- -O- -CH_Two-2-926 (b-11) (b-73) H H (a-14) -CH- -O--(CH_Two)_Two-2-927 (b-11) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-928 (b-11) (b-73) HH (a-14 ) -CH- -S- -CH_Two-2-929 (b-11) (b-73) H H (a-14) -CH- -S--(CH_Two)_Two-2-930 (b-11) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-931 (b-11) (b-73) 4-FH (a -14) -CH- -NH- -CH (Me)-2-932 (b-11) (b-73) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 933 (b-11) (b-73) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-934 (b-11) (b-73) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-935 (b-11) (b-73) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-936 (b-11) (b-73) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-937 (b-11) (b-73) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-938 (b-11) (b-73) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-939 (b-11) (b-73) HH (a-14) N -CO- -CH_Two-2-940 (b-11) (b-73) H H (a-14) N -CO--(CH_Two)_Two-2-941 (b-11) (b-73) HH (a-14) N -CO- -CH (Me)-2-942 (b-11) (b-74) HH (a-14)- CH- -NH- -CH (Me)-2-943 (b-11) (b-74) HH (a-14) -CH- -NH- -COCH (Me)-2-944 (b-11) (b-74) HH (a-14) -CH- -O- -CH (Me)-2-945 (b-11) (b-74) HH (a-14) -CH- -S- -CH (Me)-2-946 (b-11) (b-75) HH (a-14) -CH- -NH- -CH (Me)-2-947 (b-11) (b-76) HH ( a-14) -CH- -NH- -CH (Me)-2-948 (b-11) (b-76) HH (a-14) -CH- -NH- -COCH (Me)-2-949 (b-11) (b-76) HH (a-14) -CH- -O- -CH (Me)-2-950 (b-11) (b-76) HH (a-14) -CH- -S- -CH (Me)-2-951 (b-11) (b-77) HH (a-14) -CH- -NH--(CH_Two)_Two-2-952 (b-11) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-953 (b-11) (b-77) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-954 (b-11) (b-77) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-955 (b-11) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-956 (b-11) (b-77) HH (a-14 ) -CH- -O- -CH (Me)-2-957 (b-11) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-958 (b- 11) (b-77) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-959 (b-11) (b-77) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-960 (b-11) (b-77) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-961 ( b-11) (b-77) HH (a-14) N -CO- -CH (Me)-2-962 (b-11) (b-78) HH (a-14) -CH- -NH- -CH (Me)-2-963 (b-12) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-964 (b-12) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-965 (b-12) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2 -966 (b-12) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-967 (b-12) (b-34) HH (a-14)- CH- -NH- -CH (Me)-2-968 (b-12) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-969 (b-12) (b-35) HH (a-14) -CH- -NH- -CO- 2-970 (b-12) (b-35) HH (a-14) -CH- -NH- -COCH (Me) -2-971 (b-12) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-972 (b-12) (b-73) HH (a-14 ) -CH- -NH- -CH (Me)-2-973 (b-12) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-974 (b- 13) (b-7) HH (a-14) -CH- -NH- -CH ( Me)-2-975 (b-13) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-976 (b-13) (b-35) HH (a -14) -CH- -NH- -CH (Me)-2-977 (b-13) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-978 ( b-14) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-979 (b-14) (b-2) HH (a-14) -CH-- NH- -CH (Me)-2-980 (b-14) (b-7) HH (a-14) -CH- -NH- single bond 2-981 (b-14) (b-7) HH ( a-14) -CH- -NH- -CH_Two-2-982 (b-14) (b-7) H H (a-14) -CH- -NH--(CH_Two)_Two-2-983 (b-14) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-984 (b-14) (b-7) HH (a-14 ) -CH- -NH- -CH (Et)-2-985 (b-14) (b-7) HH (a-14) -CH- -NH--(CH_Two)_Three-2-986 (b-14) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-987 (b-14) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-988 (b-14) (b-7) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-989 (b-14) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-990 (b-14) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-991 (b-14) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-992 (b-14) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-993 (b-14) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-994 (b-14) (b-7) HH (a-14) -CH- -NH- -CO- 2-995 (b-14) (b-7) HH (a- 14) -CH- -NH- -COCH_Two-2-996 (b-14) (b-7) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-997 (b-14) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-998 (b-14) (b-7) HH (a-14 ) -CH- -NH- -COCH (Et)-2-999 (b-14) (b-7) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1000 (b-14) (b-7) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1001 (b-14) (b-7) H H (a-14) -CH- -O- -CH_Two-2-1002 (b-14) (b-7) H H (a-14) -CH- -O--(CH_Two)_Two-2-1003 (b-14) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-1004 (b-14) (b-7) HH (a-14 ) -CH- -S- -CH_Two-2-1005 (b-14) (b-7) H H (a-14) -CH- -S--(CH_Two)_Two-2-1006 (b-14) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-1007 (b-14) (b-7) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1008 (b-14) (b-7) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1009 (b-14) (b-7) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1010 (b-14) (b-7) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1011 (b-14) (b-7) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1012 (b-14) (b-7) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1013 (b-14) (b-7) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1014 (b-14) (b-7) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1015 (b-14) (b-7) HH (a-14) N -CO- -CH_Two-2-1016 (b-14) (b-7) H H (a-14) N -CO--(CH_Two)_Two-2-1017 (b-14) (b-7) HH (a-14) N -CO- -CH (Me)-2-1018 (b-14) (b-8) HH (a-14)- CH- -NH- -CH (Me)-2-1019 (b-14) (b-10) HH (a-14) -CH- -NH- -CH (Me)-2-1020 (b-14) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-1021 (b-14) (b-11) HH (a-14) -CH- -NH- -COCH (Me)-2-1022 (b-14) (b-11) HH (a-14) -CH- -O- -CH (Me)-2-1023 (b-14) (b-11) HH ( a-14) -CH- -S- -CH (Me)-2-1024 (b-14) (b-12) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1025 (b-14) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1026 (b-14) (b-12) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1027 (b-14) (b-12) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1028 (b-14) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-1029 (b-14) (b-12) HH (a-14 ) -CH- -O- -CH (Me)-2-1030 (b-14) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-1031 (b- 14) (b-12) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1032 (b-14) (b-12) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1033 (b-14) (b-12) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1034 ( b-14) (b-12) HH (a-14) N -CO- -CH (Me)-2-1035 (b-14) (b-13) HH (a-14) -CH- -NH- -CH (Me)-2-1036 (b-14) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-1037 (b-14) (b-14) HH (a-14) -CH- -NH- -COCH (Me)-2-1038 (b-14) (b-14) HH (a-14) -CH- -O- -CH (Me)-2 -1039 (b-14) (b-14) HH (a-14) -CH- -S- -CH (Me)-2-1040 (b-14) (b-15) HH (a-14)- CH- -NH--(CH_Two)_Two-2-1041 (b-14) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1042 (b-14) (b-15) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1043 (b-14) (b-15) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1044 (b-14) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-1045 (b-14) (b-15) HH (a-14 ) -CH- -O- -CH (Me)-2-1046 (b-14) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-1047 (b- 14) (b-15) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1048 (b-14) (b-15) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1049 (b-14) (b-15) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1050 ( b-14) (b-15) HH (a-14) N -CO- -CH (Me)-2-1051 (b-14) (b-16) HH (a-14) -CH- -NH- -CH (Me)-2-1052 (b-14) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-1053 (b-14) (b-17) HH (a-14) -CH- -NH- -COCH (Me)-2-1054 (b-14) (b-17) HH (a-14) -CH- -O- -CH (Me)-2 -1055 (b-14) (b-17) HH (a-14) -CH- -S- -CH (Me)-2-1056 (b-14) (b-23) HH (a-14)- CH- -NH- -CH (Me)-2-1057 (b-14) (b-24) HH (a-14) -CH- -NH- -CH (Me)-2-1058 (b-14) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-1059 (b-14) (b-25) HH (a-14) -CH- -NH- -COCH (Me)-2-1060 (b-14) (b-25) HH (a-14) -CH- -O- -CH (Me)-2-1061 (b-14) (b-25) HH ( a-14) -CH- -S- -CH (Me)-2-1062 (b-14) (b-27) HH (a-14) -CH- -NH- -CH (Me)-2-1063 (b-14) (b-28) H H (a-14) -CH- -NH- -CH (Me)-2-1064 (b-14) (b-30) HH (a-14) -CH- -NH- -CH (Me)-2 -1065 (b-14) (b-31) HH (a-14) -CH- -NH- -CH (Me)-2-1066 (b-14) (b-32) HH (a-14)- CH- -NH- -CH (Me)-2-1067 (b-14) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-1068 (b-14) (b-33) HH (a-14) -CH- -NH- -COCH (Me)-2-1069 (b-14) (b-33) HH (a-14) -CH- -O- -CH (Me)-2-1070 (b-14) (b-33) HH (a-14) -CH- -S- -CH (Me)-2-1071 (b-14) (b-34) HH ( a-14) -CH- -NH--(CH_Two)_Two-2-1072 (b-14) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-1073 (b-14) (b-34) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1074 (b-14) (b-34) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1075 (b-14) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-1076 (b-14) (b-34) HH (a-14 ) -CH- -O- -CH (Me)-2-1077 (b-14) (b-34) HH (a-14) -CH- -S- -CH (Me)-2-1078 (b- 14) (b-34) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1079 (b-14) (b-34) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1080 (b-14) (b-34) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1081 ( b-14) (b-34) HH (a-14) N -CO- -CH (Me)-2-1082 (b-14) (b-35) HH (a-14) -CH- -NH- single bond 2-1083 (b-14) (b-35) HH (a-14) -CH- -NH- -CH_Two-2-1084 (b-14) (b-35) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1085 (b-14) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1086 (b-14) (b-35) HH (a-14 ) -CH- -NH- -CH (Et)-2-1087 (b-14) (b-35) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1088 (b-14) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1089 (b-14) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1090 (b-14) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1091 (b-14) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1092 (b-14) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1093 (b-14) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1094 (b-14) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1095 (b-14) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1096 (b-14) (b-35) HH (a-14) -CH- -NH- -CO- 2-1097 (b-14) (b-35) HH (a- 14) -CH- -NH- -COCH_Two-2-1098 (b-14) (b-35) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1099 (b-14) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1100 (b-14) (b-35) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1101 (b-14) (b-35) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1102 (b-14) (b-35) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1103 (b-14) (b-35) H H (a-14) -CH- -O- -CH_Two-2-1104 (b-14) (b-35) H H (a-14) -CH- -O--(CH_Two)_Two-2-1105 (b-14) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-1106 (b-14) (b-35) HH (a-14 ) -CH- -S- -CH_Two-2-1107 (b-14) (b-35) H H (a-14) -CH- -S--(CH_Two)_Two-2-1108 (b-14) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-1109 (b-14) (b-35) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1110 (b-14) (b-35) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1111 (b-14) (b-35) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1112 (b-14) (b-35) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1113 (b-14) (b-35) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1114 (b-14) (b-35) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1115 (b-14) (b-35) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1116 (b-14) (b-35) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1117 (b-14) (b-35) HH (a-14) N -CO- -CH_Two-2-1118 (b-14) (b-35) H H (a-14) N -CO--(CH_Two)_Two-2-1119 (b-14) (b-35) HH (a-14) N -CO- -CH (Me)-2-1120 (b-14) (b-37) HH (a-14)- CH- -NH- single bond 2-1121 (b-14) (b-37) HH (a-14) -CH- -NH- -CH_Two-2-1122 (b-14) (b-37) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1123 (b-14) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1124 (b-14) (b-37) HH (a-14 ) -CH- -NH- -CH (Et)-2-1125 (b-14) (b-37) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1126 (b-14) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1127 (b-14) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1128 (b-14) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1129 (b-14) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1130 (b-14) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1131 (b-14) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1132 (b-14) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1133 (b-14) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1134 (b-14) (b-37) HH (a-14) -CH- -NH- -CO- 2-1135 (b-14) (b-37) HH (a- 14) -CH- -NH- -COCH_Two-2-1136 (b-14) (b-37) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1137 (b-14) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-1138 (b-14) (b-37) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1139 (b-14) (b-37) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1140 (b-14) (b-37) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1141 (b-14) (b-37) H H (a-14) -CH- -O- -CH_Two-2-1142 (b-14) (b-37) H H (a-14) -CH- -O--(CH_Two)_Two-2-1143 (b-14) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-1144 (b-14) (b-37) HH (a-14 ) -CH- -S- -CH_Two-2-1145 (b-14) (b-37) H H (a-14) -CH- -S--(CH_Two)_Two-2-1146 (b-14) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-1147 (b-14) (b-37) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1148 (b-14) (b-37) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1149 (b-14) (b-37) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1150 (b-14) (b-37) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1151 (b-14) (b-37) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1152 (b-14) (b-37) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1153 (b-14) (b-37) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1154 (b-14) (b-37) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1155 (b-14) (b-37) HH (a-14) N -CO- -CH_Two-2-1156 (b-14) (b-37) H H (a-14) N -CO--(CH_Two)_Two-2-1157 (b-14) (b-37) HH (a-14) N -CO- -CH (Me)-2-1158 (b-14) (b-38) HH (a-14)- CH- -NH- -CH (Me)-2-1159 (b-14) (b-41) HH (a-14) -CH- -NH- -CH (Me)-2-1160 (b-14) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-1161 (b-14) (b-42) HH (a-14) -CH- -NH- -COCH (Me)-2-1162 (b-14) (b-42) HH (a-14) -CH- -O- -CH (Me)-2-1163 (b-14) (b-42) HH ( a-14) -CH- -S- -CH (Me)-2-1164 (b-14) (b-43) HH (a-14) -CH- -NH- -CH (Me)-2-1165 (b-14) (b-72) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1166 (b-14) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-1167 (b-14) (b-72) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1168 (b-14) (b-72) HH (a-14) -CH- -NH- -COCH (Me)-2-1169 (b-14) (b-72) HH (a-14) -CH- -O- -CH (Me)-2-1170 (b-14) (b-72) HH (a-14) -CH- -S- -CH (Me)-2- 1171 (b-14) (b-72) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1172 (b-14) (b-72) 4-OH H ( a-14) -CH- -NH- -CH (Me)-2-1173 (b-14) (b-72) 6-OH H (a-14) -CH- -NH- -CH (Me)- 2-1174 (b-14) (b-73) HH (a-14) -CH- -NH- single bond 2-1175 (b-14) (b-73) HH (a-14) -CH-- NH- -CH_Two-2-1176 (b-14) (b-73) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1177 (b-14) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1178 (b-14) (b-73) HH (a-14 ) -CH- -NH- -CH (Et)-2-1179 (b-14) (b-73) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1180 (b-14) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1181 (b-14) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1182 (b-14) (b-73) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1183 (b-14) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1184 (b-14) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1185 (b-14) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1186 (b-14) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1187 (b-14) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1188 (b-14) (b-73) HH (a-14) -CH- -NH- -CO- 2-1189 (b-14) (b-73) HH (a- 14) -CH- -NH- -COCH_Two-2-1190 (b-14) (b-73) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1191 (b-14) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-1192 (b-14) (b-73) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1193 (b-14) (b-73) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1194 (b-14) (b-73) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1195 (b-14) (b-73) H H (a-14) -CH- -O- -CH_Two-2-1196 (b-14) (b-73) H H (a-14) -CH- -O--(CH_Two)_Two-2-1197 (b-14) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-1198 (b-14) (b-73) HH (a-14 ) -CH- -S- -CH_Two-2-1199 (b-14) (b-73) H H (a-14) -CH- -S--(CH_Two)_Two-2-1200 (b-14) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-1201 (b-14) (b-73) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1202 (b-14) (b-73) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1203 (b-14) (b-73) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1204 (b-14) (b-73) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1205 (b-14) (b-73) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1206 (b-14) (b-73) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1207 (b-14) (b-73) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1208 (b-14) (b-73) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1209 (b-14) (b-73) HH (a-14) N -CO- -CH_Two-2-1210 (b-14) (b-73) H H (a-14) N -CO--(CH_Two)_Two-2-1211 (b-14) (b-73) HH (a-14) N -CO- -CH (Me)-2-1212 (b-14) (b-74) HH (a-14)- CH- -NH- -CH (Me)-2-1213 (b-14) (b-74) HH (a-14) -CH- -NH- -COCH (Me)-2-1214 (b-14) (b-74) HH (a-14) -CH- -O- -CH (Me)-2-1215 (b-14) (b-74) HH (a-14) -CH- -S- -CH (Me)-2-1216 (b-14) (b-75) HH (a-14) -CH- -NH- -CH (Me)-2-1217 (b-14) (b-76) HH ( a-14) -CH- -NH- -CH (Me)-2-1218 (b-14) (b-76) HH (a-14) -CH- -NH- -COCH (Me)-2-1219 (b-14) (b-76) HH (a-14) -CH- -O- -CH (Me)-2-1220 (b-14) (b-76) HH (a-14) -CH- -S- -CH (Me)-2-1221 (b-14) (b-77) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1222 (b-14) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-1223 (b-14) (b-77) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1224 (b-14) (b-77) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1225 (b-14) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-1226 (b-14) (b-77) HH (a-14 ) -CH- -O- -CH (Me)-2-1227 (b-14) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-1228 (b- 14) (b-77) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1229 (b-14) (b-77) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1230 (b-14) (b-77) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1231 ( b-14) (b-77) HH (a-14) N -CO- -CH (Me)-2-1232 (b-14) (b-78) HH (a-14) -CH- -NH- -CH (Me)-2-1233 (b-15) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-1234 (b-15) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2-1235 (b-15) (b-3) HH (a-14) -CH- -NH- -CH (Me)-2 -1236 (b-15) (b-4) HH (a-14) -CH- -NH- -CH (Me)-2-1237 (b-15) (b-5) HH (a-14)- CH- -NH- -CH (Me)-2-1238 (b-15) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1239 (b-15) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1240 (b-15) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1241 (b-15) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1242 (b-15) (b-34) HH ( a-14) -CH- -NH- -CH (Me)-2-1243 (b-15) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1244 (b-15) (b-35) HH (a- 14) -CH- -NH- -COCH (Me)-2-1245 (b-15) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1246 (b -15) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1247 (b-15) (b-77) HH (a-14) -CH- -NH --CH (Me)-2-1248 (b-16) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1249 (b-17) (b-7 ) HH (a-14) -CH- -NH- -CH (Me)-2-1250 (b-17) (b-35) HH (a-14) -CH- -NH- -CH (Me)- 2-1251 (b-18) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-1252 (b-18) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2-1253 (b-18) (b-7) HH (a-14) -CH- -NH- single bond 2-1254 (b-18) (b- 7) HH (a-14) -CH- -NH- -CH_Two-2-1255 (b-18) (b-7) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1256 (b-18) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1257 (b-18) (b-7) HH (a-14 ) -CH- -NH- -CH (Et)-2-1258 (b-18) (b-7) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1259 (b-18) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1260 (b-18) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Et)-2-1261 (b-18) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1262 (b-18) (b-7) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1263 (b-18) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1264 (b-18) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1265 (b-18) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1266 (b-18) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1267 (b-18) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1268 (b-18) (b-7) HH (a-14) -CH- -NH- -CO- 2-1269 (b-18) (b-7) HH (a- 14) -CH- -NH- -COCH_Two-2-1270 (b-18) (b-7) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1271 (b-18) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1272 (b-18) (b-7) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1273 (b-18) (b-7) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1274 (b-18) (b-7) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1275 (b-18) (b-7) H H (a-14) -CH- -O- -CH_Two-2-1276 (b-18) (b-7) H H (a-14) -CH- -O--(CH_Two)_Two-2-1277 (b-18) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-1278 (b-18) (b-7) HH (a-14 ) -CH- -S- -CH_Two-2-1279 (b-18) (b-7) H H (a-14) -CH- -S--(CH_Two)_Two-2-1280 (b-18) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-1281 (b-18) (b-7) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1282 (b-18) (b-7) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1283 (b-18) (b-7) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1284 (b-18) (b-7) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1285 (b-18) (b-7) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1286 (b-18) (b-7) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1287 (b-18) (b-7) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1288 (b-18) (b-7) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1289 (b-18) (b-7) HH (a-14) N -CO- -CH_Two-2-1290 (b-18) (b-7) H H (a-14) N -CO--(CH_Two)_Two-2-1291 (b-18) (b-7) HH (a-14) N -CO- -CH (Me)-2-1292 (b-18) (b-8) HH (a-14)- CH- -NH- -CH (Me)-2-1293 (b-18) (b-10) HH (a-14) -CH- -NH- -CH (Me)-2-1294 (b-18) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-1295 (b-18) (b-11) HH (a-14) -CH- -NH- -COCH (Me)-2-1296 (b-18) (b-11) HH (a-14) -CH- -O- -CH (Me)-2-1297 (b-18) (b-11) HH ( a-14) -CH- -S- -CH (Me)-2-1298 (b-18) (b-12) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1299 (b-18) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1300 (b-18) (b-12) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1301 (b-18) (b-12) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1302 (b-18) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-1303 (b-18) (b-12) HH (a-14 ) -CH- -O- -CH (Me)-2-1304 (b-18) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-1305 (b- 18) (b-12) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1306 (b-18) (b-12) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1307 (b-18) (b-12) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1308 ( b-18) (b-12) HH (a-14) N -CO- -CH (Me)-2-1309 (b-18) (b-13) HH (a-14) -CH- -NH- -CH (Me)-2-1310 (b-18) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-1311 (b-18) (b-14) HH (a-14) -CH- -NH- -COCH (Me)-2-1312 (b-18) (b-14) HH (a-14) -CH- -O- -CH (Me)-2 -1313 (b-18) (b-14) HH (a-14) -CH- -S- -CH (Me)-2-1314 (b-18) (b-15) HH (a-14)- CH- -NH--(CH_Two)_Two-2-1315 (b-18) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1316 (b-18) (b-15) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1317 (b-18) (b-15) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1318 (b-18) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-1319 (b-18) (b-15) HH (a-14 ) -CH- -O- -CH (Me)-2-1320 (b-18) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-1321 (b- 18) (b-15) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1322 (b-18) (b-15) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1323 (b-18) (b-15) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1324 ( b-18) (b-15) HH (a-14) N -CO- -CH (Me)-2-1325 (b-18) (b-16) HH (a-14) -CH- -NH- -CH (Me)-2-1326 (b-18) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-1327 (b-18) (b-17) HH (a-14) -CH- -NH- -COCH (Me)-2-1328 (b-18) (b-17) HH (a-14) -CH- -O- -CH (Me)-2 -1329 (b-18) (b-17) HH (a-14) -CH- -S- -CH (Me)-2-1330 (b-18) (b-23) HH (a-14)- CH- -NH- -CH (Me)-2-1331 (b-18) (b-24) HH (a-14) -CH- -NH- -CH (Me)-2-1332 (b-18) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-1333 (b-18) (b-25) HH (a-14) -CH- -NH- -COCH (Me)-2-1334 (b-18) (b-25) HH (a-14) -CH- -O- -CH (Me)-2-1335 (b-18) (b-25) HH ( a-14) -CH- -S- -CH (Me)-2-1336 (b-18) (b-27) HH (a-14) -CH- -NH- -CH (Me)-2-1337 (b-18) (b-28) H H (a-14) -CH- -NH- -CH (Me)-2-1338 (b-18) (b-30) HH (a-14) -CH- -NH- -CH (Me)-2 -1339 (b-18) (b-31) HH (a-14) -CH- -NH- -CH (Me)-2-1340 (b-18) (b-32) HH (a-14)- CH- -NH- -CH (Me)-2-1341 (b-18) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-1342 (b-18) (b-33) HH (a-14) -CH- -NH- -COCH (Me)-2-1343 (b-18) (b-33) HH (a-14) -CH- -O- -CH (Me)-2-1344 (b-18) (b-33) HH (a-14) -CH- -S- -CH (Me)-2-1345 (b-18) (b-34) HH ( a-14) -CH- -NH--(CH_Two)_Two-2-1346 (b-18) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-1347 (b-18) (b-34) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1348 (b-18) (b-34) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1349 (b-18) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-1350 (b-18) (b-34) HH (a-14 ) -CH- -O- -CH (Me)-2-1351 (b-18) (b-34) HH (a-14) -CH- -S- -CH (Me)-2-1352 (b- 18) (b-34) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1353 (b-18) (b-34) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1354 (b-18) (b-34) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1355 ( b-18) (b-34) HH (a-14) N -CO- -CH (Me)-2-1356 (b-18) (b-35) HH (a-14) -CH- -NH- single bond 2-1357 (b-18) (b-35) HH (a-14) -CH- -NH- -CH_Two-2-1358 (b-18) (b-35) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1359 (b-18) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1360 (b-18) (b-35) HH (a-14 ) -CH- -NH- -CH (Et)-2-1361 (b-18) (b-35) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1362 (b-18) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1363 (b-18) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1364 (b-18) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1365 (b-18) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1366 (b-18) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1367 (b-18) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1368 (b-18) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1369 (b-18) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1370 (b-18) (b-35) HH (a-14) -CH- -NH- -CO- 2-1371 (b-18) (b-35) HH (a- 14) -CH- -NH- -COCH_Two-2-1372 (b-18) (b-35) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1373 (b-18) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1374 (b-18) (b-35) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1375 (b-18) (b-35) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1376 (b-18) (b-35) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1377 (b-18) (b-35) H H (a-14) -CH- -O- -CH_Two-2-1378 (b-18) (b-35) H H (a-14) -CH- -O--(CH_Two)_Two-2-1379 (b-18) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-1380 (b-18) (b-35) HH (a-14 ) -CH- -S- -CH_Two-2-1381 (b-18) (b-35) H H (a-14) -CH- -S--(CH_Two)_Two-2-1382 (b-18) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-1383 (b-18) (b-35) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1384 (b-18) (b-35) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1385 (b-18) (b-35) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1386 (b-18) (b-35) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1387 (b-18) (b-35) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1388 (b-18) (b-35) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1389 (b-18) (b-35) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1390 (b-18) (b-35) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1391 (b-18) (b-35) HH (a-14) N -CO- -CH_Two-2-1392 (b-18) (b-35) H H (a-14) N -CO--(CH_Two)_Two-2-1393 (b-18) (b-35) HH (a-14) N -CO- -CH (Me)-2-1394 (b-18) (b-37) HH (a-14)- CH- -NH- single bond 2-1395 (b-18) (b-37) HH (a-14) -CH- -NH- -CH_Two-2-1396 (b-18) (b-37) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1397 (b-18) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1398 (b-18) (b-37) HH (a-14 ) -CH- -NH- -CH (Et)-2-1399 (b-18) (b-37) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1400 (b-18) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1401 (b-18) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1402 (b-18) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1403 (b-18) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1404 (b-18) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1405 (b-18) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1406 (b-18) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1407 (b-18) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1408 (b-18) (b-37) HH (a-14) -CH- -NH- -CO- 2-1409 (b-18) (b-37) HH (a- 14) -CH- -NH- -COCH_Two-2-1410 (b-18) (b-37) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1411 (b-18) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-1412 (b-18) (b-37) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1413 (b-18) (b-37) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1414 (b-18) (b-37) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1415 (b-18) (b-37) H H (a-14) -CH- -O- -CH_Two-2-1416 (b-18) (b-37) H H (a-14) -CH- -O--(CH_Two)_Two-2-1417 (b-18) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-1418 (b-18) (b-37) HH (a-14 ) -CH- -S- -CH_Two-2-1419 (b-18) (b-37) H H (a-14) -CH- -S--(CH_Two)_Two-2-1420 (b-18) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-1421 (b-18) (b-37) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1422 (b-18) (b-37) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1423 (b-18) (b-37) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1424 (b-18) (b-37) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1425 (b-18) (b-37) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1426 (b-18) (b-37) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1427 (b-18) (b-37) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1428 (b-18) (b-37) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1429 (b-18) (b-37) HH (a-14) N -CO- -CH_Two-2-1430 (b-18) (b-37) H H (a-14) N -CO--(CH_Two)_Two-2-1431 (b-18) (b-37) HH (a-14) N -CO- -CH (Me)-2-1432 (b-18) (b-38) HH (a-14)- CH- -NH- -CH (Me)-2-1433 (b-18) (b-41) HH (a-14) -CH- -NH- -CH (Me)-2-1434 (b-18) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-1435 (b-18) (b-42) HH (a-14) -CH- -NH- -COCH (Me)-2-1436 (b-18) (b-42) HH (a-14) -CH- -O- -CH (Me)-2-1437 (b-18) (b-42) HH ( a-14) -CH- -S- -CH (Me)-2-1438 (b-18) (b-43) HH (a-14) -CH- -NH- -CH (Me)-2-1439 (b-18) (b-72) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1440 (b-18) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-1441 (b-18) (b-72) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1442 (b-18) (b-72) HH (a-14) -CH- -NH- -COCH (Me)-2-1443 (b-18) (b-72) HH (a-14) -CH- -O- -CH (Me)-2-1444 (b-18) (b-72) HH (a-14) -CH- -S- -CH (Me)-2- 1445 (b-18) (b-72) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1446 (b-18) (b-72) 4-OH H ( a-14) -CH- -NH- -CH (Me)-2-1447 (b-18) (b-72) 6-OH H (a-14) -CH- -NH- -CH (Me)- 2-1448 (b-18) (b-73) HH (a-14) -CH- -NH- single bond 2-1449 (b-18) (b-73) HH (a-14) -CH-- NH- -CH_Two-2-1450 (b-18) (b-73) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1451 (b-18) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1452 (b-18) (b-73) HH (a-14 ) -CH- -NH- -CH (Et)-2-1453 (b-18) (b-73) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1454 (b-18) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1455 (b-18) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1456 (b-18) (b-73) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1457 (b-18) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1458 (b-18) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1459 (b-18) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1460 (b-18) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1461 (b-18) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1462 (b-18) (b-73) HH (a-14) -CH- -NH- -CO- 2-1463 (b-18) (b-73) HH (a- 14) -CH- -NH- -COCH_Two-2-1464 (b-18) (b-73) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1465 (b-18) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-1466 (b-18) (b-73) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1467 (b-18) (b-73) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1468 (b-18) (b-73) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1469 (b-18) (b-73) H H (a-14) -CH- -O- -CH_Two-2-1470 (b-18) (b-73) H H (a-14) -CH- -O--(CH_Two)_Two-2-1471 (b-18) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-1472 (b-18) (b-73) HH (a-14 ) -CH- -S- -CH_Two-2-1473 (b-18) (b-73) H H (a-14) -CH- -S--(CH_Two)_Two-2-1474 (b-18) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-1475 (b-18) (b-73) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1476 (b-18) (b-73) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1477 (b-18) (b-73) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1478 (b-18) (b-73) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1479 (b-18) (b-73) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1480 (b-18) (b-73) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1481 (b-18) (b-73) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1482 (b-18) (b-73) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1483 (b-18) (b-73) HH (a-14) N -CO- -CH_Two-2-1484 (b-18) (b-73) H H (a-14) N -CO--(CH_Two)_Two-2-1485 (b-18) (b-73) HH (a-14) N -CO- -CH (Me)-2-1486 (b-18) (b-74) HH (a-14)- CH- -NH- -CH (Me)-2-1487 (b-18) (b-74) HH (a-14) -CH- -NH- -COCH (Me)-2-1488 (b-18) (b-74) HH (a-14) -CH- -O- -CH (Me)-2-1489 (b-18) (b-74) HH (a-14) -CH- -S- -CH (Me)-2-1490 (b-18) (b-75) HH (a-14) -CH- -NH- -CH (Me)-2-1491 (b-18) (b-76) HH ( a-14) -CH- -NH- -CH (Me)-2-1492 (b-18) (b-76) HH (a-14) -CH- -NH- -COCH (Me)-2-1493 (b-18) (b-76) HH (a-14) -CH- -O- -CH (Me)-2-1494 (b-18) (b-76) HH (a-14) -CH- -S- -CH (Me)-2-1495 (b-18) (b-77) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1496 (b-18) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-1497 (b-18) (b-77) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1498 (b-18) (b-77) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1499 (b-18) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-1500 (b-18) (b-77) HH (a-14 ) -CH- -O- -CH (Me)-2-1501 (b-18) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-1502 (b- 18) (b-77) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1503 (b-18) (b-77) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1504 (b-18) (b-77) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1505 ( b-18) (b-77) HH (a-14) N -CO- -CH (Me)-2-1506 (b-18) (b-78) HH (a-14) -CH- -NH- -CH (Me)-2-1507 (b-19) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1508 (b-19) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1509 (b-19) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2 -1510 (b-19) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1511 (b-19) (b-34) HH (a-14)- CH- -NH- -CH (Me)-2-1512 (b-19) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1513 (b-19) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1514 (b-19) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1515 (b-19) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1516 (b-19) (b-77) HH ( a-14) -CH- -NH- -CH (Me)-2-1517 (b-19) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-1518 (b-20) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-1519 (b-20) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2 -1520 (b-20) (b-7) HH (a-14) -CH- -NH- single bond 2-1521 (b-20) (b-7) HH (a-14) -CH- -NH --CH_Two-2-1522 (b-20) (b-7) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1523 (b-20) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1524 (b-20) (b-7) HH (a-14 ) -CH- -NH- -CH (Et)-2-1525 (b-20) (b-7) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1526 (b-20) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1527 (b-20) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1528 (b-20) (b-7) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1529 (b-20) (b-7) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1530 (b-20) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1531 (b-20) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1532 (b-20) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1533 (b-20) (b-7) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1534 (b-20) (b-7) HH (a-14) -CH- -NH- -CO- 2-1535 (b-20) (b-7) HH (a- 14) -CH- -NH- -COCH_Two-2-1536 (b-20) (b-7) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1537 (b-20) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1538 (b-20) (b-7) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1539 (b-20) (b-7) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1540 (b-20) (b-7) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1541 (b-20) (b-7) H H (a-14) -CH- -O- -CH_Two-2-1542 (b-20) (b-7) H H (a-14) -CH- -O--(CH_Two)_Two-2-1543 (b-20) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-1544 (b-20) (b-7) HH (a-14 ) -CH- -S- -CH_Two-2-1545 (b-20) (b-7) H H (a-14) -CH- -S--(CH_Two)_Two-2-1546 (b-20) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-1547 (b-20) (b-7) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1548 (b-20) (b-7) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1549 (b-20) (b-7) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1550 (b-20) (b-7) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1551 (b-20) (b-7) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1552 (b-20) (b-7) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1553 (b-20) (b-7) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1554 (b-20) (b-7) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1555 (b-20) (b-7) HH (a-14) N -CO- -CH_Two-2-1556 (b-20) (b-7) H H (a-14) N -CO--(CH_Two)_Two-2-1557 (b-20) (b-7) HH (a-14) N -CO- -CH (Me)-2-1558 (b-20) (b-8) HH (a-14)- CH- -NH- -CH (Me)-2-1559 (b-20) (b-10) HH (a-14) -CH- -NH- -CH (Me)-2-1560 (b-20) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-1561 (b-20) (b-11) HH (a-14) -CH- -NH- -COCH (Me)-2-1562 (b-20) (b-11) HH (a-14) -CH- -O- -CH (Me)-2-1563 (b-20) (b-11) HH ( a-14) -CH- -S- -CH (Me)-2-1564 (b-20) (b-12) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1565 (b-20) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1566 (b-20) (b-12) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1567 (b-20) (b-12) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1568 (b-20) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-1569 (b-20) (b-12) HH (a-14 ) -CH- -O- -CH (Me)-2-1570 (b-20) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-1571 (b- 20) (b-12) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1572 (b-20) (b-12) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1573 (b-20) (b-12) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1574 ( b-20) (b-12) HH (a-14) N -CO- -CH (Me)-2-1575 (b-20) (b-13) HH (a-14) -CH- -NH- -CH (Me)-2-1576 (b-20) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-1577 (b-20) (b-14) HH (a-14) -CH- -NH- -COCH (Me)-2-1578 (b-20) (b-14) HH (a-14) -CH- -O- -CH (Me)-2 -1579 (b-20) (b-14) HH (a-14) -CH- -S- -CH (Me)-2-1580 (b-20) (b-15) HH (a-14)- CH- -NH--(CH_Two)_Two-2-1581 (b-20) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1582 (b-20) (b-15) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1583 (b-20) (b-15) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1584 (b-20) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-1585 (b-20) (b-15) HH (a-14 ) -CH- -O- -CH (Me)-2-1586 (b-20) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-1587 (b- 20) (b-15) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1588 (b-20) (b-15) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1589 (b-20) (b-15) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1590 ( b-20) (b-15) HH (a-14) N -CO- -CH (Me)-2-1591 (b-20) (b-16) HH (a-14) -CH- -NH- -CH (Me)-2-1592 (b-20) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-1593 (b-20) (b-17) HH (a-14) -CH- -NH- -COCH (Me)-2-1594 (b-20) (b-17) HH (a-14) -CH- -O- -CH (Me)-2 -1595 (b-20) (b-17) HH (a-14) -CH- -S- -CH (Me)-2-1596 (b-20) (b-23) HH (a-14)- CH- -NH- -CH (Me)-2-1597 (b-20) (b-24) HH (a-14) -CH- -NH- -CH (Me)-2-1598 (b-20) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-1599 (b-20) (b-25) HH (a-14) -CH- -NH- -COCH (Me)-2-1600 (b-20) (b-25) HH (a-14) -CH- -O- -CH (Me)-2-1601 (b-20) (b-25) HH ( a-14) -CH- -S- -CH (Me)-2-1602 (b-20) (b-27) HH (a-14) -CH- -NH- -CH (Me)-2-1603 (b-20) (b-28) H H (a-14) -CH- -NH- -CH (Me)-2-1604 (b-20) (b-30) HH (a-14) -CH- -NH- -CH (Me)-2 -1605 (b-20) (b-31) HH (a-14) -CH- -NH- -CH (Me)-2-1606 (b-20) (b-32) HH (a-14)- CH- -NH- -CH (Me)-2-1607 (b-20) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-1608 (b-20) (b-33) HH (a-14) -CH- -NH- -COCH (Me)-2-1609 (b-20) (b-33) HH (a-14) -CH- -O- -CH (Me)-2-1610 (b-20) (b-33) HH (a-14) -CH- -S- -CH (Me) -2- 1611 (b-20) (b-34) HH
(A-14) -CH- -NH--(CH₂)₂− 2-1612 (b-20) (b-34) H H
(A-14) -CH- -NH- -CH (Me) -2- 1613 (b-20) (b-34) H H
(A-14) -CH- -NH- -CH₂CH (Me) -2- 1614 (b-20) (b-34) H H
(A-14) -CH- -NH- -CO (CH₂)₂-2-1615 (b-20) (b-34) H H
(A-14) -CH- -NH- -COCH (Me) -2- 1616 (b-20) (b-34) H H
(A-14) -CH- -O- -CH (Me) -2- 1617 (b-20) (b-34) HH
(A-14) -CH- -S- -CH (Me) -2- 1618 (b-20) (b-34) 6-ClH
(A-14) -CH- -NH- -CH (Me) -2- 1619 (b-20) (b-34) 4-OHH
(A-14) -CH- -NH- -CH (Me) -2- 1620 (b-20) (b-34) 6-OH H
(A-14) -CH- -NH- -CH (Me) -2-1621 (b-20) (b-34) HH
(A-14) N-CO--CH (Me) -2-1622 (b-20) (b-35) HH
(A-14) -CH- -NH- single bond 2-1623 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH₂-2-1624 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₂-2-1625 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH (Me) -2- 1626 (b-20) (b-35) HH
(A-14) -CH- -NH- -CH (Et) -2- 1627 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₃-2-1628 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH₂CH (Me) -2-1629 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH₂CH (OH) -2-1630 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH₂C (= O) -2-1631 (b-20) (b-35) H H
(A-14) -CH- -NH- -CH₂CH (Ph) -2-1632 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₂CH (Me) -2-1633 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₂CH (OH) -2-1634 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₂C (= O) -2-1635 (b-20) (b-35) H H
(A-14) -CH- -NH--(CH₂)₂CH (Ph) -2-1636 (b-20) (b-35) H H
(A-14) -CH- -NH- -CO- 2-1637 (b-20) (b-35) H H
(A-14) -CH- -NH- -COCH₂-2-1638 (b-20) (b-35) H H
(A-14) -CH- -NH- -CO (CH₂)₂− 2-1640 (b-20) (b-35) HH (a-14) -CH- -NH- -COCH (Et)-2-1641 (b-20) (b-35) HH (a-14 ) -CH- -NH- -CO (CH_Two)_Three-2-1642 (b-20) (b-35) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1643 (b-20) (b-35) H H (a-14) -CH- -O- -CH_Two-2-1644 (b-20) (b-35) H H (a-14) -CH- -O--(CH_Two)_Two-2-1645 (b-20) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-1646 (b-20) (b-35) HH (a-14 ) -CH- -S- -CH_Two-2-1647 (b-20) (b-35) H H (a-14) -CH- -S--(CH_Two)_Two-2-1648 (b-20) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-1649 (b-20) (b-35) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1650 (b-20) (b-35) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1651 (b-20) (b-35) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1652 (b-20) (b-35) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1653 (b-20) (b-35) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1654 (b-20) (b-35) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1655 (b-20) (b-35) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1666 (b-20) (b-35) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1667 (b-20) (b-35) HH (a-14) N -CO- -CH_Two-2-1668 (b-20) (b-35) H H (a-14) N -CO--(CH_Two)_Two-2-1669 (b-20) (b-35) HH (a-14) N -CO- -CH (Me)-2-1670 (b-20) (b-37) HH (a-14)- CH- -NH- single bond 2-1671 (b-20) (b-37) HH (a-14) -CH- -NH- -CH_Two-2-1672 (b-20) (b-37) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1673 (b-20) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1674 (b-20) (b-37) HH (a-14 ) -CH- -NH- -CH (Et)-2-1675 (b-20) (b-37) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1676 (b-20) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1677 (b-20) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1678 (b-20) (b-37) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1679 (b-20) (b-37) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1680 (b-20) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1681 (b-20) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1682 (b-20) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1683 (b-20) (b-37) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1684 (b-20) (b-37) HH (a-14) -CH- -NH- -CO- 2-1685 (b-20) (b-37) HH (a- 14) -CH- -NH- -COCH_Two-2-1686 (b-20) (b-37) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1687 (b-20) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-1688 (b-20) (b-37) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1689 (b-20) (b-37) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1690 (b-20) (b-37) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1691 (b-20) (b-37) H H (a-14) -CH- -O- -CH_Two-2-1692 (b-20) (b-37) H H (a-14) -CH- -O--(CH_Two)_Two-2-1693 (b-20) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-1694 (b-20) (b-37) HH (a-14 ) -CH- -S- -CH_Two-2-1695 (b-20) (b-37) H H (a-14) -CH- -S--(CH_Two)_Two-2-1696 (b-20) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-1697 (b-20) (b-37) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1698 (b-20) (b-37) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1699 (b-20) (b-37) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1700 (b-20) (b-37) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1701 (b-20) (b-37) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1702 (b-20) (b-37) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1703 (b-20) (b-37) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1704 (b-20) (b-37) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1705 (b-20) (b-37) HH (a-14) N -CO- -CH_Two-2-1706 (b-20) (b-37) H H (a-14) N -CO--(CH_Two)_Two-2-1707 (b-20) (b-37) HH (a-14) N -CO- -CH (Me)-2-1708 (b-20) (b-38) HH (a-14)- CH- -NH- -CH (Me)-2-1709 (b-20) (b-41) HH (a-14) -CH- -NH- -CH (Me)-2-1710 (b-20) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-1711 (b-20) (b-42) HH (a-14) -CH- -NH- -COCH (Me)-2-1712 (b-20) (b-42) HH (a-14) -CH- -O- -CH (Me)-2-1713 (b-20) (b-42) HH ( a-14) -CH- -S- -CH (Me)-2-1714 (b-20) (b-43) HH (a-14) -CH- -NH- -CH (Me)-2-1715 (b-20) (b-72) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1716 (b-20) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-1717 (b-20) (b-72) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1718 (b-20) (b-72) HH (a-14) -CH- -NH- -COCH (Me)-2-1719 (b-20) (b-72) HH (a-14) -CH- -O- -CH (Me)-2-1720 (b-20) (b-72) HH (a-14) -CH- -S- -CH (Me)-2- 1721 (b-20) (b-72) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1722 (b-20) (b-72) 4-OH H ( a-14) -CH- -NH- -CH (Me)-2-1723 (b-20) (b-72) 6-OH H (a-14) -CH- -NH- -CH (Me)- 2-1724 (b-20) (b-73) HH (a-14) -CH- -NH- single bond 2-1725 (b-20) (b-73) HH (a-14) -CH-- NH- -CH_Two-2-1726 (b-20) (b-73) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1727 (b-20) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1728 (b-20) (b-73) HH (a-14 ) -CH- -NH- -CH (Et)-2-1729 (b-20) (b-73) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1730 (b-20) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1731 (b-20) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1732 (b-20) (b-73) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1733 (b-20) (b-73) H H (a-14) -CH- -NH- -CH_TwoCH (Ph)-2-1734 (b-20) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1735 (b-20) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1736 (b-20) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1737 (b-20) (b-73) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Ph)-2-1738 (b-20) (b-73) HH (a-14) -CH- -NH- -CO- 2-1739 (b-20) (b-73) HH (a- 14) -CH- -NH- -COCH_Two-2-1740 (b-20) (b-73) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1741 (b-20) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-1742 (b-20) (b-73) HH (a-14 ) -CH- -NH- -COCH (Et)-2-1743 (b-20) (b-73) HH (a-14) -CH- -NH- -CO (CH_Two)_Three-2-1744 (b-20) (b-73) H H (a-14) -CH- -NH- -COCH_TwoCH (Me)-2-1745 (b-20) (b-73) H H (a-14) -CH- -O- -CH_Two-2-1746 (b-20) (b-73) H H (a-14) -CH- -O--(CH_Two)_Two-2-1747 (b-20) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-1748 (b-20) (b-73) HH (a-14 ) -CH- -S- -CH_Two-2-1749 (b-20) (b-73) H H (a-14) -CH- -S--(CH_Two)_Two-2-1750 (b-20) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-1751 (b-20) (b-73) 4-FH (a -14) -CH- -NH- -CH (Me)-2-1752 (b-20) (b-73) 6-FH (a-14) -CH- -NH- -CH (Me)-2- 1753 (b-20) (b-73) 4-Cl H (a-14) -CH- -NH- -CH (Me)-2-1754 (b-20) (b-73) 5-Cl H ( a-14) -CH- -NH- -CH (Me)-2-1755 (b-20) (b-73) 6-Cl H (a-14) -CH- -NH- -CH (Me)- 2-1756 (b-20) (b-73) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1757 (b-20) (b-73) 5-OH H (a-14) -CH- -NH- -CH (Me)-2-1758 (b-20) (b-73) 6-OH H (a-14) -CH- -NH- -CH (Me )-2-1759 (b-20) (b-73) HH (a-14) N -CO- -CH_Two-2-1760 (b-20) (b-73) H H (a-14) N -CO--(CH_Two)_Two-2-1761 (b-20) (b-73) HH (a-14) N -CO- -CH (Me)-2-1762 (b-20) (b-74) HH (a-14)- CH- -NH- -CH (Me)-2-1763 (b-20) (b-74) HH (a-14) -CH- -NH- -COCH (Me)-2-1764 (b-20) (b-74) HH (a-14) -CH- -O- -CH (Me)-2-1765 (b-20) (b-74) HH (a-14) -CH- -S- -CH (Me)-2-1766 (b-20) (b-75) HH (a-14) -CH- -NH- -CH (Me)-2-1767 (b-20) (b-76) HH ( a-14) -CH- -NH- -CH (Me)-2-1768 (b-20) (b-76) HH (a-14) -CH- -NH- -COCH (Me)-2-1769 (b-20) (b-76) HH (a-14) -CH- -O- -CH (Me)-2-1770 (b-20) (b-76) HH (a-14) -CH- -S- -CH (Me)-2-1771 (b-20) (b-77) HH (a-14) -CH- -NH--(CH_Two)_Two-2-1772 (b-20) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-1773 (b-20) (b-77) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1774 (b-20) (b-77) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1775 (b-20) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-1776 (b-20) (b-77) HH (a-14 ) -CH- -O- -CH (Me)-2-1777 (b-20) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-1778 (b- 20) (b-77) 6-Cl H (a-14) -CH- -NH- -CH (Me)-2-1779 (b-20) (b-77) 4-OH H (a-14) -CH- -NH- -CH (Me)-2-1780 (b-20) (b-77) 6-OH H (a-14) -CH- -NH- -CH (Me)-2-1781 ( b-20) (b-77) HH (a-14) N -CO- -CH (Me)-2-1782 (b-20) (b-78) HH (a-14) -CH- -NH- -CH (Me)-2-1783 (b-21) (b-1) HH (a-14) -CH- -NH- -CH (Me)-2-1784 (b-21) (b-2) HH (a-14) -CH- -NH- -CH (Me)-2-1785 (b-21) (b-3) HH (a-14) -CH- -NH- -CH (Me)-2 -1786 (b-21) (b-4) HH (a-14) -CH- -NH- -CH (Me)-2-1787 (b-21) (b-5) HH (a-14)- CH- -NH- -CH (Me)-2-1788 (b-21) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1789 (b-21) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1790 (b-21) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1791 (b-21) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1792 (b-21) (b-34) HH ( a-14) -CH- -NH- -CH (Me)-2-1793 (b-21) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1794 (b-21) (b-35) HH (a- 14) -CH- -NH- -COCH (Me)-2-1795 (b-21) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1796 (b -21) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1797 (b-21) (b-77) HH (a-14) -CH- -NH --CH (Me)-2-1798 (b-22) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1799 (b-23) (b-7 ) HH (a-14) -CH- -NH- -CH (Me)-2-1800 (b-23) (b-35) HH (a-14) -CH- -NH- -CH (Me)- 2-1801 (b-24) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1802 (b-24) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1803 (b-24) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1804 (b-24 ) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1805 (b-24) (b-34) HH (a-14) -CH- -NH-- CH (Me)-2-1806 (b-24) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1807 (b-24) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1808 (b-24) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2- 1809 (b-24) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1810 (b-24) (b-77) HH (a-14) -CH --NH- -CH (Me)-2-1811 (b-25) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1812 (b-25) ( b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1813 (b-25) (b-12) HH (a-14) -CH- -NH- -CH ( Me)-2-181 4 (b-25) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1815 (b-25) (b-34) HH (a-14) -CH --NH- -CH (Me)-2-1816 (b-25) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1817 (b-25) ( b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1818 (b-25) (b-37) HH (a-14) -CH- -NH- -CH ( (Me)-2-1819 (b-25) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1820 (b-25) (b-77) HH (a -14) -CH- -NH- -CH (Me)-2-1821 (b-26) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1822 ( b-27) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1823 (b-28) (b-35) HH (a-14) -CH-- NH- -CH (Me)-2-1824 (b-29) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1825 (b-30) (b- 35) HH (a-14) -CH- -NH- -CH (Me)-2-1826 (b-31) (b-35) HH (a-14) -CH- -NH- -CH (Me) -2-1827 (b-32) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1828 (b-33) (b-35) HH (a-14 ) -CH- -NH- -CH (Me)-2-1829 (b-34) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1830 (b- 35) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1831 (b-35) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1832 (b-36) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1833 (b-37) (b-35) HH (a-14) -CH --NH- -CH (Me)-2-1834 (b-38) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1835 (b-39) ( b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1836 (b-40) (b-35) HH (a-14) -CH- -NH- -CH ( Me)-2-1837 (b-41) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1838 (b-42) (b-35) HH (a -14) -CH- -NH- -CH (Me)-2-1839 (b-43) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1840 ( b-44) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1841 (b-45) (b-35) HH (a-14) -CH-- NH- -CH (Me)-2-1842 (b-46) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1843 (b-47) (b- 35) HH (a-14) -CH- -NH- -CH (Me)-2-1844 (b-48) (b-35) HH (a-14) -CH- -NH- -CH (Me) -2-1845 (b-49) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1846 (b-50) (b-35) HH (a-14 ) -CH- -NH- -CH (Me)-2-1847 (b-51) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1848 (b- 52) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1849 (b-53) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1850 (b-54) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1851 (b-55) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1852 (b-56) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2 -1853 (b-57) ( b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1854 (b-58) (b-35) HH (a-14) -CH- -NH- -CH ( (Me)-2-1855 (b-59) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1856 (b-60) (b-35) HH (a -14) -CH- -NH- -CH (Me)-2-1857 (b-61) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1858 ( b-62) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1859 (b-63) (b-35) HH (a-14) -CH-- NH- -CH (Me)-2-1860 (b-64) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1861 (b-65) (b- 35) HH (a-14) -CH- -NH- -CH (Me)-2-1862 (b-66) (b-35) HH (a-14) -CH- -NH- -CH (Me) -2-1863 (b-67) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1864 (b-68) (b-35) HH (a-14 ) -CH- -NH- -CH (Me)-2-1865 (b-69) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1866 (b- 70) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1867 (b-71) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1868 (b-72) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1869 (b-72) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1870 (b-72) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2 -1871 (b-72) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1872 (b-72) (b-34) HH (a-14)- CH- -NH- -CH ( (Me)-2-1873 (b-72) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1874 (b-72) (b-35) HH (a -14) -CH- -NH- -COCH (Me)-2-1875 (b-72) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1876 ( b-72) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1877 (b-72) (b-77) HH (a-14) -CH-- NH- -CH (Me)-2-1878 (b-73) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1879 (b-73) (b- 7) HH (a-14) -CH- -NH- -COCH (Me)-2-1880 (b-73) (b-7) HH (a-14) -CH- -O- -CH (Me) -2-1881 (b-73) (b-7) HH (a-14) -CH- -S- -CH (Me)-2-1882 (b-73) (b-11) HH (a-14 ) -CH- -NH- -CH (Me)-2-1883 (b-73) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1884 (b- 73) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-1885 (b-73) (b-12) HH (a-14) -CH- -O- -CH (Me)-2-1886 (b-73) (b-12) HH (a-14) -CH- -S- -CH (Me)-2-1887 (b-73) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-1888 (b-73) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2 -1889 (b-73) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2-1890 (b-73) (b-15) HH (a-14)- CH- -O- -CH (Me)-2-1891 (b-73) (b-15) HH (a-14) -CH- -S- -CH (Me)-2-1892 (b-73) (b-17) HH (a- 14) -CH- -NH- -CH (Me)-2-1893 (b-73) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-1894 (b -73) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-1895 (b-73) (b-34) HH (a-14) -CH- -NH --CH (Me)-2-1896 (b-73) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-1897 (b-73) (b-34 ) HH (a-14) -CH- -O- -CH (Me)-2-1898 (b-73) (b-34) HH (a-14) -CH- -S- -CH (Me)- 2-1899 (b-73) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1900 (b-73) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1901 (b-73) (b-35) HH (a-14) -CH- -O- -CH (Me)-2-1902 (b-73 ) (b-35) HH (a-14) -CH- -S- -CH (Me)-2-1903 (b-73) (b-37) HH (a-14) -CH- -NH-- CH (Me)-2-1904 (b-73) (b-37) HH (a-14) -CH- -NH- -COCH (Me)-2-1905 (b-73) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-1906 (b-73) (b-37) HH (a-14) -CH- -S- -CH (Me)-2- 1907 (b-73) (b-42) HH (a-14) -CH- -NH- -CH (Me)-2-1908 (b-73) (b-72) HH (a-14) -CH --NH- -CH (Me)-2-1909 (b-73) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1910 (b-73) ( b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-1911 (b-73) (b-73) HH (a-14) -CH- -O- -CH ( Me)-2-1912 (b-73) (b-73) HH (a-14) -CH- -S- -CH (Me)-2-1913 (b-73) (b-74) HH (a-14) -CH- -NH- -CH (Me)-2-1914 (b-73) (b-76) HH (a-14) -CH- -NH- -CH (Me)-2-1915 (b-73) (b -77) HH (a-14) -CH- -NH- -CH (Me)-2-1916 (b-73) (b-77) HH (a-14) -CH- -NH- -COCH (Me )-2-1917 (b-73) (b-77) HH (a-14) -CH- -O- -CH (Me)-2-1918 (b-73) (b-77) HH (a- 14) -CH- -S- -CH (Me)-2-1919 (b-74) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1920 (b -74) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1921 (b-74) (b-12) HH (a-14) -CH- -NH --CH (Me)-2-1922 (b-74) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1923 (b-74) (b-34 ) HH (a-14) -CH- -NH- -CH (Me)-2-1924 (b-74) (b-35) HH (a-14) -CH- -NH- -CH (Me)- 2-1925 (b-74) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1926 (b-74) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1927 (b-74) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1928 (b-74 ) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-1929 (b-75) (b-7) HH (a-14) -CH- -NH-- CH (Me)-2-1930 (b-75) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1931 (b-76) (b-7) HH (a-14) -CH- -N H- -CH (Me)-2-1932 (b-76) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2-1933 (b-76) (b- 12) HH (a-14) -CH- -NH- -CH (Me)-2-1934 (b-76) (b-15) HH (a-14) -CH- -NH- -CH (Me) -2-1935 (b-76) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-1936 (b-76) (b-35) HH (a-14 ) -CH- -NH- -CH (Me)-2-1937 (b-76) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1938 (b- 76) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1939 (b-76) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1940 (b-76) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2-1941 (b-77) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1942 (b-77) (b-7) HH (a-14) -CH- -NH- -COCH (Me)-2 -1943 (b-77) (b-7) HH (a-14) -CH- -O- -CH (Me)-2-1944 (b-77) (b-7) HH (a-14)- CH- -S- -CH (Me)-2-1945 (b-77) (b-11) HH (a-14) -CH- -NH- -CH (Me)-2-1946 (b-77) (b-12) HH (a-14) -CH- -NH- -CH (Me)-2-1947 (b-77) (b-12) HH (a-14) -CH- -NH- -COCH (Me)-2-1948 (b-77) (b-12) HH (a-14) -CH- -O- -CH (Me)-2-1949 (b-77) (b-12) HH ( a-14) -CH- -S- -CH (Me)-2-1950 (b-77) (b-14) HH (a-14) -CH- -NH- -CH (Me)-2-1951 (b-77) (b-15) HH (a-14) -CH- -NH- -CH (Me)-2-1952 (b-77) (b-15) HH (a-14) -CH- -NH- -COCH (Me)-2 -1953 (b-77) (b-15) HH (a-14) -CH- -O- -CH (Me)-2-1954 (b-77) (b-15) HH (a-14)- CH- -S- -CH (Me)-2-1955 (b-77) (b-17) HH (a-14) -CH- -NH- -CH (Me)-2-1956 (b-77) (b-25) HH (a-14) -CH- -NH- -CH (Me)-2-1957 (b-77) (b-33) HH (a-14) -CH- -NH- -CH (Me)-2-1958 (b-77) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-1959 (b-77) (b-34) HH ( a-14) -CH- -NH- -COCH (Me)-2-1960 (b-77) (b-34) HH (a-14) -CH- -O- -CH (Me)-2-1961 (b-77) (b-34) HH (a-14) -CH- -S- -CH (Me)-2-1962 (b-77) (b-35) HH (a-14) -CH- -NH- -CH (Me)-2-1963 (b-77) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-2-1964 (b-77) (b -35) HH (a-14) -CH- -O- -CH (Me)-2-1965 (b-77) (b-35) HH (a-14) -CH- -S- -CH (Me )-2-1966 (b-77) (b-37) HH (a-14) -CH- -NH- -CH (Me)-2-1967 (b-77) (b-37) HH (a- 14) -CH- -NH- -COCH (Me)-2-1968 (b-77) (b-37) HH (a-14) -CH- -O- -CH (Me)-2-1969 (b -77) (b-37) HH (a-14) -CH- -S- -CH (Me)-2-1970 (b-77) (b-42) HH (a-14) -CH- -NH --CH (Me)- 2-1971 (b-77) (b-72) HH (a-14) -CH- -NH- -CH (Me)-2-1972 (b-77) (b-73) HH (a-14) -CH- -NH- -CH (Me)-2-1973 (b-77) (b-73) HH (a-14) -CH- -NH- -COCH (Me)-2-1974 (b-77 ) (b-73) HH (a-14) -CH- -O- -CH (Me)-2-1975 (b-77) (b-73) HH (a-14) -CH- -S-- CH (Me)-2-1976 (b-77) (b-74) HH (a-14) -CH- -NH- -CH (Me)-2-1977 (b-77) (b-76) HH (a-14) -CH- -NH- -CH (Me)-2-1978 (b-77) (b-77) HH (a-14) -CH- -NH- -CH (Me)-2- 1979 (b-77) (b-77) HH (a-14) -CH- -NH- -COCH (Me)-2-1980 (b-77) (b-77) HH (a-14) -CH --O- -CH (Me)-2-1981 (b-77) (b-77) HH (a-14) -CH- -S- -CH (Me)-2-1982 (b-78) ( b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1983 (b-78) (b-35) HH (a-14) -CH- -NH- -CH ( Me)-2-1984 (b-79) (b-7) HH (a-14) -CH- -NH- -CH (Me)-2-1985 (b-79) (b-35) HH (a -14) -CH- -NH--(CH_Two)_Two-   2-1986   (b-2)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1987   (b-2)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1988   (b-7)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1989   (b-7)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-1990   (b-7)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1991   (b-7)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1992   (b-7)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1993   (b-7)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1994   (b-7)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-1995   (b-7)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1996   (b-7)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1997   (b-7)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1998   (b-8)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-1999   (b-9)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2000   (b-10)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2001   (b-11)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2002   (b-11)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2003   (b-11)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2004   (b-11)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2005   (b-11)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2006   (b-11)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2007   (b-11)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2008   (b-11)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2009   (b-11)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2010   (b-11)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2011   (b-12)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2012   (b-12)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2013   (b-12)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2014   (b-12)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2015   (b-13)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2016   (b-14)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2017   (b-15)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2018   (b-15)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2019   (b-15)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2020   (b-15)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2021   (b-17)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2022   (b-18)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2023   (b-18)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2024   (b-18)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2025   (b-18)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2026   (b-18)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2027   (b-18)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2028   (b-18)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2029   (b-18)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2030   (b-18)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2031   (b-18)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2032   (b-19)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2033   (b-19)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2034   (b-19)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2035   (b-19)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2036   (b-20)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2037   (b-20)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2038   (b-20)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2039   (b-20)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2040   (b-20)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2041   (b-20)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2042   (b-20)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2043   (b-20)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2044   (b-20)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2045   (b-20)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2046   (b-21)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2047   (b-21)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2048   (b-21)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2049   (b-21)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2050   (b-23)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2051   (b-24)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2052   (b-24)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2053   (b-24)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2054   (b-24)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2055   (b-25)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2056   (b-25)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2057   (b-25)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2058   (b-25)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2059   (b-35)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2060   (b-72)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2061   (b-72)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2062   (b-72)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2063   (b-72)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2064   (b-73)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2065   (b-73)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2066   (b-73)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2067   (b-73)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2068   (b-73)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2069   (b-73)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2070   (b-73)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2071   (b-73)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2072   (b-73)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2073   (b-73)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2074   (b-74)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2075   (b-74)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2076   (b-74)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2077   (b-74)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2078   (b-75)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2079   (b-76)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2080   (b-76)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2081   (b-76)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2082   (b-76)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2083   (b-77)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2084   (b-77)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2085   (b-77)   (b-12)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2086   (b-77)   (b-15)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2087   (b-77)   (b-34)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2088   (b-77)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2089   (b-77)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   2-2090   (b-77)   (b-37)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2091   (b-77)   (b-73)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2092   (b-77)   (b-77)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2093   (b-78)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2094   (b-79)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   2-2095   (b-7)   (b-35)   H   H   (a-16)   -CH-   -NH-   -CH (Me)-   2-2096   (b-11)   (b-35)   H   H   (a-16)   -CH-   -NH-   -CH (Me)-   2-2097   (b-18)   (b-35)   H   H   (a-16)   -CH-   -NH-   -CH (Me)-   2-2098   (b-7)   (b-35)   H   H   (a-17)   -CH-   -NH-   -CH (Me)-   2-2099   (b-11)   (b-35)   H   H   (a-17)   -CH-   -NH-   -CH (Me)-   2-2100   (b-18)   (b-35)   H   H   (a-17)   -CH-   -NH-   -CH (Me)-   2-2101   (b-2)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2102   (b-2)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2103   (b-7)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2104   (b-7)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2105   (b-7)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2106   (b-7)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2107   (b-7)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2108   (b-7)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2109   (b-7)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2110   (b-7)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2111   (b-7)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2112   (b-7)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2113   (b-8)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2114   (b-9)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2115   (b-10)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2116   (b-11)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2117   (b-11)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2118   (b-11)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2119   (b-11)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2120   (b-11)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2121   (b-11)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2122   (b-11)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2123   (b-11)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2124   (b-11)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2125   (b-11)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2126   (b-12)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2127   (b-12)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2128   (b-12)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2129   (b-12)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2130   (b-13)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2131   (b-14)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2132   (b-15)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2133   (b-15)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2134   (b-15)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2135   (b-15)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2136   (b-17)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2137   (b-18)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2138   (b-18)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2139   (b-18)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2140   (b-18)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2141   (b-18)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2142   (b-18)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2143   (b-18)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2144   (b-18)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2145   (b-18)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2146   (b-18)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2147   (b-19)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2148   (b-19)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2149   (b-19)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2150   (b-19)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2151   (b-20)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2152   (b-20)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2153   (b-20)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2154   (b-20)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2155   (b-20)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2156   (b-20)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2157   (b-20)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2158   (b-20)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2159   (b-20)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2160   (b-20)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2161   (b-21)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2162   (b-21)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2163   (b-21)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2164   (b-21)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2165   (b-23)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2166   (b-24)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2167   (b-24)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2168   (b-24)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2169   (b-24)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2170   (b-25)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2171   (b-25)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2172   (b-25)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2173   (b-25)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2174   (b-35)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2175   (b-72)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2176   (b-72)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2177   (b-72)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2178   (b-72)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2179   (b-73)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2180   (b-73)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2181   (b-73)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2182   (b-73)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2183   (b-73)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2184   (b-73)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2185   (b-73)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2186   (b-73)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2187   (b-73)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2188   (b-73)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2189   (b-74)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2190   (b-74)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2191   (b-74)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2192   (b-74)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2193   (b-75)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2194   (b-76)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2195   (b-76)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2196   (b-76)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2197   (b-76)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2198   (b-77)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2199   (b-77)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2200   (b-77)   (b-12)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2201   (b-77)   (b-15)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2202   (b-77)   (b-34)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2203   (b-77)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2204   (b-77)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   2-2205   (b-77)   (b-37)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2206   (b-77)   (b-73)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2207   (b-77)   (b-77)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2208   (b-78)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2209   (b-79)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   2-2210   (b-2)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2211   (b-7)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2212   (b-7)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2213   (b-7)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2214   (b-7)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2215   (b-8)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2216   (b-11)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2217   (b-11)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2218   (b-11)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2219   (b-11)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2220   (b-12)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2221   (b-12)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2222   (b-15)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2223   (b-15)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2224   (b-18)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2225   (b-18)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2226   (b-18)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2227   (b-18)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2228   (b-19)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2229   (b-19)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2230   (b-20)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2231   (b-20)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2232   (b-20)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2233   (b-20)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2234   (b-21)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2235   (b-21)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2236   (b-24)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2237   (b-24)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2238   (b-25)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2239   (b-25)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2240   (b-72)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2241   (b-72)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2242   (b-73)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2243   (b-73)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2244   (b-73)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2245   (b-73)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2246   (b-74)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2247   (b-74)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2248   (b-76)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2249   (b-76)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2250   (b-77)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2251   (b-77)   (b-7)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2252   (b-77)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   2-2253   (b-77)   (b-35)   H   H   (a-19)   -CH-   -NH-   -COCH (Me)-   2-2254   (b-2)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2255   (b-2)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2256   (b-7)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2257   (b-7)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2258   (b-7)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2259   (b-7)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2260   (b-7)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2261   (b-7)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2262   (b-7)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2263   (b-7)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2264   (b-7)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2265   (b-7)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2266   (b-8)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2267   (b-9)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2268   (b-10)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2269   (b-11)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2270   (b-11)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2271   (b-11)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2272   (b-11)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2273   (b-11)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2274   (b-11)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2275   (b-11)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2276   (b-11)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2277   (b-11)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2278   (b-11)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2279   (b-12)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2280   (b-12)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2281   (b-12)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2282   (b-12)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2283   (b-13)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2284   (b-14)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2285   (b-15)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2286   (b-15)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2287   (b-15)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2288   (b-15)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2289   (b-17)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2290   (b-18)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2291   (b-18)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2292   (b-18)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2293   (b-18)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2294   (b-18)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2295   (b-18)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2296   (b-18)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2297   (b-18)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2298   (b-18)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2299   (b-18)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2300   (b-19)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2301   (b-19)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2302   (b-19)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2303   (b-19)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2304   (b-20)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2305   (b-20)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2306   (b-20)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2307   (b-20)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2308   (b-20)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2309   (b-20)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2310   (b-20)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2311   (b-20)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2312   (b-20)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2313   (b-20)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2314   (b-21)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2315   (b-21)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2316   (b-21)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2317   (b-21)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2318   (b-23)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2319   (b-24)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2320   (b-24)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2321   (b-24)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2322   (b-24)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2323   (b-25)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2324   (b-25)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2325   (b-25)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2326   (b-25)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2327   (b-35)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2328   (b-72)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2329   (b-72)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2330   (b-72)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2331   (b-72)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2332   (b-73)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2333   (b-73)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2334   (b-73)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2335   (b-73)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2336   (b-73)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2337   (b-73)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2338   (b-73)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2339   (b-73)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2340   (b-73)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2341   (b-73)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2342   (b-74)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2343   (b-74)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2344   (b-74)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2345   (b-74)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2346   (b-75)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2347   (b-76)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2348   (b-76)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2349   (b-76)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2350   (b-76)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2351   (b-77)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2352   (b-77)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2353   (b-77)   (b-12)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2354   (b-77)   (b-15)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2355   (b-77)   (b-34)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2356   (b-77)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2357   (b-77)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   2-2358   (b-77)   (b-37)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2359   (b-77)   (b-73)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2360   (b-77)   (b-77)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2361   (b-78)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2362   (b-79)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   2-2363   (b-7)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2364   (b-7)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2365   (b-11)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2366   (b-11)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2367   (b-12)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2368   (b-15)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2369   (b-18)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2370   (b-18)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2371   (b-19)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2372   (b-20)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2373   (b-20)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2374   (b-21)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2375   (b-24)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2376   (b-25)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2377   (b-72)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2378   (b-73)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2379   (b-73)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2380   (b-74)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2381   (b-76)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2382   (b-77)   (b-7)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2383   (b-77)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   2-2384   (b-7)   (b-35)   H   H   (a-22)   -CH-   -NH-   -CH (Me)-   2-2385   (b-11)   (b-35)   H   H   (a-22)   -CH-   -NH-   -CH (Me)-   2-2386   (b-18)   (b-35)   H   H   (a-22)   -CH-   -NH-   -CH (Me)-   2-2387   (b-7)   (b-35)   H   H   (a-23)   -CH-   -NH-   -CH (Me)-   2-2388   (b-11)   (b-35)   H   H   (a-23)   -CH-   -NH-   -CH (Me)-   2-2389   (b-18)   (b-35)   H   H   (a-23)   -CH-   -NH-   -CH (Me)-   2-2390   (b-2)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2391   (b-7)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2392   (b-7)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2393   (b-7)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2394   (b-7)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2395   (b-8)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2396   (b-11)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2397   (b-11)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2398   (b-11)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2399   (b-11)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2400   (b-12)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2401   (b-12)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2402   (b-15)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2403   (b-15)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2404   (b-18)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2405   (b-18)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2406   (b-18)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2407   (b-18)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2408   (b-19)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2409   (b-19)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2410   (b-20)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2411   (b-20)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2412   (b-20)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2413   (b-20)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2414   (b-21)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2415   (b-21)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2416   (b-24)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2417   (b-24)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2418   (b-25)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2419   (b-25)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2420   (b-72)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2421   (b-72)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2422   (b-73)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2423   (b-73)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2424   (b-73)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2425   (b-73)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2426   (b-74)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2427   (b-74)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2428   (b-76)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2429   (b-76)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2430   (b-77)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2431   (b-77)   (b-7)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2432   (b-77)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   2-2433   (b-77)   (b-35)   H   H   (a-24)   -CH-   -NH-   -COCH (Me)-   2-2434   (b-7)   (b-35)   H   H   (a-25)   -CH-   -NH-   -CH (Me)-   2-2435   (b-11)   (b-35)   H   H   (a-25)   -CH-   -NH-   -CH (Me)-   2-2436   (b-18)   (b-35)   H   H   (a-25)   -CH-   -NH-   -CH (Me)-   2-2437   (b-2)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2438   (b-2)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2439   (b-7)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2440   (b-7)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2441   (b-7)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2442   (b-7)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2443   (b-7)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2444   (b-7)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2445   (b-7)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2446   (b-7)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2447   (b-7)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2448   (b-7)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2449   (b-8)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2450   (b-9)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2451   (b-10)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2452   (b-11)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2453   (b-11)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2454   (b-11)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2455   (b-11)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2456   (b-11)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2457   (b-11)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2458   (b-11)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2459   (b-11)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2460   (b-11)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2461   (b-11)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2462   (b-12)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2463   (b-12)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2464   (b-12)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2465   (b-12)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2466   (b-13)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2467   (b-14)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2468   (b-15)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2469   (b-15)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2470   (b-15)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2471   (b-15)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2472   (b-17)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2473   (b-18)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2474   (b-18)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2475   (b-18)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2476   (b-18)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2477   (b-18)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2478   (b-18)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2479   (b-18)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2480   (b-18)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2481   (b-18)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2482   (b-18)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2483   (b-19)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2484   (b-19)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2485   (b-19)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2486   (b-19)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2487   (b-20)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2488   (b-20)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2489   (b-20)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2490   (b-20)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2491   (b-20)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2492   (b-20)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2493   (b-20)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2494   (b-20)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2495   (b-20)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2496   (b-20)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2497   (b-21)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2498   (b-21)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2499   (b-21)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2500   (b-21)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2501   (b-23)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2502   (b-24)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2503   (b-24)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2504   (b-24)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2505   (b-24)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2506   (b-25)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2507   (b-25)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2508   (b-25)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2509   (b-25)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2510   (b-35)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2511   (b-72)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2512   (b-72)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2513   (b-72)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2514   (b-72)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2515   (b-73)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2516   (b-73)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2517   (b-73)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2518   (b-73)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2519   (b-73)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2520   (b-73)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2521   (b-73)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2522   (b-73)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2523   (b-73)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2524   (b-73)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2525   (b-74)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2526   (b-74)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2527   (b-74)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2528   (b-74)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2529   (b-75)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2530   (b-76)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2531   (b-76)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2532   (b-76)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2533   (b-76)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2534   (b-77)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2535   (b-77)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2536   (b-77)   (b-12)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2537   (b-77)   (b-15)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2538   (b-77)   (b-34)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2539   (b-77)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2540   (b-77)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   2-2541   (b-77)   (b-37)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2542   (b-77)   (b-73)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2543   (b-77)   (b-77)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2544   (b-78)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2545   (b-79)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   2-2546   (b-7)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2547   (b-7)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2548   (b-11)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2549   (b-11)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2550   (b-12)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2551   (b-15)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2552   (b-18)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2553   (b-18)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2554   (b-19)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2555   (b-20)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2556   (b-20)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2557   (b-21)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2558   (b-24)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2559   (b-25)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2560   (b-72)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2561   (b-73)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2562   (b-73)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2563   (b-74)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2564   (b-76)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2565   (b-77)   (b-7)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2566   (b-77)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   2-2567   (b-2)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2568   (b-7)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2569   (b-7)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2570   (b-7)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2571   (b-7)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2572   (b-8)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2573   (b-11)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2574   (b-11)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2575   (b-11)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2576   (b-11)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2577   (b-12)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2578   (b-12)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2579   (b-15)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2580   (b-15)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2581   (b-18)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2582   (b-18)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2583   (b-18)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2584   (b-18)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2585   (b-19)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2586   (b-19)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2587   (b-20)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2588   (b-20)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2589   (b-20)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2590   (b-20)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2591   (b-21)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2592   (b-21)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2593   (b-24)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2594   (b-24)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2595   (b-25)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2596   (b-25)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2597   (b-72)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2598   (b-72)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2599   (b-73)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2600   (b-73)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2601   (b-73)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2602   (b-73)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2603   (b-74)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2604   (b-74)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2605   (b-76)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2606   (b-76)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2607   (b-77)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2608   (b-77)   (b-7)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2609   (b-77)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   2-2610   (b-77)   (b-35)   H   H   (a-28)   -CH-   -NH-   -COCH (Me)-   2-2611   (b-7)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2612   (b-7)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2613   (b-11)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2614   (b-11)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2615   (b-12)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2616   (b-15)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2617   (b-18)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2618   (b-18)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2619   (b-19)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2620   (b-20)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2621   (b-20)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2622   (b-21)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2623   (b-24)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2624   (b-25)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2625   (b-72)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2626   (b-73)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2627   (b-73)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2628   (b-74)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2629   (b-76)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2630   (b-77)   (b-7)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2631   (b-77)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   2-2632   (b-7)   (b-35)   H   H   (a-30)   -CH-   -NH-   -CH (Me)-   2-2633   (b-11)   (b-35)   H   H   (a-30)   -CH-   -NH-   -CH (Me)-   2-2634   (b-18)   (b-35)   H   H   (a-30)   -CH-   -NH-   -CH (Me)-   2-2635   (b-2)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2636   (b-2)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2637   (b-7)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2638   (b-7)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2639   (b-7)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2640   (b-7)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2641   (b-7)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2642   (b-7)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2643   (b-7)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2644   (b-7)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2645   (b-7)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2646   (b-7)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2647   (b-8)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2648   (b-9)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2649   (b-10)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2650   (b-11)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2651   (b-11)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2652   (b-11)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2653   (b-11)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2654   (b-11)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2655   (b-11)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2656   (b-11)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2657   (b-11)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2658   (b-11)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2659   (b-11)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2660   (b-12)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2661   (b-12)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2662   (b-12)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2663   (b-12)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2664   (b-13)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2665   (b-14)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2666   (b-15)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2667   (b-15)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2668   (b-15)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2669   (b-15)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2670   (b-17)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2671   (b-18)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2672   (b-18)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2673   (b-18)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2674   (b-18)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2675   (b-18)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2676   (b-18)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2677   (b-18)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2678   (b-18)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2679   (b-18)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2680   (b-18)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2681   (b-19)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2682   (b-19)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2683   (b-19)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2684   (b-19)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2685   (b-20)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2686   (b-20)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2687   (b-20)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2688   (b-20)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2689   (b-20)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2690   (b-20)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2691   (b-20)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2692   (b-20)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2693   (b-20)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2694   (b-20)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2695   (b-21)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2696   (b-21)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2697   (b-21)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2698   (b-21)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2699   (b-23)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2700   (b-24)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2701   (b-24)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2702   (b-24)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2703   (b-24)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2704   (b-25)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2705   (b-25)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2706   (b-25)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2707   (b-25)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2708   (b-35)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2709   (b-72)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2710   (b-72)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2711   (b-72)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2712   (b-72)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2713   (b-73)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2714   (b-73)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2715   (b-73)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2716   (b-73)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2717   (b-73)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2718   (b-73)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2719   (b-73)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2720   (b-73)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2721   (b-73)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2722   (b-73)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2723   (b-74)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2724   (b-74)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2725   (b-74)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2726   (b-74)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2727   (b-75)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2728   (b-76)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2729   (b-76)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2730   (b-76)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2731   (b-76)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2732   (b-77)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2733   (b-77)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2734   (b-77)   (b-12)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2735   (b-77)   (b-15)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2736   (b-77)   (b-34)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2737   (b-77)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2738   (b-77)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   2-2739   (b-77)   (b-37)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2740   (b-77)   (b-73)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2741   (b-77)   (b-77)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2742   (b-78)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2743   (b-79)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   2-2744   (b-7)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2745   (b-7)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2746   (b-11)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2747   (b-11)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2748   (b-12)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2749   (b-15)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2750   (b-18)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2751   (b-18)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2752   (b-19)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2753   (b-20)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2754   (b-20)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2755   (b-21)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2756   (b-24)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2757   (b-25)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2758   (b-72)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2759   (b-73)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2760   (b-73)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2761   (b-74)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2762   (b-76)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2763   (b-77)   (b-7)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2764   (b-77)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   2-2765   (b-2)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2766   (b-7)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2767   (b-7)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2768   (b-7)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2769   (b-7)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2770   (b-8)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2771   (b-11)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2772   (b-11)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2773   (b-11)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2774   (b-11)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2775   (b-12)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2776   (b-12)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2777   (b-15)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2778   (b-15)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2779   (b-18)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2780   (b-18)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2781   (b-18)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2782   (b-18)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2783   (b-19)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2784   (b-19)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2785   (b-20)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2786   (b-20)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2787   (b-20)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2788   (b-20)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2789   (b-21)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2790   (b-21)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2791   (b-24)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2792   (b-24)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2793   (b-25)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2794   (b-25)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2795   (b-72)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2796   (b-72)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2797   (b-73)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2798   (b-73)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2799   (b-73)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2800   (b-73)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2801   (b-74)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2802   (b-74)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2803   (b-76)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2804   (b-76)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2805   (b-77)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2806   (b-77)   (b-7)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2807   (b-77)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   2-2808   (b-77)   (b-35)   H   H   (a-33)   -CH-   -NH-   -COCH (Me)-   2-2809   (b-7)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2810   (b-7)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2811   (b-11)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2812   (b-11)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2813   (b-12)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2814   (b-15)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2815   (b-18)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2816   (b-18)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2817   (b-19)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2818   (b-20)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2819   (b-20)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2820   (b-21)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2821   (b-24)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2822   (b-25)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2823   (b-72)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2824   (b-73)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2825   (b-73)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2826   (b-74)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2827   (b-76)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2828   (b-77)   (b-7)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2829   (b-77)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   2-2830   (b-7)   (b-35)   H   H   (a-35)   -CH-   -NH-   -CH (Me)-   2-2831   (b-11)   (b-35)   H   H   (a-35)   -CH-   -NH-   -CH (Me)-   2-2832   (b-18)   (b-35)   H   H   (a-35)   -CH-   -NH-   -CH (Me)-   2-2833   (b-7)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2834   (b-7)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2835   (b-11)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2836   (b-11)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2837   (b-12)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2838   (b-15)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2839   (b-18)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2840   (b-18)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2841   (b-19)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2842   (b-20)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2843   (b-20)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2844   (b-21)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2845   (b-24)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2846   (b-25)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2847   (b-72)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2848   (b-73)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2849   (b-73)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2850   (b-74)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2851   (b-76)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2852   (b-77)   (b-7)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2853   (b-77)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   2-2854   (b-7)   (b-35)   H   H   (a-37)   -CH-   -NH-   -CH (Me)-   2-2855   (b-11)   (b-35)   H   H   (a-37)   -CH-   -NH-   -CH (Me)-   2-2856   (b-18)   (b-35)   H   H   (a-37)   -CH-   -NH-   -CH (Me)-   2-2857   (b-7)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2858   (b-11)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2859   (b-18)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2860   (b-20)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2861   (b-73)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2862   (b-77)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   2-2863   (b-7)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2864   (b-7)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2865   (b-11)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2866   (b-11)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2867   (b-12)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2868   (b-15)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2869   (b-18)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2870   (b-18)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2871   (b-19)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2872   (b-20)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2873   (b-20)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2874   (b-21)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2875   (b-24)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2876   (b-25)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2877   (b-72)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2878   (b-73)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2879   (b-73)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2880   (b-74)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2881   (b-76)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2882   (b-77)   (b-7)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2883   (b-77)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   2-2884   (b-7)   (b-35)   H   H   (a-40)   -CH-   -NH-   -CH (Me)-   2-2885   (b-11)   (b-35)   H   H   (a-40)   -CH-   -NH-   -CH (Me)-   2-2886   (b-18)   (b-35)   H   H   (a-40)   -CH-   -NH-   -CH (Me)-   2-2887   (b-7)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2888   (b-11)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2889   (b-18)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2890   (b-20)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2891   (b-73)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2892   (b-77)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   2-2893   (b-7)   (b-35)   H   H   (a-42)   -CH-   -NH-   -CH (Me)-   2-2894   (b-11)   (b-35)   H   H   (a-42)   -CH-   -NH-   -CH (Me)-   2-2895   (b-18)   (b-35)   H   H   (a-42)   -CH-   -NH-   -CH (Me)-   2-2896   (b-2)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2897   (b-2)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2898   (b-7)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2899   (b-7)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2900   (b-7)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2901   (b-7)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2902   (b-7)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2903   (b-7)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2904   (b-7)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2905   (b-7)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2906   (b-7)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2907   (b-7)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2908   (b-8)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2909   (b-9)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2910   (b-10)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2911   (b-11)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2912   (b-11)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2913   (b-11)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2914   (b-11)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2915   (b-11)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2916   (b-11)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2917   (b-11)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2918   (b-11)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2919   (b-11)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2920   (b-11)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2921   (b-12)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2922   (b-12)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2923   (b-12)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2924   (b-12)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2925   (b-13)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2926   (b-14)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2927   (b-15)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2928   (b-15)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2929   (b-15)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2930   (b-15)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2931   (b-17)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2932   (b-18)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2933   (b-18)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2934   (b-18)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2935   (b-18)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2936   (b-18)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2937   (b-18)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2938   (b-18)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2939   (b-18)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2940   (b-18)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2941   (b-18)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2942   (b-19)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2943   (b-19)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2944   (b-19)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2945   (b-19)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2946   (b-20)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2947   (b-20)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2948   (b-20)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2949   (b-20)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2950   (b-20)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2951   (b-20)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2952   (b-20)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2953   (b-20)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2954   (b-20)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2955   (b-20)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2956   (b-21)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2957   (b-21)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2958   (b-21)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2959   (b-21)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2960   (b-23)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2961   (b-24)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2962   (b-24)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2963   (b-24)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2964   (b-24)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2965   (b-25)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2966   (b-25)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2967   (b-25)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2968   (b-25)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2969   (b-35)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2960   (b-72)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2961   (b-72)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2962   (b-72)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2963   (b-72)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2964   (b-73)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2965   (b-73)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2966   (b-73)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2967   (b-73)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2968   (b-73)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2969   (b-73)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2970   (b-73)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2971   (b-73)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2972   (b-73)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2973   (b-73)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2974   (b-74)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2975   (b-74)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2976   (b-74)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2977   (b-74)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2978   (b-75)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2979   (b-76)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2980   (b-76)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2981   (b-76)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2982   (b-76)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2983   (b-77)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2984   (b-77)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2985   (b-77)   (b-12)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2986   (b-77)   (b-15)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2987   (b-77)   (b-34)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2988   (b-77)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2989   (b-77)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   2-2990   (b-77)   (b-37)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2991   (b-77)   (b-73)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2992   (b-77)   (b-77)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2993   (b-78)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2994   (b-79)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   2-2995   (b-7)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-2996   (b-7)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-2997   (b-11)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-2998   (b-11)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-2999   (b-12)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3000   (b-15)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3001   (b-18)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3002   (b-18)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3003   (b-19)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3004   (b-20)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3005   (b-20)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3006   (b-21)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3007   (b-24)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3008   (b-25)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3009   (b-72)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3010   (b-73)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3011   (b-73)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3012   (b-74)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3013   (b-76)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3014   (b-77)   (b-7)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3015   (b-77)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   2-3016   (b-2)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3017   (b-7)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3018   (b-7)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3019   (b-7)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3020   (b-7)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3021   (b-8)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3022   (b-11)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3023   (b-11)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3024   (b-11)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3025   (b-11)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3026   (b-12)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3027   (b-12)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3028   (b-15)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3029   (b-15)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3030   (b-18)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3031   (b-18)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3032   (b-18)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3033   (b-18)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3034   (b-19)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3035   (b-19)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3036   (b-20)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3037   (b-20)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3038   (b-20)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3039   (b-20)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3040   (b-21)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3041   (b-21)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3042   (b-24)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3043   (b-24)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3044   (b-25)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3045   (b-25)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3046   (b-72)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3047   (b-72)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3048   (b-73)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3049   (b-73)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3050   (b-73)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3051   (b-73)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3052   (b-74)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3053   (b-74)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3054   (b-76)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3055   (b-76)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3056   (b-77)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3057   (b-77)   (b-7)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3058   (b-77)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   2-3059   (b-77)   (b-35)   H   H   (a-45)   -CH-   -NH-   -COCH (Me)-   2-3060   (b-7)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3061   (b-7)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3062   (b-11)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3063   (b-11)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3064   (b-12)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3065   (b-15)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3066   (b-18)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3067   (b-18)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3068   (b-19)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3069   (b-20)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3070   (b-20)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3071   (b-21)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3072   (b-24)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3073   (b-25)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3074   (b-72)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3075   (b-73)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3076   (b-73)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3077   (b-74)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3078   (b-76)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3079   (b-77)   (b-7)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3080   (b-77)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   2-3081   (b-7)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3082   (b-11)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3083   (b-18)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3084   (b-20)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3085   (b-73)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3086   (b-77)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   2-3087   (b-7)   (b-35)   H   H   (a-48)   -CH-   -NH-   -CH (Me)-   2-3088   (b-11)   (b-35)   H   H   (a-48)   -CH-   -NH-   -CH (Me)-   2-3089   (b-18)   (b-35)   H   H   (a-48)   -CH-   -NH-   -CH (Me)-   2-3090   (b-7)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Et)-   2-3091   (b-7)   (b-7)   H   H   (a-1)   -CH-   -NH-   -(CH_Two)_Three-2-3092 (b-7) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3093 (b-7) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (OH)-2-3094 (b-7) (b-7) H H (a-1) -CH- -NH- -CH_TwoC (= O)-2-3095 (b-7) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (Ph)-2-3096 (b-7) (b-7) HH (a-1) -CH- -NH- -CO- 2-3097 (b-7) (b-7) HH (a- 1) -CH- -NH- -COCH (Me)-2-3098 (b-7) (b-7) HH (a-1) -CH- -O- -CH (Me)-2-3099 (b -7) (b-7) HH (a-1) -CH- -S- -CH (Me)-2-3100 (b-7) (b-7) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3101 (b-7) (b-7) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3102 (b-7) (b-7) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2-3103 (b-7) (b-7) 6-Cl H (a-1) -CH --NH- -CH (Me)-2-3104 (b-7) (b-7) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3105 (b- 7) (b-7) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3106 (b-7) (b-7) HH (a-1) N -CO --CH (Me)-2-3107 (b-7) (b-8) HH (a-1) -CH- -NH- -CH (Me)-2-3108 (b-7) (b-10 ) HH (a-1) -CH- -NH- -CH (Me)-2-3109 (b-7) (b-11) HH (a-1) -CH- -NH- -CH (Me)- 2-3110 (b-7) (b-12) HH (a-1) -CH- -NH--(CH_Two)_Two-2-3111 (b-7) (b-12) HH (a-1) -CH- -NH- -CH (Et)-2-3112 (b-7) (b-13) HH (a-1 ) -CH- -NH- -CH (Me)-2-3113 (b-7) (b-14) HH (a-1) -CH- -NH- -CH (Me)-2-3114 (b- 7) (b-15) HH (a-1) -CH- -NH--(CH_Two)_Two-2-3115 (b-7) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-3116 (b-7) (b-15) HH (a-1 ) -CH- -NH- -CH_TwoCH (Me)-2-3117 (b-7) (b-16) HH (a-1) -CH- -NH- -CH (Me)-2-3118 (b-7) (b-17) HH (a-1) -CH- -NH- -CH (Me)-2-3119 (b-7) (b-23) HH (a-1) -CH- -NH- -CH (Me)-2- 3120 (b-7) (b-24) HH (a-1) -CH- -NH- -CH (Me)-2-3121 (b-7) (b-25) HH (a-1) -CH --NH- -CH (Me)-2-3122 (b-7) (b-27) HH (a-1) -CH- -NH- -CH (Me)-2-3123 (b-7) ( b-28) HH (a-1) -CH- -NH- -CH (Me)-2-3124 (b-7) (b-30) HH (a-1) -CH- -NH- -CH ( Me)-2-3125 (b-7) (b-31) HH (a-1) -CH- -NH- -CH (Me)-2-3126 (b-7) (b-32) HH (a -1) -CH- -NH- -CH (Me)-2-3127 (b-7) (b-33) HH (a-1) -CH- -NH- -CH (Me)-2-3128 ( b-7) (b-34) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3129 (b-7) (b-34) HH (a-1)- CH- -O- -CH (Me)-2-3130 (b-7) (b-34) HH (a-1) -CH- -S- -CH (Me)-2-3131 (b-7) (b-34) HH (a-1) N -CO- -CH (Me)-2-3132 (b-7) (b-35) HH (a-1) -CH- -NH- single bond 2- 3133 (b-7) (b-35) HH (a-1) -CH- -NH- -CH_Two-2-3134 (b-7) (b-35) H H (a-1) -CH- -NH-(CH_Two)_Two-2-3135 (b-7) (b-35) HH (a-1) -CH- -NH- -CH (Et)-2-3136 (b-7) (b-35) HH (a-1 ) -CH- -NH- -C (Me)_Two-2-3137 (b-7) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3138 (b-7) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (OH)-2-3139 (b-7) (b-35) H H (a-1) -CH- -NH- -CH_TwoC (= O)-2-3140 (b-7) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Ph)-2-3141 (b-7) (b-35) HH (a-1) -CH- -NH- -CO- 2-3142 (b-7) (b-35) HH (a- 1) -CH- -NH- -COCH_Two-2-3143 (b-7) (b-35) HH (a-1) -CH- -O- -CH (Me)-2-3144 (b-7) (b-35) HH (a-1 ) -CH- -S- -CH (Me)-2-3145 (b-7) (b-35) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3146 ( b-7) (b-35) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3147 (b-7) (b-35) 4-Cl H (a-1 ) -CH- -NH- -CH (Me)-2-3148 (b-7) (b-35) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3149 (b-7) (b-35) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3150 (b-7) (b-35) 6-MeO H (a -1) -CH- -NH- -CH (Me)-2-3151 (b-7) (b-35) HH (a-1) N -CO- -CH (Me)-2-3152 (b- 7) (b-37) HH (a-1) -CH- -NH- -CO- 2-3153 (b-7) (b-37) HH (a-1) -CH- -NH- -COCH_Two-2-3154 (b-7) (b-37) HH (a-1) -CH- -O- -CH (Me)-2-3155 (b-7) (b-37) HH (a-1 ) -CH- -S- -CH (Me)-2-3156 (b-7) (b-37) HH (a-1) N -CO- -CH (Me)-2-3157 (b-7) (b-38) HH (a-1) -CH- -NH- -CH (Me)-2-3158 (b-7) (b-41) HH (a-1) -CH- -NH- -CH (Me)-2-3159 (b-7) (b-42) HH (a-1) -CH- -NH- -CH (Me)-2-3160 (b-7) (b-43) HH ( a-1) -CH- -NH- -CH (Me)-2-3161 (b-8) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-3162 (b-8) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3163 (b-8) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-3164 (b-8) (b-28) HH (a-1) -CH- -NH- -CH (Me)-2-3165 (b-8) (b -35) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3166 (b-11) (b-1) HH (a-1) -CH- -NH-- CH (Me)-2-3167 (b-11) (b-2) HH (a-1) -CH- -NH- -CH (Me)-2-3168 (b-11) (b-7) HH (a-1) -CH- -NH- single bond 2-3169 (b-11) (b-7) HH (a-1) -CH- -NH- -CH_Two-2-3170 (b-11) (b-7) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3171 (b-11) (b-7) HH (a-1) -CH- -NH- -CH (Et)-2-3172 (b-11) (b-7) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3173 (b-11) (b-7) HH (a-1) -CH- -NH- -CO- 2-3174 (b-11) (b-7) HH (a-1) -CH --NH- -COCH_Two-2-3175 (b-11) (b-7) HH (a-1) -CH- -O- -CH (Me)-2-3176 (b-11) (b-7) HH (a-1 ) -CH- -S- -CH (Me)-2-3177 (b-11) (b-7) HH (a-1) N -CO- -CH (Me)-2-3178 (b-11) (b-8) HH (a-1) -CH- -NH- -CH (Me)-2-3179 (b-11) (b-10) HH (a-1) -CH- -NH- -CH (Me)-2-3180 (b-11) (b-11) HH (a-1) -CH- -NH- -CH (Me)-2-3181 (b-11) (b-12) HH ( a-1) -CH- -NH- -COCH (Me)-2-3182 (b-11) (b-12) HH (a-1) -CH- -O- -CH (Me)-2-3183 (b-11) (b-12) HH (a-1) -CH- -S- -CH (Me)-2-3184 (b-11) (b-12) HH (a-1) N -CO --CH (Me)-2-3185 (b-11) (b-13) HH (a-1) -CH- -NH- -CH (Me)-2-3186 (b-11) (b-14 ) HH (a-1) -CH- -NH- -CH (Me)-2-3187 (b-11) (b-15) HH (a-1) -CH- -NH- -COCH (Me)- 2-3188 (b-11) (b-15) HH (a-1) -CH- -O- -CH (Me)-2-3189 (b-11) (b-15) HH (a-1) -CH- -S- -CH (Me)-2-3190 (b-11) (b-15) HH (a-1) N -CO- -CH (Me)-2-3191 (b-11) ( b-16) HH (a-1) -CH- -NH- -CH (Me)-2-3192 (b-11) (b-17) HH (a-1) -CH- -NH- -CH ( Me)-2-3193 (b-11) (b-23) HH (a-1) -CH- -NH- -CH (Me)-2-3194 (b-11) (b-24) HH (a -1) -CH- -NH- -CH (Me)-2-3195 (b-11) (b-25) HH (a-1) -CH- -NH- -CH (Me)-2-3196 (b-11) (b-27) HH (a-1) -CH- -NH- -CH (Me)-2-3197 (b-11) (b-28) HH (a-1) -CH- -NH- -CH (Me)-2-3198 (b-11) (b-30) HH ( a-1) -CH- -NH- -CH (Me)-2-3199 (b-11) (b-31) HH (a-1) -CH- -NH- -CH (Me)-2-3200 (b-11) (b-32) HH (a-1) -CH- -NH- -CH (Me)-2-3201 (b-11) (b-33) HH (a-1) -CH- -NH- -CH (Me)-2-3202 (b-11) (b-34) HH (a-1) -CH- -NH- -COCH (Me)-2-3203 (b-11) (b -34) HH (a-1) -CH- -O- -CH (Me)-2-3204 (b-11) (b-34) HH (a-1) -CH- -S- -CH (Me )-2-3205 (b-11) (b-34) HH (a-1) N -CO- -CH (Me)-2-3206 (b-11) (b-35) HH (a-1) -CH- -NH- single bond 2-3207 (b-11) (b-35) HH (a-1) -CH- -NH- -CH_Two-2-3208 (b-11) (b-35) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3209 (b-11) (b-35) HH (a-1) -CH- -NH- -CH (Et)-2-3210 (b-11) (b-35) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3211 (b-11) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3212 (b-11) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (OH)-2-3213 (b-11) (b-35) H H (a-1) -CH- -NH- -CH_TwoC (= O)-2-3214 (b-11) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Ph)-2-3215 (b-11) (b-35) HH (a-1) -CH- -O- -CH (Me)-2-3216 (b-11) (b-35) HH (a-1) -CH- -S- -CH (Me)-2-3217 (b-11) (b-35) 4-FH (a-1) -CH- -NH- -CH (Me)- 2-3218 (b-11) (b-35) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3219 (b-11) (b-35) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2-3220 (b-11) (b-35) 6-Cl H (a-1) -CH- -NH- -CH (Me) -2-3221 (b-11) (b-35) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3222 (b-11) (b-35) 6- MeO H (a-1) -CH- -NH- -CH (Me)-2-3223 (b-11) (b-35) HH (a-1) N -CO- -CH (Me)-2- 3224 (b-11) (b-37) HH (a-1) -CH- -NH- single bond 2-3225 (b-11) (b-37) HH (a-1) -CH- -NH- -CH_Two-2-3226 (b-11) (b-37) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3227 (b-11) (b-37) HH (a-1) -CH- -NH- -CH (Et)-2-3228 (b-11) (b-37) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3229 (b-11) (b-37) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3230 (b-11) (b-37) H H (a-1) -CH- -NH- -CH_TwoCH (OH)-2-3231 (b-11) (b-37) H H (a-1) -CH- -NH- -CH_TwoC (= O)-2-3232 (b-11) (b-37) H H (a-1) -CH- -NH- -CH_TwoCH (Ph)-2-3233 (b-11) (b-37) HH (a-1) -CH- -NH- -COCH (Me)-2-3234 (b-11) (b-37) HH (a-1) -CH- -O- -CH (Me)-2-3235 (b-11) (b-37) HH (a-1) -CH- -S- -CH (Me)-2- 3236 (b-11) (b-37) HH (a-1) N -CO- -CH (Me)-2-3237 (b-11) (b-38) HH (a-1) -CH-- NH- -CH (Me)-2-3238 (b-11) (b-41) HH (a-1) -CH- -NH- -CH (Me)-2-3239 (b-11) (b- 42) HH (a-1) -CH- -NH- -CH (Me)-2-3240 (b-11) (b-43) HH (a-1) -CH- -NH- -CH (Me) -2-3241 (b-11) (b-72) HH (a-1) -CH- -NH- -CH (Me)-2-3242 (b-11) (b-72) 6-Cl H ( a-1) -CH- -NH- -CH (Me)-2-3243 (b-11) (b-72) 4-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3244 (b-11) (b-72) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3245 (b-11) (b-73) HH (a -1) -CH- -NH- -COCH (Me)-2-3246 (b-11) (b-73) HH (a-1) -CH- -O- -CH (Me)-2-3247 ( b-11) (b-73) HH (a-1) -CH- -S- -CH (Me)-2-3248 (b-11) (b-73) 4-FH (a-1) -CH --NH- -CH (Me)-2-3249 (b-11) (b-73) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3250 (b-11 ) (b-73) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2-3251 (b-11) (b-73) 6-Cl H (a-1)- CH- -NH- -CH (Me)-2-3252 (b-11) (b-73) 4-M eO H (a-1) -CH- -NH- -CH (Me)-2-3253 (b-11) (b-73) 6-MeO H (a-1) -CH- -NH- -CH ( Me)-2-3254 (b-11) (b-73) HH (a-1) N -CO- -CH (Me)-2-3255 (b-11) (b-74) HH (a-1 ) -CH- -NH- -CH (Me)-2-3256 (b-11) (b-76) HH (a-1) -CH- -NH- -CH (Me)-2-3257 (b- 11) (b-77) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3258 (b-11) (b-77) 6-Cl H (a-1)- CH- -NH- -CH (Me)-2-3259 (b-11) (b-77) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3260 (b -11) (b-77) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3261 (b-14) (b-7) HH (a-1) -CH --NH- single bond 2-3262 (b-14) (b-7) HH (a-1) -CH- -NH- -CH_Two-2-3263 (b-14) (b-7) H H (a-1) -CH- -NH-(CH_Two)_Two-2-3264 (b-14) (b-7) HH (a-1) -CH- -NH- -CH (Me)-2-3265 (b-14) (b-7) HH (a-1 ) -CH- -NH- -CH (Et)-2-3266 (b-14) (b-7) HH (a-1) -CH- -NH--(CH_Two)_Three-2-3267 (b-14) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3268 (b-14) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (OH)-2-3269 (b-14) (b-7) H H (a-1) -CH- -NH- -CH_TwoC (= O)-2-3270 (b-14) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (Ph)-2-3271 (b-14) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-3272 (b-14) (b-7) HH (a-1) -CH- -O- -CH (Me) 2- 2-3273 (b-14) (b-7) HH (a-1) -CH- -S- -CH (Me)-2 -3274 (b-14) (b-7) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3275 (b-14) (b-7) 6-FH (a -1) -CH- -NH- -CH (Me)-2-3276 (b-14) (b-7) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2 -3277 (b-14) (b-7) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3278 (b-14) (b-7) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3279 (b-14) (b-7) 6-MeO H (a-1) -CH- -NH- -CH (Me) -2-3280 (b-14) (b-7) HH (a-1) N -CO- -CH (Me)-2-3281 (b-14) (b-11) HH (a-1)- CH- -NH- -CH (Me)-2-3282 (b-14) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3283 (b-14) (b-12) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3284 (b-14) (b-12) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3285 (b-14) (b-12) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3286 (b-14 ) (b-14) HH (a-1) -CH- -NH- -CH (Me)-2-3287 (b-14) (b-15) HH (a-1) -CH- -NH-- CH (Me)-2-3288 (b-14) (b-15) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3289 (b-14) (b- 15) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3290 (b-14) (b-15) 6 -MeO H (a-1) -CH- -NH- -CH (Me)-2-3291 (b-14) (b-17) HH (a-1) -CH- -NH- -CH (Me) -2-3292 (b-14) (b-25) HH (a-1) -CH- -NH- -CH (Me)-2-3293 (b-14) (b-33) HH (a-1 ) -CH- -NH- -CH (Me)-2-3294 (b-14) (b-34) HH (a-1) -CH- -NH- -CH (Me)-2-3295 (b- 14) (b-34) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3296 (b-14) (b-34) 6-FH (a-1)- CH- -NH- -CH (Me)-2-3297 (b-14) (b-34) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3298 (b -14) (b-35) HH (a-1) -CH- -NH- single bond 2-3299 (b-14) (b-35) HH (a-1) -CH- -NH- -CH_Two-2-3300 (b-14) (b-35) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3301 (b-14) (b-35) HH (a-1) -CH- -NH- -CH (Et)-2-3302 (b-14) (b-35) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3303 (b-14) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3304 (b-14) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-3305 (b-14) (b-35) HH (a-1) -CH- -O- -CH (Me)-2-3306 (b-14) (b-35) HH (a-1) -CH- -S- -CH (Me)-2- 3307 (b-14) (b-35) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3308 (b-14) (b-35) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3309 (b-14) (b-35) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3310 (b-14) (b-35) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-33311 (b-14) (b-35) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3312 (b-14) (b-35) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3313 (b-14) (b-35) HH (a-1) N -CO- -CH (Me)-2-3314 (b-14) (b-37) HH (a-1) -CH --NH- single bond 2-3315 (b-14) (b-37) HH (a-1) -CH- -NH- -CH_Two-2-3316 (b-14) (b-37) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3317 (b-14) (b-37) HH (a-1) -CH- -NH- -CH (Me)-2-3318 (b-14) (b-37) HH (a-1 ) -CH- -NH- -CH (Et)-2-3319 (b-14) (b-37) HH (a-1) -CH- -NH--(CH_Two)_Three-2-3320 (b-14) (b-37) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3321 (b-14) (b-37) HH (a-1) -CH- -NH- -COCH (Me)-2-3322 (b-14) (b-37) HH (a-1) -CH- -O- -CH (Me)-2-3323 (b-14) (b-37) HH (a-1) -CH- -S- -CH (Me)-2- 3324 (b-14) (b-37) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3325 (b-14) (b-37) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3326 (b-14) (b-37) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3327 (b-14) (b-37) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3328 (b-14) (b-37) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3329 (b-14) (b-37) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3330 (b-14) (b-37) HH (a-1) N -CO- -CH (Me)-2-3331 (b-14) (b-42) HH (a-1) -CH --NH- -CH (Me)-2-3332 (b-14) (b-72) HH (a-1) -CH- -NH- -CH (Me)-2-3333 (b-14) ( b-72) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3334 (b-14) (b-72) 6-FH (a-1) -CH-- NH- -CH (Me)-2-3335 (b-14) (b-72) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3336 (b-14) (b-73) HH (a-1) -CH- -NH- single bond 2-3337 (b-14) (b-73) HH (a-1) -CH- -NH- -CH_Two-2-3338 (b-14) (b-73) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3339 (b-14) (b-73) HH (a-1) -CH- -NH- -CH (Me)-2-3340 (b-14) (b-73) HH (a-1 ) -CH- -NH- -CH (Et)-2-3341 (b-14) (b-73) HH (a-1) -CH- -NH--(CH_Two)_Three-2-3342 (b-14) (b-73) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3343 (b-14) (b-73) HH (a-1) -CH- -NH- -COCH (Me)-2-3344 (b-14) (b-73) HH (a-1) -CH- -O- -CH (Me)-2-3345 (b-14) (b-73) HH (a-1) -CH- -S- -CH (Me)-2- 3346 (b-14) (b-73) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3347 (b-14) (b-73) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3348 (b-14) (b-73) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3349 (b-14) (b-73) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3350 (b-14) (b-73) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3351 (b-14) (b-73) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3352 (b-14) (b-73) HH (a-1) N -CO- -CH (Me)-2-3353 (b-14) (b-74) HH (a-1) -CH --NH- -CH (Me)-2-3354 (b-14) (b-76) HH (a-1) -CH- -NH- -CH (Me)-2-3355 (b-14) ( b-77) HH (a-1) -CH- -NH- -CH (Me)-2-3356 (b-14) (b-77) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3357 (b-14) (b-77) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3358 (b-14) (b- 77) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3359 (b-18) (b-7) HH (a-1) -CH- -NH- single bond 2-3360 (b-18) (b-7) HH (a-1) -CH- -NH- -CH_Two-2-3361 (b-18) (b-7) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3362 (b-18) (b-7) HH (a-1) -CH- -NH- -CH (Et)-2-3363 (b-18) (b-7) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3364 (b-18) (b-7) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3365 (b-18) (b-7) HH (a-1) -CH- -NH- -COCH (Me)-2-3366 (b-18) (b-7) HH (a-1) -CH- -O- -CH (Me)-2-3367 (b-18) (b-7) HH (a-1) -CH- -S- -CH (Me)-2- 3368 (b-18) (b-7) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3369 (b-18) (b-7) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3370 (b-18) (b-7) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3371 (b-18) (b-7) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3372 (b-18) (b-7) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3373 (b-18) (b-7) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3374 (b-18) (b-7) HH (a-1) N -CO- -CH (Me)-2-3375 (b-18) (b-11) HH (a-1) -CH --NH- -CH (Me)-2-3376 (b-18) (b-12) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3377 (b- 18) (b-12) 4-MeO 5-MeO (a-1) -CH- -NH- -CH (Me)-2-3378 (b-18) (b-12) 4-MeO H (a- 1) -CH- -NH- -CH (Me)-2-3379 (b-18) (b-14) HH (a-1) -CH- -NH- -CH (Me)-2-3380 (b -18) (b-15) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3381 (b-18) (b-15) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3382 (b-18) (b-15) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3383 ( b-18) (b-17) HH (a-1) -CH- -NH- -CH (Me)-2-3384 (b-18) (b-25) HH (a-1) -CH- -NH- -CH (Me)-2-3385 (b-18) (b-27) HH (a-1) -CH- -NH- -CH (Me)-2-3386 (b-18) (b-28) HH (a-1) -CH- -NH- -CH (Me)-2-3387 (b-18) (b-33) HH ( a-1) -CH- -NH- -CH (Me)-2-3388 (b-18) (b-34) 6-Cl H (a-1) -CH- -NH- -CH (Me)- 2-3389 (b-18) (b-34) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3390 (b-18) (b-34) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3391 (b-18) (b-35) HH (a-1) -CH- -NH- single bond 2-3392 (b- 18) (b-35) HH (a-1) -CH- -NH- -CH_Two-2-3393 (b-18) (b-35) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3394 (b-18) (b-35) HH (a-1) -CH- -NH- -CH (Et)-2-3395 (b-18) (b-35) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3396 (b-18) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3397 (b-18) (b-35) HH (a-1) -CH- -NH- -COCH (Me)-2-3398 (b-18) (b-35) HH (a-1) -CH- -O- -CH (Me)-2-3399 (b-18) (b-35) HH (a-1) -CH- -S- -CH (Me)-2- 3400 (b-18) (b-35) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3401 (b-18) (b-35) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3402 (b-18) (b-35) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3403 (b-18) (b-35) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3404 (b-18) (b-35) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3405 (b-18) (b-35) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3406 (b-18) (b-35) 4-MeO 5-MeO (a-1) -CH- -NH- -CH (Me)-2-3407 (b-18) (b-35) HH (a-1) N -CO- -CH (Me)-2-3408 (b-18) (b-37) 4-FH (a-1) -CH- -NH- -CH (Me)-2- 3409 (b-18) (b-37) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3410 (b-18) (b-37) 4-Cl H (a -1) -CH- -NH- -CH (Me)-2-3411 (b-18) (b-37) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2 -3412 (b-18) (b-37) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3413 (b-18) (b-37) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3414 (b-18) (b-42) HH (a-1) -CH- -NH- -CH (Me)-2- 3415 (b-18) (b-72) HH (a-1) -CH- -NH- -CH (Me)-2- 3416 (b-18) (b-73) HH (a-1) -CH- -NH- single bond 2-3417 (b-18) (b-73) HH (a-1) -CH- -NH- -CH_Two-2-3418 (b-18) (b-73) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3419 (b-18) (b-73) HH (a-1) -CH- -NH- -CH (Et)-2-3420 (b-18) (b-73) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3421 (b-18) (b-73) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3422 (b-18) (b-73) HH (a-1) -CH- -NH- -COCH (Me)-2-3423 (b-18) (b-73) HH (a-1) -CH- -O- -CH (Me)-2-3424 (b-18) (b-73) HH (a-1) -CH- -S- -CH (Me)-2- 3425 (b-18) (b-73) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3426 (b-18) (b-73) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3427 (b-18) (b-73) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3428 (b-18) (b-73) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3429 (b-18) (b-73) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3430 (b-18) (b-73) 6-MeO H (a-1) -CH- -NH- -CH (Me)- 2-3431 (b-18) (b-73) HH (a-1) N -CO- -CH (Me)-2-3432 (b-18) (b-74) HH (a-1) -CH --NH- -CH (Me)-2-3433 (b-18) (b-76) HH (a-1) -CH- -NH- -CH (Me)-2-3434 (b-18) ( b-77) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3435 (b-18) (b-77) 6-FH (a-1) -CH-- NH- -CH (Me)-2-3436 (b-18) (b-77) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3437 (b-18) (b-78) HH (a-1) -CH- -NH- -CH (Me)-2-3438 (b-18) (b-80) HH (a-1) -CH- -NH- -CH (Me)-2-3439 (b-18) (b-83) HH (a-1) -CH- -NH- -CH (Me)-2-3440 (b-19) (b-77) HH ( a-1) -CH- -NH- -CH (Me)-2-3441 (b-20) (b-7 ) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3442 (b-20) (b-7) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3443 (b-20) (b-7) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2-3444 (b-20) (b-7 ) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3445 (b-20) (b-7) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3446 (b-20) (b-7) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3447 (b-20) (b -11) HH (a-1) -CH- -NH- -CH (Me)-2-3448 (b-20) (b-12) 6-Cl H (a-1) -CH- -NH-- CH (Me)-2-3449 (b-20) (b-12) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3450 (b-20) (b-12 ) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3451 (b-20) (b-14) HH (a-1) -CH- -NH- -CH ( Me)-2-3452 (b-20) (b-15) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3453 (b-20) (b-15) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3454 (b-20) (b-15) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3455 (b-20) (b-17) HH (a-1) -CH- -NH- -CH (Me)-2-3456 (b-20) (b-25) HH ( a-1) -CH- -NH- -CH (Me)-2-3457 (b-20) (b-28) HH (a-1) -CH- -NH- -CH (Me)-2-3458 (b-20) (b-33) HH (a-1) -CH- -NH- -CH (Me)-2-3459 (b-20) (b-34) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3460 (b-20) (b-34) 6-FH (a-1) -C H- -NH- -CH (Me)-2-3461 (b-20) (b-34) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3462 (b -20) (b-35) HH (a-1) -CH- -NH- single bond 2-3463 (b-20) (b-35) HH (a-1) -CH- -NH- -CH_Two-2-3464 (b-20) (b-35) H H (a-1) -CH- -NH--(CH_Two)_Two-2-3465 (b-20) (b-35) HH (a-1) -CH- -NH- -CH (Et)-2-3466 (b-20) (b-35) HH (a-1 ) -CH- -NH--(CH_Two)_Three-2-3467 (b-20) (b-35) H H (a-1) -CH- -NH- -CH_TwoCH (Me)-2-3468 (b-20) (b-35) HH (a-1) -CH- -NH- -COCH (Et)-2-3469 (b-20) (b-35) HH (a-1) -CH- -O- -CH (Me)-2-3470 (b-20) (b-35) HH (a-1) -CH- -S- -CH (Me)-2- 3471 (b-20) (b-35) 4-FH (a-1) -CH- -NH- -CH (Me)-2-3472 (b-20) (b-35) 6-FH (a- 1) -CH- -NH- -CH (Me)-2-3473 (b-20) (b-35) 4-Cl H (a-1) -CH- -NH- -CH (Me)-2- 3474 (b-20) (b-35) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2-3475 (b-20) (b-35) 4-MeO H ( a-1) -CH- -NH- -CH (Me)-2-3476 (b-20) (b-35) 4-MeO 5-MeO (a-1) -CH- -NH- -CH (Me )-2-3477 (b-20) (b-35) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3478 (b-20) (b-35) HH (a-1) N -CO- -CH (Me)-2-3479 (b-20) (b-37) 4-FH (a-1) -CH- -NH- -CH (Me)-2- 3480 (b-20) (b-37) 6-FH (a-1) -CH- -NH- -CH (Me)-2-3481 (b-20) (b-37) 4-Cl H (a -1) -CH- -NH- -CH (Me)-2-3482 (b-20) (b-37) 6-Cl H (a-1) -CH- -NH- -CH (Me)-2 -3483 (b-20) (b-37) 4-MeO H (a-1) -CH- -NH- -CH (Me)-2-3484 (b-20) (b-37) 6-MeO H (a-1) -CH- -NH- -CH (Me)-2-3485 (b-20) (b-40) HH (a-1) -CH- -NH- -CH (Me)-2- 3486 (b-20) (b-42) HH (a-1) -CH- -NH- -CH (Me)-2- 3487 (b-20) (b-74) HH (a-1) -CH- -NH- -CH (Me)-2-3488 (b-20) (b-76) HH (a-1) -CH --NH- -CH (Me)-2-3489 (b-20) (b-84) HH (a-1) -CH- -NH- -CH (Me)-2-3490 (b-20) ( b-85) HH (a-1) -CH- -NH- -CH (Me)-2-3491 (b-28) (b-35) HH (a-1) -CH- -NH- -CH ( (Me)-2-3492 (b-29) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3493 (b-30) (b-35) HH (a -1) -CH- -NH- -CH (Me)-2-3494 (b-31) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3495 ( b-32) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3496 (b-33) (b-35) HH (a-1) -CH-- NH- -CH (Me)-2-3497 (b-34) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3498 (b-35) (b- 7) HH (a-1) -CH- -NH- -CH (Me)-2-3499 (b-36) (b-35) HH (a-1) -CH- -NH- -CH (Me) -2-3500 (b-37) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3501 (b-38) (b-12) HH (a-1 ) -CH- -NH- -CH (Me)-2-3502 (b-81) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3503 (b- 81) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-3504 (b-81) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3505 (b-82) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3506 (b-86) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3 507 (b-87) (b-15) HH (a-1) -CH- -NH- -CH (Me)-2-3508 (b-88) (b-7) HH (a-1) -CH --NH- -CH (Me)-2-3509 (b-88) (b-12) HH (a-1) -CH- -NH- -CH (Me)-2-3510 (b-88) ( b-15) HH (a-1) -CH- -NH- -CH (Me)-2-3511 (b-88) (b-28) HH (a-1) -CH- -NH- -CH ( Me)-2-3512 (b-88) (b-35) HH (a-1) -CH- -NH- -CH (Me)-2-3513 (b-18) (b-35) HH (a -49) -CH- -NH- -CH (Me)-2-3514 (b-18) (b-35) HH (a-50) -CH- -NH- -CH (Me)-  .

[0082]

[Table 3]

[0083]

Embedded image

[0084]  Compd. R¹ R^Two R^Three R^Four A D E G No. Substituent No. Substituent No. Substituent No.   3-1   (b-2)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-2   (b-7)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-3   (b-7)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-4   (b-7)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-5   (b-7)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-6   (b-8)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-7   (b-11)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-8   (b-11)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-9   (b-11)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-10   (b-11)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-11   (b-12)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-12   (b-12)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-13   (b-15)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-14   (b-15)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-15   (b-18)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-16   (b-18)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-17   (b-18)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-18   (b-18)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-19   (b-19)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-20   (b-19)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-21   (b-20)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-22   (b-20)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-23   (b-20)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-24   (b-20)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-25   (b-21)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-26   (b-21)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-27   (b-24)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-28   (b-24)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-29   (b-25)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-30   (b-25)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-31   (b-72)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-32   (b-72)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-33   (b-73)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-34   (b-73)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-35   (b-73)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-36   (b-73)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-37   (b-74)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-38   (b-74)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-39   (b-76)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-40   (b-76)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-41   (b-77)   (b-7)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-42   (b-77)   (b-7)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-43   (b-77)   (b-35)   H   H   (a-1)   -CH-   -NH-   -CH (Me)-   3-44   (b-77)   (b-35)   H   H   (a-1)   -CH-   -NH-   -COCH (Me)-   3-45   (b-7)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-46   (b-11)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-47   (b-18)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-48   (b-20)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-49   (b-73)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-50   (b-77)   (b-35)   H   H   (a-2)   -CH-   -NH-   -CH (Me)-   3-51   (b-7)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-52   (b-7)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-53   (b-11)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-54   (b-11)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-55   (b-12)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-56   (b-15)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-57   (b-18)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-58   (b-18)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-59   (b-19)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-60   (b-20)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-61   (b-20)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-62   (b-21)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-63   (b-24)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-64   (b-25)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-65   (b-72)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-66   (b-73)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-67   (b-73)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-68   (b-74)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-69   (b-76)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-70   (b-77)   (b-7)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-71   (b-77)   (b-35)   H   H   (a-3)   -CH-   -NH-   -CH (Me)-   3-72   (b-7)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-73   (b-11)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-74   (b-18)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-75   (b-20)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-76   (b-73)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-77   (b-77)   (b-35)   H   H   (a-4)   -CH-   -NH-   -CH (Me)-   3-78   (b-2)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-79   (b-7)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-80   (b-7)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-81   (b-7)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-82   (b-7)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-83   (b-8)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-84   (b-11)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-85   (b-11)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-86   (b-11)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-87   (b-11)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-88   (b-12)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-89   (b-12)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-90   (b-15)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-91   (b-15)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-92   (b-18)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-93   (b-18)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-94   (b-18)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-95   (b-18)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-96   (b-19)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-97   (b-19)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-98   (b-20)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-99   (b-20)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-100   (b-20)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-101   (b-20)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-102   (b-21)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-103   (b-21)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-104   (b-24)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-105   (b-24)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-106   (b-25)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-107   (b-25)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-108   (b-72)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-109   (b-72)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-110   (b-73)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-111   (b-73)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-112   (b-73)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-113   (b-73)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-114   (b-74)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-115   (b-74)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-116   (b-76)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-117   (b-76)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-118   (b-77)   (b-7)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-119   (b-77)   (b-7)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-120   (b-77)   (b-35)   H   H   (a-5)   -CH-   -NH-   -CH (Me)-   3-121   (b-77)   (b-35)   H   H   (a-5)   -CH-   -NH-   -COCH (Me)-   3-122   (b-7)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-123   (b-11)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-124   (b-18)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-125   (b-20)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-126   (b-73)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-127   (b-77)   (b-35)   H   H   (a-6)   -CH-   -NH-   -CH (Me)-   3-128   (b-7)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-129   (b-7)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-130   (b-11)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-131   (b-11)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-132   (b-12)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-133   (b-15)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-134   (b-18)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-135   (b-18)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-136   (b-19)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-137   (b-20)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-138   (b-20)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-139   (b-21)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-140   (b-24)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-141   (b-25)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-142   (b-72)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-143   (b-73)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-144   (b-73)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-145   (b-74)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-146   (b-76)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-147   (b-77)   (b-7)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-148   (b-77)   (b-35)   H   H   (a-7)   -CH-   -NH-   -CH (Me)-   3-149   (b-7)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-150   (b-11)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-151   (b-18)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-152   (b-20)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-153   (b-73)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-154   (b-77)   (b-35)   H   H   (a-8)   -CH-   -NH-   -CH (Me)-   3-155   (b-7)   (b-35)   H   H   (a-10)   -CH-   -NH-   -CH (Me)-   3-156   (b-11)   (b-35)   H   H   (a-10)   -CH-   -NH-   -CH (Me)-   3-157   (b-18)   (b-35)   H   H   (a-10)   -CH-   -NH-   -CH (Me)-   3-158   (b-7)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-159   (b-11)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-160   (b-18)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-161   (b-20)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-162   (b-73)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-163   (b-77)   (b-35)   H   H   (a-11)   -CH-   -NH-   -CH (Me)-   3-164   (b-7)   (b-35)   H   H   (a-12)   -CH-   -NH-   -CH (Me)-   3-165   (b-11)   (b-35)   H   H   (a-12)   -CH-   -NH-   -CH (Me)-   3-166   (b-18)   (b-35)   H   H   (a-12)   -CH-   -NH-   -CH (Me)-   (   3-167   (b-2)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-168   (b-2)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-169   (b-7)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-170   (b-7)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-171   (b-7)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-172   (b-7)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-173   (b-7)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-174   (b-7)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-175   (b-7)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-176   (b-7)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-177   (b-7)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-178   (b-7)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-179   (b-8)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-180   (b-9)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-181   (b-10)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-182   (b-11)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-183   (b-11)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-184   (b-11)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-185   (b-11)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-186   (b-11)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-187   (b-11)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-188   (b-11)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-189   (b-11)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-190   (b-11)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-191   (b-11)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-192   (b-12)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-193   (b-12)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-194   (b-12)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-195   (b-12)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-196   (b-13)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-197   (b-14)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-198   (b-15)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-199   (b-15)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-200   (b-15)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-201   (b-15)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-202   (b-17)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-203   (b-18)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-204   (b-18)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-205   (b-18)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-206   (b-18)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-207   (b-18)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-208   (b-18)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-209   (b-18)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-210   (b-18)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-211   (b-18)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-212   (b-18)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-213   (b-19)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-214   (b-19)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-215   (b-19)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-216   (b-19)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-217   (b-20)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-218   (b-20)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-219   (b-20)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-220   (b-20)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-221   (b-20)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-222   (b-20)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-223   (b-20)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-224   (b-20)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-225   (b-20)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-226   (b-20)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-227   (b-21)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-228   (b-21)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-229   (b-21)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-230   (b-21)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-231   (b-23)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-232   (b-24)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-233   (b-24)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-234   (b-24)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-235   (b-24)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-236   (b-25)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-237   (b-25)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-238   (b-25)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-239   (b-25)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-240   (b-35)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-241   (b-72)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-242   (b-72)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-243   (b-72)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-244   (b-72)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-245   (b-73)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-246   (b-73)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-247   (b-73)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-248   (b-73)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-249   (b-73)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-250   (b-73)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-251   (b-73)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-252   (b-73)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-253   (b-73)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-254   (b-73)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-255   (b-74)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-256   (b-74)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-257   (b-74)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-258   (b-74)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-259   (b-75)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-260   (b-76)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-261   (b-76)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-262   (b-76)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-263   (b-76)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-264   (b-77)   (b-7)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-265   (b-77)   (b-7)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-266   (b-77)   (b-12)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-267   (b-77)   (b-15)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-268   (b-77)   (b-34)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-269   (b-77)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-270   (b-77)   (b-35)   H   H   (a-14)   -CH-   -NH-   -COCH (Me)-   3-271   (b-77)   (b-37)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-272   (b-77)   (b-73)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-273   (b-77)   (b-77)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-274   (b-78)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-275   (b-79)   (b-35)   H   H   (a-14)   -CH-   -NH-   -CH (Me)-   3-276   (b-2)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-277   (b-7)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-278   (b-7)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-279   (b-7)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-280   (b-7)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-281   (b-8)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-282   (b-11)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-283   (b-11)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-284   (b-11)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-285   (b-11)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-286   (b-12)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-287   (b-12)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-288   (b-15)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-289   (b-15)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-290   (b-18)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-291   (b-18)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-292   (b-18)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-293   (b-18)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-294   (b-19)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-295   (b-19)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-296   (b-20)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-297   (b-20)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-298   (b-20)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-299   (b-20)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-300   (b-21)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-301   (b-21)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-302   (b-24)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-303   (b-24)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-304   (b-25)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-305   (b-25)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-306   (b-72)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-307   (b-72)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-308   (b-73)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-309   (b-73)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-310   (b-73)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-311   (b-73)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-312   (b-74)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-313   (b-74)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-314   (b-76)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-315   (b-76)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-316   (b-77)   (b-7)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-317   (b-77)   (b-7)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-318   (b-77)   (b-35)   H   H   (a-15)   -CH-   -NH-   -CH (Me)-   3-319   (b-77)   (b-35)   H   H   (a-15)   -CH-   -NH-   -COCH (Me)-   3-320   (b-2)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-321   (b-7)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-322   (b-7)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-323   (b-7)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-324   (b-7)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-325   (b-8)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-326   (b-11)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-327   (b-11)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-328   (b-11)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-329   (b-11)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-330   (b-12)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-331   (b-12)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-332   (b-15)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-333   (b-15)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-334   (b-18)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-335   (b-18)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-336   (b-18)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-337   (b-18)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-338   (b-19)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-339   (b-19)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-340   (b-20)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-341   (b-20)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-342   (b-20)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-343   (b-20)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-344   (b-21)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-345   (b-21)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-346   (b-24)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-347   (b-24)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-348   (b-25)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-349   (b-25)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-350   (b-72)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-351   (b-72)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-352   (b-73)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-353   (b-73)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-354   (b-73)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-355   (b-73)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-356   (b-74)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-357   (b-74)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-358   (b-76)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-359   (b-76)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-360   (b-77)   (b-7)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-361   (b-77)   (b-7)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-362   (b-77)   (b-35)   H   H   (a-18)   -CH-   -NH-   -CH (Me)-   3-363   (b-77)   (b-35)   H   H   (a-18)   -CH-   -NH-   -COCH (Me)-   3-364   (b-7)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-365   (b-7)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-366   (b-11)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-367   (b-11)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-368   (b-12)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-369   (b-15)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-370   (b-18)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-371   (b-18)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-372   (b-19)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-373   (b-20)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-374   (b-20)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-375   (b-21)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-376   (b-24)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-377   (b-25)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-378   (b-72)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-379   (b-73)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-380   (b-73)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-381   (b-74)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-382   (b-76)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-383   (b-77)   (b-7)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-384   (b-77)   (b-35)   H   H   (a-19)   -CH-   -NH-   -CH (Me)-   3-385   (b-2)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-386   (b-7)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-387   (b-7)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-388   (b-7)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-389   (b-7)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-390   (b-8)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-391   (b-11)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-392   (b-11)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-393   (b-11)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-394   (b-11)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-395   (b-12)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-396   (b-12)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-397   (b-15)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-398   (b-15)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-399   (b-18)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-400   (b-18)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-401   (b-18)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-402   (b-18)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-403   (b-19)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-404   (b-19)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-405   (b-20)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-406   (b-20)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-407   (b-20)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-408   (b-20)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-409   (b-21)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-410   (b-21)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-411   (b-24)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-412   (b-24)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-413   (b-25)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-414   (b-25)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-415   (b-72)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-416   (b-72)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-417   (b-73)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-418   (b-73)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-419   (b-73)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-420   (b-73)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-421   (b-74)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-422   (b-74)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-423   (b-76)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-424   (b-76)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-425   (b-77)   (b-7)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-426   (b-77)   (b-7)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-427   (b-77)   (b-35)   H   H   (a-20)   -CH-   -NH-   -CH (Me)-   3-428   (b-77)   (b-35)   H   H   (a-20)   -CH-   -NH-   -COCH (Me)-   3-429   (b-7)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-430   (b-11)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-431   (b-18)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-432   (b-20)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-433   (b-73)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-434   (b-77)   (b-35)   H   H   (a-21)   -CH-   -NH-   -CH (Me)-   3-435   (b-7)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-436   (b-7)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-437   (b-11)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-438   (b-11)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-439   (b-12)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-440   (b-15)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-441   (b-18)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-442   (b-18)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-443   (b-19)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-444   (b-20)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-445   (b-20)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-446   (b-21)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-447   (b-24)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-448   (b-25)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-449   (b-72)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-450   (b-73)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-451   (b-73)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-452   (b-74)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-453   (b-76)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-454   (b-77)   (b-7)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-455   (b-77)   (b-35)   H   H   (a-24)   -CH-   -NH-   -CH (Me)-   3-456   (b-2)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-457   (b-7)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-458   (b-7)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-459   (b-7)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-460   (b-7)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-461   (b-8)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-462   (b-11)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-463   (b-11)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-464   (b-11)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-465   (b-11)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-466   (b-12)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-467   (b-12)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-468   (b-15)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-469   (b-15)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-470   (b-18)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-471   (b-18)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-472   (b-18)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-473   (b-18)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-474   (b-19)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-475   (b-19)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-476   (b-20)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-477   (b-20)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-478   (b-20)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-479   (b-20)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-480   (b-21)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-481   (b-21)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-482   (b-24)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-483   (b-24)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-484   (b-25)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-485   (b-25)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-486   (b-72)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-487   (b-72)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-488   (b-73)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-489   (b-73)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-490   (b-73)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-491   (b-73)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-492   (b-74)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-493   (b-74)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-494   (b-76)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-495   (b-76)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-496   (b-77)   (b-7)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-497   (b-77)   (b-7)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-498   (b-77)   (b-35)   H   H   (a-26)   -CH-   -NH-   -CH (Me)-   3-499   (b-77)   (b-35)   H   H   (a-26)   -CH-   -NH-   -COCH (Me)-   3-500   (b-7)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-501   (b-11)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-502   (b-18)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-503   (b-20)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-504   (b-73)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-505   (b-77)   (b-35)   H   H   (a-27)   -CH-   -NH-   -CH (Me)-   3-506   (b-7)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-507   (b-7)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-508   (b-11)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-509   (b-11)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-510   (b-12)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-511   (b-15)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-512   (b-18)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-513   (b-18)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-514   (b-19)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-515   (b-20)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-516   (b-20)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-517   (b-21)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-518   (b-24)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-519   (b-25)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-520   (b-72)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-521   (b-73)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-522   (b-73)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-523   (b-74)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-524   (b-76)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-525   (b-77)   (b-7)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-526   (b-77)   (b-35)   H   H   (a-28)   -CH-   -NH-   -CH (Me)-   3-527   (b-7)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-528   (b-11)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-529   (b-18)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-530   (b-20)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-531   (b-73)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-532   (b-77)   (b-35)   H   H   (a-29)   -CH-   -NH-   -CH (Me)-   3-533   (b-2)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-534   (b-7)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-535   (b-7)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-536   (b-7)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-537   (b-7)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-538   (b-8)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-539   (b-11)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-540   (b-11)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-541   (b-11)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-542   (b-11)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-543   (b-12)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-544   (b-12)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-545   (b-15)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-546   (b-15)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-547   (b-18)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-548   (b-18)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-549   (b-18)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-550   (b-18)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-551   (b-19)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-552   (b-19)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-553   (b-20)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-554   (b-20)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-555   (b-20)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-556   (b-20)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-557   (b-21)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-558   (b-21)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-559   (b-24)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-560   (b-24)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-561   (b-25)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-562   (b-25)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-563   (b-72)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-564   (b-72)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-565   (b-73)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-566   (b-73)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-567   (b-73)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-568   (b-73)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-569   (b-74)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-570   (b-74)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-571   (b-76)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-572   (b-76)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-573   (b-77)   (b-7)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-574   (b-77)   (b-7)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-575   (b-77)   (b-35)   H   H   (a-31)   -CH-   -NH-   -CH (Me)-   3-576   (b-77)   (b-35)   H   H   (a-31)   -CH-   -NH-   -COCH (Me)-   3-577   (b-7)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-578   (b-11)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-579   (b-18)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-580   (b-20)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-581   (b-73)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-582   (b-77)   (b-35)   H   H   (a-32)   -CH-   -NH-   -CH (Me)-   3-583   (b-7)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-584   (b-7)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-585   (b-11)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-586   (b-11)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-587   (b-12)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-588   (b-15)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-589   (b-18)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-590   (b-18)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-591   (b-19)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-592   (b-20)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-593   (b-20)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-594   (b-21)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-595   (b-24)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-596   (b-25)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-597   (b-72)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-598   (b-73)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-599   (b-73)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-600   (b-74)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-601   (b-76)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-602   (b-77)   (b-7)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-603   (b-77)   (b-35)   H   H   (a-33)   -CH-   -NH-   -CH (Me)-   3-604   (b-7)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-605   (b-11)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-606   (b-18)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-607   (b-20)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-608   (b-73)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-609   (b-77)   (b-35)   H   H   (a-34)   -CH-   -NH-   -CH (Me)-   3-610   (b-7)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-611   (b-11)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-612   (b-18)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-613   (b-20)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-614   (b-73)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-615   (b-77)   (b-35)   H   H   (a-36)   -CH-   -NH-   -CH (Me)-   3-616   (b-7)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   3-617   (b-11)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   3-618   (b-18)   (b-35)   H   H   (a-38)   -CH-   -NH-   -CH (Me)-   3-619   (b-7)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-620   (b-11)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-621   (b-18)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-622   (b-20)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-623   (b-73)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-624   (b-77)   (b-35)   H   H   (a-39)   -CH-   -NH-   -CH (Me)-   3-625   (b-7)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   3-626   (b-11)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   3-627   (b-18)   (b-35)   H   H   (a-41)   -CH-   -NH-   -CH (Me)-   3-628   (b-2)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-629   (b-7)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-630   (b-7)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-631   (b-7)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-632   (b-7)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-633   (b-8)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-634   (b-11)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-635   (b-11)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-636   (b-11)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-637   (b-11)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-638   (b-12)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-639   (b-12)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-640   (b-15)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-641   (b-15)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-642   (b-18)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-643   (b-18)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-644   (b-18)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-645   (b-18)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-646   (b-19)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-647   (b-19)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-648   (b-20)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-649   (b-20)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-650   (b-20)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-651   (b-20)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-652   (b-21)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-653   (b-21)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-654   (b-24)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-655   (b-24)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-656   (b-25)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-657   (b-25)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-658   (b-72)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-659   (b-72)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-660   (b-73)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-661   (b-73)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-662   (b-73)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-663   (b-73)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-664   (b-74)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-665   (b-74)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-666   (b-76)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-667   (b-76)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-668   (b-77)   (b-7)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-669   (b-77)   (b-7)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-670   (b-77)   (b-35)   H   H   (a-43)   -CH-   -NH-   -CH (Me)-   3-671   (b-77)   (b-35)   H   H   (a-43)   -CH-   -NH-   -COCH (Me)-   3-672   (b-7)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-673   (b-11)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-674   (b-18)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-675   (b-20)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-676   (b-73)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-677   (b-77)   (b-35)   H   H   (a-44)   -CH-   -NH-   -CH (Me)-   3-678   (b-7)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-679   (b-7)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-680   (b-11)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-681   (b-11)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-682   (b-12)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-683   (b-15)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-684   (b-18)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-685   (b-18)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-686   (b-19)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-687   (b-20)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-688   (b-20)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-689   (b-21)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-690   (b-24)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-691   (b-25)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-692   (b-72)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-693   (b-73)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-694   (b-73)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-695   (b-74)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-696   (b-76)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-697   (b-77)   (b-7)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-698   (b-77)   (b-35)   H   H   (a-45)   -CH-   -NH-   -CH (Me)-   3-699   (b-7)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-700   (b-11)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-701   (b-18)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-702   (b-20)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-703   (b-73)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-704   (b-77)   (b-35)   H   H   (a-46)   -CH-   -NH-   -CH (Me)-   3-705   (b-7)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   3-706   (b-11)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-   3-707   (b-18)   (b-35)   H   H   (a-47)   -CH-   -NH-   -CH (Me)-  .

[0085]

[Table 4]

[0086]

Embedded image

[0087]  Compd. R¹ R^Two R^Three R^Four A G No. Substituent No. Substituent No. Substituent No.  4-1 (b-2) (b-35) HH (a-1) -CH (Me)-4-2 (b-7) (b-7) HH (a-1) -CH (Me)- 4-3 (b-7) (b-7) HH (a-1) -COCH (Me)-4-4 (b-7) (b-35) HH (a-1) -CH2 4-5 (b-7) (b-35) HH (a-1) -CH (Me)-4-6 (b-8) (b-35) HH (a-1) -CH (Me) -4- 7 (b-11) (b-7) HH (a-1) -CH (Me)-4-8 (b-11) (b-7) HH (a-1) -COCH (Me)-4- 9 (b-11) (b-35) HH (a-1) -CH (Me)-4-10 (b-11) (b-35) HH (a-1) -COCH (Me)-4- 11 (b-12) (b-7) HH (a-1) -CH (Me)-4-12 (b-12) (b-35) HH (a-1) -CH (Me)-4- 13 (b-15) (b-7) HH (a-1) -CH (Me)-4-14 (b-15) (b-35) HH (a-1) -CH (Me)-4- 15 (b-18) (b-7) HH (a-1) -CH (Me)-4-16 (b-18) (b-7) HH (a-1) -COCH (Me)-4- 17 (b-18) (b-35) HH (a-1) -CH (Me)-4-18 (b-18) (b-35) HH (a-1) -COCH (Me)-4- 19 (b-19) (b-7) HH (a-1) -CH (Me)-4-20 (b-19) (b-35) HH (a-1) -CH (Me)-4- 21 (b-20) (b-7) HH (a-1) -CH (Me)-4-22 (b-20) (b-7) HH (a-1) -COCH (Me)-4- 23 (b-20) (b-35) HH (a-1) -CH (Me)-4-24 (b-20) (b-35) HH (a-1) -COCH (Me)-4- 25 (b-21) (b-7) HH (a-1) -CH (Me)-4-26 (b-21) (b-35) HH (a-1) -CH (Me) -4- 27 (b-24) (b-7) HH (a-1) -CH (Me)-4-28 (b-24) (b-35) HH (a-1) -CH (Me)-4-29 (b-25) (b-7) HH (a-1) -CH (Me)-4-30 (b-25) (b-35) HH (a-1) -CH (Me)-4-31 (b-72) (b-7) HH (a-1) -CH (Me)-4-32 (b-72) (b-35) HH (a-1) -CH (Me)-4-33 (b-73) (b-7) HH (a-1) -CH (Me)-4-34 (b-73) (b-7) HH (a-1) -COCH (Me)-4-35 (b-73) (b-35) HH (a-1) -CH (Me)-4-36 (b-73) (b-35) HH (a-1) -COCH (Me)-4-37 (b-74) (b-7) HH (a-1) -CH (Me)-4-38 (b-74) (b-35) HH (a-1) -CH (Me)-4-39 (b-76) (b-7) HH (a-1) -CH (Me)-4-40 (b-76) (b-35) HH (a-1) -CH (Me)-4-41 (b-77) (b-7) HH (a-1) -CH (Me)-4-42 (b-77) (b-7) HH (a-1) -COCH (Me)-4-43 (b-77) (b-35) HH (a-1) -CH (Me)-4-44 (b-77) (b-35) HH (a-1) -COCH (Me)-4-45 (b-7) (b-35) HH (a-2) -CH (Me)-4-46 (b-11) (b-35) HH (a-2) -CH (Me)-4-47 (b-18) (b-35) HH (a-2) -CH (Me)-4-48 (b-20) (b-35) HH (a-2) -CH (Me)-4-49 (b-73) (b-35) HH (a-2) -CH (Me)-4-50 (b-77) (b-35) HH (a-2) -CH (Me)-4-51 (b-7) (b-7) HH (a-3) -CH (Me)-4-52 (b-7) (b-35) HH (a-3) -CH (Me)-4-53 (b-11) (b-7) HH (a-3) -CH (Me)-4-54 (b -11) (b-35) HH (a-3) -CH (Me)-4-55 (b-12) (b-35) HH (a-3) -CH (Me)-4-56 (b -15) (b-35) HH (a-3) -CH (Me)-4-57 (b-18) (b-7) HH (a-3) -CH (Me) -4-58 (b -18) (b-35) HH (a-3) -CH (Me)-4-59 (b-19) (b-35) HH (a-3) -CH (Me)-4-60 (b -20) (b-7) HH (a-3) -CH (Me)-4-61 (b-20) (b-35) HH (a-3) -CH (Me)-4-62 (b -21) (b-35) HH (a-3) -CH (Me)-4-63 (b-24) (b-35) HH (a-3) -CH (Me)-4-64 (b -25) (b-35) HH (a-3) -CH (Me)-4-65 (b-72) (b-35) HH (a-3) -CH (Me) -4-66 (b -73) (b-7) HH (a-3) -CH (Me)-4-67 (b-73) (b-35) HH (a-3) -CH (Me)-4-68 (b -74) (b-35) HH (a-3) -CH (Me)-4-69 (b-76) (b-35) HH (a-3) -CH (Me)-4-70 (b -77) (b-7) HH (a-3) -CH (Me)-4-71 (b-77) (b-35) HH (a-3) -CH (Me)-4-72 (b -7) (b-35) HH (a-4) -CH (Me)-4-73 (b-11) (b-35) HH (a-4) -CH (Me)-4-74 (b -18) (b-35) HH (a-4) -CH (Me)-4-75 (b-20) (b-35) HH (a-4) -CH (Me)-4-76 (b -73) (b-35) HH (a-4) -CH (Me)-4-77 (b-77) (b-35) HH (a-4) -CH (Me)-4-78 (b -2) (b-35) HH (a-5) -CH (Me)-4-79 (b-7) (b-7) HH (a-5) -CH (Me)-4-80 (b -7) (b-7) HH (a-5) -COCH (Me)-4-81 (b-7) (b-35) HH (a-5) -CH (Me)-4-82 (b-7) (b-35) HH (a-5) -COCH (Me)-4-83 (b-8) (b-35) HH (a-5) -CH (Me)-4-84 (b-11) (b-7) HH (a-5) -CH (Me)-4-85 (b-11) (b-7) HH (a-5) -COCH (Me)-4-86 (b-11) (b-35) HH (a-5) -CH (Me)-4-87 (b-11) (b-35) HH (a-5) -COCH (Me)-4-88 (b-12) (b-7) HH (a-5) -CH (Me)-4-89 (b-12) (b-35) HH (a-5) -CH (Me)-4-90 (b-15) (b-7) HH (a-5) -CH (Me)-4-91 (b-15) (b-35) HH (a-5) -CH (Me)-4-92 (b-18) (b-7) HH (a-5) -CH (Me)-4-93 (b-18) (b-7) HH (a-5) -COCH (Me)-4-94 (b-18) (b-35) HH (a-5) -CH (Me)-4-95 (b-18) (b-35) HH (a-5) -COCH (Me)-4-96 (b-19) (b-7) HH (a-5) -CH (Me)-4-97 (b-19) (b-35) HH (a-5) -CH (Me)-4-98 (b-20) (b-7) HH (a-5) -CH (Me)-4-99 (b-20) (b-7) HH (a-5) -COCH (Me) -4-100 (b-20) (b-35) HH (a-5) -CH (Me)-4-101 (b-20) (b-35) HH (a-5) -COCH (Me)-4-102 (b-21) (b-7) HH (a-5) -CH (Me)-4-103 (b-21) (b-35) HH (a-5) -CH (Me)-4-104 (b-24) (b-7) HH (a-5) -CH (Me)-4-105 (b-24) (b-35) HH (a-5) -CH (Me)-4-106 (b-25) (b-7) HH (a-5) -CH ( (Me)-4-107 (b-25) (b-35) HH (a-5) -CH (Me)-4-108 (b-72) (b-7) HH (a-5) -CH ( (Me)-4-109 (b-72) (b-35) HH (a-5) -CH (Me)-4-110 (b-73) (b-7) HH (a-5) -CH ( (Me)-4-111 (b-73) (b-7) HH (a-5) -COCH (Me)-4-112 (b-73) (b-35) HH (a-5) -CH ( (Me)-4-113 (b-73) (b-35) HH (a-5) -COCH (Me)-4-114 (b-74) (b-7) HH (a-5) -CH ( (Me)-4-115 (b-74) (b-35) HH (a-5) -CH (Me)-4-116 (b-76) (b-7) HH (a-5) -CH ( (Me)-4-117 (b-76) (b-35) HH (a-5) -CH (Me)-4-118 (b-77) (b-7) HH (a-5) -CH ( (Me)-4-119 (b-77) (b-7) HH (a-5) -COCH (Me)-4-120 (b-77) (b-35) HH (a-5) -CH ( (Me)-4-121 (b-77) (b-35) HH (a-5) -COCH (Me)-4-122 (b-7) (b-35) HH (a-6) -CH ( Me)-4-123 (b-11) (b-35) HH (a-6) -CH (Me)-4-124 (b-18) (b-35) HH (a-6) -CH ( (Me)-4-125 (b-20) (b-35) HH (a-6) -CH (Me)-4-126 (b-73) (b-35) HH (a-6) -CH ( (Me)-4-127 (b-77) (b-35) HH (a-6) -CH (Me)-4-128 (b-7) (b-7) HH (a-7) -CH ( (Me)-4-129 (b-7) (b-35) HH (a-7) -CH (Me)-4-130 (b-11) (b-7) HH (a-7) -CH ( (Me)-4-131 (b-11) (b-35) HH (a-7) -CH (Me)-4-132 (b-12) (b-35) HH (a-7) -CH (Me)-4-133 (b-15) (b-35) HH (a-7) -CH (Me) -4-134 (b-18) (b-7) HH (a-7) -CH (Me)-4-135 (b-18) (b-35) HH (a-7) -CH (Me)-4-136 (b-19) (b-35) HH (a-7) -CH (Me)-4-137 (b-20) (b-7) HH (a-7) -CH (Me)-4-138 (b-20) (b-35) HH (a-7) -CH (Me)-4-139 (b-21) (b-35) HH (a-7) -CH (Me)-4-140 (b-24) (b-35) HH (a-7) -CH (Me)-4-141 (b-25) (b-35) HH (a-7) -CH (Me)-4-142 (b-72) (b-35) HH (a-7) -CH (Me)-4-143 (b-73) (b-7) HH (a-7) -CH (Me)-4-144 (b-73) (b-35) HH (a-7) -CH (Me)-4-145 (b-74) (b-35) HH (a-7) -CH (Me)-4-146 (b-76) (b-35) HH (a-7) -CH (Me)-4-147 (b-77) (b-7) HH (a-7) -CH (Me) -4-148 (b-77) (b-35) HH (a-7) -CH (Me)-4-149 (b-7) (b-35) HH (a-8) -CH (Me)-4-150 (b-11) (b-35) HH (a-8) -CH (Me)-4-151 (b-18) (b-35) HH (a-8) -CH (Me)-4-152 (b-20) (b-35) HH (a-8) -CH (Me)-4-153 (b-73) (b-35) HH (a-8) -CH (Me)-4-154 (b-77) (b-35) HH (a-8) -CH (Me)-4-155 (b-7) (b-35) HH (a-10) -CH (Me)-4-156 (b-11) (b-35) HH (a-10) -CH (Me)-4-157 (b-18) (b-35) HH (a-10) -CH (Me)-4-158 (b-7) ( b-35) HH (a-11) -CH (Me)-4-159 (b-11) (b-35) HH (a-11) -CH (Me)-4-160 (b-18) ( b-35) HH (a-11) -CH (Me)-4-161 (b-20) (b-35) HH (a-11) -CH (Me)-4-162 (b-73) ( b-35) HH (a-11) -CH (Me)-4-163 (b-77) (b-35) HH (a-11) -CH (Me)-4-164 (b-7) ( b-35) HH (a-12) -CH (Me)-4-165 (b-11) (b-35) HH (a-12) -CH (Me)-4-166 (b-18) ( b-35) HH (a-12) -CH (Me)-4-167 (b-2) (b-7) HH (a-14) -CH (Me)-4-168 (b-2) ( b-35) HH (a-14) -CH (Me)-4-169 (b-7) (b-7) HH (a-14) -CH (Me)-4-170 (b-7) ( b-7) HH (a-14) -COCH (Me)-4-171 (b-7) (b-12) HH (a-14) -CH (Me)-4-172 (b-7) ( b-15) HH (a-14) -CH (Me)-4-173 (b-7) (b-34) HH (a-14) -CH (Me)-4-174 (b-7) ( b-35) HH (a-14) -CH (Me)-4-175 (b-7) (b-35) HH (a-14) -COCH (Me)-4-176 (b-7) ( b-37) HH (a-14) -CH (Me)-4-177 (b-7) (b-73) HH (a-14) -CH (Me)-4-178 (b-7) ( b-77) HH (a-14) -CH (Me)-4-179 (b-8) (b-35) HH (a-14) -CH (Me)-4-180 (b-9) ( b-35) HH (a-14) -CH (Me)-4-181 (b-10) (b-35) HH (a-14) -CH (Me)-4-182 (b-11) ( b-7) HH (a-14) -CH (Me)-4-183 (b-11) (b-7) HH (a-14) -COCH (Me)-4-184 (b-11) (b-12) HH (a-14) -CH (Me)-4-185 (b-11) (b-15) HH (a-14) -CH (Me)-4-186 (b-11) (b-34) HH (a-14) -CH (Me)-4-187 (b-11) (b-35) HH (a-14) -CH (Me)-4-188 (b-11) (b-35) HH (a-14) -COCH (Me)-4-189 (b-11) (b-37) HH (a-14) -CH (Me)-4-190 (b-11) (b-73) HH (a-14) -CH (Me)-4-191 (b-11) (b-77) HH (a-14) -CH (Me)-4-192 (b-12) (b-7) HH (a-14) -CH (Me)-4-193 (b-12) (b-7) HH (a-14) -COCH (Me)-4-194 (b-12) (b-35) HH (a-14) -CH (Me)-4-195 (b-12) (b-35) HH (a-14) -COCH (Me)-4-196 (b-13) (b-35) HH (a-14) -CH (Me)-4-197 (b-14) (b-35) HH (a-14) -CH (Me)-4-198 (b-15) (b-7) HH (a-14) -CH (Me)-4-199 (b-15) (b-7) HH (a-14) -COCH (Me)-4-200 (b-15) (b-35) HH (a-14) -CH (Me)-4-201 (b-15) (b-35) HH (a-14) -COCH (Me)-4-202 (b-17) (b-35) HH (a-14) -CH (Me)-4-203 (b-18) (b-7) HH (a-14) -CH (Me)-4-204 (b-18) (b-7) HH (a-14) -COCH (Me)-4-205 (b-18) (b-12) HH (a-14) -CH (Me)-4-206 (b-18) (b-15) HH (a-14) -CH (Me)-4-207 (b-18) (b-34) HH (a-14) -CH (Me)-4-208 (b-18) (b-35) H H (a-14) -CH (Me)-4-209 (b-18) (b-35) HH (a-14) -COCH (Me)-4-210 (b-18) (b-37) HH (a-14) -CH (Me)-4-211 (b-18) (b-73) HH (a-14) -CH (Me)-4-212 (b-18) (b-77) HH (a-14) -CH (Me)-4-213 (b-19) (b-7) HH (a-14) -CH (Me)-4-214 (b-19) (b-7) HH (a-14) -COCH (Me)-4-215 (b-19) (b-35) HH (a-14) -CH (Me)-4-216 (b-19) (b-35) HH (a-14) -COCH (Me)-4-217 (b-20) (b-7) HH (a-14) -CH (Me)-4-218 (b-20) (b-7) HH (a-14) -COCH (Me)-4-219 (b-20) (b-12) HH (a-14) -CH (Me)-4-220 (b-20) (b-15) HH (a-14) -CH (Me)-4-221 (b-20) (b-34) HH (a-14) -CH (Me)-4-222 (b-20) (b-35) HH (a-14) -CH (Me)-4-223 (b-20) (b-35) HH (a-14) -COCH (Me)-4-224 (b-20) (b-37) HH (a-14) -CH (Me)-4-225 (b-20) (b-73) HH (a-14) -CH (Me)-4-226 (b-20) (b-77) HH (a-14) -CH (Me)-4-227 (b-21) (b-7) HH (a-14) -CH (Me)-4-228 (b-21) (b-7) HH (a-14) -COCH (Me)-4-229 (b-21) (b-35) HH (a-14) -CH (Me)-4-230 (b-21) (b-35) HH (a-14) -COCH (Me)-4-231 (b-23) (b-35) HH (a-14) -CH (Me)-4-232 (b-24) (b-7) HH (a-14) -CH (Me)-4-233 (b-24) (b -7) HH (a-14) -COCH (Me)-4-234 (b-24) (b-35) HH (a-14) -CH (Me)-4-235 (b-24) (b -35) HH (a-14) -COCH (Me)-4-236 (b-25) (b-7) HH (a-14) -CH (Me)-4-237 (b-25) (b -7) HH (a-14) -COCH (Me)-4-238 (b-25) (b-35) HH (a-14) -CH (Me)-4-239 (b-25) (b -35) HH (a-14) -COCH (Me)-4-240 (b-35) (b-35) HH (a-14) -CH (Me)-4-241 (b-72) (b -7) HH (a-14) -CH (Me)-4-242 (b-72) (b-7) HH (a-14) -COCH (Me)-4-243 (b-72) (b -35) HH (a-14) -CH (Me)-4-244 (b-72) (b-35) HH (a-14) -COCH (Me)-4-245 (b-73) (b -7) HH (a-14) -CH (Me)-4-246 (b-73) (b-7) HH (a-14) -COCH (Me)-4-247 (b-73) (b -12) HH (a-14) -CH (Me)-4-248 (b-73) (b-15) HH (a-14) -CH (Me)-4-249 (b-73) (b -34) HH (a-14) -CH (Me)-4-250 (b-73) (b-35) HH (a-14) -CH (Me)-4-251 (b-73) (b -35) HH (a-14) -COCH (Me)-4-252 (b-73) (b-37) HH (a-14) -CH (Me)-4-253 (b-73) (b -73) HH (a-14) -CH (Me)-4-254 (b-73) (b-77) HH (a-14) -CH (Me)-4-255 (b-74) (b -7) HH (a-14) -CH (Me)-4-256 (b-74) (b-7) HH (a-14) -COCH (Me)-4-257 (b-74) (b -35) HH (a-14) -CH (Me)-4-258 (b-74) (b-35) HH (a-14) -COCH (Me)-4-259 (b-75) (b-35) HH (a-14) -CH (Me)-4-260 (b-76) (b-7) HH (a-14) -CH (Me)-4-261 (b-76) (b-7) HH (a-14) -COCH (Me)-4-262 (b-76) (b-35) HH (a-14) -CH (Me)-4-263 (b-76) (b-35) HH (a-14) -COCH (Me)-4-264 (b-77) (b-7) HH (a-14) -CH (Me)-4-265 (b-77) (b-7) HH (a-14) -COCH (Me)-4-266 (b-77) (b-12) HH (a-14) -CH (Me)-4-267 (b-77) (b-15) HH (a-14) -CH (Me)-4-268 (b-77) (b-34) HH (a-14) -CH (Me)-4-269 (b-77) (b-35) HH (a-14) -CH (Me)-4-270 (b-77) (b-35) HH (a-14) -COCH (Me)-4-271 (b-77) (b-37) HH (a-14) -CH (Me)-4-272 (b-77) (b-73) HH (a-14) -CH (Me)-4-273 (b-77) (b-77) HH (a-14) -CH (Me)-4-274 (b-78) (b-35) HH (a-14) -CH (Me)-4-275 (b-79) (b-35) HH (a-14) -CH (Me)-4-276 (b-2) (b-35) HH (a-15) -CH (Me)-4-277 (b-7) (b-7) HH (a-15) -CH (Me)-4-278 (b-7) (b-7) HH (a-15) -COCH (Me)-4-279 (b-7) (b-35) HH (a-15) -CH (Me)-4-280 (b-7) (b-35) HH (a-15) -COCH (Me)-4-281 (b-8) (b-35) HH (a-15) -CH (Me)-4-282 (b-11) (b-7) HH (a-15) -CH (Me)-4-283 (b-11) (b-7) HH (a-15) -COCH (Me)-4-284 (b-11) (b-35) HH (a-15) -CH (Me)-4-285 (b-11) (b-35) HH (a-15) -COCH (Me)-4-286 (b-12) (b-7) HH (a-15) -CH (Me)-4-287 (b-12) (b-35) HH (a-15) -CH (Me)-4-288 (b-15) (b-7) HH (a-15) -CH (Me)-4-289 (b-15) (b-35) HH (a-15) -CH (Me)-4-290 (b-18) (b-7) HH (a-15) -CH (Me)-4-291 (b-18) (b-7) HH (a-15) -COCH (Me)-4-292 (b-18) (b-35) HH (a-15) -CH (Me)-4-293 (b-18) (b-35) HH (a-15) -COCH (Me)-4-294 (b-19) (b-7) HH (a-15) -CH (Me)-4-295 (b-19) (b-35) HH (a-15) -CH (Me)-4-296 (b-20) (b-7) HH (a-15) -CH (Me)-4-297 (b-20) (b-7) HH (a-15) -COCH (Me)-4-298 (b-20) (b-35) HH (a-15) -CH (Me)-4-299 (b-20) (b-35) HH (a-15) -COCH (Me)-4-300 (b-21) (b-7) HH (a-15) -CH (Me)-4-301 (b-21) (b-35) HH (a-15) -CH (Me)-4-302 (b-24) (b-7) HH (a-15) -CH (Me)-4-303 (b-24) (b-35) HH (a-15) -CH (Me)-4-304 (b-25) (b-7) HH (a-15) -CH (Me)-4-305 (b-25) (b-35) HH (a-15) -CH (Me)-4-306 (b-72) (b-7) HH (a-15) -CH (Me)-4-307 (b-72) (b-35) HH (a-15) -CH (Me)-4-308 (b-73) (b-7) HH (a-15) -CH (Me)-4-309 (b-73) (b-7) HH (a-15) -COCH (Me)-4-310 (b-73) (b-35) HH (a-15) -CH (Me)-4-311 (b-73) (b-35) HH (a-15) -COCH (Me)-4-312 (b-74) (b-7) HH (a-15) -CH (Me)-4-313 (b-74) (b-35) HH (a-15) -CH (Me)-4-314 (b-76) (b-7) HH (a-15) -CH (Me)-4-315 (b-76) (b-35) HH (a-15) -CH (Me)-4-316 (b-77) (b-7) HH (a-15) -CH (Me)-4-317 (b-77) (b-7) HH (a-15) -COCH (Me)-4-318 (b-77) (b-35) HH (a-15) -CH (Me)-4-319 (b-77) (b-35) HH (a-15) -COCH (Me)-4-320 (b-2) (b-35) HH (a-18) -CH (Me)-4-321 (b-7) (b-7) HH (a-18) -CH (Me)-4-322 (b-7) (b-7) HH (a-18) -COCH (Me)-4-323 (b-7) (b-35) HH (a-18) -CH (Me)-4-324 (b-7) (b-35) HH (a-18) -COCH (Me)-4-325 (b-8) (b-35) HH (a-18) -CH (Me)-4-326 (b-11) (b-7) HH (a-18) -CH (Me)-4-327 (b-11) (b-7) HH (a-18) -COCH (Me)-4-328 (b-11) (b-35) HH (a-18) -CH (Me)-4-329 (b-11) (b-35) HH (a-18) -COCH (Me) -4- 4-330 (b-12) (b-7) HH (a-18) -CH (Me)-4-331 (b-12) (b-35) HH (a-18) -CH (Me)-4-332 (b-15) (b-7) HH (a-18) -CH (Me)-4-333 ( b-15) (b-35) HH (a-18) -CH (Me)-4-334 (b-18) (b-7) HH (a-18) -CH (Me)-4-335 ( b-18) (b-7) HH (a-18) -COCH (Me)-4-336 (b-18) (b-35) HH (a-18) -CH (Me) -4-337 ( b-18) (b-35) HH (a-18) -COCH (Me)-4-338 (b-19) (b-7) HH (a-18) -CH (Me)-4-339 ( b-19) (b-35) HH (a-18) -CH (Me)-4-340 (b-20) (b-7) HH (a-18) -CH (Me)-4-341 ( b-20) (b-7) HH (a-18) -COCH (Me)-4-342 (b-20) (b-35) HH (a-18) -CH (Me)-4-343 ( b-20) (b-35) HH (a-18) -COCH (Me) -4-344 (b-21) (b-7) HH (a-18) -CH (Me) -4-345 ( b-21) (b-35) HH (a-18) -CH (Me)-4-346 (b-24) (b-7) HH (a-18) -CH (Me)-4-347 ( b-24) (b-35) HH (a-18) -CH (Me)-4-348 (b-25) (b-7) HH (a-18) -CH (Me)-4-349 ( b-25) (b-35) HH (a-18) -CH (Me)-4-350 (b-72) (b-7) HH (a-18) -CH (Me)-4-351 ( b-72) (b-35) HH (a-18) -CH (Me)-4-352 (b-73) (b-7) HH (a-18) -CH (Me) -4-353 ( b-73) (b-7) HH (a-18) -COCH (Me)-4-354 (b-73) (b-35) HH (a-18) -CH (Me) -4-355 ( b-73) (b-35) HH (a-18) -COCH (Me)-4-356 (b-74) (b-7) HH (a-18) -CH (Me)-4-357 ( b-74) (b-35) HH (a-18) -CH (Me)-4-358 ( b-76) (b-7) HH (a-18) -CH (Me)-4-359 (b-76) (b-35) HH (a-18) -CH (Me)-4-360 ( (b-77) (b-7) HH (a-18) -CH (Me)-4-361 (b-77) (b-7) HH (a-18) -COCH (Me)-4-362 ( b-77) (b-35) HH (a-18) -CH (Me)-4-363 (b-77) (b-35) HH (a-18) -COCH (Me) -4-364 ( b-7) (b-7) HH (a-19) -CH (Me)-4-365 (b-7) (b-35) HH (a-19) -CH (Me)-4-366 ( b-11) (b-7) HH (a-19) -CH (Me)-4-367 (b-11) (b-35) HH (a-19) -CH (Me)-4-368 ( b-12) (b-35) HH (a-19) -CH (Me)-4-369 (b-15) (b-35) HH (a-19) -CH (Me)-4-370 ( b-18) (b-7) HH (a-19) -CH (Me)-4-371 (b-18) (b-35) HH (a-19) -CH (Me)-4-372 ( b-19) (b-35) HH (a-19) -CH (Me)-4-373 (b-20) (b-7) HH (a-19) -CH (Me)-4-374 ( b-20) (b-35) HH (a-19) -CH (Me)-4-375 (b-21) (b-35) HH (a-19) -CH (Me)-4-376 ( b-24) (b-35) HH (a-19) -CH (Me)-4-377 (b-25) (b-35) HH (a-19) -CH (Me)-4-378 ( b-72) (b-35) HH (a-19) -CH (Me)-4-379 (b-73) (b-7) HH (a-19) -CH (Me)-4-380 ( b-73) (b-35) HH (a-19) -CH (Me)-4-381 (b-74) (b-35) HH (a-19) -CH (Me) -4-382 ( b-76) (b-35) HH (a-19) -CH (Me)-4-383 (b-77) (b-7) HH (a-19) -CH (Me)-4-384 (b-77) (b-35) HH (a-19) -CH (Me)-4-385 (b-2) (b-35) HH (a-20) -CH (Me)-4-386 (b-7) (b-7) HH (a-20) -CH (Me)-4-387 (b-7) (b-7) HH (a-20) -COCH (Me)-4-388 (b-7) (b-35) HH (a-20) -CH (Me)-4-389 (b-7) (b-35) HH (a-20) -COCH (Me)-4-390 (b-8) (b-35) HH (a-20) -CH (Me)-4-391 (b-11) (b-7) HH (a-20) -CH (Me)-4-392 (b-11) (b-7) HH (a-20) -COCH (Me)-4-393 (b-11) (b-35) HH (a-20) -CH (Me)-4-394 (b-11) (b-35) HH (a-20) -COCH (Me)-4-395 (b-12) (b-7) HH (a-20) -CH (Me)-4-396 (b-12) (b-35) HH (a-20) -CH (Me)-4-397 (b-15) (b-7) HH (a-20) -CH (Me)-4-398 (b-15) (b-35) HH (a-20) -CH (Me)-4-399 (b-18) (b-7) HH (a-20) -CH (Me)-4-400 (b-18) (b-7) HH (a-20) -COCH (Me)-4-401 (b-18) (b-35) HH (a-20) -CH (Me)-4-402 (b-18) (b-35) HH (a-20) -COCH (Me)-4-403 (b-19) (b-7) HH (a-20) -CH (Me) -4-404 (b-19) (b-35) HH (a-20) -CH (Me) -4-405 (b-20) (b-7) HH (a-20) -CH (Me)-4-406 (b-20) (b-7) HH (a-20) -COCH (Me)-4-407 (b-20) (b-35) HH (a-20) -CH (Me)-4-408 (b-20) (b-3 5) HH (a-20) -COCH (Me)-4-409 (b-21) (b-7) HH (a-20) -CH (Me)-4-410 (b-21) (b- 35) HH (a-20) -CH (Me)-4-411 (b-24) (b-7) HH (a-20) -CH (Me)-4-412 (b-24) (b- 35) HH (a-20) -CH (Me)-4-413 (b-25) (b-7) HH (a-20) -CH (Me)-4-414 (b-25) (b- 35) HH (a-20) -CH (Me)-4-415 (b-72) (b-7) HH (a-20) -CH (Me) -4-416 (b-72) (b- 35) HH (a-20) -CH (Me)-4-417 (b-73) (b-7) HH (a-20) -CH (Me) -4- 418 (b-73) (b- 7) HH (a-20) -COCH (Me)-4-419 (b-73) (b-35) HH (a-20) -CH (Me)-4-420 (b-73) (b- 35) HH (a-20) -COCH (Me)-4-421 (b-74) (b-7) HH (a-20) -CH (Me)-4-422 (b-74) (b- 35) HH (a-20) -CH (Me)-4-423 (b-76) (b-7) HH (a-20) -CH (Me) -4-424 (b-76) (b- 35) HH (a-20) -CH (Me)-4-425 (b-77) (b-7) HH (a-20) -CH (Me)-4-426 (b-77) (b- 7) HH (a-20) -COCH (Me)-4-427 (b-77) (b-35) HH (a-20) -CH (Me)-4-428 (b-77) (b- 35) HH (a-20) -COCH (Me)-4-429 (b-7) (b-35) HH (a-21) -CH (Me)-4-430 (b-11) (b- 35) HH (a-21) -CH (Me) -4-431 (b-18) (b-35) HH (a-21) -CH (Me) -4-432 (b-20) (b- 35) HH (a-21) -CH (Me)-4-433 (b-73) (b-35 ) HH (a-21) -CH (Me) -4-434 (b-77) (b-35) HH (a-21) -CH (Me) -4-435 (b-2) (b-35 ) HH (a-26) -CH (Me)-4-436 (b-7) (b-7) HH (a-26) -CH (Me) -4-437 (b-7) (b-7 ) HH (a-26) -COCH (Me)-4-438 (b-7) (b-35) HH (a-26) -CH (Me)-4-439 (b-7) (b-35 ) HH (a-26) -COCH (Me)-4-440 (b-8) (b-35) HH (a-26) -CH (Me)-4-441 (b-11) (b-7 ) HH (a-26) -CH (Me)-4-442 (b-11) (b-7) HH (a-26) -COCH (Me)-4-443 (b-11) (b-35 ) HH (a-26) -CH (Me)-4-444 (b-11) (b-35) HH (a-26) -COCH (Me)-4-445 (b-12) (b-7 ) HH (a-26) -CH (Me)-4-446 (b-12) (b-35) HH (a-26) -CH (Me) -4-447 (b-15) (b-7 ) HH (a-26) -CH (Me)-4-448 (b-15) (b-35) HH (a-26) -CH (Me)-4-449 (b-18) (b-7 ) HH (a-26) -CH (Me)-4-450 (b-18) (b-7) HH (a-26) -COCH (Me)-4-451 (b-18) (b-35 ) HH (a-26) -CH (Me)-4-452 (b-18) (b-35) HH (a-26) -COCH (Me)-4-453 (b-19) (b-7 ) HH (a-26) -CH (Me)-4-454 (b-19) (b-35) HH (a-26) -CH (Me)-4-455 (b-20) (b-7 ) HH (a-26) -CH (Me)-4-456 (b-20) (b-7) HH (a-26) -COCH (Me)-4-457 (b-20) (b-35 ) HH (a-26) -CH (Me)-4-458 (b-20) (b-35) H H (a-26) -COCH (Me)-4-459 (b-21) (b-7) HH (a-26) -CH (Me)-4-460 (b-21) (b-35) HH (a-26) -CH (Me)-4-461 (b-24) (b-7) HH (a-26) -CH (Me)-4-462 (b-24) (b-35) HH (a-26) -CH (Me)-4-463 (b-25) (b-7) HH (a-26) -CH (Me) -4-464 (b-25) (b-35) HH (a-26) -CH (Me)-4-465 (b-72) (b-7) HH (a-26) -CH (Me) -4-466 (b-72) (b-35) HH (a-26) -CH (Me)-4-467 (b-73) (b-7) HH (a-26) -CH (Me) -4-468 (b-73) (b-7) HH (a-26) -COCH (Me)-4-469 (b-73) (b-35) HH (a-26) -CH (Me)-4-470 (b-73) (b-35) HH (a-26) -COCH (Me)-4-471 (b-74) (b-7) HH (a-26) -CH (Me)-4-472 (b-74) (b-35) HH (a-26) -CH (Me)-4-473 (b-76) (b-7) HH (a-26) -CH (Me) -4-474 (b-76) (b-35) HH (a-26) -CH (Me)-4-475 (b-77) (b-7) HH (a-26) -CH (Me)-4-476 (b-77) (b-7) HH (a-26) -COCH (Me)-4-477 (b-77) (b-35) HH (a-26) -CH (Me)-4-478 (b-77) (b-35) HH (a-26) -COCH (Me)-4-479 (b-2) (b-35) HH (a-31) -CH (Me)-4-480 (b-7) (b-7) HH (a-31) -CH (Me)-4-481 (b-7) (b-7) HH (a-31) -COCH (Me)-4-482 (b-7) (b-35) HH (a-31) -CH (Me)-4-483 (b-7) (b-35) HH (a -31) -COCH (Me)-4-484 (b-8) (b-35) HH (a-31) -CH (Me)-4-485 (b-11) (b-7) HH (a -31) -CH (Me)-4-486 (b-11) (b-7) HH (a-31) -COCH (Me)-4-487 (b-11) (b-35) HH (a -31) -CH (Me)-4-488 (b-11) (b-35) HH (a-31) -COCH (Me)-4-489 (b-12) (b-7) HH (a -31) -CH (Me)-4-490 (b-12) (b-35) HH (a-31) -CH (Me)-4-491 (b-15) (b-7) HH (a -31) -CH (Me)-4-492 (b-15) (b-35) HH (a-31) -CH (Me)-4-493 (b-18) (b-7) HH (a -31) -CH (Me)-4-494 (b-18) (b-7) HH (a-31) -COCH (Me)-4-495 (b-18) (b-35) HH (a -31) -CH (Me)-4-496 (b-18) (b-35) HH (a-31) -COCH (Me)-4-497 (b-19) (b-7) HH (a -31) -CH (Me)-4-498 (b-19) (b-35) HH (a-31) -CH (Me)-4-499 (b-20) (b-7) HH (a -31) -CH (Me)-4-500 (b-20) (b-7) HH (a-31) -COCH (Me)-4-501 (b-20) (b-35) HH (a -31) -CH (Me)-4-502 (b-20) (b-35) HH (a-31) -COCH (Me)-4-503 (b-21) (b-7) HH (a -31) -CH (Me)-4-504 (b-21) (b-35) HH (a-31) -CH (Me)-4-505 (b-24) (b-7) HH (a -31) -CH (Me)-4-506 (b-24) (b-35) HH (a-31) -CH (Me)-4-507 (b-25) (b-7) HH (a -31) -CH (Me)-4-508 (b-25) (b-35) HH ( a-31) -CH (Me)-4-509 (b-72) (b-7) HH (a-31) -CH (Me)-4-510 (b-72) (b-35) HH ( a-31) -CH (Me)-4-511 (b-73) (b-7) HH (a-31) -CH (Me)-4-512 (b-73) (b-7) HH ( a-31) -COCH (Me)-4-513 (b-73) (b-35) HH (a-31) -CH (Me)-4-514 (b-73) (b-35) HH ( a-31) -COCH (Me)-4-515 (b-74) (b-7) HH (a-31) -CH (Me)-4-516 (b-74) (b-35) HH ( a-31) -CH (Me)-4-517 (b-76) (b-7) HH (a-31) -CH (Me)-4-518 (b-76) (b-35) HH ( a-31) -CH (Me)-4-519 (b-77) (b-7) HH (a-31) -CH (Me)-4-520 (b-77) (b-7) HH ( a-31) -COCH (Me)-4-521 (b-77) (b-35) HH (a-31) -CH (Me)-4-522 (b-77) (b-35) HH ( a-31) -COCH (Me)-4-523 (b-7) (b-7) HH (a-33) -CH (Me)-4-524 (b-7) (b-35) HH ( a-33) -CH (Me)-4-525 (b-11) (b-7) HH (a-33) -CH (Me)-4-526 (b-11) (b-35) HH ( a-33) -CH (Me)-4-527 (b-12) (b-35) HH (a-33) -CH (Me)-4-528 (b-15) (b-35) HH ( a-33) -CH (Me)-4-529 (b-18) (b-7) HH (a-33) -CH (Me)-4-530 (b-18) (b-35) HH ( a-33) -CH (Me)-4-531 (b-19) (b-35) HH (a-33) -CH (Me)-4-532 (b-20) (b-7) HH ( a-33) -CH (Me)-4-533 (b-20) (b-35) HH (a-33) -CH (Me)-4-534 (b-21) (b-35) HH (a-33) -CH (Me)-4-535 (b-24) (b-35) HH (a-33) -CH (Me)-4-536 (b-25) (b-35) HH (a-33) -CH (Me)-4-537 (b-72) (b-35) HH (a-33) -CH (Me)-4-538 (b-73) (b-7) HH (a-33) -CH (Me)-4-539 (b-73) (b-35) HH (a-33) -CH (Me)-4-540 (b-74) (b-35) HH (a-33) -CH (Me)-4-541 (b-76) (b-35) HH (a-33) -CH (Me)-4-542 (b-77) (b-7) HH (a-33) -CH (Me)-4-543 (b-77) (b-35) HH (a-33) -CH (Me)-  In the above Table 1-4, the active ingredient of the pharmaceutical composition of the present invention
A cyclobutene derivative having the above general formula (I),
Examples of suitable compounds include the exemplified compound numbers: 1-41 and 1-
78, 1-86, 1-92, 2-1-2-64, 2-74-2-86, 2-89 -2-1
06, 2-116, 2-117, 2-237, 2-377, 2-403, 2-407, 2-45
0, 2-479, 2-480, 2-481, 2-492, 2-499, 2-500, 2-55
4, 2-574, 2-577, 2-583, 2-584, 2-585, 2-592, 2-69
1, 2-698, 2-699, 2-713, 2-755, 2-762, 2-763, 2-83
5, 2-838, 2-844, 2-845, 2-846, 2-815, 2-952, 2-108
5, 2-1256, 2-1286, 2-1287, 2-1288, 2-1299, 2-1306,
 2-1307, 2-1359, 2-1360, 2-1379, 2-1382, 2-1388, 2
-1389, 2-1390, 2-1496, 2-1523, 2-1565, 2-1625, 2-1
627, 2-1628, 2-1654, 2-1655, 2-1666, 2-1772, 2-183
1, 2-1941, 2-1946, 2-1962, 2-2256, 2-2274, 2-2295,
 2-2309, 2-3090-2-3514, 3-79, 3-94, 3-100, 3-16
9, 3-187, 3-208, 3-401, 4-94, 4-208 and 4-401
Examples of more suitable compounds include, for example,
Article number: 2-2-2-58, 2-74, 2-81, 2-237, 2-450, 2-47
9, 2-480, 2-481, 2-492, 2-499, 2-500, 2-554, 2-58
3, 2-584, 2-585, 2-691, 2-713, 2-755, 2-762, 2-763,
 2-835, 2-838, 2-844, 2-845, 2-846, 2-815, 2-952,
2-1085,2-1256, 2-1286, 2-1287, 2-1288, 2-1299, 2-1
306, 2-1307, 2-1359, 2-1360,2-1379, 2-1382, 2-138
8, 2-1389, 2-1390, 2-1496, 2-1523, 2-1565, 2-1625,
2-1627, 2-1628, 2-1654, 2-1655, 2-1666, 2-1772, 2-
1831, 2-1941, 2-1962, 2-2274, 2-2295, 2-2309, 2-310
8-2-3118, 2-3136, 2-3157-2-3165, 2-3178- 2-318
0, 2-3185, 2-3186, 2-3191-2-3201, 2-3217-2-322
2, 2-3376-2-3390, 2-3400-2-3406, 2-3414, 2-343
8-2-3461, 2-3471-2-3477, 2-3479- 2-3514, 3-79,
 List 3-94, 3-100, 3-169, 3-187 and 3-208
Examples of the more preferable compounds include:
2-5, 2-6, 2-8, 2-13, 2-16, 2-18, 2-19, 2-21, 2-37,
 2-39,2-40, 2-42, 2-51, 2-53, 2-54, 2-56, 2-237, 2
-450, 2-479, 2-480, 2-481,2-492, 2-554, 2-583, 2-5
84, 2-585, 2-691, 2-713, 2-755, 2-815, 2-844, 2-84
5, 2-846, 2-1085, 2-1256, 2-1299, 2-1359, 2-1388,
2-1389, 2-1390, 2-1496, 2-1523, 2-1565, 2-1625, 2-
1772, 2-1831, 2-1962, 2-2274, 2-2295, 2-2309, 2-31
36, 2-3161, 2-3162, 2-3164, 2-3197, 2-3377, 2-338
6, 2-3400, 2-3457, 2-3485, 2-3497, 2-3502, 2-3504,
 3-94 and 3-208 can be mentioned, and even more preferable
As the compound, Exemplified Compound No. 2-5: 3- (3-
｛(4-fluorophenyl)-(1-phenylethyla
Mino) methyl @ phenylamino) -4-hydroxy-3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-
6: 3- (3-{(4-chlorophenyl)-(1-fe
Nylethylamino) methyl @ phenylamino) -4-h
Droxy-3-cyclobutene-1,2-dione, exemplified
Compound No. 2-8: 3-hydroxy-4- (3-{(4-me
Toxiphenyl)-(1-phenylethylamino) methyl
(Ruphenylamino) -3-cyclobutene-1,2-di
ON, Exemplified Compound No. 2-13: 3-hydroxy-4- {3
-[(4-methoxyphenyl)-(1- (naphthalene-
1-yl) ethylamino) methyl] phenylamino}-
3-cyclobutene-1,2-dione, exemplified compound No. 2-
16: 4- {3-[(1- (3-fluorophenyl) ethyl
Ruamino) -phenylmethyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione, exemplified
Compound number 2-18: 3- (3-{(4-fluorophenyl)
)-[1- (3-fluorophenyl) ethylamino]
Methyl @ phenylamino) -4-hydroxy-3-cycl
Lobutene-1,2-dione, Exemplified Compound No. 2-19: 4-
{3-[(4-chlorophenyl)-(1- (3-fluoro
Lphenyl) ethylamino) methyl] phenylamino
-3-Hydroxy-3-cyclobutene-1,2-dio
Compound number 2-21: 3- {3-[[1- (3-f
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamino} -4-hydroxy-3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-3
7: 4- {3-[(1- (3,4-difluorophenyl)
Ru) ethylamino) -phenylmethyl] phenylami
NO-3-Hydroxy-3-cyclobutene-1,2-di
ON, Exemplified Compound No. 2-39: 3- {3-[[1- (3,
4-difluorophenyl) ethylamino]-(4-fur
Orophenyl) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione, exemplified compound
No. 2-40: 4- {3-[(4-chlorophenyl)-(1
-(3,4-difluorophenyl) ethylamino) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione, Exemplified Compound No. 2-42: 4- {3
-[(1- (3,4-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
ON, Exemplified Compound No. 2-53: 4- {3-[(1- (3,
5-difluorophenyl) ethylamino)-(4-fur
Orophenyl) methyl] phenylamino} -3-hydro
Xy-3-cyclobutene-1,2-dione, exemplified compound
No. 2-54: 4- {3-[(4-chlorophenyl)-(1
-(3,5-difluorophenyl) ethylamino) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione, Exemplified Compound No. 2-56: 4- {3
-[(1- (3,5-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
ON, Exemplified Compound No. 2-128: 4- {3-[(1-
(3,5-difluorophenyl) ethylamino) -fe
Nylmethyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione, Exemplified Compound No. 2-23
7: 3-amino-4- [3-((4-methoxyphenyi)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione, exemplified compound No. 2-492: 3-amino-
4- [3-((4-fluorophenyl)-(1-phenyl)
Ruethylamino) methyl) phenylamino] -3-cycl
Lobutene-1,2-dione, Exemplified Compound No. 2-554: 3
-Amino-4- [3-((4-methoxyphenyl)-
(1-phenylethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione, exemplified compound
No. 2-691: 3-amino-4- [3- (4-pyridyl-
(1-phenylethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione, exemplified compound
No. 2-815: 3-amino-4- [3-((4-methoxy
Phenyl)-(1- (3-fluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione, exemplified compound No. 2-1299: 3-amino-
4- [3-((4-fluorophenyl)-(1- (3,
4-difluorophenyl) ethylamino) methyl) fe
Nylamino] -3-cyclobutene-1,2-dione, examples
Compound No. 2-1359: 3-amino-4- [3- (4-me
Toxiphenyl- (1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-si
Clobutene-1,2-dione, Exemplified Compound No. 2-149
6: 3-amino-4- [3- (4-pyridyl- (1-
(3,4-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON, Exemplified Compound No. 2-1523: 3-amino-4- [3-
(Phenyl- (1- (3,5-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
1,2-dione, exemplified compound No. 2-1565: 3-amido
No-4- [3-((4-fluorophenyl)-(1-
(3,5-difluorophenyl) ethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-di
Compound No. 2-1625: 3-amino-4- [3-
((4-methoxyphenyl)-(1- (3,5-difur
Orophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione, exemplified compound
No. 2-1962: 3-amino-4- [3-((4-methoxy
Phenyl)-(1- (4-pyridyl) ethylamino) methyl
Tyl) phenylamino] -3-cyclobutene-1,2-
Dione, Exemplified Compound No. 2-2295: 3-amino-4- [3
-((4-methoxyphenyl)-(1- (3,4-diph
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione, exemplified compound
No. 2-3136: 3- {3-[(4-chlorophenyl)-
(1- (Naphthalen-1-yl) ethylamino) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
Ten-1,2-dione, exemplified compound number 2-3161: 3-h
Droxy-4- {3-[(1- (1-naphthyl) ethyl
Amino) -phenylmethyl] phenylamino} -3-si
Clobutene-1,2-dione, Exemplified Compound No. 2-3162:
3- {3-[(4-fluorophenyl)-(1- (naph
Taren-1-yl) ethylamino) methyl] phenyla
Mino} -4-hydroxy-3-cyclobutene-1,2-
Dione, Exemplified Compound No. 2-3164: 3-hydroxy-4-
{3-[(1- (1-naphthyl) ethylamino)-(p
-Tolyl) methyl] phenylamino} -3-cyclobute
1,2-dione, Exemplified Compound No. 2-3197: 3- (3
-{[1- (3-fluorophenyl) ethylamino]-
(P-tolyl) methyl @ phenylamino) -4-hydro
Xy-3-cyclobutene-1,2-dione, exemplified compound
No. 2-3386: 3- (3-{[1- (3,4-difluoro)
Phenylamino) ethylamino]-(p-tolyl) methyl
(Ruphenylamino) -4-hydroxy-3-cyclobu
Ten-1,2-dione and Exemplified Compound No. 2-3457: 4- {3- [1- (3,5-di
Fluorophenyl) ethylamino]-(4-methylphen
Nyl) methyl] phenylamino} -3-hydroxy-3
-Cyclobutene-1,2-dione; the most preferred compound is exemplified by
Compound number 2-18: 3- (3-{(4-fluorophenyl)
)-[1- (3-fluorophenyl) ethylamino]
Methyl @ phenylamino) -4-hydroxy-3-cycl
Lobutene-1,2-dione, Exemplified Compound No. 2-42: 4-
{3-[(1- (3,4-difluorophenyl) ethyl]
Amino)-(4-methoxyphenyl) methyl] phenyl
Amino} -3-hydroxy-3-cyclobutene-1,2
-Dione and Exemplified Compound No. 2-56: 4- {3-[(1- (3,5-di
Fluorophenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl] phenylamino} -3-hydroxy-
3-cyclobutene-1,2-dione can be mentioned.

[0088]

BEST MODE FOR CARRYING OUT THE INVENTION A cyclobutene derivative having the general formula (I), which is an active ingredient of the pharmaceutical composition of the present invention, can be produced according to the method described below.

Method A is a method for producing compound (I).

[0090]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
D, E, G, X, Y, Z and the dashed line have the same meanings as described above, and R ^1a is a group in which the amino, hydroxy and / or carboxy group contained as a substituent in the R ¹ group is protected. And R ^2a , R ^3a , R ^4a and R ^6a are the same as defined in the definition of R ¹ , which may be amino, hydroxy and / or carboxy, and R ² , R ³ , R ⁴ and The amino and / or hydroxy group contained as a substituent in the R ⁶ group is an amino and / or hydroxy group which may be protected, and is the same as the group in the definition of R ² , R ³ , R ⁴ and R ^6. R ^5a represents a group similar to the group in the definition of R ⁵ , in which the hydroxy group contained as a substituent in the R ⁵ group may be protected, and Q is usually Is not particularly limited as long as it is a group leaving as a nucleophilic residue. Preferably, halogen atoms such as chlorine, bromine and iodine; lower alkoxy groups such as methoxy and ethoxy; trihalogenomethyloxy groups such as trichloromethyloxy; Lower alkanesulfonyloxy group; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy And most preferably a halogen atom and a lower alkoxy group.

In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^1a , R ^2a , R ^3a , R ^4a and R ^6a is an amino group used in the field of synthetic organic chemistry. The protective group is not particularly limited, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, lower aliphatic acyl groups such as crotonoyl, chloroacetyl, dichloro "Aliphatic acyls" such as halogeno lower alkylcarbonyl groups such as acetyl, trichloroacetyl and trifluoroacetyl, and lower alkoxycarbonyl groups substituted with lower alkoxy such as methoxyacetyl; ₇ -C ₁₁ aromatic acyl group, 2- Buromobe Benzoyl, 4-chlorobenzoyl halogeno C ₇ -C ₁₁ aromatic acyl group such as yl, 2,4,6
Trimethyl benzoyl, 4-C ₇ -C ₁₁ aromatic acyl group substituted with a lower alkyl as toluoyl, C ₇ -C substituted by lower alkoxy such as 4-anisoyl
₁₁ C ₇ -C ₁₁ aromatic acyl groups, substituted by nitro such as 4-nitrobenzoyl, 2-nitrobenzoyl, substituted by lower alkoxycarbonyl such as 2- (methoxycarbonyl) benzoyl C ₇ -C
₁₁ aromatic acyl groups, “aromatic acyls” such as C ₇ -C ₁₁ aromatic acyl groups substituted with aryl such as 4-phenylbenzoyl; the lower alkoxycarbonyl group,
"Alkoxycarbonyls" such as lower alkoxycarbonyl groups substituted by halogen or tri-lower alkylsilyl such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; such as vinyloxycarbonyl and allyloxycarbonyl "Alkenyloxycarbonyls"; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4
"Aralkyloxycarbonyls" wherein the aryl ring may be substituted with one or two lower alkoxy or nitro, such as -dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-
Three substituted with a group selected from tri-lower alkylsilyl groups such as t-butylsilyl and triisopropylsilyl, aryls such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl, and lower alkyl. "Silyls" such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group substituted with 1 to 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenyl Methyl, 2
-Nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4
Lower alkyl such as cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl,
"Aralkyls" such as lower alkyl groups substituted with one to three aryl groups in which the aryl ring is substituted with lower alkoxy, nitro, halogen, cyano; or N, N-dimethylaminomethylene, benzylidene , 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5
"Substituted methylene groups forming Schiff bases", such as chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene;
And preferably a lower aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group or an alkoxycarbonyl group, more preferably a lower aliphatic acyl group or a lower alkoxycarbonyl group, and most preferably It is an acetyl group or a t-butoxycarbonyl group.

In the above, R ^1a , R ^2a , R ^3a , R ^4a ,
The “protecting group” of the “optionally protected hydroxy group” in the definition of R ^5a and R ^6a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of organic synthetic chemistry. Shows the same meaning as "a general protecting group in such a reaction for an ester of a hydroxy group", preferably,
It is a lower aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or an alkoxymethyl group, more preferably an aromatic acyl group or an alkoxymethyl group, and most preferably a benzoyl group or a methoxymethyl group. .

In the above, the “protecting group” of the “optionally protected carboxy group” in the definition of R ^1a is not particularly limited as long as it is a carboxy group protecting group used in the field of organic synthetic chemistry. For example, it has the same meaning as the above “general protecting group in the reaction for the ester of the carboxy group”, preferably a lower alkyl group or an aralkyl group, and most preferably a methyl group, an ethyl group or a benzyl group. It is.

Step A1 is a step for producing a compound having the general formula (I), in which a compound having the general formula (II) is reacted with a compound having the general formula (III) in an inert solvent. Thereafter, if desired, R ^1a , R ^2a , R ^3a , R ^4a ,
It is carried out by removing the protecting group of the amino, hydroxy and / or carboxy group in R ^5a and R ^6a .

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric acid triamide;
Water; or a mixed solvent of the above solvents, preferably alcohols (most preferably methanol).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably 0 ° C
To 50 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 5 minutes to 24 hours (preferably 15 minutes to 12 hours).

In the compound (I), R ⁶ is a lower alkoxy group in an inert solvent (preferably alcohols or ethers) at -20 ° C. to 150 ° C.
(Preferably 0 ° C. to 50 ° C.) for 5 minutes to 24 hours (preferably 15 minutes to 12 hours) with ammonia or HR ′ (wherein R ′ represents an amine residue). Thus, a compound in which R ⁶ is an amine residue can be produced.

Further, in the compound (I), a compound wherein R ⁶ is a lower alkoxy group is reacted with an inert solvent (preferably an alcohol or a mixed solvent of alcohol and water) in the presence of a base (preferably an organic solvent). Amines), -20 ° C to 150
5 ° C. (preferably 0 ° C. to 50 ° C.) for 5 minutes to 24 hours (preferably 15 minutes to 12 hours).
V) H ₂ NR ″ (IV) wherein R ″ is a sulfo lower alkyl group or a carboxy lower alkyl group. To produce a compound in which R ⁶ is an amino group substituted with a “sulfo lower alkyl group” or a “carboxy lower alkyl group”.

Further, in the compound (I), a compound wherein R ⁶ is a lower alkoxy group in an inert solvent (preferably alcohols or halogenated hydrocarbons) at −20 ° C. to 150 ° C. (preferably (0 ° C. to 50 ° C.) for 5 minutes to 24 hours (preferably 15 minutes to 12 hours) to produce a compound in which R ⁶ is a hydroxy group.

The removal of the protecting groups for the amino, hydroxy and carboxy groups depends on the type of the protecting group.
(Protective Groups in Organic Synthesis), John Wi
ley & Sons: JFWMcOmis, (Protective Groups in Or
ganicChemistry), by the method described in Plenum Press as follows.

When the protecting group for the amino group is a silyl, a compound which generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride is usually used. And removed by treating with.

The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Is preferred.

The reaction temperature and the reaction time are not particularly limited, but usually the reaction temperature is 0 ° C. to 50 ° C., and the reaction time is 10 minutes to 18 hours.

When the protecting group for the amino group is an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl or a substituted methylene group forming a Schiff base, an acid or a base is added in the presence of an aqueous solvent. Can be removed.

The acid used in the above reaction is not particularly limited as long as it is a usual acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, and phosphoric acid. And an inorganic acid such as nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate. Salts; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; or aqueous ammonia And ammonia such as concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction.
For example, methanol, ethanol, n-propanol,
Isopropanol, n-butanol, isobutanol,
alcohols such as t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Ters; water; or a mixed solvent of water and the above organic solvent, preferably ethers (most preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid or base to be used, and are not particularly limited. Let react for ~ 10 hours.

When the amino-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). The method of removing or using an oxidizing agent is preferred.

The solvent used for removal by catalytic reduction is
There is no particular limitation as long as it is inert to this reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; Esters such as methyl, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propano-
, Isopropanol, n-butanol, isobutanol
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; organic acids such as acetic acid; water; or a mixed solvent of the above solvent and water And preferably alcohols, ethers, organic acids or water (most preferably alcohols or organic acids).

The catalyst used for removal by catalytic reduction is
Usually, there is no particular limitation as long as it is used for the catalytic reduction reaction, but preferably, palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used.

Although the pressure is not particularly limited, it is usually 1 to 1
Performed at 0 atm.

The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but the reaction temperature is usually from 0 ° C. to 100 ° C., and the reaction time is from 5 minutes to 24 hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction, but is preferably a water-containing organic solvent.

Such organic solvents include, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers such as, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide;
Or sulfoxides such as dimethyl sulfoxide; sulfolane, preferably halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

The oxidizing agent used in the above reaction is not particularly limited as long as it is generally used for oxidation.
Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)
Is used.

The reaction temperature and reaction time vary depending on the starting compound, oxidizing agent, solvent and the like.
To 150 ° C., and the reaction time is 10 minutes to 24 hours.

When the protecting group for the amino group is an aralkyl, the protecting group can be removed using an acid.

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride; Tin chloride, boron trichloride, boron trifluoride,
A Lewis acid such as boron tribromide; or an acidic ion exchange resin, preferably an inorganic or organic acid (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or, it is water or a mixed solvent of the above solvents, preferably ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

The reaction temperature depends on the starting compound, the acid used,
Although it depends on the solvent and the like, it is usually from -20 ° C to the boiling point (preferably 0 ° C to 100 ° C).

The reaction time depends on the starting compound, the acid used,
The time is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours), although it depends on the solvent, the reaction temperature and the like.

When the amino-protecting group is an alkenyloxycarbonyl, the amino-protecting group is usually the above-mentioned aliphatic acyl, aromatic acyl, alkoxycarbonyl or a substituted methylene group forming a Schiff base. It is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of a group.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be performed with few side reactions.

When the protecting group for the hydroxy group is a silyl group, compounds which generate a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride are usually used. Or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid And by treatment with an organic acid such as trifluoromethanesulfonic acid.

When removing with a fluorine anion,
The reaction may be accelerated by adding organic acids such as formic acid, acetic acid, propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, but is preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or the like. Ethers such as diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and the reaction time vary depending on the starting compound, organic acid, solvent and the like.
To 100 ° C (preferably 10 ° C to 50 ° C),
The reaction time ranges from 1 hour to 24 hours.

When the hydroxy-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). The method of removing or using an oxidizing agent is preferred.

The solvent used for the removal by catalytic reduction is
There is no particular limitation as long as it is not involved in this reaction, but aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as toluene, benzene, xylene; ethyl acetate, acetic acid Esters such as propyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol Alcohols such as -yl, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphoric acid triamide; fatty acids such as formic acid and acetic acid; water; or a mixed solvent of the above solvents. , Alcohols (most preferably, methanol).

The catalyst used for removal by catalytic reduction is
Generally, there is no particular limitation as long as it is used for the catalytic reduction reaction. For example, palladium-carbon, palladium-
Black, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate, preferably palladium-carbon.

Although the pressure is not particularly limited, it is usually 1 to 1
Performed at 0 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 20 ° C. to 70 ° C.) for 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent.

Preferred as such organic solvents are ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran; Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide.

The oxidizing agent used in the removal by oxidation is preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3
-Dichloro-5,6-dicyano-p-benzoquinone (D
DQ).

The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but usually the reaction temperature is from 0 ° C. to 150 ° C., and the reaction time is from 10 minutes to 24 hours.

In liquid ammonia or methanol
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
-78 ° C in alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve.
At a temperature of from 0 ° C. to 0 ° C., it can also be removed by the action of alkali metals such as metallic lithium and metallic sodium.

Further, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; a nitrile such as acetonitrile. Or a mixed solvent of the above solvents.

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the like.
° C and the reaction time is 5 minutes to 72 hours.

When the reaction substrate has a sulfur atom,
Preferably, aluminum chloride-sodium iodide is used.

When the protecting group for the hydroxy group is a lower aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, sodium Metal alkoxides such as ethoxide and potassium-t-butoxide; or ammonia such as aqueous ammonia and concentrated ammonia-methanol.
They are alkali metal hydroxides, metal alkoxides or ammonia (most preferably, alkali metal hydroxides or metal alkoxides).

The solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction. Examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Such ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol;
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Water; or a mixed solvent of the above solvents.

The reaction temperature and reaction time vary depending on the starting compound, the base used, the solvent and the like, and are not particularly limited.
In order to suppress side reactions, the reaction temperature is usually -20 ° C.
At ~ 150 ° C, the reaction time is 1-10 hours.

When the protecting group for the hydroxy group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, the acid is usually dissolved in an acid in a solvent. And is removed by treating with

The acid used in the above reaction is usually
There is no particular limitation as long as it is used as a Bronsted acid or Lewis acid, and preferably, hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid; or acetic acid, trifluoroacetic acid, methanesulfonic acid, or p- A Bronsted acid such as an organic acid such as toluenesulfonic acid; or a Lewis acid such as boron trifluoride, but a strongly acidic cation exchange resin such as Dowex 50W can also be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, toluene , Aromatic hydrocarbons such as xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran; Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-
Propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol
Alcohols such as toluene, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; Are ethers or alcohols (most preferably, tetrahydrofuran or methanol).

The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent and the like.
° C), and the reaction time is 5 minutes to 48 hours (preferably 30 minutes to 10 hours).

When the protecting group for the hydroxy group is an alkenyloxycarbonyl group, the conditions for the removal reaction when the protecting group for the hydroxy group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group are usually used. In the same manner as in the above, it is achieved by treating with a base.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is simple and is carried out with few side reactions. Can be.

When the protecting group for the carboxy group is a lower alkyl group, a lower alkynyl group, a lower alkenyl group, a hydroxy lower alkyl group or a lower aliphatic acyl lower alkyl group, the protecting group for the hydroxy group is usually the above-mentioned aliphatic group. The protective group can be removed by treating with a base in the same manner as in the removal reaction for an aromatic acyl group, aromatic acyl group or alkoxycarbonyl group.

When the protecting group for the carboxy group is an aralkyl group or a halogeno lower alkyl group, it is usually removed by reduction in a solvent.

As a reduction method, when the protecting group of the carboxy group is a halogeno lower alkyl group, a method by chemical reduction such as zinc-acetic acid is preferable. The method is carried out by a catalytic reduction method using a catalyst such as carbon or platinum, or a chemical reduction method using an alkali metal sulfide such as potassium sulfide or sodium sulfide.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; A fatty acid such as acetic acid; or a mixed solvent of the above organic solvent and water is suitable.

The reaction temperature and reaction time vary depending on the starting compound, solvent, reduction method and the like.
0 ° C. to room temperature, and the reaction time is 5 minutes to 12 minutes.
Time.

When a silyl group is used as the carboxy-protecting group, it is usually treated with an acid in the same manner as in the removal reaction when the hydroxy-protecting group is a silyl group. it is possible to remove the protecting group.

The removal of the protecting group for the amino, hydroxy and / or carboxy groups can be carried out in any order in the order of the desired removal reaction.

After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In Method B, D in compound (I) is -C
A compound (Ic) in which E is a group having -NH-, a compound (Id) in which D is a group having -CH- and E is an oxygen atom or a sulfur atom, and a compound (Id) in which D is -CH- −
A group having E is -NH- G is -CO-G _a
- group (. In the above formula, G _a is a single bond or a C ₁ -C ₅ alkylene group) having, Compound (Ie), D is is E a group having a carbon atom = N-O-a This is a method for producing a compound (If) which is a group having the compound (Ig) and a compound (Ig) wherein D is a group having the formula —CH— and E is a group having the formula —CO—.

[0164]

Embedded image

[0165]

Embedded image

In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ ,
R ^3a , R ⁴ , R ^4a , A, G, Ga and Q are as defined above, R ⁷ is a formyl, carboxy or lower alkoxycarbonyl group, R ⁸ is lithium, magnesium, A ′ represents a metal atom such as zinc, cadmium, tin or cerium, and A ′ represents an amino and / or hydroxy group contained as a substituent in the definition of A
X represents an oxygen atom or a sulfur atom; and W represents a halogen atom.

Step B1 is a step of producing a compound having the general formula (VII), and converting the compound having the general formula (V) into a compound having the general formula (VI) or an acid addition salt thereof in an inert solvent. (For example, mineral salts such as hydrochloride, nitrate and sulfate), for example, by heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or titanium tetrachloride. The condensation is carried out using such a Lewis acid or acidic ion exchange resin.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or water or a mixture of the above solvents; preferably, halogenated hydrocarbons (most preferably, dichloromethane)
It is.

In the above reaction, compound (VI)
Is a acid addition salt, the reaction can be carried out using a base. Such bases include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate,
Alkali metal bicarbonates such as potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide Substances; lithium methoxide, sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide, potassium t-butoxide; or triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5. 4.0] -7-undecene (DB
Organic amines such as U), preferably organic amines (most preferably triethylamine).

[0170] inert solvent used in the above reaction is not particularly limited as long as the present reaction inert, e.g., hexane, heptane, ligroin, aliphatic hydrocarbons such as petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide ; water; or a water or a mixed solvent of the above solvents, preferably a halogenated hydrocarbon (most preferably dichloromethane) are.

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 200 ° C. When the condensation is carried out using a Lewis acid, it is preferably from 10 ° C to 4 ° C.
The temperature is 0 ° C., and preferably 50 ° C. to 150 ° C. when heat condensation is carried out using an organic sulfonic acid as a catalyst.

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 1 hour to 30 hours).

After completion of the reaction, the desired compound (VI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B2 is a step of producing compound (Ic). After reducing compound (VII) in an inert solvent, if necessary, R ^1a , R ^2a , R ^3a , R ^4a and A ′ It is carried out by removing the protecting groups of the amino, hydroxy and / or carboxy groups.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide Water; or water or a mixed solvent of the above solvents, preferably esters, alcohols or ethers (most preferably acetic acid, ethanol or tetrahydrofuran).
It is.

The reducing agent used in the above reaction is, for example,
Alkali metal borohydrides such as sodium borohydride, lithium borohydride and sodium cyanoborohydride; aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride and lithium triethoxyaluminum hydride; Or bromine, preferably alkali metal borohydrides (most preferably sodium cyanoborohydride).

[0177] The reaction temperature, starting compound, the reducing agent used may vary depending on the kind of solvent, etc., usually, -20 ° C. to 0.99 ° C. (preferably, 10 ° C. to 80 ° C.) it is.

The reaction time varies depending on the starting compound, the reducing agent used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 24 hours (preferably from 30 minutes to 16 hours).

R ^1a , R ^2a , R ^3a , R
Method of removing amino, a protective group for hydroxy and / or carboxy group in ^4a and A ', the amino of the Method A Step A1 is carried out in the same manner as the method for removing the protective group of the hydroxy and / or carboxy groups.

After completion of the reaction, the desired compound (Ic)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B3 is a step for producing a compound (Id), in which a compound having the general formula (VIII) is reacted with a base in the presence or absence (preferably in the presence) of an inert solvent. Is then reacted with a compound having the general formula (IX) and, if desired, R ^1a , R ^2a , R ^3a , R ^4a and A ′
By removing the amino, hydroxy and / or carboxy group protecting group in

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method B, Step B1, preferably alkali metal hydrides (most preferably, Sodium hydride).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide;
Amides such as dimethylacetamide and hexamethylphosphoric acid triamide; or a mixed solvent of the above solvents, preferably amides (most preferably dimethylformamide).

The reaction temperature for reacting compound (VIII) with a base varies depending on the starting compound, the base used, the solvent and the like. ).

The reaction time for reacting the compound (VIII) with a base varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 1 hour To 10 hours).

Next, the reaction temperature for the reaction with the compound (IX) is usually -20 ° C to 200 ° C (preferably 0 ° C to 200 ° C).
° C to 150 ° C).

The reaction time for the reaction with the compound (IX) is usually 15 minutes to 48 hours (preferably 3 minutes).
0 minute to 24 hours).

R ^1a , R ^2a , R ^3a , R
Method of removing amino, a protective group for hydroxy and / or carboxy group in ^4a and A ', the amino of the Method A Step A1 is carried out in the same manner as the method for removing the protective group of the hydroxy and / or carboxy groups.

After the completion of the reaction, the target compound (Id) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B4 is a step of separately preparing compound (Id). In step B4, the group having —XH of the compound having general formula (X) is added in an inert solvent in the presence or absence of a Lewis acid. Converting to a leaving group Q, and then reacting with compound (IX) to remove, if desired, protecting groups for amino, hydroxy and / or carboxy groups in R ^1a , R ^2a , R ^3a , R ^4a and A ′. It is performed by

Examples of the reagent forming the leaving group Q include sulfonyl halides such as methanesulfonyl chloride and P-toluenesulfonyl chloride; thionyl halides such as thionyl chloride, thionyl bromide and thionyl iodide; sulfuryl chloride and sulfuryl Sulfuryl halides such as bromide and sulfuryl iodide; phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide and phosphorus triiodide; phosphorus pentachloride, phosphorus pentabromide and phosphorus pentaiodide Halogenating agents such as phosphorus pentahalides; phosphorus oxyhalides such as phosphorus oxychloride, phosphorus oxybromide and phosphorus oxyiodide; or rhenium reagents such as methyltrioxorhenium (VII). And preferably a rhenium reagent.

The Lewis acids used in the above reaction include, for example, zinc halides such as zinc iodide and zinc chloride; tin halides such as tin tetrachloride; boron trichloride;
Boron halides such as boron trifluoride and boron tribromide, preferably zinc halide (most preferably zinc iodide).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as, toluene, xylene; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide;
Dimethylformamide, dimethylacetamide, amides such as hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or sulfolane, preferably an aromatic hydrocarbon (most preferably benzene) is.

The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from -20 ° C to 100 ° C.
° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 150 hours (preferably from 30 minutes to 100 hours).
It is.

R ^1a , R ^2a , R ^3a , R
Method of removing amino, a protective group for hydroxy and / or carboxy group in ^4a and A ', the amino of the Method A Step A1 is carried out in the same manner as the method for removing the protective group of the hydroxy and / or carboxy groups.

[0197] After the reaction, the desired compound of this reaction (Id)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B5 is a step of producing a compound having the general formula (XII), and using a reducing agent such as triphenylphosphine in an inert solvent to prepare the compound represented by the general formula (XII).
It is carried out by reducing the compound having I).

The inert solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction.
It is the same as that used in Step B1 of Method B, and is preferably a mixed solvent of ethers and water (most preferably a mixed solvent of tetrahydrofuran and water).

The reaction temperature varies depending on the starting compound, reducing agent, solvent and the like, but is usually from 20 ° C. to 150 ° C. (preferably from 50 ° C. to 100 ° C.).

The reaction time depends on the starting compound, reducing agent, solvent,
Although it varies depending on the reaction temperature and the like, it is usually 15 minutes to 24 hours (preferably 1 hour to 12 hours).

After the completion of the reaction, the desired compound (XI)
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B6 is a step for producing a compound having the general formula (Ie), in an inert solvent in the presence or absence of a base (preferably in the presence) of a compound (XI)
After reacting I) or an acid addition salt thereof with a compound having the general formula (XIII), R ^1a , R ^2a , R ^3a , R ^3
This is done by removing the protecting groups of the amino, hydroxy and / or carboxy groups in ^4a and A '.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
An amide such as hexamethylphosphoric acid triamide; a nitrile such as acetonitrile; water; or water or a mixed solvent of the above solvents, preferably a nitrile.

As the base used in the above reaction, for example, those similar to the ones used in the above-mentioned Method B, Step B1 can be mentioned. Preferably, organic amines (most preferably, triethylamine ).

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably from 0 ° C to 100 ° C).

[0207] The reaction time varies depending on the starting material, base, solvent, the reaction temperature or the like, usually, 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

The compound (Ie) can be separately produced by reacting the compound (XII) or an acid addition salt thereof with a compound having the general formula (XIV).

When R ⁷ in the compound (XIV) is a formyl group, the reaction is carried out by reacting the compound (XII) or an acid addition salt thereof with the compound (XIV) in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene and the like aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-
Butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide. Sulfolane; or a mixed solvent of the above solvents; and preferably ethers (most preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from 0 ° C. to 200 ° C. (preferably from 10 ° C. to 120 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

When R ⁷ is a carboxy group in compound (XIV), compound (XIV) or a reactive derivative thereof (acid halides, active esters or mixed acid anhydrides) is converted to compound (XII) in an inert solvent. ) Or an acid addition salt thereof.

In the acid halide method, compound (XIV) is converted into a halogenating agent (eg, oxalyl chloride,
Thionyl chloride, thionyl bromide, oxalic acid chloride, oxalic acid dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) to produce acid halides, and the acid halides and compound (XII) or the compound (XII) The reaction is carried out by reacting an acid addition salt in an inert solvent in the presence or absence (preferably in the presence) of a base.

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method B, Step B1, and preferably, organic amines (most preferably, pyridine) It is.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Kind;
Sulfoxides such as dimethylsulfoxide; or sulfolane, preferably halogenated hydrocarbons, ethers or amides (most preferably dichloromethane,
Chloroform, tetrahydrofuran or dimethylformamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but the reaction between the halogenating agent and the compound (XIV) and the reaction between the acid halides and the compound (XII) or an acid addition salt thereof are usually at -20 ° C. To 150 ° C., and preferably, the reaction between the halogenating agent and the compound (X) is carried out at −10 ° C.
To 100 ° C., acid halides and compound (XII)
Alternatively, the reaction with the acid addition salt is at -20 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but the reaction between the halogenating agent and the compound (XIV) and the reaction between the acid halides and the compound (XII) or an acid addition salt thereof are usually carried out. It is 30 minutes to 80 hours (preferably 1 hour to 48 hours).

In the active ester method, compound (XIV) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent in the presence or absence of a base (preferably In the presence of), compound (XII) or an acid addition salt thereof.

The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or the like. Compounds; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; and a condensing agent such as triphenylphosphine.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide and dimethylformamide Amides such as dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; or sulfolane, preferably ethers or amides (most preferably dioxane, tetrahydrofuran or dimethylformamide). It is.

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned acid halide method.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -70 ° C to 150 ° C (preferably from -10 ° C to 100 ° C) in the active esterification reaction.
In the reaction between the active ester and the compound (XII) or an acid addition salt thereof, the reaction is carried out at -20 ° C to 100 ° C (preferably 0 ° C
To 50 ° C.).

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like. The active esterification reaction and the reaction of the active ester with the compound (XII) or an acid addition salt thereof are usually carried out for 30 minutes to 80 hours ( (1 hour to 48 hours).

In the mixed acid anhydride method, the compound (X) is prepared in an inert solvent in the presence or absence (preferably in the presence) of a base.
IV) is reacted with a mixed acid anhydride agent to produce mixed acid anhydrides, and then reacted with the mixed acid anhydrides and compound (XII) or an acid addition salt thereof in an inert solvent.

The base used in the above reaction includes, for example, the same bases as those used in the above-mentioned acid halide method, and is preferably an organic amine (most preferably, pyridine). .

Examples of the mixed anhydride agent used in the above reaction include lower alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; lower alkanoyl halides such as pivaloyl chloride; diethyl cyanophosphonate; Di-lower alkyl or diaryl cyanophosphoric acid such as diphenyl phosphonate, preferably di-lower alkyl or diaryl cyanophosphoric acid (most preferably diethyl cyanophosphonate).

The inert solvent used in producing the mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, heptane, ligroin Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether Ethers such as, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and dimethyl sulfoxide Sulfoxy Kind; or a sulfolane,
Preferably, they are ethers or amides (most preferably, tetrahydrofuran or dimethylformamide).

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents and the like.
It is -50 ° C to 100 ° C (preferably 0 ° C to 60 ° C).

The reaction time in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and the compound (XII) or an acid addition salt thereof is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base. The base and the inert solvent are the same as those used in the reaction for producing the mixed acid anhydrides described above.

The reaction temperature in the reaction of the mixed acid anhydrides with the compound (XII) or an acid addition salt thereof is as follows:
Usually varies from -30 ° C to 100 ° C
(Preferably 0 ° C. to 80 ° C.).

The reaction time in the reaction of the mixed acid anhydrides with the compound (XII) or an acid addition salt thereof is as follows:
Reagent, the reaction temperature or the like, usually, 5 minutes to 2
4 hours (preferably 30 minutes to 16 hours).

When di-lower alkyl cyanophosphoric acid or diaryl cyanophosphoric acid is used in this reaction, compound (XII) and compound (X
IV) can also be reacted directly.

In the case where R ⁷ is a lower alkoxycarbonyl group in the compound (XIV), in the presence or absence (preferably without) of an inert solvent, in the presence or absence of a base (preferably (In the absence)) by reacting compound (XII) or an acid addition salt thereof with compound (XIV).

The base used in the reaction of compound (XII) or an acid addition salt thereof with compound (XIV) can be, for example, the same base as that used in the above-mentioned Method B, Step B1. , Preferably organic amines (most preferably pyridine).

The inert solvent used in the reaction of the compound (XII) or an acid addition salt thereof with the compound (XIV) is not particularly limited as long as it is inert to the reaction. Aliphatic hydrocarbons such as heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-
Butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or mixed solvents of the above solvents, preferably ethers or Amides (most preferably tetrahydrofuran, dioxane or dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 50 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

R ^1a , R ^2a , R ^3a , R
Method of removing amino, a protective group for hydroxy and / or carboxy group in ^4a and A ', the amino of the Method A Step A1 is carried out in the same manner as the method for removing the protective group of the hydroxy and / or carboxy groups.

After completion of the reaction, the desired compound (Ie) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B7 is a step for producing a compound having the general formula (If). In an inert solvent, the compound (V) is converted to a compound having the general formula (XV) or an acid addition salt thereof (for example, hydrochloric acid). Mineral salts such as salts, nitrates, sulfates)
And optionally removing the protecting group of the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a , R ^4a and A ′, to give the compound (V). )), For example,
It is carried out by a method of heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or a method of condensation using a Lewis acid such as titanium tetrachloride. The method of reacting the compound (V) with the compound (XV) is carried out in the same manner as in the above-mentioned Method B, Step B1, and R ^1a ,
R ^2a, R ^3a, a method of removing amino, a protective group for hydroxy and / or carboxy group in R ^4a and A ', removing the protecting group of the amino, hydroxy and / or carboxy group of the Method A Step A1 It is carried out in the same manner as the method.

After completion of the reaction, the desired compound (If) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B8 is a step for producing a compound having the general formula (XVI), which is carried out by reacting compound (VIII) with an alkali metal cyanide in an inert solvent.

[0245] Te alkali metal cyanide used in the reaction includes, for example, lithium cyanide, sodium cyanide, potassium cyanide.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as, toluene, xylene; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide;
Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; or sulfolane, preferably ethers (most preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from 0 ° C. to 200 ° C. (preferably from 10 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

After completion of the reaction, the desired compound (XV
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B9 is a step for producing a compound having the general formula (XVII), which is carried out by hydrolyzing compound (XVI) with an acid or alkali in an inert solvent.

Hydrolysis with an acid is performed at room temperature to 100 ° C. for 1 hour to 10 hours (preferably 3 hours to 7 hours) with a hydrous mineral acid such as aqueous hydrochloric acid, aqueous sulfuric acid, and aqueous nitric acid.
(Preferably at 50 ° C. to 100 ° C.).

The hydrolysis with an alkali is carried out in an amount of 1 to 10 equivalents (preferably 1 to 5 equivalents) of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, calcium hydroxide, or hydroxide. An alkaline earth metal hydroxide such as barium is used in an amount of 1 to 10 equivalents (preferably 1 to 10 equivalents).
To 6 equivalents) in an inert solvent (preferably water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these solvents) in a temperature of 0 ° C to 120 ° C (preferably Has 20
C. to 100 C.) for 30 minutes to 48 hours (preferably 1
(24 hours to 24 hours).

After completion of the reaction, the desired compound of the present reaction (XVI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B10 is a step of producing a compound having the general formula (XVIII), which is carried out by converting the carboxy group of the compound (XVII) into a group having -COQ in an inert solvent. The step is the same as that in the B method B4.
The step is carried out in the same manner as in the step of converting the group having -XH of the compound (X) into the leaving group Q.

Step B11 has the general formula (Ig)
This is a process for producing a compound, in an inert solvent,
Compound (XVIII) in the presence or absence of a catalyst
After reacting with a compound having the general formula (XIX),
By R^1a, R^2a, R^3a, R ^4aAnd A 'in A'
Protecting groups for amino, hydroxy and / or carboxy groups
It is done by doing.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as, toluene, xylene; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide;
Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; or sulfolane, preferably ethers (most preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, the solvent and the like, but is generally -80 ° C to 50 ° C (preferably -50 ° C).
° C to 0 ° C).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the desired compound (Ig) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In the method C, in the compound (I), D is a nitrogen atom, E is a group having -NH, and G is -CO-G
_a compound (Ih) which is a group having _a- , a compound (Ii) wherein D is a nitrogen atom and E is an oxygen atom or a sulfur atom,
D is a group having it E is -NH- nitrogen atom compound (Ij), the compound D is a group having the -NH- is a nitrogen atom E G is C ₁ -C ₆ alkylene group ( Ij
This is a method for producing a compound (Ik) in which a) and D are nitrogen atoms and E is a group having —CO—.

[0261]

Embedded image

In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ ,
R ^3a , R ⁴ , R ^4a , R ⁷ , A, A ′, G, G _a , Q, X and W have the same meanings as described above, and G _b is C ₁ -C
_{6 represents an} alkylene group.

Step C1 is a step for producing a compound (Ih), wherein the compound of the formula (XX) or an acid addition salt thereof (preferably a hydrochloride) is reacted with a compound (XIII) or (XIV) in an inert solvent. ), And if desired, R ^1a , R ^2a ,
Amino, hydroxy and / or R ^3a , R ^4a and A ′
Alternatively, this step is performed by removing the protecting group of the carboxy group, and this step is performed in the same manner as in the above-mentioned Method B, Step B6.

Step C2 is a step for producing a compound (Ii). The compound having the general formula (XXI) can be prepared by reacting a compound having the general formula (XXI) in an inert solvent in the presence or absence (preferably in the presence) of a base. After reacting with a compound having the formula (XXII)
If desired, the reaction is carried out by removing the protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a , R ^4a and A ′, and this step is carried out in the same manner as the above-mentioned Method B, Step B4. .

Step C3 is a step of separately producing compound (Ii). In step C3, an organic base (preferably,
Reacting a compound having the general formula (XXIII) with a compound having the general formula (XXIV) in the presence of triethylamine), and optionally amino, hydroxy and R ′ in R ^1a , R ^2a , R ^3a , R ^4a and A ′ This step is performed in the same manner as in the above-mentioned Method B, Step B3.

Step C4 is a step of producing compound (Ij). Compound (XX) is reacted with compound (XXI) in an inert solvent in the presence or absence (preferably in the presence) of a base.
After reaction with I), R ^1a , R ^2a , R ^3a , R
This step is carried out by removing the protecting group for the amino, hydroxy and / or carboxy group in ^4a and A ′, and this step is carried out in the same manner as the above-mentioned Method A, Step A1.

Step C5 is a step for producing a compound having the general formula (XXV), and a compound having the general formula (XIVa) and a compound (XX) or an acid addition salt thereof (for example, hydrochloric acid) in an inert solvent. A mineral acid salt such as a salt, a nitrate, or a sulfate), for example, a method of performing heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or a Lewis acid such as titanium tetrachloride. This step is performed in the same manner as in the above-mentioned Method B, Step B1.

The step C6 is a step for producing the compound (Ija). After reacting the compound (XXV) with a reducing agent, if necessary, the amino group in R ^1a , R ^2a , R ^3a , R ^4a and A ′ is obtained. This step is carried out by removing a protecting group for a hydroxyl group and / or a carboxy group.
It is performed in the same manner as in the two steps.

The compound (XXV) was subjected to catalytic reduction.
Later, if desired, R^1a, R^2a, R^3a, R ^4aAnd in A '
Amino, hydroxy and / or carboxy group protecting groups
To produce the compound (Ija) also by removing
be able to.

The solvent used in the catalytic reduction reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; toluene, Aromatic hydrocarbons such as benzene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; organic acids such as acetic acid; water; a mixed solvent of the above solvent and water;
Preferably they are alcohols, ethers, organic acids or water (most preferably alcohols or organic acids).

The catalyst used in the catalytic reduction reaction is not particularly limited as long as it is usually used in the catalytic reduction reaction. Examples thereof include palladium-carbon, Raney-nickel, platinum oxide, platinum oxide Black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium-carbon. The pressure is not particularly limited, but is usually 1 to 1
Performed at 0 atm.

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

R ^1a , R ^2a , R ^3a , R
Method of removing amino, a protective group for hydroxy and / or carboxy group in ^4a and A ', the amino of the Method A Step A1 is carried out in the same manner as the method for removing the protective group of the hydroxy and / or carboxy groups.

After completion of the reaction, the desired compound (Ij
a) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step C7 is a step for producing a compound (Ik). The compound having the general formula (XXVI) and a compound (XXIII) or an acid addition salt thereof (for example, hydrochloride, nitrate) in an inert solvent (A mineral salt such as a sulfate), and then, if desired, R ^1a , R ^2a , R ^3a , R ^4a and A ′.
By removing the protecting group of the amino, hydroxy and / or carboxy group in the compound (XXV)
In this method, the compound (XXIII) or the acid addition salt thereof is reacted with the compound (XIII) in Step B6 of Method B described above.
IV) The reaction is carried out in the same manner as in the case where R ⁷ is a formyl group, and the optional protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a , R ^4a and A ′ is The removing method is performed in the same manner as the method of removing the protecting group for the amino, hydroxy and / or carboxy group in Step A1 of Method A.

Starting compounds (II), (V) and (VII)
I), (X), (XI), (XX), (XXI) and (XXIII) can also be produced, for example, by the following method.

In Method D, compound (II) and compound (II) wherein R ^5a is a hydrogen atom in compound (II)
This is a method for producing a compound (IIb) wherein a) and Z are C ₁ -C ₆ alkylene groups and R ^5a is a hydrogen atom.

[0279]

Embedded image

In the above formula, R ^1a , R ^2a , R ^3a , R ^4a ,
^{R 5a, D, E, G} , Z and Q have the same meanings as described above, Z _a is a single bond or C ₁ -C ₅ alkylene group, Z _b is C ₁ -C ₆ alkylene Represents a group.

[0281] The Step D1 is a step for preparing a compound (IIa), in an inert solvent (preferably alcohol - Le acids or e - ethers), a reducing agent a compound having the general formula (XXVII) ( Preferably, tin (II) chloride, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride) and -20 ° C to 150 ° C
(Preferably 10 ° C. to 80 ° C.) for 5 minutes to 24 hours (preferably 10 minutes to 16 hours).

This step can also be carried out by using a catalytic reduction method or a general nitro group reduction method such as zinc-acetic acid method, tin-alcohol method or tin-hydrochloric acid method.

Step D2 is a step for producing a compound (IIb). In an inert solvent (preferably alcohols or ethers), the compound having the general formula (XXVIII) is reduced with a reducing agent ( (Preferably, an aluminum hydride compound).
It performed in the same manner as in the step.

Step D3 is a step for producing a compound having the general formula (XXX), and in an inert solvent (preferably an amide), a base (preferably an alkali metal bicarbonate or an organic amine) ) In the presence of compound (IIa) and a compound having the general formula (XXIX), and this step is performed in the same manner as in the above-mentioned Method A, Step A1.

Step D4 is a step of producing compound (II), which is carried out by reducing compound (XXX) in an inert solvent. This step is carried out in the same manner as in the above method D, step D1. .

After completion of the reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In Method E, compounds (XXVII) and (XXV)
The following general formula (XXXI) containing III) and (IIa)

[0288]

Embedded image

[Wherein R ^1a , R ^2a , R ^3a , R ^4a ,
D, E, G and Z have the same meanings as described above, R
⁹ represents an amino group, a cyano group or a nitro group which may be protected. Is a process for producing a compound having the formula: That is, in the compound (XXXI), D is -CH-
Wherein E is a group having -NH-, D is a group having -CH-, E is an oxygen atom or a sulfur atom (XXXIb), and D is -CH-. a group E is G is a group having the formula -NH- is -CO-G _a have - compound is a group having the (XX
XIc), a compound (XXXId) in which D is a carbon atom and E is a group having ＮN—O— and a compound (XX) in which D is a group having —CH— and E is a group having —CO—
XIe).

[0290]

Embedded image

[0291]

Embedded image

In the above formula, R ^1a , R ^2a , R ^3a , R ^4a ,
R ⁷ , R ⁸ , R ⁹ , G, G _a , Q, X, W and Z have the same meaning as described above.

Step E1 is a step for producing a compound having the general formula (XXXIII), and converting the compound having the general formula (XXXII) into a compound (VI) or an acid addition salt thereof (for example, hydrochloric acid) in an inert solvent. This step is carried out in the same manner as in the above-mentioned Method B, Step B1.

Step E2 is a step for producing a compound (XXXIa), and the compound (XXXIIa) is prepared in an inert solvent.
This step is carried out by reducing I), and this step is carried out in the same manner as the above-mentioned Method B, Step B2.

The step E3 is a step for producing the compound (XXXIb), in which the compound having the general formula (XXXIV) is reacted with a base in the presence or absence (preferably in the presence) of an inert solvent. Thereafter, the reaction is carried out by reacting with compound (IX), and this step is carried out in the same manner as in the above-mentioned Method B, Step B3.

Step E4 is a step of separately preparing compound (XXXIb), which is carried out in an inert solvent using a compound represented by the general formula (XXXX)
V) is converted to a leaving group Q in the presence or absence of a Lewis acid in a compound having -XH, and then reacted with compound (IX). This is performed in the same manner as in the step B4.

Step E5 is a step for producing a compound having the general formula (XXXVI), wherein the group having -XH of the compound having the general formula (XXXV) is prepared in an inert solvent.
This step is carried out in the presence or absence of a base by converting the compound into a leaving group Q. This step is a reaction for converting the group having -XH of the compound (X) of the compound (X) in Step B4 of Method B into a leaving group Q. Is performed in the same manner as

Step E6 is a step for producing a compound having the general formula (XXXVII), which is carried out by azide-forming the compound (XXXVI) in an inert solvent. The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene Halogenated hydrocarbons such as chloride and chloroform; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; Nitriles such as acetonitrile, preferably amides (most preferably,
Dimethylformamide).

The reagents used in the azidation of the above reaction include, for example, a diarylphosphate azide derivative such as diphenylphosphate azide; trialkylsilyl azides such as trimethylsilyl azide and triethylsilyl azide; or sodium azide, It is an alkali metal azide such as potassium, preferably an alkali metal azide (most preferably sodium azide).

A catalyst may be used in the above reaction,
Examples thereof include trialkylsilyl triflates such as trimethylsilyl triflate and triethylsilyl triflate, and Lewis acids such as trifluoroborane etherate, aluminum chloride and zinc chloride.

The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from -20 ° C to 100 ° C.
° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 50 hours (preferably from 30 minutes to 12 hours).

The step E7 is represented by the general formula (XXXVIII)
Is a step of producing a compound having, in an inert solvent,
This step is carried out by reducing compound (XXXVII) using a reducing agent such as triphenylphosphine, and this step is carried out in the same manner as in the above-mentioned Method B, Step B5.

Step E8 is a step of producing compound (XXXIc), which is carried out by reacting compound (XXXVIII) with compound (XIII) or (XIV). The same is done.

Step E9 is a step for producing a compound (XXXId), which is carried out in an inert solvent.
This step is carried out by reacting I) with compound (XV) or an acid addition salt thereof (for example, a mineral salt such as hydrochloride, nitrate or sulfate). divide.

Step E10 is a step for producing a compound having the general formula (XXXIX), which is carried out by reacting the compound (XXXIV) with an alkali metal cyanide in an inert solvent. This is performed in the same manner as in the method B8.

Step E11 is a step for producing a compound having the general formula (XXXX), which is carried out by hydrolyzing the compound (XXXIX) with an acid or an alkali in an inert solvent. This is performed in the same manner as in the method B9.

Step E12 is a step for producing a compound having the general formula (XXXXXX), which is carried out by converting the carboxy group of the compound (XXXX) into a group having -COQ in an inert solvent. The process is the above-mentioned Method B B1
This is performed in the same manner as in step 0.

[0309] The E13 step is a step for preparing a compound having the compound (XXXIe), in an inert solvent in the presence or absence of a palladium catalyst, a compound (XXXX
This step is carried out by reacting I) with compound (XIX). This step is carried out in the same manner as in the above-mentioned Method B, Step B11.

After completion of the reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In the method F, the compound (XXXI)
Is a nitrogen atom, E is a group having -NH-, and G is-
A compound (XXXIf) which is a group having CO-G _a- ,
A compound (XXXIg) in which D is a nitrogen atom and E is an oxygen atom or a sulfur atom, wherein D is a nitrogen atom and E is -NH-
Compound is a group having a (XXXIh), the compound D is a group G is C ₁ -C ₆ alkylene group having the -NH- is a nitrogen atom E (XXXIha) and D is a nitrogen atom E A compound having a group having —CO— (XXX
This is a method for producing Ii).

[0312]

Embedded image

[0313] In the above ^{formulas, R 1a, R 2a, R} 3a, R 4a,
R ⁷ , R ⁹ , G, G _a , G _b , Q, X, W and Z have the same meaning as described above.

Step F1 is a step for producing a compound (XXXIf) in an inert solvent in the presence or absence (preferably in the presence) of a base in the presence of a compound of the formula (XXXXXXII)
Or an acid addition salt thereof (preferably a hydrochloride) with a compound (X
This step is carried out by reacting with (III) or (XIV), and this step is carried out in the same manner as the above-mentioned Method B, Step B6.

Step F2 is a step of producing compound (XXXIg) in an inert solvent in the presence or absence (preferably in the presence) of a base in the presence of a compound of the formula (XXXXXXIII).
Is carried out by reacting a compound having the following formula with compound (XXII). This step is carried out in the same manner as in the above-mentioned Method B, Step B4.

Step F3 is a step of separately producing compound (XXXIg), which is carried out in an inert solvent in the presence of an organic base (preferably triethylamine) in the presence of a compound of the formula (XXXXXX)
This step is carried out by reacting the compound having (IV) with the compound (XXIV). This step is carried out in the same manner as in the above-mentioned Method B, Step B3.

Step F4 is a step of producing compound (XXXIh). Compound (XXXII) is converted to compound (XXII) in an inert solvent in the presence or absence (preferably in the presence) of a base. This step is performed in the same manner as the above-mentioned Method A, Step A1.

Step F5 is a step of producing a compound having the general formula (XXXXV). In an inert solvent, compound (XIVa) is converted to compound (XXXXII) or an acid addition salt thereof (eg, hydrochloride, nitrate, (A mineral salt such as a sulfate), for example, a method of heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or a condensation using a Lewis acid such as titanium tetrachloride. This step is performed according to Method B
This is performed in the same manner as in one step.

Step F6 is a step of producing compound (XXXIha), which is carried out by reducing compound (XXXV). This step is carried out in the same manner as in Method C, step C6.

Step F7 is a process for producing a compound having the compound (XXXIi), and converting the compound having the general formula (XXXXXX) into a compound (XXXX) in an inert solvent.
IV) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate, sulfate).
This step is performed in the same manner as in the B method step B1.

After completion of the reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Further, starting compounds (V), (VIII) and
(X) and (XI) are represented by the following general formula (XXXXVII)

[0323]

Embedded image

[Wherein R ^2a , R ^3a , R ^4a and Z are
R ^9a has the same meaning as described above, and R ^9a is the same as the group in the definition of the group of R ⁹ , in which the amino group which may be protected and which is included in the definition of R ⁹ is an amino group, R ^10, when the broken line represents a single bond, a halogen atom,
Group (wherein, X is. Showing the same meanings as defined above) with an azide or -XH indicates, if the broken line represents a double bond, an oxygen atom. With a compound (I)
It can be produced by reacting with compound (III) in the same manner as in the method described in the above-mentioned Method A, instead of using I).

Further, the starting compounds (XX), (XXI) and (XXIII) are represented by the following general formula (XXXXVIII)

[0326]

Embedded image

[In the above formula, R ^2a , R ^3a , R ^4a , R ^9a and Z have the same meanings as described above, and R ¹¹ is a hydrogen atom, an amino group or a group having -XH (the above formula) In the formula, X represents the same meaning as described above.) ] In place of compound (II) and reacting with compound (III) in the same manner as described in the above-mentioned Method A.

Method G is a method for producing compound (XXXII).

[0329]

Embedded image

In the above formula, R ^2a , R ^3a , R ^4a , R ⁹ , W and Z have the same meanings as described above, and R ^2b is a phenyl group or a substituent group a ′ (substituent group a ′ 'Is an amino and / or hydroxy group included in the definition of the group of the substituent group a,
It is an amino and / or hydroxy group which may be protected, and has the same meaning as the group included in the definition of the group of the substituent group a. ) Represents a phenyl group substituted with 1 to 3 groups selected from R), and R ¹² represents a lower alkyl group.

Step G1 is a step for producing a compound (XXXII), wherein the compound having the general formula (IL) is
In an inert solvent (preferably hexane, cyclohexane,
Hydrocarbons such as benzene, toluene and xylene),
Compound having general formula (L) and -20 ° C to 200 ° C
(Preferably 0 ° C. to 150 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

The step G2 is a step of separately preparing the compound (XXXII). The compound having the general formula (LI) is dissolved in an inert solvent (preferably hexane, cyclohexane, benzene, toluene, xylene or the like). Hydrocarbons or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether), bases (preferably n-butyl lithium, t-butyl lithium, phenyl lithium, etc.) A compound having the general formula (LII) in the presence of an organolithium);
150 ° C to 50 ° C (preferably -100 ° C to 0 ° C)
For 15 minutes to 24 hours (preferably 30 minutes to 16 hours)
Time) to carry out the reaction. The reaction can be carried out in the presence of an organic amine or the like (preferably N, N, N ', N'-tetramethylethylenediamine) in order to supplement the acid generated with the progress of the reaction.

Step G3 is a step for producing a compound having the general formula (XXXIIa),
In an inert solvent (preferably, hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene) with a compound having the general formula (LIII) at -20 ° C.
The reaction is performed at a temperature of 200 to 200 ° C. (preferably 0 ° C. to 150 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 20 hours).

The compound (IL) is dissolved in an inert solvent (preferably, halogen hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, and sulfoxides such as dimethyl sulfoxide). LI
II) and Lewis acids (preferably aluminum chloride,
It is also carried out by condensation with zinc chloride),
20 ° C to 200 ° C (preferably 50 ° C to 150 ° C)
For 15 minutes to 24 hours (preferably 30 minutes to 16 hours)
Time) to carry out the reaction.

After completion of the reaction, the target compound of each step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Starting compounds (III), (IV) and (V
I), (IX), (XIII), (XIV), (X
V), (XIX), (XXII), (XXIV), (X
XIVa), (XXVI), (XXIX), (XXXI)
V), (XXXV), (XXXXII), (XXXXI)
II), (XXXXXXIV), (XXXXVI), (I
L), (L), (LI), (LII) and (LIII)
Is readily produced according to known or known methods or methods analogous thereto. [For example, J. Org. Chem., 56, 1
445-1453 (1991), Organic Reaction, vol. 5, 301-330.
(1949), Acta. Chim. Acad. Humg., 34, 75-76 (1962)
Chem. Ber., 28, 1625 (1895), Chem. Abstr., 71, 12
3951j (1969) and the like].

The HMG-CoA reductase inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, is disclosed in JP-A-57-22
No. 40 (US Pat. No. 4,346,227), JP-A-57-163.
No. 374 (US Pat. No. 4,231,938), JP-A-56-12.
No. 2375 (US Pat. No. 4,444,784), Tokuyo Sho 60-5
00015 (US Pat. No. 4,739,073);
No. 16974 (US Pat. No. 5,006,530);
No. 8967 (US Pat. No. 5,273,995);
No. 9866 (US Pat. Nos. 5,854,259 and 5,856)
336) or JP-A-5-178841 (USP 526).
According to the method described in (0440), it can be easily produced.

The pharmaceutical composition of the present invention comprising a cyclobutene derivative having the above general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, and an HMG-CoA reductase inhibitor is excellent. Has a lipid-lowering effect, and also has an excellent progression-inhibiting effect on arteriosclerosis in the aorta, has an excellent onset suppression effect on xanthomas that develop in the limb joints, and has low toxicity, It is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for hyperlipidemia, arteriosclerosis or xanthoma in warm-blooded animals (particularly humans). still,
The cyclobutene derivative of the present invention having the above general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, and the HMG-CoA reductase inhibitor are each used in combination with each other. It shows superior effects as compared to the case where it is administered as a single agent.

The cyclobutene derivative having the above general formula (I), its pharmacologically acceptable salt, its ester or other derivative, which is an active ingredient of the pharmaceutical composition of the present invention, and the HMG-CoA reductase inhibitor, Each of them can be prepared alone or in separate unit dosage forms or mixed together to form a physically single unit dosage form.

When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for the above-mentioned diseases, the cyclobutene derivative having the above general formula (I), which is an active ingredient of the pharmaceutical composition of the present invention, and its pharmacology Mixing the above acceptable salts, esters or other derivatives thereof, and the HMG-CoA reductase inhibitor with itself or an appropriate pharmacologically acceptable excipient, diluent, etc., for example, It can be administered orally by tablets, capsules, granules, powders or syrups or parenterally by injections or suppositories.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; corn starch, potato starch,
α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives can be mentioned.) Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, , Low-substituted hydroxypropyl Cellulose derivatives such as loin, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked sodium carboxymethylcellulose; and chemically modified starch celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (e.g., commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

Administration of a cyclobutene derivative having the above general formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof, and an HMG-CoA reductase inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention. The amount and dosage ratio can vary depending on various conditions such as the activity of the individual drug, the condition, age, and weight of the patient.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 per each.
mg (preferably 0.5mg), upper limit 1000mg (preferably 5
00 mg), for parenteral administration, a lower limit of 0.01 mg (preferably 0.05 mg) and an upper limit of 100 mg (preferably 50 mg) per adult is 1 to 6 per day.
It can be administered simultaneously or separately at intervals depending on the condition.

The HMG-CoA reductase inhibitor is more effective in preventing or treating arteriosclerosis in the present invention than in the dose as an antihyperlipidemic agent, which is an essential use.
Those doses may be lower and the general formula (I)
The dose can be further reduced due to the excellent effect of the combined use of a cyclobutene derivative having the following formula, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof.

Further, a cyclobutene derivative having the above general formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof, which is an active ingredient of the pharmaceutical composition of the present invention, and an HMG-CoA reductase inhibitor Can also vary greatly, for example, a cyclobutene derivative having the above general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, and HM
The dose ratio of the G-CoA reductase inhibitor is expressed by weight,
It can be in the range of 1: 500 to 500: 1.

[0346]

EXAMPLES The present invention will be described in more detail below with reference to Production Examples, Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

Note that Ac and Et shown below have the same meanings as described above.

Production Example 1 3-Amino-4- [3- (phenyl-((R) -1-F
Enylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-4)
50) (1a) N-[(3-nitrophenyl) -phenylmethyl
3] -N-[(R) -1-phenylethyl] amine 3-nitrobenzophenone and 3.4 ml of (R) -1-phenylethylamine in 60 ml of anhydrous dichloromethane.
And 7.3 ml of triethylamine was added. The reaction solution was ice-cooled, and a solution of 1.74 ml of titanium tetrachloride in 17 ml of anhydrous dichloromethane was slowly added dropwise, followed by stirring at room temperature for 2 hours. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain 5.41 g of an imine compound as a dark brown oil. The obtained oil was dissolved in 100 ml of ethanol, 3.3 g of sodium cyanoborohydride and 1.1 ml of acetic acid were added, and the mixture was heated under reflux for 1.5 hours. The solvent of the reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 19/1)
Pressure chromatography using a gel and a rover column (elution solvent: cyclohexane / ethyl acetate = 19/1)
And 1.43 g of the title compound isomer (A) was obtained as a yellow oil, and 1.12 g of isomer (B) was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J = 6.8H)
z), 3.62 (1H, q, J = 6.8Hz), 4.72 (1H, s), 7.18-7.40 (1
0H, m), 7.48 (1H, t, J = 8.0Hz), 7.69 (1H, d, J = 7.6H
z), 8.10 (1H, dd, J = 2.0, 8.0Hz), 8.27 (1H, d, J = 2.0H
z). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J = 6.6H)
z), 3.69 (1H, q, J = 6.6Hz), 4.69 (1H, s), 7.24-7.40 (1
1H, m), 7.59 (1H, d, J = 8.0Hz), 8.02 (1H, dd, J = 2.0,
8.0Hz), 8.24 (1H, d, J = 1.7Hz).

(1b) 3- [phenyl-((R) -1-
Phenylethylamino) methyl] phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
[(R) -1-phenylethyl] amine isomer (A)
1.43 g was dissolved in methanol 30 ml, and nickel chloride hexahydrate 2.04 g was added. Under ice cooling, 650 mg of sodium borohydride was added in small portions, and the mixture was stirred for 30 minutes. Acetone was added to the reaction solution, and after stirring for 20 minutes, the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the residue, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 3/1) to obtain 1.24 g of the isomer (A) of the title compound as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.72 (1H, q, J = 6.6Hz), 4.53 (1H, s), 6.57 (1H, d
d, J = 2.5, 8.1Hz), 6.67 (1H, d, J = 2.0Hz), 6.71 (1H,
d, J = 7.7Hz), 7.10 (1H, t, J = 7.7Hz), 7.13-7.35 (10H,
m). N-[(3-nitrophenyl) -phenylmethyl] -N
1.71 g of the isomer (B) of-((R) -1-phenylethyl) amine was dissolved in 30 ml of methanol, and 2.42 g of nickel chloride hexahydrate and 772 mg of sodium borohydride were used for the production example (1b). ) Isomer (A)
Was carried out in the same manner as in the production of the above compound to obtain 1.41 g of the title compound isomer (B) as a yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.65 (1H, q, J = 6.7Hz), 4.53 (1H, s), 6.50 (1H, d
d, J = 2.0, 8.0Hz), 6.62 (1H, d, J = 1.7Hz), 6.66 (1H,
d, J = 7.7Hz), 7.03 (1H, t, J = 8.4Hz), 7.21-7.35 (10H,
m).

(1c) 3-methoxy-4- [3- (Fe
Nyl-((R) -1-phenylethylamino) methyl)
1.24 g of isomer (A) of phenylamino] -3-cyclobutene-1,2-dione 3- [phenyl-((R) -1-phenylethylamino) methyl] phenylamine
Is dissolved in 30 ml of methanol and 3,4-dimethoxy-
1.17 g of 3-cyclobutene-1,2-dione were added at room temperature. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1/1) to obtain 1.21 g of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.6H)
z), 3.67 (1H, q, J = 6.6Hz), 4.41 (3H, s), 4.63 (1H,
s), 7.13-7.36 (14H, m). 1.41 g of isomer (B) of 3- [phenyl-((R) -1-phenylethylamino) methyl] phenylamine.
Is dissolved in 30 ml of methanol and 3,4-dimethoxy-
796 mg of 3-cyclobutene-1,2-dione was added,
The reaction was carried out in the same manner as in the method of producing isomer (A) of Production Example (1c), to obtain 1.21 g of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 4.41 (3H, s), 4.61 (1H,
s), 7.08 (1H, d, J = 7.6Hz), 7.22-7.37 (13H, m).

(1d) 3-amino-4- [3- (phenyl
-((R) -1-phenylethylamino) methyl)
Enylamino] -3-cyclobutene-1,2-dione 3-methoxy-4- [3- (phenyl-((R) -1-
Phenylethylamino) methyl) phenylamino] -3
-Isomer of cyclobutene-1,2-dione (A) 1.2
1 g was dissolved in 25 ml of ethanol, 12 ml of a 2N ammonia-ethanol solution was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent of the reaction solution under reduced pressure, the precipitated solid was suspended in ethyl acetate and collected by filtration to obtain 574 mg of isomer (A) of the title compound as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.31 (3H, d, J = 6.6)
Hz), 3.57 (1H, q, J = 6.5Hz), 4.49 (1H, s), 6.98 (1H,
d, J = 7.5 Hz), 7.15-7.43 (13H, m). Melting point: 189-191 ° C. Optical rotation: [α] _D = −0.61 (c = 1.0, Et
OH) 3-methoxy-4- [3- (phenyl-((R) -1-
Phenylethylamino) methyl) phenylamino] -3
-Isomer of cyclobutene-1,2-dione (B) 1.4
3 g was dissolved in 30 ml of ethanol, 15 ml of a 2 N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in the method of producing isomer (A) of Production Example (1d) to give isomer (B) of the title compound. 546 mg were obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.7)
Hz), 3.51 (1H, q, J = 6.5Hz), 4.46 (1H, s), 6.91 (1H,
d, J = 7.8 Hz), 7.18-7.35 (13H, m). Melting point: 196-198 ° C. Optical rotation: [α] _D = + 10.3 (c = 1.0, Et
OH).

Production Example 2 3-Amino-4- [3- (phenyl-((S) -1-F
Enylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-4)
50) A reaction was performed using 3-nitrobenzophenone and (S) -1-phenylethylamine in the same manner as in Production Example 1, and the mixture was purified to give 461 mg of the isomer (A) and 431 mg of isomer (B) of the title compound. Obtained. Isomer (A) Melting point: 177 ° C. (dec) Optical rotation: [α] _D = + 1.0 (c = 1.0, EtO
H) Isomer (B) Melting point: 165 ° C. (dec) Optical rotation: [α] _D = −9.9 (c = 1.0, EtO)
H).

Production Example 3 3-amino-4- [3-((4-methoxyphenyl)-
(3-phenylpropylamino) methyl) phenylamido
No] -3-cyclobutene-1,2-dione (exemplary compound
No. 2-556) (3a) N-[(4-methoxyphenyl)-(3- nitro)
Lophenyl) methyl] -N- (3-phenylpropyl)
Amine 3-nitro-4'-methoxybenzophenone 2 g and 3-
Dissolve 2.22 ml of phenylpropylamine in 20 ml of anhydrous dichloromethane and 4.33 ml of triethylamine.
Was added. The reaction solution was cooled on ice, and titanium tetrachloride (1.03 ml) was added.
Then, a 10 ml diluted solution of anhydrous dichloromethane was slowly added dropwise, followed by stirring at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the imine compound as a dark brown oil.
26 g were obtained.

The obtained oil was dissolved in ethanol (60 ml), sodium cyanoborohydride (1.96 g) and acetic acid (0.67 ml) were added, and the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a pale yellow oil. 2.79 g was obtained as a product. NMR spectrum (CDCl ₃ ) δ ppm: 1.82-1.89 (2H, m),
2.53-2.70 (4H, m), 3.78 (3H, s), 4.84 (1H, s), 6.83-
6.86 (2H, m), 7.15-7.18 (3H, m), 7.24-7.28 (4H, m),
7.44 (1H, t, J = 8.0Hz), 7.72 (1H, d, J = 7.5Hz), 8.05 (1
H, d, J = 7.9Hz), 8.29 (1H, d, J = 1.9Hz).

(3b) 3-[(4-methoxyphenyl)-
(3-phenylpropylamino) methyl] phenylamido
Emissions N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl]-N-(3-phenylpropyl) amine 2.79g was dissolved in methanol 60 ml, nickel chloride hexahydrate 3.52g and hydrogen Sodium borohydride
The reaction was carried out in the same manner as in Production Example (1b) using 12 g to obtain 2.02 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.79-1.87 (2H, m),
2.57-2.71 (4H, m), 3.77 (3H, s), 4.66 (1H, s), 6.52 (1
H, d, J = 8.1Hz), 6.71 (1H, d, J = 7.8Hz), 6.76 (1H, d,
J = 7.8Hz), 6.80-6.84 (2H, m), 7.07 (1H, t, J = 7.7Hz),
7.15-7.18 (3H, m), 7.24-7.30 (4H, m).

(3c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(3-phenylpropylamido
No) methyl) phenylamino] -3-cyclobutene-
2.02 g of 1,2-dione 3-[(4-methoxyphenyl)-(3-phenylpropylamino) methyl] phenylamine was dissolved in 40 ml of methanol, and 3,4-dimethoxy-3-cyclobutene-1,2- 867 mg of dione was added and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.82 g of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.84-1.89 (2H, m),
2.58-2.68 (4H, m), 3.77 (3H, s), 4.44 (3H, s), 4.77 (1
H, br.s), 6.84 (2H, d, J = 8.5Hz), 7.09-7.29 (11H,
m).

(3d) 3-amino-4- [3-((4-
Methoxyphenyl)-(3-phenylpropylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(3-Phenylpropylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 1.82 g
Then, 8 ml of a 2 N ammonia-ethanol solution was added thereto, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 1.58 g of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.72-1.79 (2H, m),
2.50-2.51 (2H, m), 2.61 (2H, t, J = 7.7Hz), 3.70 (3H,
s), 4.70 (1H, br.s), 6.84 (2H, d, J = 8.6Hz), 7.03 (1H, br.s)
d, J = 7.6 Hz), 7.12-7.40 (10H, m). Melting point: 178-180 ° C.

Production Example 4 3-amino-4- [3-((4-methoxyphenyl)-
(2-phenylethylamino) methyl) phenylamido
No] -3-cyclobutene-1,2-dione (exemplary compound
No. 2-553) (4a) N-[(4-methoxyphenyl)-(3- nitro)
L-phenyl) methyl] -N- (2-phenylethyl) a
2 g of min 3-nitro-4'-methoxybenzophenone and 2-
1.97 ml of phenylethylamine was dissolved in 20 ml of anhydrous dichloromethane, and 4.33 ml of triethylamine was added. The reaction solution was ice-cooled, a solution of titanium tetrachloride (1.03 ml) in anhydrous dichloromethane (10 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the imine compound as an orange oil.
91 g were obtained. The obtained oil was dissolved in 60 ml of ethanol, and 1.96 g of sodium borohydride cyanide and 0.67 ml of acetic acid were added to carry out a reaction in the same manner as in Production Example (1a). 70 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.75-2.90 (4H, m),
3.77 (3H, s), 4.86 (1H, s), 5.82 (2H, d, J = 8.7Hz), 7.
15-7.45 (8H, m), 7.68 (1H, d, J = 7.7Hz), 8.04 (1H, dd,
J = 2.0, 8.0Hz), 8.26 (1H, t, J = 2.0Hz).

(4b) 3-[(4-methoxyphenyl)
-(2-phenylethylamino) methyl] phenylamido
1. N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- (2-phenylethyl) amine
70 g was dissolved in methanol 60 ml, and nickel chloride 6
3.52 g of hydrate and sodium borohydride 1.1
The reaction was carried out in the same manner as in Production Example (1b) using 2 g to obtain 1.74 g of the title compound as a colorless transparent oil. NMR spectrum (CDCl ₃ ) δ ppm: 2.80-2.86 (4H, m),
3.76 (3H, s), 4.68 (1H, s), 6.51 (1H, dd, J = 3.1, 8.1H
z), 6.65 (1H, s), 6.71 (1H, d, J = 7.9Hz), 6.80 (2H, d,
J = 8.7Hz), 7.05 (1H, t, J = 7.6Hz), 7.15-7.40 (7H,
m).

(4c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(2-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
- dione 3 - a - [(4-methoxyphenyl) (2-phenyl-ethylamino) methyl] phenylamine 1.74g were dissolved in methanol 40 ml, 3,4-dimethoxy-3-cyclobutene-776mg In addition, the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.88 g of the title compound as a yellow foam. NMR spectrum _{(CDCl 3) δppm: 2.70-3.00 (} 4H, m),
3.75 (3H, s), 4.42 (3H, s), 4.46 (1H, s), 6.70-7.35 (1
3H, m).

(4d) 3-amino-4- [3-((4-
Methoxyphenyl)-(2-phenylethylamino) meth
Tyl) phenylamino] -3-cyclobutene-1,2-
Dione 3-methoxy-4- [3-((4-methoxyphenyl)
8.4 ml of a 2N ammonia-ethanol solution was added to 1.88 g of-(2-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1d) to obtain 1.66 g of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.60-2.85 (4H, m),
3.70 (3H, s), 4.78 (1H, s), 6.84 (2H, d, J = 8.6Hz), 7.
00-7.45 (11H, m). Melting point: 174-176 ° C.

Production Example 5 3-amino-4- [3-((4-methoxyphenyl)-
(2-phenylpropylamino) methyl) phenylamido
No] -3-cyclobutene-1,2-dione (exemplary compound
No. 2-557) (5a) N-[(4-methoxyphenyl)-(3- nitro)
Lophenyl) methyl] -N- (2-phenylpropyl)
Dissolve 2.0 g of the amine 3-nitro-4'-methoxybenzophenone and 2.27 ml of 2-phenylpropylamine in 20 ml of anhydrous dichloromethane and obtain 4.33 of triethylamine.
ml was added. The reaction solution was cooled on ice, and titanium tetrachloride was added in an amount of 1.03.
After slowly adding dropwise 10 ml of a diluted solution of 10 ml of anhydrous dichloromethane, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain an imine compound. The obtained oil was dissolved in 60 ml of ethanol, and 1.96 g of sodium borohydride cyanide and 0.67 ml of acetic acid were added. The reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil. 17 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.25-1.27 (3H, m),
2.66-2.79 (2H, m), 2.93-2.98 (1H, m), 3.76 (3H, s),
4.78 and 4.80 (total 1H, each s), 6.78-6.83 (2H, m),
7.14-7.44 (8H, m), 7.61 and 7.67 (total 1H, each d,
J = 7.9Hz), 8.01-8.05 (1H, m), 8.18 and 8.24 (total 1
H, each d, J = 1.8, 1.9Hz).

(5b) 3-[(4-methoxyphenyl)-
(2-phenylpropylamino) methyl] phenylamido
Emissions N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl]-N-(2-phenylpropyl) amine 3.17g was dissolved in methanol 60 ml, nickel chloride hexahydrate 3.7g and hydrogen Sodium borohydride
The reaction was carried out in the same manner as in Production Example (1b) using 18 g, to give 2.52 g of the title compound as a purple transparent oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.24 (3H, d, J = 7.2H)
z), 2.71-2.74 (2H, m), 2.92-2.97 (1H, m), 3.75 (3H,
s), 4.62 (1H, s), 6.48-6.81 (5H, m), 7.00-7.05 (1H,
m), 7.15-7.31 (7H, m).

(5c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(2-phenylpropylamido)
No) methyl) phenylamino] -3-cyclobutene-
2.52 g of 1,2-dione 3-[(4-methoxyphenyl)-(2-phenylpropylamino) methyl] phenylamine was dissolved in 25 ml of methanol, and 3,4-dimethoxy-3-cyclobutene-1,2- 1.09 g of dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.35 g of the title compound as a pink foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.25 (3H, d, J = 7.3H)
z), 2.69-2.79 (2H, br), 2.94-3.02 (1H, br), 3.75 (3H,
s), 4.42 (3H, s), 4.73 (1H, br.s), 6.78-6.82 (2H, m),
7.00-7.34 (11H, m).

(5d) 3-amino-4- [3-((4-
Methoxyphenyl)-(2-phenylpropylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(2-phenylpropylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 2.35 g
Was added thereto and reacted in the same manner as in Production Example (1d) to obtain 1.87 g of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.21 (3H, d, J = 6.9)
Hz), 2.54-2.65 (2H, m), 2.88-2.95 (1H, m), 3.686 and
3.694 (total 3H, each s), 4.69 and 4.70 (total 1H, e
ach s), 6.82 (2H, t, J = 8.5Hz), 6.95-7.01 (1H, m), 7.
14-7.39 (10H, m). Melting point: 192-194 ° C.

Production Example 6 3-amino-4- [3-((4-methoxyphenyl)-
(3,3-diphenylpropylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione (example
( Compound No. 2-564) (6a) N-[(4-methoxyphenyl)-(3- nitro)
Rophenyl) methyl] -N- (3,3-diphenylpro
Pill) amine 3-nitro-4'-methoxybenzophenone 2 g and 3,
Dissolve 2.09 ml of 3-diphenylpropylamine in 20 ml of anhydrous dichloromethane and obtain 4.3 of triethylamine.
3 ml was added. The reaction solution was ice-cooled, and titanium tetrachloride 1.0
After slowly dropping a 10 ml diluted solution of 3 ml of anhydrous dichloromethane, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 3.62 g of an imine compound as a brown oil. 60 ml of the obtained oil is ethanol
And 1.96 g of sodium cyanoborohydride
And 0.67 ml of acetic acid were added, and the reaction was carried out in the same manner as in Production Example (1a). The title compound was converted into an orange oily substance by 3.5.
3 g were obtained. NMR spectrum _{(CDCl 3) δppm: 2.27 (} 2H, q, J = 7.5H
z), 2.45-2.65 (2H, m), 3.77 (3H, s), 4.06 (1H, t, J =
7.5Hz), 4.76 (1H, s), 6.82 (2H, d, J = 8.6Hz), 7.10-7.
35 (12H, m), 7.39 (1H, t, J = 8.0Hz), 7.63 (1H, d, J = 7.
5Hz), 8.00-8.05 (1H, m), 8.23 (1H, t, J = 1.6Hz).

(6b) 3-[(4-methoxyphenyl)-
(3,3-diphenylpropylamino) methyl] phenyl
Dissolve 3.53 g of L- amine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- (3,3-diphenylpropyl) amine in 70 ml of ethanol and 3.71 g of nickel chloride hexahydrate And 1.18 g of sodium borohydride were reacted in the same manner as in Production Example (1b) to obtain 2.67 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 2.25 (2H, q, J = 7.5H
z), 2.50-2.60 (2H, m), 3.76 (3H, s), 4.05 (1H, t, J =
7.5Hz), 4.59 (1H, s), 6.62 (1H, t, J = 1.5Hz), 6.48-6.
51 (1H, m), 6.68 (1H, d, J = 7.7Hz), 6.79 (2H, d, J = 8.7
Hz), 7.03 (1H, t, J = 7.8Hz), 7.10-7.35 (12H, m).

(6c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(3,3-diphenylpropyl
Amino) methyl) phenylamino] -3-cyclobutene
1.99 g of 1,2-dione 3-[(4-methoxyphenyl)-(3,3-diphenylpropylamino) methyl] phenylamine was dissolved in 40 ml of methanol, and 3,4-dimethoxy-3 was dissolved.
-Cyclobutene-1,2-dione (701 mg) was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.86 g of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 2.35-2.45 (2H, m),
2.60-2.70 (2H, m), 3.76 (3H, s), 4.02 (1H, t, J = 7.7H
z), 4.41 (3H, s), 4.80 (1H, s), 6.82 (2H, d, J = 8.6H
z), 7.00-7.40 (16H, m).

(6d) 3-amino-4- [3-((4-
Methoxyphenyl)-(3,3-diphenylpropyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(3,3-diphenylpropylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione
7 ml of a 2N ammonia-ethanol solution was added to 86 g, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 1.36 g of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.10-2.70 (4H, m),
3.70 (3H, s), 4.09 (1H, t, J = 7.6Hz), 4.70 (1H, br),
6.70-7.50 (18H, m). Melting point: 132-134 ° C.

Production Example 7 3-amino-4- [3-((4-methoxyphenyl)-
(2,2-diphenylethylamino) methyl] phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound No. 2-560) (7a) N-[(4-methoxyphenyl)-(3- nitro)
Rophenyl) methyl] -N- (2,2-diphenylethyl
L) Amine 3-nitro-4'-methoxybenzophenone (1.5 g) and 2,2-diphenylethylamine (2.29 g ) were dissolved in anhydrous dichloromethane (15 ml), and triethylamine (3.2) was dissolved.
2 ml was added. The reaction solution was cooled on ice and titanium tetrachloride 0.7
After slowly adding a 10 ml diluted solution of 7 ml of anhydrous dichloromethane, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3.82 g of an imine compound as an orange oil.

The obtained oil was dissolved in ethanol (60 ml), and sodium cyanoborohydride (1.46 g) and acetic acid (0.5 ml) were added. The reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil. 2.54 g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.19-3.24 (2H, m),
3.76 (3H, s), 4.22 (1H, t, J = 7.5Hz), 4.87 (1H, s), 6.
81 (2H, d, J = 8.7Hz), 7.17-7.30 (12H, m), 7.41 (1H, t,
J = 8.0Hz), 7.64 (1H, d, J = 7.5Hz), 8.03 (1H, d, J = 7.9
Hz), 8.22 (1H, d, J = 1.9Hz).

(7b) 3-[(4-methoxyphenyl)-
(2,2-diphenylethylamino) methyl] phenyl
2.54 g of amine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- (2,2-diphenylethyl) amine was dissolved in 50 ml of methanol, and 2.76 g of nickel chloride hexahydrate was dissolved. The reaction was carried out in the same manner as in Production Example (1b) using 878 mg of sodium borohydride and 2.02 g of the title compound as a colorless transparent oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.18 (2H, d, J = 7.8H)
z), 3.75 (3H, s), 4.21 (1H, t, J = 7.8Hz), 4.69 (1H,
s), 6.50 (1H, d, J = 7.0Hz), 6.58-6.59 (1H, m), 6.67 (1
H, d, J = 7.5Hz), 6.78 (2H, d, J = 8.7Hz), 7.03 (1H, t,
J = 7.7Hz), 7.15-7.29 (12H, m).

(7c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(2,2-diphenylethyla
Mino) methyl) phenylamino] -3-cyclobutene-
2.02 g of 1,2-dione 3-[(4-methoxyphenyl)-(2,2-diphenylethylamino) methyl] phenylamine was dissolved in 40 ml of methanol, and 3,4-dimethoxy-3-
731 mg of cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.35 g of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 3.12-3.17 (1H, m),
3.21-3.26 (1H, m), 3.76 (3H, s), 4.19 (1H, t, J = 7.5H
z), 4.38 (3H, s), 4.79 (1H, s), 6.80 (2H, d, J = 8.7H
z), 7.07-7.29 (16H, m).

(7d) 3-amino-4- [3-((4-
Methoxyphenyl)-(2,2-diphenylethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(2,2-diphenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 1.3
5.2 ml of 2N ammonia-ethanol solution was added to 5 g, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 1.36 g of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.07 (2H, d, J = 6.9)
Hz), 3.69 (3H, s), 4.22 (1H, t, J = 6.9Hz), 4.79 (1H, b
rs), 6.82 (2H, d, J = 8.5Hz), 6.98 (1H, d, J = 7.7Hz),
7.14-7.28 (14H, m), 7.36 (1H, d, J = 7.9 Hz). Melting point: 193-196 ° C.

Production Example 8 3-amino-4- [3-((4-methoxyphenyl)-
(2- (3-fluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-814) (8a) N-[(4-methoxyphenyl)-(3- nitro)
L-phenyl) methyl] -N- [2- (3-fluorophene
Nyl) ethyl] amine 2.0 g of 3-nitro-4'-methoxybenzophenone and 2.04 m of 2- (3-fluorophenyl) ethylamine
was dissolved in 20 ml of anhydrous dichloromethane, and 4.33 ml of triethylamine was added. The reaction solution was ice-cooled, a solution of titanium tetrachloride (1.03 ml) in anhydrous dichloromethane (10 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution,
The precipitated insoluble matter was removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 2.76 g of an imine compound as an orange oil. The obtained oil was dissolved in 60 ml of ethanol, and 1.96 g of sodium borohydride cyanide and 0.67 ml of acetic acid were added. The reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil. 51 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.78-2.88 (4H, m),
3.77 (3H, s), 4.85 (1H, s), 6.82-6.97 (5H, m), 7.21-
7.26 (3H, m), 7.43 (1H, t, J = 7.8Hz), 7.68 (1H, d, J = 7.
8Hz), 8.05 (1H, d, J = 8.0Hz), 8.25-8.26 (1H, m).

[0376] (8b) 3 - [(4- methoxyphenyl)
-(2- (3-fluorophenyl) ethylamino) methyl
Le] phenylamine N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl]-N-[2-(3-fluorophenyl) ethyl] amine 2.51g was dissolved in methanol 50 ml, nickel chloride 6 The reaction was carried out in the same manner as in Production Example (1b) using 3.14 g of hydrate and 1.0 g of sodium borohydride, and 1.94 g of the title compound was obtained as a yellow oil.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.79-2.85 (4H, m),
3.77 (3H, s), 4.67 (1H, s), 6.51 (1H, d, J = 8.2Hz), 6.
66 (1H, d, J = 1.9Hz), 6.72 (1H, d, J = 7.4Hz), 6.81 (2H,
d, J = 8.7Hz), 6.89 (2H, d, J = 8.9Hz), 6.96 (1H, d, J =
7.8Hz), 7.05 (1H, t, J = 7.7Hz), 7.19-7.26 (3H, m).

(8c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(2- (3-fluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-si
1.94 g of clobutene-1,2-dione 3-[(4-methoxyphenyl)-(2- (3-fluorophenyl) ethylamino) methyl] phenylamine was dissolved in 40 ml of methanol to give 3,4-dimethoxy-3. -Cyclobutene-1,2-dione 824 m
g, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.07 g of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 2.77-2.88 (4H, m),
3.76 (3H, s), 4.44 (3H, s), 4.78 (1H, br.s), 6.79-6.9
7 (5H, m), 7.03-7.28 (7H, m).

(8d) 3-amino-4- [3-((4-
Methoxyphenyl)-(2- (3-fluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(2- (3-Fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione (2.07 g) and 2N ammonia-ethanol solution 9
The reaction was carried out in the same manner as in Production Example (1d) to obtain 1.73 g of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.67 (2H, br.s),
2.77-2.80 (2H, m), 3.70 (3H, s), 4.76 (1H, br.s), 6.8
4 (2H, d, J = 8.5Hz), 6.96-7.03 (4H, m), 7.21-7.39 (6H,
m). Melting point: 139-141 ° C.

Production Example 9 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,5-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 2-1625) (9a) N-[(4-methoxyphenyl)-(3-nitto
Rophenyl) methyl] -N- [1- (3,5-difluoro
Phenyl) ethyl] amine 3-nitro-4′-methoxybenzophenone (1.5 g) and 1- (3,5-difluorophenyl) ethylamine hydrochloride (2.26 g) were dissolved in anhydrous dichloromethane (30 ml).
4.8 ml of triethylamine were added. The reaction solution was cooled on ice, and 0.77 ml of titanium tetrachloride in anhydrous dichloromethane 1 was added.
After slowly adding 0 ml of the diluted solution, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the imine compound as an orange oil (3.12 g). The obtained oily substance was dissolved in ethanol (60 ml), and sodium cyanoborohydride (1.46 g) and acetic acid (0.5 ml) were added. The reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil. 65 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.38 (3H, m),
3.58-3.70 (1H, m), 3.76and 3.82 (total 3H, each s),
4.63 and 4.69 (total 1H, each s), 6.65-7.93 (5H, m),
7.15-7.20 (2H, m), 7.38-7.68 (2H, m), 8.02-8.28 (2H, m
m).

(9b) 3-[(4-methoxyphenyl)
-(1- (3,5-difluorophenyl) ethylamido
(D) Methyl] phenylamine 2.65 g of N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- [1- (3,5-difluorophenyl) ethyl] amine is dissolved in 50 ml of methanol. The reaction was carried out in the same manner as in Production Example (1b) using 3.16 g of nickel chloride hexahydrate and 1.0 g of sodium borohydride to obtain 2.24 g of the title compound as a pale orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.55-3.73 (1H, m), 3.76 and 3.80 (total 3H, each
s), 4.47 (1H, s), 6.50-7.26 (11H, m).

(9c) 3-methoxy-4- [3-((4
-Methoxyphenyl)-(1- (3,5-difluorophenyl)
Enyl) ethylamino) methyl) phenylamino] -3
Dissolve 2.24 g of -cyclobutene -1,2-dione 3-[(4-methoxyphenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl] phenylamine in 20 ml of methanol to give 3,4
-Dimethoxy-3-cyclobutene-1,2-dione 95
0 mg was added, and the reaction was carried out in the same manner as in Production Example (1c).
2.2 g of the title compound were obtained as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.32-1.37 (3H, m),
3.65 (1H, q, J = 6.6Hz), 3.76 and 3.81 (total 3H, each
s), 4.44 (3H, s), 4.55 and 4.58 (total 1H, each s),
6.63-7.35 (11H, m).

(9d) 3-amino-4- [3-((4-
Methoxyphenyl)-(1- (3,5-difluorophene)
Nyl) ethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,5-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
To 2.2 g of 1,2-dione was added 9.2 ml of a 2N ammonia-ethanol solution, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 1.86 g of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26-1.31 (3H, m),
3.50-3.65 (1H, m), 3.69 and 3.73 (total 3H, each
s), 4.43 and 4.46 (total 1H, each s), 6.80-7.50 (11
H, m). Melting point: 177-181 ° C.

Production Example 10 3-amino-4- [3-((4-methoxyphenyl)-
(1- (4-pyridyl) ethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione (example
( Compound No. 2-1962) (10a) N-[(4-methoxyphenyl)-(3-ni
Trophenyl) methyl] -N- [1- (4-pyridyl) e
Tyl] amine 3-nitro-4'-methoxybenzophenone (2 g) and 1-
1.91 g of (4-pyridyl) ethylamine was dissolved in 40 ml of anhydrous dichloromethane, and 4.33 of triethylamine was dissolved.
ml was added. The reaction solution was cooled on ice, and titanium tetrachloride was added in an amount of 1.03.
After slowly adding dropwise 10 ml of a diluted solution of 10 ml of anhydrous dichloromethane, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the imine compound as an orange oil (3.13 g). The obtained oily substance was washed with ethanol 60
dissolved in 1.9 ml of sodium borohydride sodium 1.9
6 g and 0.7 ml of acetic acid were added, and the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil (2.41 g).
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.36-1.41 (3H, m),
3.58-3.72 (1H, m), 3.76and 3.81 (total 3H, each s),
4.61 and 4.66 (total 1H, each s), 6.79-6.92 (2H, m),
7.10-7.23 (4H, m), 7.40 and 7.48 (total 1H, each t,
J = 7.9Hz), 7.58and 7.64 (total 1H, each d, J = 7.9H
z), 8.02-8.13 (1H, m), 8.23-8.28 (1H, m), 8.52-8.62 (2
H, m).

(10b) 3-[(4-methoxyphenyl)
-(1- (4-pyridyl) ethylamino) methyl] phenyl
Triethanolamine N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl] -N- an [1- (4-pyridyl) ethyl] amine 2.41g was dissolved in ethanol 40 ml, nickel chloride hexahydrate 3 Using .14 g and 1.0 g of sodium borohydride, the reaction was carried out in the same manner as in Production Example (1b) to obtain 1.09 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.55-3.75 (1H, m), 3.76 and 3.80 (total 3H, each
s), 4.44 (1H, s), 6.50-7.25 (10H, m), 8.52-8.60 (2H,
m).

(10c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (4-pyridyl) e
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-[(4-methoxyphenyl)-(1- (4-pyridyl)
Ethylamino) methyl] phenylamine (1.09 g) was dissolved in methanol (20 ml) to give 3,4-dimethoxy-3-
511 mg of cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.21 g of the title compound as a yellow foam. NMR spectrum (CDCl ₃ )
δppm: 1.25-1.40 (3H, m), 3.60-3.75 (1H, m), 3.75an
d 3.80 (total 3H, each s), 4.50-4.60 (1H, m), 6.65-
8.65 (12H, m).

(10d) 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (4-pyridyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (4-pyridyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 1.2
1 g was dissolved in 10 ml of ethanol, 6 ml of a 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d) to give 1.0 g of the title compound as a yellow solid
Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.20-1.35 (3H, m),
3.50-3.62 (1H, m), 3.69 and 3.73 (total 3H, each
s), 4.41 and 4.45 (total 1H, each s), 7.15-7.45 (7H,
m), 7.80-8.00 (3H, m), 8.48-8.52 (2H, m). Melting point: 125 ° C (dec).

Production Example 11 3-amino-4- [3-((4-methoxyphenyl)-
(1- (2-thienyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound No. 2-1899) (11a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -N- [1- (2-thienyl) e
Tyl] amine 3-nitro-4'-methoxybenzophenone 1.41 g
And 1.78 g of 1- (2-thienyl) ethylamine hydrochloride were dissolved in 20 ml of anhydrous dichloromethane, and 4.6 ml of triethylamine was added. The reaction solution was ice-cooled, and a solution of 0.73 ml of titanium tetrachloride in 10 ml of anhydrous dichloromethane was slowly added dropwise, followed by stirring at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 2.35 g of an imine compound as a red oil. The obtained oil is washed with ethanol 4
0 ml of sodium borohydride sodium.
38 g and acetic acid (0.48 ml) were added, and the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil in 2.1.
1 g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.45-1.52 (3H, m),
3.76 and 3.81 (total 3H, each s), 3.87-4.01 (1H, m),
4.84 and 4.86 (total 1H, each s), 6.75-7.00 (4H, m),
7.15-7.30 (3H, m), 7.41 and 7.49 (total 1H, t, J = 8.
0Hz), 7.65 and 7.74 (total 1H, each d, J = 7.4Hz), 8.
00-8.12 (1H, m), 8.22-8.33 (1H, m).

(11b) 3-[(4-methoxyphenyl)
-(1- (2-thienyl) ethylamino) methyl] phenyl
Triethanolamine N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl] -N- an [1- (2-thienyl) ethyl] amine 2.11g was dissolved in ethanol 40 ml, nickel chloride hexahydrate 2 Using 0.71 g and 863 mg of sodium borohydride, the reaction was carried out in the same manner as in Production Example (1b) to obtain 1.66 g of the title compound as a dark brown oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (3H, d, J = 6.6H)
z), 3.75 and 3.80 (total3H, each s), 3.90-4.02 (1H,
m), 4.68 (1H, s), 6.47-7.30 (11H, m).

(11c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (2-thienyl) e
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-[(4-methoxyphenyl)-(1- (2-thienyl)
Ethylamino) methyl] phenylamine (1.66 g) was dissolved in methanol (30 ml) to give 3,4-dimethoxy-3-
767 mg of cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.97 g of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.45-1.51 (3H, m),
3.76 and 3.81 (total 3H, each s), 3.90-4.00 (1H, m),
4.44 (3H, s), 4.76 and 4.78 (total 1H, each s), 6.78
-7.35 (11H, m).

(11d) 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (2-thienyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (2-thienyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 1.9
7 g was dissolved in 40 ml of ethanol, 10 ml of a 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
9 g were obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.35-1.45 (3H, m),
3.69 and 3.73 (total 3H, each s), 3.75-3.90 (1H,
m), 4.63 and 4.66 (total 1H, each s), 6.80-7.50 (11
H, m). Melting point: 178-180 ° C.

Production Example 12 3-amino-4- [3- (phenyl- (1- (3,5-
Difluorophenyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound No. 2-1523) (12a) N - [ (3- nitrophenyl) - phenyl -
Methyl] -N- [1- (3,5-difluorophenyl) e
[ Tyl ] amine 3-nitrobenzophenone (2.0 g) and 1- (3,5-difluorophenyl) ethylamine hydrochloride (3.41 g) were dissolved in anhydrous dichloromethane (40 ml), and triethylamine (7.3 ml) was added. The reaction solution was ice-cooled, and a solution of 1.16 ml of titanium tetrachloride in 11 ml of anhydrous dichloromethane was slowly added dropwise thereto, followed by stirring at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain an imine compound. The obtained imine compound is dissolved in 60 ml of ethanol, and 2.21 g of sodium cyanoborohydride and 0.76 of acetic acid are dissolved.
The reaction mixture was separated and purified in the same manner as in Production Example (1a), and 904 mg of the title compound isomer (A) was obtained as a colorless oil, and 897 mg of the isomer (B) was obtained as a white solid.
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.63 (1H, q, J = 6.6Hz), 4.73 (1H, s), 6.65-6.80 (3
H, m), 7.20-7.35 (5H, m), 7.50 (1H, t, J = 7.8Hz), 7.6
6 (1H, d, J = 7.4Hz), 8.10-8.13 (1H, m), 8.26-8.28 (1H,
m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.67 (1H, q, J = 6.6Hz), 4.68 (1H, s), 6.65-6.85 (3
H, m), 7.20-7.45 (6H, m), 7.61 (1H, d, J = 7.4Hz), 8.0
4 (1H, dd, J = 1.8, 7.8 Hz), 8.24 (1H, br.s). Melting point: 119-121 ° C.

(12b) 3- [phenyl- (1- (3,
5-difluorophenyl) ethylamino) methyl] fe
Niruamin N - [(3- nitrophenyl) - phenylmethyl] -N-
900 mg of the isomer (A) of [1- (3,5-difluorophenyl) ethyl] amine is dissolved in 20 ml of methanol, and 1.14 g of nickel chloride hexahydrate and 363 mg of sodium borohydride are used for the production example (1b). ), And 739 mg of the title compound isomer (A) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.6H)
z), 3.70 (1H, q, J = 6.6Hz), 4.51 (1H, s), 6.55-6.87 (6
H, m), 7.07-7.40 (6H, m).

890 mg of the isomer (B) of N-[(3-nitrophenyl) -phenylmethyl] -N- [1- (3,5-difluorophenyl) ethyl] amine was added to methanol 2
0 ml, and reacted in the same manner as in Production Example (1b) using 1.14 g of nickel chloride hexahydrate and 363 mg of sodium borohydride to obtain 791 mg of the title compound isomer (B) as a colorless oil. Was. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.7H)
z), 3.64 (1H, q, J = 6.7Hz), 4.52 (1H, s), 6.50-7.35 (1
2H, m).

(12c) 3-methoxy-4- [3- (f
Enyl- (1- (3,5-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3- [phenyl- (1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamine isomer (A)
733 mg was dissolved in methanol (10 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (341 m) was dissolved.
The reaction was carried out in the same manner as in Production Example (1c) to obtain 814 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 4.43 (3H, s), 4.62 (1H,
s), 6.65-6.85 (3H, m), 7.10-7.40 (9H, m). Melting point: 155-157 ° C 3- [phenyl- (1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamine isomer (B)
785 mg was dissolved in methanol 10 ml, and 3,4-dimethoxy-3-cyclobutene-1,2-dione 355 m
g was added and the reaction was carried out in the same manner as in Production Example (1c) to obtain 888 mg of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.65 (1H, d, J = 6.6Hz), 4.43 (3H, s), 4.60 (1H,
s), 6.65-7.40 (12H, m).

(12d) 3-amino-4- [3- (Fe
Nyl- (1- (3,5-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [3- (phenyl- (1- (3,5
-Difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (A) (810 mg) was dissolved in tetrahydrofuran (5 ml), and 2N ammonia-ethanol solution (3.6 ml) was added thereto. The reaction was conducted in the same manner as in (1d) to obtain 733 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 3.61 (1H, q, J = 6.6Hz), 4.50 (1H, s), 6.95-7.45
(12H, m). Melting point: 184 ° C (dec) 3-Methoxy-4- [3- (phenyl- (1- (3,5
-Difluorophenyl) -ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (B) (880 mg) was dissolved in ethanol (5 ml).
4.0 ml of a normal ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 708 mg of the title compound isomer (B) as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.28 (3H, d, J = 6.6
Hz), 3.55 (1H, q, J = 6.6Hz), 4.49 (1H, s), 6.80-7.45
(12H, m). Melting point: 197 ° C (dec).

Production Example 13 3-Amino-4- [3-((3,4-dimethylphenyi)
)-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-533) (13a) N-[(3-nitrophenyl)-(3,4-di
Methylphenyl) methyl] -N-((S) -1-phenyl
1. ethyl) amine 3-nitro-3 ', 4'-dimethylbenzophenone
0 g and (S) -1-phenylethylamine 1.99 ml
Was dissolved in 20 ml of anhydrous dichloromethane, and 4.33 ml of triethylamine was added. The reaction solution was ice-cooled, a solution of titanium tetrachloride (1.03 ml) in anhydrous dichloromethane (10 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 2.92 g of an imine compound as a yellow oil. The obtained oil was dissolved in ethanol (60 ml), and 2.21 g of sodium borohydride cyanide and 0.76 ml of acetic acid were added thereto to prepare Production Example (1a).
The reaction was carried out in the same manner as described above, and the mixture was separated and purified to give 1.10 g of isomer (A) of the title compound as a colorless oil and 1.19 g of isomer (B) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.7H)
z), 2.20 (6H, s), 3.60 (1H, q, J = 6.7Hz), 4.65 (1H,
s), 6.97-7.37 (8H, m), 7.46 (1H, t, J = 7.9Hz), 7.69 (1H
H, d, J = 7.5Hz), 8.08 (1H, d, J = 8.0Hz), 8.26-8.28 (1
H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H)
z), 2.25 (6H, s), 3.70 (1H, q, J = 6.7Hz), 4.63 (1H,
s), 7.01-7.02 (2H, m), 7.11 (1H, d, J = 8.2Hz), 7.22-
7.38 (6H, m), 7.59 (1H, d, J = 7.4Hz), 8.01 (1H, d, J =
8.0Hz), 8.23-8.24 (1H, m).

(13b) 3-[(3,4-dimethylphene)
Nil)-((S) -1-phenylethylamino) methyl]
1.10 g of isomer (A) of phenylamine N-[(3-nitrophenyl)-(3,4-dimethylphenyl) methyl] -N-((S) -1-phenylethyl) amine is dissolved in 20 ml of methanol. Then, the reaction was carried out in the same manner as in Production Example (1b) using 1.45 g of nickel chloride hexahydrate and 469 mg of sodium borohydride to obtain 954 mg of the title compound isomer (A) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.6H)
z), 2.19 (6H, s), 3.70 (1H, q, J = 6.6Hz), 4.47 (1H,
s), 6.55 (1H, d, J = 8.2Hz), 6.68-6.69 (1H, m), 6.71 (1
H, d, J = 7.7Hz), 7.03 (1H, s), 7.09 (1H, t, J = 7.7Hz),
7.22-7.34 (7H, m). Isomer of N-[(3-nitrophenyl)-(3,4-dimethylphenyl) methyl] -N-((S) -1-phenylethyl) amine (B) 1 .19 g of methanol 20
and 1.57 g of nickel chloride hexahydrate and 500 mg of sodium borohydride.
The reaction was carried out in the same manner as in b) to obtain 849 mg of the isomer (B) of the title compound as a colorless oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.9H)
z), 2.23 (6H, s), 3.67 (1H, q, J = 6.9Hz), 4.47 (1H,
s), 6.49 (1H, d, J = 8.1Hz), 6.62-6.63 (1H, m), 6.66 (1
H, d, J = 7.6Hz), 7.00-7.09 (4H, m), 7.24-7.35 (5H,
m).

(13c) 3-methoxy-4- [3-
((3,4-dimethylphenyl)-((S) -1-phenyl
Ruethylamino) methyl) phenylamino] -3-cycl
950 mg of isomer (A) of lobutene-1,2-dione 3-[(3,4-dimethylphenyl)-((S) -1-phenylethylamino) methyl] phenylamine was dissolved in 15 ml of methanol, and
4-dimethoxy-3-cyclobutene-1,2-dione 4
30 mg was added, and the reaction was carried out in the same manner as in Production Example (1c) to give 97% of the isomer (A) of the title compound as a white foam.
6 mg were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 2.20 (6H, s), 3.65 (1H, q, J = 6.6Hz), 4.42 (3H,
s), 4.56 (1H, s), 6.98-7.04 (3H, m), 7.13-7.36 (9H,
m).

3-[(3,4-dimethylphenyl)-
((S) -1-phenylethylamino) methyl] phenylamine isomer (B) (845 mg)
1,3,4-dimethoxy-3-cyclobutene-
382 mg of 1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.04 g of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 2.25 (6H, s), 3.68 (1H, q, J = 6.6Hz), 4.42 (3H,
s), 4.55 (1H, s), 7.03-7.12 (5H, m), 7.20-7.35 (7H,
m).

(13d) 3-amino-4- [3-
((3,4-dimethylphenyl)-((S) -1-phenyl)
Ruethylamino) methyl) phenylamino] -3-cycl
Lobutene-1,2-dione 3-methoxy-4- [3-((3,4-dimethylphenyl)-((S) -1-phenylethylamino) methyl)
970 mg of isomer (A) of phenylamino] -3-cyclobutene-1,2-dione was dissolved in 10 ml of ethanol, 4.4 ml of a 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d). Thus, 604 mg of the title compound isomer (A) was obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 2.13 (3H, s), 2.14 (3H, s), 3.55 (1H, q, J = 6.6H
z), 4.42 (1H, s), 6.96 (1H, d, J = 7.6Hz), 6.99-7.03 (2
H, m), 7.08 (1H, s), 7.21-7.33 (7H, m), 7.41 (1H, d,
J = 7.9 Hz). Melting point: 182-185 ° C. 3-Methoxy-4- [3-((3,4-dimethylphenyl)-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione isomer (B) (1.04 g) was dissolved in ethanol (10 ml), 2N ammonia-ethanol solution (4.8 ml) was added, and the reaction was carried out in the same manner as in Production Example (1d). Was carried out to obtain 899 mg of an isomer (B) of the title compound as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J = 6.6)
Hz), 2.18 (3H, s), 2.19 (3H, s), 3.52 (1H, q, J = 6.6H
z), 4.39 (1H, s), 6.90 (1H, d, J = 7.6Hz), 7.03-7.08 (3
H, m), 7.17-7.33 (7H, m), 7.43 (1H, d, J = 8.0 Hz). Melting point: 222-225 ° C.

Production Example 14 3-amino-4- [2-chloro-5- (phenyl-
((S) -1-phenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione hydrochloride
(Exemplified Compound No. 2-478) (14a) N-[(4-chloro-3-nitrophenyl)
-Phenylmethyl] -N-((S) -1-phenylethyl
The reaction was carried out in the same manner as in Production Example (1a) using 2.0 g of amine 4-chloro-3-nitrobenzophenone, 1.94 ml of (S) -1-phenylethylamine, 4.2 ml of triethylamine and 1.16 ml of titanium tetrachloride. Performed to obtain an imine compound. Using the obtained imine compound, 1.91 g of sodium cyanoborohydride, and 0.65 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.89 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.43 (3H, m),
3.55-3.70 (1H, m), 4.61and 4.64 (total 1H, each s),
7.15-7.53 (12H, m), 7.88-7.95 (1H, m).

(14b) 2-chloro-3- [phenyl-
((S) -1-phenylethylamino) methyl] phenyl
Triethanolamine N - [(4-chloro-3-nitro-phenyl) - phenylmethyl] -N - ((S) -1- phenylethyl) amine 2.89 g, nickel chloride hexahydrate 3.76g and sodium borohydride Production example (1b) using 1.2 g
The reaction was carried out in the same manner as in, to obtain 2.36 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.32-1.40 (3H, m),
3.60-3.72 (1H, m), 4.49and 4.50 (total 1H, each s),
6.58-6.77 (2H, m), 7.08-7.40 (11H, m).

(14c) 3-methoxy-4- [2-chloro
B-5- (Phenyl-((S) -1-phenylethyla)
Mino) methyl) phenylamino] -3-cyclobutene-
2.36 g of 1,2-dione 2-chloro-3- [phenyl-((S) -1-phenylethylamino) methyl] phenylamine,
Using 1.05 g of 3,4-dimethoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.42 g of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.45 (3H, m),
3.65 (1H, q, J = 6.6Hz), 4.36 and 4.39 (total 3H, each
s), 4.60 and 4.61 (total 1H, each s), 7.00-7.40 (13
H, m).

(14d) 3-amino-4- [2-chloro
-5- (phenyl-((S) -1-phenylethylamido)
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione hydrochloride 3-methoxy-4- [2-chloro-5- (phenyl-
((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione 2.4
2 g was dissolved in 25 ml of ethanol, and 10.8 ml of a 2N ammonia-ethanol solution was added, to thereby prepare a production example (1d).
The reaction was carried out in the same manner as described above. The crude product obtained by concentrating the reaction solution was dissolved in 20 ml of ethyl acetate, and 5.4 ml of 4N HCl / ethyl acetate was added to generate a hydrochloride. The solid was suspended in ether and collected by filtration to obtain 2.32 g of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J = 6.3)
Hz), 4.23 and 4.40 (total 1H, each br), 5.00 and 5.
30 (total 1H, each br), 7.15-7.80 (13H, m). Melting point: 187-194 ° C.

Production Example 15 3-amino-4- [4-chloro-5- (phenyl-
((S) -1-phenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione (example
( Compound No. 2-476) (15a) N-[(2-chloro-5-nitrophenyl)
-Phenylmethyl] -N-((S) -1-phenylethyl
B) 2.0 g of amine 2-chloro-5-nitrobenzophenone, 1.94 ml of (S) -1-phenylethylamine, 4.2 ml of triethylamine and 1.0 ml of titanium tetrachloride
Was used in the same manner as in Production Example (1a) to give an imine compound. Using the obtained imine compound, 1.91 g of sodium borohydride cyanide, and 0.65 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.58 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.40-1.44 (3H, m),
3.59 and 3.75 (total 1H, each q, J = 6.6Hz), 5.07 and
5.20 (total 1H, each s), 7.15-7.50 (11H, m), 7.90-7.
95 and 8.04-8.09 (total 1H, each m), 8.57 and 8.83
(total 1H, each d, J = 2.8Hz).

(15b) 4-chloro-3- [phenyl-
((S) -1-phenylethylamino) methyl] phenyl
Triethanolamine N - [(2-chloro-5-nitrophenyl) - phenylmethyl] -N - ((S) -1- phenylethyl) amine 2.58 g, nickel chloride hexahydrate 3.33g and sodium borohydride Production Example (1) using 1.06 g
The reaction was carried out in the same manner as in b) and the mixture was separated and purified to give 771 mg of the isomer (A) of the title compound as a colorless oil and 659 mg of isomer (B) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H)
z), 3.65-3.75 (1H, m), 4.98 (1H, s), 6.53 (1H, dd, J =
2.8, 8.2Hz), 7.02 (1H, d, J = 2.9Hz), 7.06 (1H, d, J =
8.2 Hz), 7.15-7.37 (10H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.6H)
z), 3.70 (1H, q, J = 6.6Hz), 5.13 (1H, s), 6.45 (1H, d
d, J = 2.8, 8.2Hz), 6.82 (1H, d, J = 2.8Hz), 7.02 (1H,
d, J = 8.2Hz), 7.20-7.45 (10H, m).

(15c) 3-methoxy-4- [4-chloro
B-5- (Phenyl-((S) -1-phenylethyla)
Mino) methyl) phenylamino] -3-cyclobutene-
Isomer of 1,2-dione 2-chloro-3- [phenyl-((S) -1-phenylethylamino) methyl] phenylamine (A)
Production Example (1c) using 765 mg and 339 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in the above to give 800 mg of the title compound isomer (A) as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, d, J = 6.6H)
z), 3.63 (1H, q, J = 6.6Hz), 4.47 (3H, s), 5.07 (1H,
s), 7.10-7.40 (12H, m), 7.76 (1H, d, J = 2.7 Hz). Isomerism of 2-chloro-3- [phenyl-((S) -1-phenylethylamino) methyl] phenylamine Body (B)
Production Example (1c) using 654 mg and 290 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in to give 246 mg of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, d, J = 6.6H)
z), 3.69 (1H, q, J = 6.6Hz), 4.42 (3H, s), 5.19 (1H,
s), 7.00-7.42 (12H, m), 7.50 (1H, d, J = 2.8Hz).

(15d) 3-amino-4- [4-chloro
-5- (phenyl-((S) -1-phenylethylamido)
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3-methoxy-4- [4-chloro-5- (phenyl-
Using (800 mg) of the ((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (A) and 3.6 ml of a 2N ammonia-ethanol solution, Production Example (1d) ), To give 620 mg of the title compound isomer (A) as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.33 (3H, d, J = 6.6)
Hz), 3.55 (1H, q, J = 6.6Hz), 4.88 (1H, s), 7.15-7.35
(11H, m), 7.45-7.55 (1H, m), 7.85 (1H, d, J = 2.5 Hz). Melting point: 177-179 ° C.

3-Methoxy-4- [4-chloro-5-
(Phenyl-((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-
Production Example (1d) using 246 mg of the dione isomer (B) and 1.2 ml of a 2N ammonia-ethanol solution.
The reaction was carried out in the same manner as in to give 133 mg of the isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.52 (1H, q, J = 6.6Hz), 4.91 (1H, s), 7.20-7.40
(11H, m), 7.48-7.55 (1H, m), 7.66 (1H, d, J = 2.7 Hz). Melting point: 210-212 ° C.

Production Example 16 3-amino-4- [2-methoxy-5-((4-fluoro
Rophenyl)-((S) -1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 2-501) (16a) N-[(4-methoxy-3-nitrophenyl)
)-(4-fluorophenyl) methyl] -N-((S)
1-phenylethyl) amine 4-methoxy-3-nitro-4'-fluoro-benzophenone 2.0 g (S) -1-phenylethylamine 1.
The reaction was carried out in the same manner as in Production Example (1a) using 98 ml, 4.3 ml of triethylamine and 1.03 ml of titanium tetrachloride to obtain 2.96 g of an imine compound as a yellow oil.
Using the obtained imine compound, 1.96 g of sodium cyanoborohydride and 0.67 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a), and the mixture was separated and purified to give the isomer (A) of the title compound as a yellow oil. The compound (678 mg) and 1.31 g of the isomer (B) were obtained as a white solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 3.62 (1H, q, J = 6.6Hz), 3.75 (3H, m), 4.93 (1H,
s), 6.85-6.96 (3H, m), 7.15-7.37 (7H, m), 8.18 (1H, d
d, J = 2.9, 8.9 Hz), 8.54 (1 H, d, J = 2.9 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6 H)
z), 3.63 (1H, q, J = 6.6Hz), 3.77 (3H, m), 4.97 (1H,
s), 6.79 (1H, d, J = 9.1Hz), 7.00 (2H, t, J = 8.6Hz), 7.1
7-7.35 (7H, m), 8.09 (1H, dd, J = 2.9, 9.3Hz), 8.36 (1
H, d, J = 2.9Hz).

(16b) 2-methoxy-5-[(4-f
Fluorophenyl)-((S) -1-phenylethylamido
D) methyl] phenylamine N-[(4-methoxy-3-nitrophenyl)-(4-fluorophenyl) methyl] -N-((S) -1-phenylethyl) amine isomer (A) 670 mg 856 mg of nickel chloride hexahydrate and sodium borohydride 2
The reaction was carried out in the same manner as in Production Example (1b) using 72 mg,
The isomer (A) of the title compound was converted into a yellow oil (584 m).
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.56 (3H, s), 3.69 (1H, q, J = 6.6Hz), 4.78 (1H,
s), 6.58 (1H, dd, J = 2.9, 8.6Hz), 6.69-6.73 (2H, m),
6.89 (2H, t, J = 8.7Hz), 7.20-7.35 (7H, m).

N-[(4-methoxy-3-nitrophenyl)-(4-fluorophenyl) methyl] -N-((S)
1.4 g of isomer (B) of -1-phenylethyl) amine
And 1.76 g of nickel chloride hexahydrate and 560 mg of sodium borohydride were reacted in the same manner as in Production Example (1b) to obtain 844 mg of the title compound isomer (B) as a colorless oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.6H)
z), 3.58 (3H, s), 3.63 (1H, q, J = 6.6Hz), 4.94 (1H,
s), 6.49-6.65 (3H, m), 6.95-7.01 (2H, m), 7.20-7.40
(7H, m).

(16c) 3-methoxy-4- [2-metho
Xy-5-((4-fluorophenyl)-((S) -1-
Phenylethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione 2-methoxy-5-[(4-fluorophenyl)-
((S) -1-phenylethylamino) methyl] phenylamine isomer (A) 635 mg and 3,4-dimethoxy-3-cyclobutene-1,2-dione 254 mg
Was used in the same manner as in Production Example (1c) to give 635 mg of the title compound isomer (A) as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.60-3.70 (1H, m), 3.66 (3H, s), 4.42 (3H, s), 4.
94 (1H, s), 6.83 (1H, d, J = 8.7Hz), 6.91 (2H, t, J = 8.7H
z), 7.10-7.45 (9H, m). 2-methoxy-5-[(4-fluorophenyl)-
((S) -1-phenylethylamino) methyl] phenylamine isomer (B) (840 mg) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (358 mg)
Was used in the same manner as in Production Example (1c) to give 811 mg of the title compound isomer (B) as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.62 (1H, q, J = 6.6Hz), 3.68 (3H, s), 4.39 (3H,
s), 4.99 (1H, s), 6.76 (1H, d, J = 8.7Hz), 6.97-7.40 (1
1H, m).

(16d) 3-Amino-4- [4-methoxy
C-5-((4-fluorophenyl)-((S) -1-F
Enylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3-methoxy-4- [2-methoxy-5-((4-fluorophenyl)-((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-
Using 630 mg of 1,2-dione isomer (A) and 2.8 ml of 2N ammonia-ethanol solution, the reaction was carried out in the same manner as in Production Example (1d) to convert the title compound isomer (A) into a yellow solid. 491 mg was obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.3)
Hz), 3.42-3.52 (1H, m), 3.59 (3H, s), 4.83 (1H, s), 6.
87 (1H, d, J = 8.6 Hz), 7.05-7.45 (11H, m). Melting point: 189-192 ° C. 3-methoxy-4- [2-methoxy-5-((4-fluorophenyl)-(( S) -1-Phenylethylamino) methyl) phenylamino] -3-cyclobutene-
Using 805 mg of 1,2-dione isomer (B) and 3.4 ml of 2N ammonia-ethanol solution, the reaction was carried out in the same manner as in Production Example (1d) to convert the isomer (B) of the title compound into a yellow solid. 700 mg was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.5
Hz), 3.55-3.65 (1H, m), 3.58 (3H, s), 4.85 (1H, s), 6.
94 (1H, d, J = 8.8Hz), 7.05 (2H, t, J = 8.8Hz), 7.20-7.4
2 (8H, m), 7.53 (1H, d, J = 2.6 Hz). Melting point: 196-198 ° C.

Production Example 17 3-amino-4- [2,3-dimethoxy-5-((4-
Fluorophenyl)-((S) -1-phenylethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-502) (17a) N-[(3,4-dimethoxy-5-nitroph)
Enyl)-(5-fluorophenyl) methyl] -N-
2.0 g of ((S) -1-phenylethyl ) amine 3,4-dimethoxy-5-nitro-4'-fluorobenzophenone, 1.68 ml of (S) -1-phenylethylamine, 3.66 ml of triethylamine and titanium tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 0.87 ml to obtain an imine compound. The obtained imine compound and sodium cyanoborohydride 1.67
and 0.57 ml of acetic acid in the same manner as in Production Example (1a) to give the title compound as an orange oil.
73 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.40 (3H, m),
3.58-3.65 (1H, m), 3.80and 3.88 (total 3H, each s),
3.91 and 3.97 (total 3H, each s), 4.56 (1H, s), 6.93
-7.40 (11H, m).

(17b) 2,3-Dimethoxy-5
[(4-fluorophenyl)-((S) -1-phenyle
Tylamino) methyl] phenylamine N-[(3,4-dimethoxy-5-nitrophenyl)-
2.73 g of N- (4-fluorophenyl) methyl]-((S) -1-phenylethyl) amine, 3.19 g of nickel chloride hexahydrate and 1.01 g of sodium borohydride
The reaction was carried out in the same manner as in Production Example (15b) and the mixture was separated and purified to give the isomer (A) of the title compound as a yellow oil (8).
95 mg, isomer (B) 319 m as a pale yellow oil
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.71 (1H, q, J = 6.6Hz), 3.80 (3H, s), 3.82 (3H,
s), 4.42 (1H, s), 6.27 (1H, d, J = 1.9Hz), 6.34 (1H, d,
J = 1.9Hz), 6.92 (2H, t, J = 8.7Hz), 7.20-7.42 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, d, J = 6.6H)
z), 3.60 (1H, q, J = 6.6Hz), 3.75 (6H, s), 4.44 (1H,
s), 6.22 (1H, d, J = 1.7Hz), 6.28 (1H, d, J = 1.7Hz), 7.0
0 (2H, t, J = 8.7Hz), 7.18-7.38 (7H, m).

(17c) 3-methoxy-4- [2,3-
Dimethoxy-5-((4-fluorophenyl)-((S)
-1-phenylethylamino) methyl) phenylamido
No] -3-cyclobutene-1,2-dione 2,3-dimethoxy-5-[(4-fluorophenyl)-
890 mg of isomer (A) of ((S) -1-phenylethylamino) methyl] phenylamine and 343 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione
Was used in the same manner as in Production Example (1c) to give 762 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.6H)
z), 3.60-3.70 (1H, m), 3.83 (3H, s), 3.90 (3H, s), 4.
41 (3H, s), 4.53 (1H, s), 6.63 (1H, s), 6.95 (2H, t, J =
8.7 Hz), 7.20-7.40 (8H, m) .2,3-dimethoxy-5-[(4-fluorophenyl)-
1.15 g of ((S) -1-phenylethylamino) methyl] phenylamine isomer (B) and 455 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione
Was used in the same manner as in Production Example (1c) to give 789 mg of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 3.62 (1H, q, J = 6.6Hz), 3.78 (3H, s), 3.85 (3H,
s), 4.42 (3H, s), 4.54 (1H, s), 6.58 (1H, s), 7.04 (2
H, t, J = 8.5Hz), 7.20-7.40 (8H, m).

(17d) 3-Amino-4- [2,3-di
Methoxy-5-((4-fluorophenyl)-((S)-
1-phenylethylamino) methyl) phenylamino]
-3-cyclobutene-1,2-dione 3-methoxy-4- [2,3-dimethoxy-5-((4
-Fluorophenyl)-((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (A) 755 mg and 2N ammonia-ethanol solution 3.0 ml were used. The reaction was carried out in the same manner as in Production Example (1d) to obtain 638 mg of the isomer (A) of the title compound as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 3.55-3.65 (1H, m), 3.75 (3H, s), 3.78 (3H, s), 4.
41 (1H, s), 6.76 (1H, s), 7.05 (2H, t, J = 6.9Hz), 7.15
-7.40 (7H, m), 7.57 (1H, s). Melting point: 120-122 ° C.

3-methoxy-4- [2,3-dimethoxy-5-((4-fluorophenyl)-((S) -1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2 -785 mg of the dione isomer (B)
The reaction was carried out in the same manner as in Production Example (1d) using 3.2 ml of a 2N ammonia-ethanol solution, and 680 mg of the title compound isomer (B) was obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.45-3.55 (1H, m), 3.70 (3H, s), 3.74 (3H, s), 4.
46 (1H, s), 6.72 (1H, s), 7.05-7.45 (9H, m), 7.54 (1H,
s). Melting point: 130-132 ° C.

Production Example 18 3-amino-4- [3- (4-methoxyphenyl-
((R) -1- (3,4-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cyclobutene
-1,2-dione (Exemplified Compound No. 2-1359) (18a) N-[(3-nitrophenyl)-(4- methoate)
[Xyphenyl) methyl] -N-((R) -1- (3,4
-Difluorophenyl ) ethyl) amine 3 g of 4-methoxy-3'-nitro-benzophenone and 3.96 g of (R) -1- (3,4-difluorophenyl) ethylamine mandelic acid salt, triethylamine 9.
The reaction was carried out in the same manner as in Production Example (1a) using 75 ml, 1.54 ml of titanium tetrachloride, 3.26 g of sodium borohydride, and 1.0 ml of acetic acid to obtain 1.27 g of the title compound as an orange oil. . NMR spectrum (CDCl ₃ ) δ ppm: 1.35 and 1.36 (total
3H, each d, J = 6.4, 6.5Hz), 3.57-3.69 (1H, m), 3.77
and 3.82 (total 3H, each s), 4.60 and 4.66 (total 1
H, each s), 6.82 and 6.89 (total 2H, each d, J = 8.7,
8.7Hz), 6.94-7.12 (5H, m), 7.40 and 7.45 (total 1H,
each t, J = 8.0, 8.0Hz), 7.59 and 7.65 (total 1H, ea
ch d, J = 7.8, 7.6Hz), 8.03 and 8.10 (total 1H, dd, J
= 2.0, 8.0and 1.8, 8.0Hz), 8.23 (1H, d, J = 8.0Hz).

(18b) 3-[(4-methoxyphenyi)
)-((R) -1- (3,4-difluorophenyl)
1.27 g of ethylamino) methyl] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N-((R) -1- (3,4-difluorophenyl) ethyl) amine Methanol 5
0 ml, and reacted in the same manner as in Production Example (1b) using 1.52 g of nickel chloride hexahydrate and 510 mg of sodium borohydride. The diastereomer was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate / toluene = 1/8), 235 mg of the title compound isomer (A) as a yellow oil, and isomer (B) as a yellow oil 240 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.60-3.70 (1H, m), 3.76 (3H, s), 4.44 (1H, s), 6.
56-6.77 (3H, m), 6.79 (2H, d, J = 8.7Hz), 6.94-6.97 (1
H, m), 7.05-7.20 (5H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.60-3.64 (1H, m), 3.80 (3H, s), 4.44 (1H, s), 6.
49-6.52 (1H, m), 6.61 (1H, d, J = 1.9Hz), 6.65 (1H, d,
J = 7.3Hz), 6.86 (2H, d, J = 8.7Hz), 6.92-6.95 (1H, m),
7.02-7.20 (5H, m).

(18c) 3-methoxy-4- [3-
((4-methoxyphenyl)-((R) -1- (3,4
-Difluorophenyl) ethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1-
225 mg of (3,4-difluorophenyl) ethylamino) methyl] phenylamine isomer (A) is dissolved in 5 ml of methanol, and 174 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione is used as a production example. (1
The reaction was carried out in the same manner as in c) to obtain 293 mg of the isomer (A) of the title compound as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.44 (3H,
s), 4.55 (1H, s), 6.81 (2H, d, J = 8.7Hz), 6.92-6.95 (1
H, m), 7.06-7.34 (8H, m). 3-[(4-methoxyphenyl)-((R) -1-
230 mg of isomer (B) of (3,4-difluorophenyl) ethylamino) methyl] phenylamine is dissolved in 5 ml of methanol, and prepared using 177 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione. The reaction was carried out in the same manner as in Example (1c) to give 320 mg of the isomer (B) of the title compound as a yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 3.81 (3H, s), 4.44 (3H,
s), 4.52 (1H, s), 6.89 (2H, d, J = 8.7Hz), 6.91-6.96 (1
H, m), 7.06-7.24 (8H, m).

(18d) 3-amino-4- [3-((4
-Methoxyphenyl)-((R) -1- (3,4-diph
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
280 mg of the isomer (A) of-((R) -1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione is dissolved in 5 ml of ethanol, and 2N. 1 ml of an ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
mg. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.7)
Hz), 3.56 (1H, q, J = 6.7Hz), 3.69 (3H, s), 4.42 (1H,
s), 6.81 (2H, d, J = 8.7Hz), 6.97 (1H, d, J = 4.7Hz), 7.
06-7.09 (1H, m), 7.21-7.27 (3H, m), 7.30-7.42 (4H,
m). Melting point: 171 to 173 ° C. Optical rotation: [α] _D : −33.8 (c = 1.0, EtO
H) 3-Methoxy-4- [3-((4-methoxyphenyl)
280 mg of-((R) -1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (B) is dissolved in 5 ml of ethanol, and 2N 1 ml of an ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.6
Hz), 3.52 (1H, q, J = 6.6Hz), 3.73 (3H, s), 4.40 (1H,
s), 6.88 (2H, d, J = 8.5Hz), 6.91 (1H, d, J = 7.8Hz), 7.
06-7.07 (1H, m), 7.18-7.42 (7H, m). Melting point: 191-194 ° C. Optical rotation: [α] _D : +38.2 (c = 1.0, EtO
H).

Production Example 19 3-amino-4- [3- (4-methoxyphenyl-
((S) -1- (3,4-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cyclobutene
-1,2-dione (Exemplified Compound No. 2-1359) (19a) N-[(3-nitrophenyl)-(4- methoate)
[Xyphenyl) methyl] -N-[(S) -1- (3,4
-Difluorophenyl ) ethyl] amine 4-methoxy-3'-nitro-benzophenone (3 g) and (S) -1- (3,4-difluorophenyl) -ethylamine mandelate (5.41 g), triethylamine (9.75 ml), titanium tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 1.54 ml, 3.26 g of sodium cyanoborohydride, and 1.0 ml of acetic acid to obtain 1.60 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 and 1.36 (total
3H, each d, J = 6.4, 6.5Hz), 3.57-3.69 (1H, m), 3.77
and 3.82 (total 3H, each s), 4.60 and 4.66 (total
1H, each s), 6.82 and 6.89 (total 2H, each d, J = 8.
7, 8.7Hz), 6.94-7.12 (5H, m), 7.40 and 7.45 (total 1
H, each t, J = 8.0, 8.0Hz), 7.59 and 7.65 (total 1H,
each d, J = 7.8, 7.6Hz), 8.03 and 8.10 (total 1H, dd,
J = 2.0, 8.0and 1.8, 8.0Hz), 8.23 (1H, d, J = 8.0Hz).

(19b) 3-[(4-methoxyphenyl)
)-((S) -1- (3,4-difluorophenyl)
1.50 g of ethylamino) methyl] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N-[(S) -1- (3,4-difluorophenyl) ethyl] amine Methanol 5
The reaction was carried out in the same manner as in Production Example (1b) using 1.79 g of nickel chloride hexahydrate and 600 mg of sodium borohydride. The diastereomer was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate / toluene = 1/8), and 199 mg of isomer (A) of the title compound as a yellow oily substance, and isomer (B) of a yellow oily substance 290 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.60-3.70 (1H, m), 3.76 (3H, s), 4.43 (1H, s), 6.
56-6.61 (2H, m), 6.67 (1H, d, J = 7.6Hz), 6.74 (2H, d,
J = 8.7 Hz), 6.92-6.97 (1H, m), 7.05-7.19 (5H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.7H)
z), 3.55-3.65 (1H, m), 3.80 (3H, s), 4.44 (1H, s), 6.
50-6.66 (3H, m), 6.86 (2H, d, J = 8.6Hz), 6.92-6.95 (1
H, m), 7.02-7.20 (5H, m).

(19c) 3-methoxy-4- [3-
((4-methoxyphenyl)-((S) -1- (3,4
-Difluorophenyl) ethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((S) -1-
180 mg of isomer (A) of (3,4-difluorophenyl) ethylamino) methyl] phenylamine is dissolved in 10 ml of methanol, and 139 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione is used as a production example. The reaction was carried out in the same manner as in (1c) to give 220 mg of the title compound isomer (A) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.64 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.44 (3H,
s), 4.55 (1H, s), 6.81 (2H, d, J = 8.7Hz), 6.92-6.95 (1
H, m), 7.06-7.19 (6H, m), 7.28-7.34 (2H, m). 3-[(4-methoxyphenyl)-((S) -1-
270 mg of isomer (B) of (3,4-difluorophenyl) ethylamino) methyl] phenylamine is dissolved in 10 ml of methanol, and 208 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione is used for the preparation. The reaction was carried out in the same manner as (1c) to give 160 mg of the isomer (B) of the title compound as a pale yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 3.81 (3H, s), 4.44 (3H,
s), 4.52 (1H, s), 6.89 (2H, d, J = 8.5Hz), 6.91-6.96 (1
H, m), 7.06-7.24 (8H, m).

(19d) 3-Amino-4- [3-((4
-Methoxyphenyl)-((S) -1- (3,4-diph
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
220 mg of-((S) -1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (A) is dissolved in 5 ml of ethanol and 2N 1 ml of an ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
mg. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.56 (1H, q, J = 6.5Hz), 3.69 (3H, s), 4.43 (1H,
s), 6.81 (2H, d, J = 8.7Hz), 6.97 (1H, d, J = 7.6Hz), 7.
07-7.09 (1H, m), 7.21-7.27 (3H, m), 7.31-7.43 (4H,
m). Melting point: 171 to 173 ° C. Optical rotation: [α] _D : +32.5 (c = 1.0, EtO
H) 3-Methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione isomer (B) (150 mg) was dissolved in ethanol (5 ml), and 2N was added. 1 ml of an ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d), to give the isomer (B) of the title compound as a yellow solid in 130 mg
mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.6
Hz), 3.52 (1H, q, J = 6.8Hz), 3.73 (3H, s), 4.40 (1H,
s), 6.88 (2H, d, J = 8.5Hz), 6.91 (1H, d, J = 7.7Hz), 7.
66 (1H, m), 7.18-7.42 (7H, m). Melting point: 195-197 ° C Optical rotation: [α] _D : -41.6 (c = 1.0, EtO
H).

Production Example 20 3-amino-4- [3-((4-methoxyphenyl)-
((S) -1- (3-fluorophenyl) ethylami
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-815) (20a) N-[(3-nitrophenyl)-(4-meth
[Xyphenyl) methyl] -N-[(S) -1- (3-f
Fluorophenyl) ethyl] amine 4-methoxy-3′-nitrobenzophenone (2.0 g) and (S) -1- (3-fluorophenyl) ethylamine hydrochloride (2.73 g), triethylamine (6.50 ml), titanium tetrachloride (1.03 ml), Production Example (1) using 2.15 g of sodium cyanoborohydride and 0.67 ml of acetic acid
The reaction was carried out in the same manner as in a) to give 2.77 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 and 1.38 (total
3H, each d, J = 6.5, 6.6Hz), 3.59-3.69 (1H, m), 3.76
and 3.81 (total 3H, each s), 4.63 and 4.68 (total 1
H, each s), 6.81 and 6.89 (total 2H, each d, J = 8.6,
8.7Hz), 6.91-7.03 (3H, m), 7.17 (2H, dd, J = 8.3, 8.5
Hz), 7.27-7.33 (1H, m), 7.37-7.50 (1H, m), 7.60 and
7.67 (total 1H, each d, J = 7.9, 7.9Hz), 8.01-8.11 (1
H, m), 8.22 and 8.26 (total 1H, each s).

(20b) 3-[(4-methoxyphenyi)
)-((S) -1- (3-fluorophenyl) ethyl
Amino) methyl] phenylamine 2.70 g of N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N-[(S) -1- (3-fluorophenyl) ethyl] amine in 100 ml of methanol
and 3.37 g of nickel chloride hexahydrate and 1.13 g of sodium borohydride.
The reaction was carried out in the same manner as in b) to give 2.32 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.7H
z), 3.59-3.71 (1H, m), 3.75 and 3.80 (total 3H, each
s), 4.47 (1H, s), 6.49-6.70 (3H, m), 6.78 and6.86 (t
otal 2H, each d, J = 8.6, 8.7Hz), 6.91-7.30 (7H, m).

(20c) 3-methoxy-4- [3-
((4-methoxyphenyl)-((S) -1- (3-f
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenylamine in 2.50 g of methanol
The reaction was carried out in the same manner as in Production Example (1c) using 1.84 g of 4-dimethoxy-3-cyclobutene-1,2-dione. The crude product was subjected to reverse phase HPLC [elution solvent: acetonitrile / acetate buffer (water: acetic acid: triethylamine = 1000:
2: 2) = 40/60] to give 145 mg of the isomer (A) of the title compound as a pale yellow foam and 350 mg of the isomer (B) as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.43 (3H,
s), 4.58 (1H, s), 6.80 (2H, d, J = 8.7Hz), 6.93-7.04 (3
H, m), 7.10-7.19 (4H, m), 7.29-7.36 (3H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.66 (1H, q, J = 6.6Hz), 3.81 (3H, s), 4.43 (3H,
s), 4.55 (1H, s), 6.88 (2H, d, J = 8.5Hz), 6.90-7.31 (1
0H, m).

(20d) 3-Amino-4- [3-((4
-Methoxyphenyl)-((S) -1- (3-fluoro
Phenyl) ethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
130 mg of 1,2-dione isomer (A) was dissolved in 5 ml of ethanol, and 2N ammonia-ethanol solution 1
The reaction was carried out in the same manner as in Production Example (1d) to obtain 110 mg of the isomer (A) of the title compound as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 3.58 (1H, m), 3.69 (3H, s), 4.45 (1H, d, J = 4.9H
z), 6.82 (2H, d, J = 8.7Hz), 6.96 (1H, d, 7.7Hz), 7.03-
7.09 (2H, m), 7.16-7.41 (7H, m). Melting point: 170-172 ° C Optical rotation: [α] _D : +48.1 (c = 0.5, EtO
H) 3-Methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
330 mg of 1,2-dione isomer (B) is dissolved in 5 ml of ethanol, and 2N ammonia-ethanol solution 2
The reaction was carried out in the same manner as in Production Example (1d) to obtain 282 mg of the title compound isomer (B) as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.28 (3H, d, J = 6.6
Hz), 3.57 (1H, m), 3.73 (3H, s), 4.42 (1H, d, J = 4.7H
z), 6.88 (2H, d, J = 8.6Hz), 6.91 (1H, d, J = 7.7Hz), 7.
01-7.07 (2H, m), 7.14-7.27 (5H, m), 7.32-7.37 (1H,
m), 7.42 (1H, dd, J = 1.9, 8.0 Hz). Melting point: 178-181 ° C Optical rotation: [α] _D : -106.8 (c = 0.5, EtO
H).

Production Example 21 3-amino-4- [3- (2-thienyl-((S) -1)
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-646) (21a) N-[(3-nitrophenyl) -2-thienyl
Methyl] -N-((S) -1-phenylethyl) ami
Using 2.0 g of (3-nitrophenyl) -2-thienyl ketone, 1.94 ml of (S) -1-phenylethylamine, 4.2 ml of triethylamine and 1.0 ml of titanium tetrachloride in the same manner as in Production Example (1a). The reaction was performed to obtain an imine compound. Using the obtained imine compound, 1.91 g of sodium borohydride cyanide, and 0.65 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.58 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 and 1.40 (total
3H, each d, J = 6.6Hz), 3.59 and 3.83 (total 1H, each
q, J = 6.6Hz), 4.91 and 4.98 (total 1H, eachs), 6.65
-7.00 (2H, m), 7.18-7.70 (8H, m), 8.05-8.27 (2H, m).

(21b) 3-[((S) -1-phenyle
[Cylamino) -2-thienylmethyl] phenylamine N-[(3-nitrophenyl ) -2-thienylmethyl ]
-N-((S) -1-phenylethyl) amine 4.56
g, 6.42 g of nickel chloride hexahydrate and 2.04 g of sodium borohydride, followed by purification in the same manner as in Production Example (15b) to give the isomer (A) of the title compound as a pale yellow oil And 380 mg of isomer (B) were obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.70 (1H, q, J = 6.6Hz), 4.65 (1H, s), 6.60-6.72 (4
H, m), 6.83-6.88 (1H, m), 7.10-7.43 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.80 (1H, q, J = 6.6Hz), 4.80 (1H, s), 6.54 (1H, d
d, J = 2.0, 8.2Hz), 6.65-6.72 (2H, m), 6.82 (1H, d, J =
3.4Hz), 6.91-6.95 (1H, m), 7.06 (1H, t, J = 7.7Hz), 7.
20-7.37 (6H, m).

(21c) 3-methoxy-4- [3- (2
-Thienyl-((S) -1-phenylethylamino) me
Tyl) -phenylamino] -3-cyclobutene-1,2
-Dione 3-[((S) -1-phenylethylamino) -2-thienylmethyl] -phenylamine isomer (A) 930 m
g, 3,4-dimethoxy-3-cyclobutene-1,2-
The reaction was carried out in the same manner as in Production Example (1c) using 466 mg of dione to obtain 932 mg of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.65 (1H, q, J = 6.6Hz), 4.42 (3H, s), 4.79 (1H,
s), 6.67 (1H, d, J = 3.3Hz), 6.85-6.90 (1H, m), 7.05-
7.40 (10H, m). 375 mg of isomer of 3-[((S) -1-phenylethylamino) -2-thienylmethyl] phenylamine (B),
Using 185 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (B) of the title compound as a white foam.
71 mg were obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.6H)
z), 3.81 (1H, q, J = 6.6Hz), 4.42 (3H, s), 4.90 (1H,
s), 6.83-6.87 (1H, m), 6.95-6.98 (1H, m), 7.05-7.40
(10H, m).

(21d) 3-amino-4- [3- [2-
Thienyl-((S) -1-phenylethylamino) methyl
[Phenylamino] -3-cyclobutene-1,2-di
On 3-methoxy-4- [3- (2-thienyl-((S)-
1-phenylethylamino) methyl) phenylamino]
Isomer (A) 9 of -3-cyclobutene-1,2-dione
3. 27 mg and 2N ammonia-ethanol solution
Using 4 ml, a reaction was carried out in the same manner as in Production Example (1d).
654 mg of isomer (A) of the title compound as a yellow solid
Obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.52-3.62 (1H, m), 4.64 (1H, s), 6.69 (1H, d, J =
3.3Hz), 6.85-6.90 (1H, m), 6.99 (1H, d, J = 7.6Hz), 7.
20-7.40 (8H, m), 7.51 (1H, d, J = 7.9 Hz). Melting point: 180-182 ° C Optical rotation: [α] _D = -31.7 (c = 1.00, E
tOH) 3-methoxy-4- [3- (2-thienyl-((S)-
1-phenylethylamino) methyl) phenylamino]
Isomer (B) 4 of -3-cyclobutene-1,2-dione
1. 65 mg and 2N ammonia-ethanol solution
Using 2 ml, the reaction was carried out in the same manner as in Production Example (1d).
391 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 3.62-3.72 (1H, m), 4.76 (1H, s), 6.85-7.00 (3H,
m), 7.20-7.55 (9H, m). Melting point: 188-190 ° C Optical rotation: [α] _D = + 23.4 (c = 1.00, E
tOH).

Production Example 22 3-amino-4- [3- (2-thienyl-((R) -1)
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-646) Using 2.0 g of (3-nitrophenyl) -2-thienyl ketone and 1.94 ml of (R) -1-phenylethylamine, the reaction was carried out in the same manner as in Production Example 21 to give an isomer of the title compound ( 1.25 g of A) and 762 mg of isomer (B) were obtained. Isomer (A) Melting point: 162 ° C. (dec) Optical rotation: [α] _D = + 32.4 (c = 1.00, E
tOH) Isomer (B) Melting point: 190-192 ° C Optical rotation: [α] _D = -18.7 (c = 1.00, E
tOH).

Production Example 23 3-amino-4- [3- (4-pyridyl-((S) -1)
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-691) (23a) N-[(3-nitrophenyl) -4-pyridi
Methyl] -N-((S) -1-phenylethyl) ami
Down (3-nitrophenyl) -4-pyridyl ketone 2.0g and (S) -1- phenylethylamine 2.24 ml, triethylamine 4.89ml and titanium tetrachloride 1.16
The reaction was carried out in the same manner as in Production Example (1a) using ml, to obtain an imine compound.

The obtained imine compound was reacted with 2.21 g of sodium borohydride cyanide and 0.76 ml of acetic acid in the same manner as in Production Example (1a) to give the isomer (A) of the title compound as a pale yellow oil. 1.09 g of the product and 1.02 g of isomer (B) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 4.67 (1H, s), 7.19-7.37 (7
H, m), 7.42 (1H, t, J = 8.0Hz), 7.55 (1H, d, J = 7.4Hz),
8.08 (1H, dd, J = 1.9, 7.9Hz), 8.19 (1H, d, J = 1.9Hz),
8.60-8.61 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J = 6.6H)
z), 3.60 (1H, q, J = 6.6Hz), 4.69 (1H, s), 7.19-7.38 (7
H, m), 7.53 (1H, t, J = 7.8Hz), 7.63 (1H, d, J = 7.5Hz),
8.14-8.17 (1H, m), 8.20-8.21 (1H, m), 8.50-8.52 (2H,
m).

(23b) 3-[((S) -1-phenyle
Tylamine) -4-pyridylmethyl] phenylamine N-[(3-nitrophenyl) -4-pyridylmethyl]
As in Production Example (1b), using 1.09 g of isomer (A) of -N-((S) -1-phenylethyl) amine, 1.57 g of nickel chloride hexahydrate and 500 mg of sodium borohydride. The reaction was carried out to give 752 mg of isomer (A) of the title compound as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.8H)
z), 3.61 (1H, q, J = 6.8Hz), 4.49 (1H, s), 6.52-6.56 (2
H, m), 6.60 (1H, d, J = 7.9Hz), 7.04 (1H, t, J = 7.7Hz),
7.19-7.36 (7H, m), 8.53-8.54 (2H, m). N-[(3-nitrophenyl) -4-pyridylmethyl]
As in Production Example (1b), using 1.02 g of isomer (B) of -N-((S) -1-phenylethyl) amine, 1.47 g of nickel chloride hexahydrate and 470 mg of sodium borohydride. The reaction was carried out to obtain 694 mg of the isomer (B) of the title compound as a pale yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.72 (1H, q, J = 6.6Hz), 4.47 (1H, s), 6.57-6.64 (3
H, m), 7.12 (1H, t, J = 7.7Hz), 7.22-7.35 (7H, m), 8.4
5-8.46 (2H, m).

(23c) 3-methoxy-4- [3- (4
-Pyridyl-((S) -1-phenylethylamino) me
Tyl) phenylamino] -3-cyclobutene-1,2-
745 mg of isomer of dione 3-[((S) -1-phenylethylamine) -4-pyridylmethyl] phenylamine (A) and 3,4-dimethoxy-3-cyclobutene-1,2-
The reaction was carried out in the same manner as in Production Example (1c) using 373 mg of dione to obtain 805 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J = 6.7H)
z), 3.63 (1H, q, J = 6.7Hz), 4.42 (3H, s), 4.59 (1H,
s), 7.03 (1H, d, J = 7.7Hz), 7.14-7.37 (10H, m), 8.56-
8.57 (2H, m). 690 mg of isomer (B) of 3-[((S) -1-phenylethylamine) -4-pyridylmethyl] phenylamine and 3,4-dimethoxy-3-cyclobutene-1,2-
The reaction was carried out in the same manner as in Production Example (1c) using 355 mg of dione to obtain 604 mg of the title compound isomer (B) as a pale yellow solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J = 6.6H)
z), 3.69 (1H, q, J = 6.6Hz), 4.41 (3H, s), 4.60 (1H,
s), 7.05 (1H, d, J = 7.5Hz), 7.21-7.36 (10H, m), 8.47-
8.48 (2H, m).

(23d) 3-amino-4- [3- (4-
Pyridyl-((S) -1-phenylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
On 3-methoxy-4- [3- (4-pyridyl-((S)-
1-phenylethylamino) methyl) phenylamino]
Isomer (A) 8 of -3-cyclobutene-1,2-dione
2. 00 mg and 2N ammonia-ethanol solution
Using 8 ml, the reaction was carried out in the same manner as in Production Example (1d).
The isomer (A) of the title compound was converted to an orange solid by 62%.
5 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 3.49 (1H, q, J = 6.6Hz), 4.49 (1H, s), 6.93 (1H,
d, J = 7.8Hz), 7.21-7.44 (10H, m), 8.50 (2H, d, J = 5.3H
z). Melting point: 152-154 ° C. Optical rotation: [α] _D +16.8 (c = 1.0, Et
OH) 3-methoxy-4- [3- (4-pyridyl-((S)-
1-phenylethylamino) methyl) phenylamino]
Isomer (B) 6 of -3-cyclobutene-1,2-dione
2. 00 mg and 2N ammonia-ethanol solution
Using 0 ml, the reaction was carried out in the same manner as in Production Example (1d).
The isomer (B) of the title compound was converted into a pale yellow solid in an amount of 412 m
g was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.31 (3H, d, J = 6.6)
Hz), 3.57 (1H, q, J = 6.6Hz), 4.49 (1H, s), 6.99 (1H,
d, J = 7.5Hz), 7.20-7.35 (9H, m), 7.42 (1H, d, J = 8.0H
z), 8.43 (2H, d, J = 5.7 Hz). Melting point: 168-171 ° C. Optical rotation: [α] _D = + 23.5 (c = 1.0, Et
OH).

Production Example 24 3-Amino-4- [3- (4-pyridyl-((R) -1)
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-691) (3-Nitrophenyl) -4-pyridyl ketone and (R)-
The reaction was carried out in the same manner as in Production Example 23 using 1-phenylethylamine to obtain an isomer (A) and an isomer (B) of the title compound. Isomer (A) Melting point: 109 ° C. (dec) Optical rotation: [α] _D = 16.1 (c = 1.0, Et
OH) Isomer (B) Melting point: 141-143 ° C. Optical rotation: [α] _D = −3.87 (c = 0.1, Et
OH).

Production Example 25 3-Amino-4- [3-((3,4-dimethoxyphenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione and its hydrochloride (Exemplary Compound No. 2-
1397) (25a) 3-[(3,4-dimethoxyfe
Nyl)-(1- (3,4-difluorophenyl) ethyl
Amino) methyl] -phenylamine 3,4-dimethoxy-3'-nitro-benzophenone (2.0 g) and 1- (3,4-difluorophenyl) ethylamine hydrochloride (2.48 g) were treated with anhydrous dichloromethane (60 m).
and triethylamine (5.82 ml) was added.
The reaction solution was ice-cooled, and a solution of titanium tetrachloride (0.92 ml) in anhydrous dichloromethane (10 ml) was slowly added dropwise, followed by stirring at room temperature for 2 hours. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the imine compound as an oil. The obtained oil was dissolved in 100 ml of methanol, and 3.31 g of nickel chloride hexahydrate was dissolved.
Was added. 1.11 g of sodium borohydride under ice-cooling
Was added in small portions and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 5/1).
The title compound was isolated as a yellow oil in 1.4.
5 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.317 and 1.325 (tot
al, 3H, each d, J = 6.6,6.6Hz), 3.59-3.69 (1H, m), 3.
81, 3.83, 3.85 and 3.88 (total 6H, each s), 4.42 an
d 4.44 (total 1H, each s), 6.50-7.17 (10H, m).

(25b) 3-methoxy-4- [3-
((3,4-dimethoxyphenyl)-(1- (3,4-
Difluorophenyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione 3-[(3,4-dimethoxyphenyl)-(1- (3,
4-difluorophenyl) ethylamino) methyl] phenylamine (500 mg) was dissolved in methanol (10 ml),
357 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 450 mg of the title compound as a brown foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.33-1.37 (3H, m),
3.63-3.66 (1H, m), 3.82,3.83, 3.85 and 3.89 (total 6
H, each s), 4.45 (3H, s), 4.50 and 4.55 (total1H, ea
ch s), 6.75-7.34 (10H, m).

(25c) 3-Amino-4- [3-
((3,4-dimethoxyphenyl)-(1- (3,4-
Difluorophenyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione 3-methoxy-4- [3-((3,4-dimethoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] 450 mg of -3-cyclobutene-1,2-dione was dissolved in 5 ml of ethanol, and 1 ml of a 2N ammonia-ethanol solution was added.
The reaction was carried out in the same manner as in Production Example (1d) to obtain 298 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27-1.30 (3H, m),
3.50-3.60 (1H, m), 3.68, 3.70, 3.72 and 3.73 (total
6H, each s), 4.38 and 4.45 (total 1H, each s), 6.8
2-7.01 (4H, m), 7.07-7.10 (1H, m), 7.18-7.43 (5H, m). Melting point: 134-136 ° C.

(25d) 3-Amino-4- [3- (3,
4-dimethoxyphenyl)-(1- (3,4-difluoro)
Rophenyl) ethylamino) methyl) phenylamino]
-3-cyclobutene-1,2-dione hydrochloride 3-amino-4- [3-((3,4-dimethoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
145 mg of 1,2-dione was dissolved in 5 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added to the solution.
For a minute. The precipitated solid product was collected by filtration and washed with diethyl ether to give the title compound as a pale yellow solid (155 ml).
g was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65-1.66 (3H, m),
3.73, 3.76, 3.80 and3.81 (total 6H, each s), 4.21
-4.30 (1H, m), 5.06-5.21 (1H, m), 6.95-7.00 (total 1
(H, d, J = 6.95, 7.00Hz), 7.07-7.12 (1H, m), 7.23-7.58
(8H, m). Melting point: 160-162 ° C.

Production Example 26 3-amino-4- [3-((4-fluorophenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 2-1299) (26a) N-[(3-nitrophenyl)-(4- fur
Orophenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 4-fluoro-3'-nitro-benzophenone 2.0 g
And 3.16 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 6.82 ml of triethylamine, 1.08 ml of titanium tetrachloride, 2.28 g of sodium borohydride cyanide and 0.7 ml of acetic acid (1
The reaction was carried out in the same manner as in a) to give 3.03 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 and 1.37 (total
3H, each d, J = 6.6, 6.6Hz), 3.59 and 3.63 (total 1
H, each q, J = 6.7, 6.8Hz), 4.65 and 4.69 (total1H, e
ach s), 6.87-7.00 (2H, m), 7.03-7.16 (3H, m), 7.19-
7.26 (2H, m), 7.41and 7.51 (total 1H, each dd, J = 8.
0, 8.0Hz), 7.57 and 7.63 (total 1H, eachd, J = 7.9,
7.9Hz), 8.04-8.14 (1H, m), 8.20-8.23 (1H, m).

(26b) 3-[(4-Fluorophenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl] phenylamine 3.0 g of N-[(3-nitrophenyl)-(4-fluorophenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine is dissolved in 50 ml of methanol. , Nickel chloride hexahydrate and 3.24 g of sodium borohydride, and the reaction was carried out in the same manner as in Production Example (15b), and the mixture was separated and purified to give the isomer (A) of the title compound as a pale yellow oil 630 mg, isomer (B)
Was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.67 (1H, q, J = 6.6Hz), 4.45 (1H, s), 6.56-6.59 (2
H, m), 6.64 (1H, d, J = 7.4Hz), 6.90-6.97 (3H, m), 7.0
6-7.14 (3H, m), 7.23 (2H, dd, J = 3.0, 5.5 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.6H)
z), 3.63 (1H, q, J = 6.6Hz), 4.47 (1H, s), 6.52 (1H, d,
J = 10.0Hz), 6.58 (1H, s), 6.63 (1H, d, J = 7.9Hz), 6.8
9-6.93 (1H, m), 6.98-7.13 (5H, m), 7.22-7.28 (2H,
m).

(26c) 3-methoxy-4- [3-
((4-fluorophenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) phenylami
520 mg of isomer (A) of [ no] -3-cyclobutene-1,2-dione 3-[(4-fluorophenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine in 20 ml of methanol Dissolved in 3,4-dimethoxy-3-cyclobutene-1,
The reaction was carried out in the same manner as in Production Example (1c) using 174 mg of 2-dione to obtain 650 mg of the title compound isomer (A) as a colorless foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.64 (1H, q, J = 6.6Hz), 4.44 (3H, s), 4.57 (1H,
s), 6.92-6.98 (3H, m), 7.06-7.15 (3H, m), 7.18-7.35
(5H, m). 550 mg of isomer (B) of 3-[(4-fluorophenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine was dissolved in 20 ml of methanol. 4-dimethoxy-3-cyclobutene-1,
The same reaction as in Production Example (1c) was carried out using 439 mg of 2-dione to obtain 670 mg of the title compound isomer (B) as a colorless foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.61 (1H, q, J = 6.6Hz), 4.45 (3H, s), 4.56 (1H,
s), 6.91-6.95 (1H, m), 7.02-7.14 (6H, m), 7.24-7.27
(4H, m).

(26d) 3-amino-4- [3-((4
-Fluorophenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [3-((4-fluorophenyl)
-(1- (3,4-difluorophenyl) ethylamino) ethyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione isomer (A) was dissolved in 20 ml of ethanol, 5 ml of a 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
The title compound isomer (A) was converted into a pale yellow solid in 366 m
g was obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.58 (1H, q, J = 6.5Hz), 4.49 (1H, s), 6.99 (1H,
d, J = 7.6Hz), 7.05-7.10 (3H, m), 7.27 (1H, dd, J = 7.7,
7.9 Hz), 7.30-7.42 (6H, m). Melting point: 204-206 ° C 3-methoxy-4- [3-((4-fluorophenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione isomer (B) was dissolved in 20 ml of ethanol, 5 ml of a 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
362 m of the isomer (B) of the title compound as a pale yellow solid
g was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J = 6.6)
Hz), 3.48-3.52 (1H, m), 4.48 (1H, s), 6.93 (1H, d, J =
7.7Hz), 7.05-7.08 (1H, m), 7.14 (2H, t, J = 8.8Hz), 7.
21 (1H, d, J = 7.7, 7.9Hz), 7.30 (1H, s), 7.33-7.41 (5
H, m). Melting point: 210-212 ° C.

Production Example 27 3-amino-4- [3- (3-methoxyphenyl-
((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-802) (27a) N-[(3-nitrophenyl)-(3-meth
[Xyphenyl) methyl] -N-[(S) -1- (3-full
Orophenyl) ethyl] amine 3-methoxy-3'-nitro-benzophenone 2.0 g
And (S) -1- (3-fluorophenyl) ethylamine hydrochloride (2.73 g), triethylamine (6.50 ml),
Using 1.03 ml of titanium tetrachloride, 2.15 g of sodium cyanoborohydride and 0.67 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.93 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 and 1.39 (total
3H, each d, J = 6.6, 6.7Hz), 3.62 and 3.71 (total 1
H, each q, J = 6.6, 6.6Hz), 3.76 and 3.80 (total3H, e
ach s), 4.64 and 4.69 (total 1H, each s), 6.75-6.86
(3H, m), 6.91-7.04 (3H, m), 7.20-7.33 (2H, m), 7.39
and 7.48 (total 1H, each t, J = 7.8, 7.9Hz), 7.61 and
7.68 (total 1H, each t, J = 7.9, 8.1Hz), 8.02-8.12 (1
H, m), 8.23 and 8.26 (total 1H, each dd, J = 1.8 and
1.9Hz).

(27b) 3-[(3-methoxyphenyl
)-((S) -1- (3-fluorophenyl) ethyl
Amino) methyl] phenylamine 2.79 g of N-[(3-nitrophenyl)-(3-methoxyphenyl) methyl] -N-[(S) -1- (3-fluorophenyl) ethyl] amine in 50 ml of methanol After dissolving and reacting in the same manner as in Production Example (1b) using 3.49 g of nickel chloride hexahydrate and 1.17 g of sodium borohydride, the residue was subjected to silica gel column chromatography (elution solvent: toluene / acetic acid). Ethyl = 8 /
1-5 / 1) and reverse phase medium pressure chromatography using a rover column [elution solvent: acetonitrile / acetic acid buffer aqueous solution (water: acetic acid: triethylamine = 1000: 2: 2)]
= 35/65] to give 700 mg of the title compound isomer (A) as a yellow oil and 220 mg of isomer (B) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.71 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.49 (1H,
s), 6.57 (1H, dd, J = 1.9, 8.2Hz), 6.64 (1H, d, J = 2.0H
z), 6.69-6.73 (2H, m), 6.85-6.95 (3H, m), 7.00-7.04
(2H, m), 7.06-7.18 (2H, m), 7.24-7.30 (1H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.7H)
z), 3.68 (1H, q, J = 6.7Hz), 3.79 (3H, s), 4.48 (1H,
s), 6.51 (1H, dd, J = 2.2, 7.8Hz), 6.62 (1H, d, J = 1.9H
z), 6.67 (1H, d, J = 7.7Hz), 6.78 (1H, dd, J = 2.1, 8.0H
z), 6.88-7.05 (6H, m), 7.21-7.30 (2H, m).

(27c) 3-methoxy-4- [3-
((3-methoxyphenyl)-((S) -1- (3-f
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-[(3-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenylamine isomer (A) (640 mg) in methanol (20 ml)
Dissolved in 3,4-dimethoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 519 mg of 1,2-dione to give the title compound as a pale yellow foam in the form of 8
00 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.67 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.43 (3H,
s), 4.60 (1H, s), 6.73-6.76 (1H, m), 6.84-6.86 (2H,
m), 6.92-7.01 (3H, m), 7.11-7.33 (6H, m). 3-[(3-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenylamine isomer (B) (210 mg) in methanol (10 ml)
And 3,4-dimethoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 170 mg of dione to give the title compound as a pale-yellow foam (267 m).
g was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.69 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.44 (3H,
s), 4.56 (1H, s), 6.80-7.10 (8H, m), 7.22-7.31 (4H,
m).

(27d) 3-amino-4- [3-((3
-Methoxyphenyl)-((S) -1- (3-fluoro
Phenyl) ethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione 3-methoxy-4- [3-((3-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino-3-cyclobutene-1,
200 mg of 2-dione isomer (A) was added to ethanol 10
dissolved in 1 ml of 2N ammonia-ethanol solution
The reaction was carried out in the same manner as in Production Example (1d) to obtain 147 mg of the isomer (A) of the title compound as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.31 (3H, d, J = 6.6)
Hz), 3.59 (1H, q, J = 6.5Hz), 3.70 (3H, s), 4.48 (1H,
s), 6.73-6.75 (1H, m), 6.87-7.43 (11H, m). Melting point: 155 to 156 ° C Optical rotation: [α] _D : +13.2 (c = 0.5, EtO
H) 3-Methoxy-4- [3-((3-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
200 mg of 1,2-dione isomer (B) was dissolved in 10 ml of ethanol, 1 ml of 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
158 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.56 (1H, q, J = 6.6Hz), 3.73 (3H, s), 4.44 (1H,
s), 6.78-6.80 (1H, m), 6.87-7.43 (11H, m). Melting point: 171-173 ° C Optical rotation: [α] _D : -60.3 (c = 0.5, EtO
H).

Production Example 28 2- [3,4-dioxo (2- (3- (3-methoxyphenyl)
Enyl)-((S) -1- (3-fluorophenyl) e
Tylamino) methyl) phenylamino) -1-cyclobu
[Tenylamino] ethanesulfonic acid (Exemplary Compound No. 2-
2918) The 3-methoxy-4- [3-((3-
Methoxyphenyl)-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3
-Isomer of cyclobutene-1,2-dione (A) 200
mg, 2-aminoethanesulfonic acid 109 mg and triethylamine 0.12 ml were added to ethanol 5 ml-water 2
The mixture was dissolved in a 1 ml mixed solution and stirred at room temperature for 1 hour. Dilute the reaction solution with ethyl acetate and saturate aqueous sodium hydrogen carbonate solution,
After washing with a saturated saline solution, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether and dried to obtain 130 mg of a 40% sodium salt of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.30 (3H, d, J = 6.6)
Hz), 2.72 (2H, t, J = 6.0Hz), 3.59 (1H, q, J = 6.5Hz),
3.70 (3H, s), 3.89 (2H, br), 4.46 (1H, s), 6.37 (1H, d
d, J = 2.1, 8.1 Hz), 6.86-7.42 (11H, m). Melting point: 240-244 ° C.

Production Example 29 3-amino-4- [3- (2-methoxyphenyl-
((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-797) (29a) N-[(3-nitrophenyl)-(2-meth
[Xyphenyl) methyl] -N-[(S) -1- (3-full
Orophenyl) ethyl] amine 2-methoxy-3'-nitro-benzophenone 2.0 g
And (S) -1- (3-fluorophenyl) ethylamine hydrochloride (2.73 g), triethylamine (6.50 ml),
The reaction was carried out in the same manner as in Production Example (1a) using 1.03 ml of titanium tetrachloride, 2.15 g of sodium borohydride and 0.67 ml of acetic acid to obtain 3.10 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 and 1.37 (total
3H, each d, J = 6.6, 6.6Hz), 3.53-3.70 (1H, m), 3.70
and 3.72 (total 3H, each s), 4.87 and 5.12 (total 1
H, each s), 6.81-7.08 (5H, m), 7.20-7.47 (4H, m), 7.
60 and 7.70 (total 1H, each d, J = 8.0, 7.4Hz), 8.00
and 8.07 (total 1H, each dd, J = 1.9, 8.2and 1.8, 7.8
Hz), 8.26 and 8.28 (total 1H, each d, J = 2.1, 1.9H
z).

(29b) 3-[(2-methoxyphenyl)
)-((S) -1- (3-fluorophenyl) -ethyl
2.96 g of l -amino) methyl] phenylamine N-[(3-nitrophenyl)-(2-methoxyphenyl) methyl] -N-[(S) -1- (3-fluorophenyl) ethyl] amine in 50 ml of methanol It melt | dissolved, and reacted similarly to manufacture example (1b) using 3.70 g of nickel chloride hexahydrate and 1.24 g of sodium borohydride. The crude product was separated and purified by reverse phase HPLC [elution solvent: acetonitrile / acetate buffer aqueous solution (water: acetic acid: triethylamine = 1000: 2: 2) = 40/60], and the isomer (A) of the title compound was yellow. 5 as an oil
40 mg, isomer (B) 800 mg as a yellow oil
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.7H)
z), 3.65 (1H, q, J = 6.7Hz), 3.67 (3H, s), 4.85 (1H,
s), 6.48-6.50 (1H, m), 6.68-6.70 (2H, m), 6.85-7.06
(6H, m), 7.16-7.35 (3H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.7H)
z), 3.71-3.76 (1H, m), 3.73 (3H, s), 4.95 (1H, s), 6.
55-6.58 (1H, m), 6.73-7.28 (11H, m).

(29c) 3-methoxy-4- [3-
((2-methoxyphenyl)-((S) -1- (3-f
Fluorophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-[(2-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenylamine isomer (A) (400 mg) in methanol (10 ml)
Dissolved in 3,4-dimethoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 324 mg of 1,2-dione to obtain 470 mg of the title compound isomer (A) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 3.68 (3H, s), 4.42 (3H,
s), 4.85 (1H, s), 6.89-7.12 (7H, m), 7.18-7.31 (5H,
m).

3-[(2-methoxyphenyl)-
((S) -1- (3-fluorophenyl) ethylamino) methyl] phenylamine isomer (B) 730 mg
Is dissolved in 10 ml of methanol and 3,4-dimethoxy-
The reaction was carried out in the same manner as in Production Example (1c) using 592 mg of 3-cyclobutene-1,2-dione to obtain 850 mg of the isomer (B) of the title compound as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.7H)
z), 3.69 (1H, q, J = 6.7Hz), 3.72 (3H, s), 4.40 (3H,
s), 5.05 (1H, s), 6.82 (1H, d, J = 8.1Hz), 6.86-7.04 (4
H, m), 7.15-7.32 (7H, m).

(29d) 3-amino-4- [3-((2
-Methoxyphenyl)-((S) -1- (3-fluoro
Phenyl) ethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione 3-methoxy-4- [3-((2-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
390 mg of 1,2-dione isomer (A) was dissolved in 10 ml of ethanol, 2 ml of 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
323 mg of isomer (A) of the title compound as a yellow solid
Obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J = 6.5
Hz), 3.53 (1H, q, J = 6.5Hz), 3.62 (3H, s), 4.86 (1H,
s), 6.87 (1H, d, J = 7.7Hz), 6.94-7.25 (8H, m), 7.31-
7.37 (1H, m), 7.46 (1H, d, J = 7.9Hz), 7.55 (1H, d, J =
7.2 Hz). Melting point: 187-189 ° C Optical rotation: [α] _D : -32.8 (c = 0.5, EtO
H) 3-Methoxy-4- [3-((2-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
300 mg of 1,2-dione isomer (B) was dissolved in 10 ml of ethanol, 2 ml of 2N ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
235 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.28 (3H, d, J = 6.6
Hz), 3.58-3.62 (1H, m), 3.67 (3H, s), 4.90 (1H, s), 6.
88-6.95 (3H, m), 7.04 (2H, d, J = 8.1Hz), 7.15-7.36 (5
H, m), 7.40-7.45 (2H, m). Melting point: 190-193 ° C Optical rotation: [α] _D : +69.7 (c = 0.5, EtO
H).

Production Example 30 3-amino-4- [3- (4-methoxyphenyl-
((R) -1-cyclohexylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-436) (30a) N-[(3-nitrophenyl)-(4- methoxy)
[Xyphenyl) methyl] -N-((R) -1-cyclo
Xylethyl) amine 4-methoxy-3'-nitro-benzophenone 2.0 g
And 2.36 m of (R) -1-cyclohexylethylamine
1, 4.33 ml of triethylamine, titanium tetrachloride
03 ml, sodium cyanoborohydride 2.15
g, acetic acid 0.67 ml, and the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil (2.68 g).
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.97-1.82 (14H, m),
2.30-2.42 (1H, m), 3.77and 3.78 (total 3H, each s),
5.00 and 5.02 (total 1H, each s), 6.83-6.87 (2H, m),
7.26-7.29 (2H, m), 7.41-7.46 (1H, m), 7.76 (1H, dd,
J = 8.0, 8.2Hz), 8.05 (1H, d, J = 8.0Hz), 8.30-8.34 (1H,
m).

(30b) 3-[(4-methoxyphenyi)
)-((R) -1-cyclohexylethylamino) me
2.60 g of tyl ] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N-((R) -1-cyclohexylethyl) amine are dissolved in 50 ml of methanol,
The reaction was carried out in the same manner as in Production Example (1b) using 3.35 g of nickel chloride hexahydrate and 1.12 g of sodium borohydride, and 1.83 g of the title compound was obtained as a colorless oil.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.95-1.74 (14H, m),
2.34-2.44 (1H, m), 3.76and 3.77 (total 3H, each s),
4.82 (1H, s), 6.50-6.53 (1H, m), 6.73 (1H, s), 6.76-6.
84 (3H, m), 7.03-7.09 (1H, m), 7.29-7.31 (2H, m).

(30c) 3-methoxy-4- [3-
((4-methoxyphenyl)-((R) -1-cyclo
Xylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3- [4-methoxyphenyl)-((R) -1-cyclohexylethylamino) methyl] phenylamine 1.6
5 g was dissolved in 50 ml of methanol and reacted in the same manner as in Production Example (1c) using 1.39 g of 3,4-dimethoxy-3-cyclobutene-1,2-dione to give the title compound as a colorless foam. 1.77 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.96-1.36 (9H, m),
1.64-1.75 (5H, m), 2.38 (1H, q, J = 5.9Hz), 3.77 and
3.78 (total 3H, each s), 4.46 (3H, s), 4.91 (1H, s),
6.82-6.86 (2H, m), 7.11-7.33 (6H, m).

(30d) 3-amino-4- [3-((4
-Methoxyphenyl)-((R) -1-cyclohexyl
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
500 mg of-((R) -1-cyclohexylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione was dissolved in 20 ml of ethanol, and 5 ml of a 2N ammonia-ethanol solution was added thereto.
The reaction was carried out in the same manner as in d) to obtain 412 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.94-1.37 (9H, m),
1.60-1.77 (5H, m), 2.24-2.25 (1H, m), 3.71 (3H, s),
4.87 (1H, s), 6.85 (2H, d, J = 7.5Hz), 7.02-7.39 (6H,
m). Melting point: 194 ° -196 ° C. Optical rotation: [α] _D = −49.5 (c = 0.5, Et.
OH).

Production Example 31 3-amino-4- [3- (4-methoxyphenyl-
((S) -1-cyclohexylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-436) (31a) N-[(3-nitrophenyl)-(4- methoxy)
[Xyphenyl) methyl] -N-((S) -1-cyclo
Xylethyl) amine 4-methoxy-3'-nitro-benzophenone 2.0 g
And 2.4 of (S) -1-cyclohexyl-ethylamine
4 g, 4.33 ml of triethylamine, 1.03 ml of titanium tetrachloride, sodium borohydride 2.1
The reaction was carried out in the same manner as in Production Example (1a) using 5 g and 0.67 ml of acetic acid to give the title compound as a yellow oil (2.73).
g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.97-1.82 (14H, m),
2.30-2.42 (1H, m), 3.77and 3.78 (total 3H, each s),
5.00 and 5.02 (total 1H, each s), 6.82-6.87 (2H,
m), 7.27-7.29 (2H, m), 7.41-7.46 (1H, m), 7.76 (1H, d
d, J = 7.9, 8.2Hz), 8.03-8.06 (1H, m), 8.30-8.34 (1H,
m).

(31b) 3-[(4-methoxyphenyl)
-((S) -1-cyclohexylethylamino) methyl] f
Dissolve 2.63 g of enylamine N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N-((S) -1-cyclohexylethyl) amine in 50 ml of methanol,
The reaction was carried out in the same manner as in Production Example (1b) using 3.39 g of nickel chloride hexahydrate and 1.14 g of sodium borohydride, and 2.42 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.93-1.38 (9H, m),
1.64-1.74 (5H, m), 2.34-2.45 (1H, m), 3.76 and 3.77
(total 3H, each s), 4.82 (1H, s), 6.50-6.53 (1H, m),
6.73 (1H, s), 6.76-6.83 (3H, m), 7.04-7.10 (1H, m),
7.30 (2H, dd, J = 1.3, 8.6Hz).

(31c) 3-methoxy-4- [3-
((4-methoxyphenyl)-((S) -1-cyclo
Xylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((S) -1-cyclohexylethylamino) methyl] phenylamine
35 g was dissolved in 50 ml of methanol, and the reaction was carried out in the same manner as in Production Example (1c) using 1.13 g of 3,4-dimethoxy-3-cyclobutene-1,2-dione to give the title compound as a yellow foam. 1.01 g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.96-1.36 (9H, m),
1.64-1.75 (5H, m), 2.38 (1H, q, J = 5.6Hz), 3.77 and
3.78 (total 3H, each s), 4.46 (3H, s), 4.91 (1H, s),
6.82-6.86 (2H, m), 7.18-7.33 (6H, m).

(31d) 3-amino-4- [3- (4-
Methoxyphenyl-((S) -1-cyclohexylethyl
Lamino) methyl) phenylamino] -3-cyclobute
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
960 mg of-((S) -1-cyclohexylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione was dissolved in 20 ml of ethanol, and 5 ml of a 2N ammonia-ethanol solution was added.
The reaction was carried out in the same manner as in d) to obtain 780 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.89-1.37 (9H, m),
1.60-1.77 (5H, m), 2.22-2.29 (1H, m), 3.70 (3H, s),
4.87 (1H, s), 6.85 (2H, d, J = 8.2Hz), 7.01-7.39 (6H,
m). Melting point: 191-193 ° C. Optical rotation: [α] _D = + 58.9 (c = 0.55, Et
OH).

Production Example 32 3-Amino-4- [3- (cyclohexyl- (1-
(3,4-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-1252) (32a) 3- [cyclohexyl- (1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
Min-cyclohexyl-3-nitrophenyl ketone 3.0 g,
4.98 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 10.8 ml of triethylamine, 1.70 ml of titanium tetrachloride, nickel chloride hexahydrate 6.11
g and 2.05 g of sodium borohydride, and the reaction was carried out in the same manner as in Production Example (25a) to obtain 1.59 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.81-1.69 (12H, m),
1.72-1.76 (1H, m), 2.03 (1H, d, J = 12.7Hz), 3.31 (1H,
d, J = 7.4Hz), 3.56 (1H, q, J = 6.4Hz), 6.49 (1H, d, J = 1.
9Hz), 6.55 (2H, dd, J = 2.5, 7.3Hz), 6.90-6.93 (1H,
m), 6.97-7.12 (3H, m).

(32b) 3-methoxy-4- [3-
((Cyclohexyl- (1- (3,4-difluorophenyl
Nyl) ethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3- [cyclohexyl- (1- (3,4-difluorophenyl) ethylamino) -methyl] phenylamine 50
0 mg was dissolved in 50 ml of methanol, and the reaction was carried out in the same manner as in Production Example (1c) using 413 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione to obtain 650 mg of the title compound as a yellow foam. . NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.65 (12H, m),
1.75-1.78 (1H, m), 1.95 (1H, d, J = 6.5Hz), 3.43 (1H,
d, J = 7.3Hz), 3.54 (1H, q, J = 6.4Hz), 4.46 (3H, s), 6.
87-7.14 (6H, m), 7.23-7.26 (1H, m).

(32c) 3-amino-4- [3- (cyclo
Rohexyl- (1- (3,4-difluorophenyl) e
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-methoxy-4- [3- (cyclohexyl- (1-
300 mg of (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione was dissolved in 10 ml of ethanol, and 2 ml of 2N ammonia-ethanol solution was added.
The reaction was carried out in the same manner as in d) to obtain 230 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.76-1.58 (12H,
m), 1.70 (1H, d, J = 12.4Hz), 2.02 (1H, d, J = 11.6Hz),
3.37 (1H, d, J = 7.3Hz), 3.52 (1H, q, J = 6.4Hz), 6.86 (1
H, d, J = 7.6Hz), 7.05-7.08 (1H, m), 7.19-7.37 (5H,
m). Melting point: 202-205 ° C.

Production Example 33 3-amino-4- [3-((4-methoxyphenyl)-
(1- (4-hydroxyphenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-1816) (33a) N-[(3-nitrophenyl)-(4-meth
[Xyphenyl) methyl] -N- [1- (4-acetylo
[Xyphenyl) ethyl] amine 4-methoxy-3'-nitrobenzophenone 500 mg
And acetic acid 4- (1-aminoethyl) phenyl ester
Production Example (1) using 1.0 g of hydrochloride, 1.63 ml of triethylamine, 0.26 ml of titanium tetrachloride, 543 mg of sodium borohydride cyanide, and 0.17 ml of acetic acid.
The reaction was carried out in the same manner as in a) to give 215 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 and 1.37 (total
3H, each d, J = 6.6, 6.6Hz), 2.30 and 2.32 (total 3
H, each s), 3.60-3.72 (1H, m), 3.76 and 3.81 (total
3H, each s), 4.64 and 4.69 (total 1H, each s), 6.81
and 6.89 (total 2H, each d, J = 8.7, 8.7Hz), 7.04 an
d 7.07 (total 2H, each d, J = 8.6, 8.6Hz), 7.14-7.27 (4
H, m), 7.38 and 7.47 (total 1H, each t, J = 8.0 and
8.0Hz), 7.57 and 7.66 (total 1H, each d, J = 7.6, 7.9
Hz), 8.01-8.10 (1H, m), 8.23-8.27 (1H, m).

(33b) 3-[(4-methoxyphenyi)
)-(1- (4-acetyloxyphenyl) ethyla
Mino) methyl] phenylamine 200 mg of N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N- [1- (4-acetyloxyphenyl) ethyl] amine was dissolved in 10 ml of ethanol, and tin chloride was dissolved. 451 mg was added, and the mixture was heated under reflux for 1 hour.
Ethyl acetate-saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the precipitated insoluble material was separated by filtration. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound as a yellow oil.
0 mg was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 2.30 (3H, s), 3.53-3.73 (1H, m), 3.75 and 3.79 (t
otal 3H, each s), 4.47 and, 4.49 (total 1H, each
s), 6.48-6.87 (6H, m), 7.01-7.28 (6H, m).

(33c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (4-acetylo
Xyphenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione 160 mg of 3-[(4-methoxyphenyl)-(1- (4-acetyloxyphenyl) ethylamino) methyl] phenylamine was dissolved in 5 ml of methanol. 4
-Dimethoxy-3-cyclobutene-1,2-dione 11
The reaction was carried out in the same manner as in Production Example (1c) using 6 mg, and
172 mg of the title compound was obtained as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 and 1.36 (total
3H, each d, J = 6.6, 6.7Hz), 2.31 (3H, s), 3.65-3.70
(1H, m), 3.76 and 3.81 (total 3H, each s), 4.42 an
d 4.42 (total 3H, each s), 4.58 and 4.59 (total 1H,
each s), 6.80 and 6.88 (total 2H, each d, J = 8.5,
8.7Hz), 7.00-7.33 (10H, m).

(33d) 3-Amino-4- [3-((4
-Methoxyphenyl)-(1- (4-hydroxyphenyl)
Ru) ethylamino) methyl) phenylamino] -3-si
Clobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (4-acetyloxyphenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
Dissolve 160 mg of 1,2-dione in 5 ml of ethanol, add 2 ml of 2N ammonia-ethanol solution,
Stirred overnight at room temperature. The solvent was distilled off under reduced pressure, the residue was triturated with a mixed solvent of diethyl ether-ethyl acetate, collected by filtration, and the solid was washed with diethyl ether to obtain 115 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.23-1.26 (3H, m),
3.36-3.45 (1H, m), 3.69 and 3.73 (total 3H, each
s), 4.40 and 4.44 (total 1H, each s), 6.70 (2H, d, J =
8.0Hz), 6.80-7.45 (10H, m). Melting point: 127-129 ° C.

Production Example 34 3-amino-4- [3- (4-methoxyphenyl- (1
-(3,4-difluorophenyl) ethyloxy) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-1379) (34a) N-[(3-nitrophenyl)-(4-meth
[Xyphenyl) methyl] -N- [1- (3,4-difur
(Orophenyl) ethyl] ether 920 mg of 1- (3,4-difluorophenyl) ethyl alcohol and 151 mg of 4-methoxy-3′-nitro-diphenylmethanol are dissolved in 50 ml of anhydrous benzene, and 29 mg of methyltrioxorhenium (VII) is added. For 3 days and further for 4 hours under reflux with heating. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 10/1 to 8/1) to obtain 160 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.45 and 1.48 (total
3H, each d, J = 6.5, 6.5Hz), 3.77 and 3.82 (total 3
H, each s), 4.40 (1H, q, J = 6.5Hz), 5.18 and 5.33 (to
tal 1H, each s), 6.83 and, 6.92 (total 2H, each d,
J = 8.7, 8.7Hz), 6.96-7.01 (1H, m), 7.09-7.22 (4H, m),
7.41-7.68 (2H, m), 8.06-8.22 (2H, m).

(34b) 3-[(4-methoxyphenyi)
)-(1- (3,4-difluorophenyl) ethyl)
[Xy] methyl] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] ether 150 mg and methanol 10 ml
And 179 mg of nickel chloride hexahydrate and 60 mg of sodium borohydride were reacted in the same manner as in Production Example (1b) to give the title compound as a yellow oil in the form of 1
25 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.42 and 1.43 (total
3H, each d, J = 6.4, 6.5Hz), 3.76 and 3.81 (total 3
H, each s), 4.36-4.46 (1H, m), 5.08 and 5.09 (total
1H, each s), 6.52-6.73 (3H, m), 6.80 and 6.88 (total
2H, each d, J = 8.5, 8.7Hz), 6.99-7.23 (6H, m).

(34c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethyloxy) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethyloxy) methyl] phenylamine (115 mg) was dissolved in methanol (10 ml).
-Dimethoxy-3-cyclobutene-1,2-dione 8
The reaction was carried out in the same manner as in Production Example (1c) using 8.5 mg to obtain 135 mg of the title compound as a yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.44 and 1.46 (total
3H, each d, J = 6.5, 6.5Hz), 3.77 and 3.82 (total 3
H, each s), 4.38-4.42 (1H, m), 4.436 and 4.441 (tota
l 3H, each s), 5.13 and 5.21 (total 1H, each s), 6.
82 and 6.91 (total2H, each d, J = 8.7, 8.7Hz), 6.98-
7.38 (9H, m).

(34d) 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethyloxy) methyl) phenylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethyloxy) methyl) phenylamino] -3-cyclobutene-
130 mg of 1,2-dione was dissolved in 5 ml of ethanol, and 1 ml of 2N ammonia-ethanol solution was added.
The reaction was carried out in the same manner as in Production Example (1d) to obtain 104 mg of the title compound as a yellow solid. NMR spectrum _{(DMSO-d 6) δppm:} 1.37 and 1.41 (tot
al 3H, each d, J = 6.4,6.5Hz), 3.70 and 3.74 (total 3
H, each s), 4.42-4.51 (1H, m), 5.21 and 5.25 (total
1H, each s), 6.83-6.99 (3H, m), 7.17-7.46 (8H, m). Melting point: 170-172 ° C.

Production Example 35 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-1359) (35a) N-[(3-nitrophenyl)-(4- methoate)
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 3-nitro-4'-methoxybenzophenone 6.40 g
And 8.71 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride were dissolved in 120 ml of anhydrous dichloromethane and 17.3 ml of triethylamine. The reaction solution was cooled on ice, and 3.0 ml of titanium tetrachloride in 30 ml of anhydrous dichloromethane was added.
After slowly dropping the diluted solution, the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 10.7 g of an imine compound as a dark brown oil. The obtained oil was dissolved in 80 ml of methanol, 6.28 g of sodium borohydride cyanide and 2.1 ml of acetic acid were added, and the mixture was heated under reflux for 1 hour. The solvent of the reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 8/1) to obtain 7.17 g of a diastereomer mixture of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 and 1.36 (total
3H, each d, J = 6.6Hz), 3.54-3.67 (1H, m), .3.77 and
3.82 (total 3H, each s), 4.60 and 4.66 (total1H, eac
hs), 6.82 and 6.90 (total 2H, each d, J = 8.7Hz), 6.
80-7.17 (3H, m), 7.15 (2H, each d, J = 8.7Hz), 7.40 an
d 7.49 (total 1H, each t, J = 8.0Hz), 7.59 and 7.65 (t
otal 1H, each d, J = 8.0Hz), 8.02 and 8.10 (total 1H,
each dd, J = 1.9,8.0Hz), 8.22 and 8.24 (total 1H, ea
ch d, J = 1.9Hz).

(35b) 3-[(4-methoxyphenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl] phenylamine 6.84 g of N-[(3-nitrophenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine is dissolved in 140 ml of methanol. And 8.26 g of nickel chloride hexahydrate and 2.60 g of sodium borohydride were added and reacted in the same manner as in Production Example (15b) to purify the compound. 2.35 g of the product and 3.16 g of the highly polar isomer (B) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.67 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.44 (1H,
s), 6.58 (1H, d, J = 8.0Hz), 6.61 (1H, s), 6.67 (1H, d,
J = 7.7Hz), 6.79 (2H, d, J = 8.6Hz), 6.79-7.21 (4H, m),
7.18 (2H, d, J = 8.6 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.7H)
z), 3.62 (1H, q, J = 6.7Hz), 3.80 (3H, s), 4.44 (1H,
s), 6.51 (1H, dd, J = 1.7,7.3Hz), 6.61 (1H, d, J = 1.7H
z), 6.65 (1H, d, J = 7.3Hz), 6.86 (2H, d, J = 8.8Hz), 6.
91-7.23 (4H, m), 7.19 (2H, d, J = 8.8Hz).

(35c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) phenylami
252 mg of the isomer (A) of [ no] -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine in 8 ml of methanol Dissolved in 3,4-dimethoxy-3-cyclobutene-1,2
To this was added 194 mg of -dione, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 301 mg of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.63 (1H, q, J = 6.7Hz), 3.76 (3H, s), 4.44 (3H,
s), 4.55 (1H, s), 6.81 (2H, d, J = 8.7Hz), 6.90-7.34
(7H, m), 7.17 (2H, d, J = 8.7 Hz). 3-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine isomer ( B) 247 mg was dissolved in 10 ml of methanol, and 3,4-dimethoxy-3-cyclobutene-1,
190 mg of 2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 259 mg of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 3.81 (3H, s), 4.44 (3H,
s), 4.52 (1H, s), 6.89 (2H, d, J = 8.7Hz), 6.89-7.52
(7H, m), 7.17 (2H, d, J = 8.7Hz).

Production Example 36 3- (N-methylamino) -4- [3-((4-methoxy
Cyphenyl)-(1- (3,4-difluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione (Exemplary Compound No. 2-247)
8) The 3-methoxy-4- [3-((4-
Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-
178 mg of isomer (B) of cyclobutene-1,2-dione
Was dissolved in 7.5 ml of ethanol, and 2N methylamine- was dissolved.
2.5 ml of an ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
g was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.5
Hz), 3.21 (3H, s), 3.51 (1H, q, J = 6.5Hz), 3.73 (3H,
s), 4.39 (1H, s), 6.87 (2H, d, J = 8.4Hz), 6.91 (1H, d,
J = 7.8Hz), 6.94-7.57 (6H, m), 7.25 (2H, d, J = 8.4H
z).

Production Example 37 3- (N, N-dimethylamino) -4- [3-((4-
Methoxyphenyl)-(1- (3,4-difluorophene)
Nyl) ethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-2)
676) The 3-methoxy-4- [3-((4-
Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-
Isomer of cyclobutene-1,2-dione (B) 181m
was dissolved in 8 ml of ethanol, and 2.5 ml of a 2N dimethylamine-methanol solution was added. The reaction was carried out in the same manner as in Production Example (1d).
mg. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.5
Hz), 3.21 (6H, s), 3.51 (1H, q, J = 6.5Hz), 3.72 (3H,
s), 4.38 (1H, s), 6.87 (2H, d, J = 8.5Hz), 6.95 (1H, d,
J = 7.4Hz), 6.98-7.54 (6H, m), 7.25 (2H, d, J = 8.5Hz). Melting point: 98-100 ° C.

Production Example 38 3-Amino-4- [N- (3-((4-methoxyphenyi)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenyl) -N-methylamino] -3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-2)
142) (38a) [3-((4-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
L) phenyl] carbamic acid methyl ester Production Example (35b) of 3-[(4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl] phenylamine was dissolved in 10 ml of N, N-dimethylacetamide, and 1.1 ml of methyl chloroformate was added under ice cooling.
Was added dropwise, followed by stirring for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to obtain 563 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.3H
z), 3.62 (1H, q, J = 6.3Hz), 3.80 (3H, s), 3.85 (3H,
s), 4.56 (1H, s), 6.91 (2H, d, J = 8.7Hz), 6.78-7.30
(9H, m).

(38b) N-methyl-N- [3-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) phenyl] amine [3-((4-methoxyphenyl)-(1- (3,4-
560 mg of difluorophenyl) ethylamino) methyl) phenyl] carbamic acid methyl ester was dissolved in 15 ml of anhydrous tetrahydrofuran, 250 mg of lithium aluminum hydride was added, and the mixture was heated under reflux for 4 hours. After adding 4.0 g of sodium sulfate decahydrate under ice cooling, the insolubles were filtered through celite. The filtrate was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4
/ 1) to give the title compound as a yellow oil (215m).
g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 2.78 (3H, s), 3.64 (1H, q, J = 6.6Hz), 3.80 (3H,
s), 4.47 (1H, s), 6.85 (2H, d, J = 8.7Hz), 6.80-7.26 (7
H, m), 7.21 (2H, d, J = 8.7Hz).

(38c) 3-methoxy-4- [N-methyl
Ru-N- (3-((4-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
Ru) -phenyl) amino] -3-cyclobutene-1,2
-Dione N- [3-((4-methoxyphenyl)-(1- (3,
4-difluorophenyl) ethylamino) methyl) phenyl] -N-methylamine (210 mg)
of the title compound as a white foam by reacting as in Production Example (1c).
92 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.68-3.72 (1H, m), 3.81 (3H, s), 4.18-4.32 (3H, b
r), 4.53 (1H, s), 6.88 (2H, d, J = 8.6Hz), 6.90-7.28 (7
H, m), 7.18 (2H, d, J = 8.6Hz).

(38d) 3-amino-4- [N- (3-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) phenyl) -N
-Methylamino] -3-cyclobutene-1,2-dione 3-methoxy-4- [N-methyl-N- (3-((4-
Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenyl) amino] -3
188 mg of cyclobutene-1,2-dione is dissolved in 6 ml of ethanol, and a 2N ammonia-ethanol solution is dissolved.
2 ml was added, and the reaction was carried out in the same manner as in Production Example (1d).
140 mg of the title compound was obtained as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.5
Hz), 3.53 (1H, q, J = 6.5Hz), 3.61 (3H, s), 3.72 (3H,
s), 4.44 (1H, s), 6.87 (2H, d, J = 8.5Hz), 6.98 (1H, d,
J = 8.0 Hz), 7.05-7.48 (6H, m), 7.27 (2H, d, J = 8.0 Hz). Melting point: 164-167 ° C.

Production Example 39 3-amino-4- [4-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) -phenylamino] -3-cyclobutene-1,
2-dione (Exemplified Compound No. 3-208) (39a) N-[(4-nitrophenyl)-(4- methoate)
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 4-nitro-4'-methoxybenzophenone 2.13
g, 2.90 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 5.8 ml of triethylamine, 1.0 ml of titanium tetrachloride, 2.09 g of sodium borohydride cyanide, and 0.7 ml of acetic acid. The reaction was carried out in the same manner as in (1a) to obtain 3.21 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.34 and 1.35 (total
3H, each d, J = 6.6Hz), 3.58 and 3.66 (total 1H, each
q, J = 6.6Hz), 3.76 and 3.81 (total 3H, each s), 4.61
and 4.64 (total 1H, each s), 6.82 and 6.88 (total 2
H, each d, J = 7.9Hz), 6.85-7.18 (5H, m), 7.54 and 7.
56 (total 2H, each d, J = 7.8Hz), 8.09 and 8.19 (total
2H, each d, J = 7.80Hz).

(39b) 4-[(4-methoxyphenyi)
)-(1- (3,4-difluorophenyl) ethyla
3.20 g of mino) methyl] phenylamine N-[(4-nitrophenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine are dissolved in 60 ml of methanol. And 3.81 g of nickel chloride hexahydrate and 1.21 g of sodium borohydride were reacted and purified in the same manner as in Production Example (1b) to obtain a low-polar isomer (A) of the title compound.
As pale yellow oil, 720 mg, highly polar isomer (B)
Was obtained as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.43 (1H,
s), 6.65 (2H, d, J = 8.5Hz), 6.78 (2H, d, J = 8.6Hz), 7.0
2-7.21 (3H, m), 7.04 (2H, d, J = 8.5Hz), 7.17 (2H, d, J
Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J = 6.6H)
z), 3.61 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.44 (1H,
s), 6.58 (2H, d, J = 8.4Hz), 6.86 (2H, d, J = 8.6Hz), 7.
02-7.20 (3H, m), 7.03 (2H, d, J = 8.4Hz), 7.18 (2H, d,
J = 8.6Hz).

(39c) 3-methoxy-4- [4-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) phenylami
710 mg of isomer (A) of [ no] -3-cyclobutene-1,2-dione 4-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine in 15 ml of methanol Dissolved in 3,4-dimethoxy-3-cyclobutene-1,
410 mg of 2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 597 mg of the title compound isomer (A) as a colorless oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.61 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.51 (3H,
s), 4.54 (1H, s), 6.80 (2H, d, J = 8.6Hz), 6.89-7.32 (7
H, m), 7.16 (2H, d, J = 8.6 Hz). An isomer of 4-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine (B 790 mg) was dissolved in 15 ml of methanol, and 3,4-dimethoxy-3-cyclobutene-1,
456 mg of 2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 480 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.7H)
z), 3.63 (1H, q, J = 6.7Hz), 3.81 (3H, s), 4.49 (3H,
s), 4.51 (1H, s), 6.88 (2H, d, J = 8.5Hz), 6.85-7.28 (7
H, m), 7.17 (2H, d, J = 8.5Hz).

(39d) 3-Amino-4- [4-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [4-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
570 mg of 1,2-dione isomer (A) was dissolved in 5 ml of ethanol, and 1.5 ml of a 2N ammonia-ethanol solution was added. A) as a pale yellow solid 24
6 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J = 6.6)
Hz), 3.52 (1H, q, J = 6.6Hz), 3.67 (3H, s), 4.40 (1H,
s), 6.81 (2H, d, J = 8.6Hz), 7.02-7.42 (7H, m), 7.20 (2H
H, d, J = 8.6 Hz). Melting point: 146 ° C. (dec) 3-methoxy-4- [4-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
390 mg of 1,2-dione isomer (B) is dissolved in 5 ml of ethanol, and 2N ammonia-ethanol solution 5
The reaction was carried out in the same manner as in Production Example (1d) to obtain 298 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.6
Hz), 3.51 (1H, q, J = 6.6Hz), 3.73 (3H, s), .4.39 (1H,
s), 6.87 (2H, d, J = 8.6Hz), 7.03-7.42 (7H, m), 7.23 (2
H, d, J = 8.6 Hz). Melting point: 205 ° C. (dec).

Production Example 40 3-Amino-4- [2-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 1-86) (40a) 2-[(4-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
Le] phenylamine 2-amino-4'-methoxybenzophenone 2.12
g, 3.60 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 7.8 ml of triethylamine, 1.1 ml of titanium tetrachloride, 2.34 g of sodium borohydride cyanide, and 0.8 ml of acetic acid. The reaction was carried out in the same manner as in (1a) to obtain 2.05 g of a diastereomer mixture of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.34 and 1.36 (total
3H, each d, J = 6.6Hz), 3.61-3.74 (1H, m), 3.78 and
3.83 (total3H, each s), 4.11 and 4.14 (total1H, eac
hs), 6.59-7.24 (9H, m), 6.84 and 6.92 (total 2H, d,
J = 8.6Hz).

(40b) 3-methoxy-4- [2-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) phenylami
1.30 g of [ no] -3-cyclobutene-1,2-dione 2-[(4-methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamine was dissolved in 20 ml of methanol, 3,4
-Dimethoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Production Example (1c).
The diastereomeric mixture of the title compound as a white solid 9
52 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.51 and 1.53 (total
3H, each d, J = 6.5Hz), 3.61-3.73 (1H, m), 3.84 and 3.
91 (total 3H, each s), 4.55 and 4.57 (total 3H, s),
4.73 and 4.84 (total 1H, each s), 6.64-7.37 (11H,
m).

(40c) 3-amino-4- [2-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [2-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
Dissolve 305 mg of 1,2-dione in 6 ml of methylene chloride, add 3 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Production Example (1d) to obtain 204 mg of a diastereomer mixture of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 and 1.32 (tot
al 3H, each d, J = 6.5Hz), 3.45 and 3.59 (total 1H,
q, J = 6.5Hz), 3.69 and 3.74 (total 3H, s), 4.77 (1H,
s), 6.84 and 6.91 (total 2H, d, J = 8.6Hz), 6.97-7.34
(9H, m). Melting point: 106-111 ° C (dec).

Production Example 41 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) benzylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 2-2027) (41a) N-[(3-cyanophenyl)-(4- methoate)
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 3-cyano-4′-methoxybenzophenone 1.40 g
And 1.83 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 4.1 ml of triethylamine, 0.7 ml of titanium tetrachloride, 1.49 g of sodium borohydride cyanide, and 0.5 ml of acetic acid. The reaction was carried out in the same manner as in 1a) to obtain 2.16 g of a diastereomer mixture of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 and 1.35 (total
3H, each d, J = 6.6Hz), 3.57 and 3.63 (total 1H, each
q, J = 6.6Hz), 3.77 and 3.82 (total 3H, eachs), 4.52
and 4.58 (total 1H, each s), 6.81 and 6.89 (total 2
H, d, J = 8.7Hz), 6.87-7.52 (8H, m), 7.63 and 7.68 (to
tal 1H, each s).

(41b) N-[(3-Aminomethyl-f
Enyl)-(4-methoxyphenyl) methyl] -N-
[1- (3,4-Difluorophenyl) ethyl] amine N-[(3-cyanophenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine 1 .65 g was dissolved in anhydrous tetrahydrofuran (20 ml), and a 1 N lithium aluminum hydride / tetrahydrofuran solution (15 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 4 hours. 15 g of sodium sulfate decahydrate was added to the reaction solution, the insolubles were filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 20/1) to obtain 1.59 g of a diastereomer mixture of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.7H)
z), 3.63 (1H, q, J = 6.7Hz), 3.76 and 3.81 (total 3H,
each s), 3.80 and 3.85 (total 2H, each s), 4.53 and
4.56 (total 1H, s), 6.79 and 6.86 (total 2H, d, J =
8.5Hz), 6.89-7.32 (9H, m).

(41c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) benzylamido
290 mg of [ no] -3-cyclobutene-1,2-dione N-[(3-aminomethylphenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine 8m methanol
1,3,4-dimethoxy-3-cyclobutene-
216 mg of 1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 272 mg of a diastereomer mixture of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.57-3.68 (1H, m), 3.76 and 3.81 (total 3H, each
s), 4.37 and 4.38 (total 3H, each s), 4.47-4.60 (2
H, br), 4.53 and 4.57 (total 1H, each s), 6.80 and
6.88 (total 2H, d, J = 8.5Hz), 6.88-7.35 (9H, m).

(41d) 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) benzylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) benzylamino] -3-cyclobutene-
Dissolve 268 mg of 1,2-dione in 4 ml of ethanol, add 4 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Production Example (1d) to obtain 160 mg of a diastereomer mixture of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.0
Hz), 3.38-3.51 (1H, m), 3.68 and 3.72 (total 3H, ea
ch s), 4.41 and 4.42 (total 1H, each s), 4.55-4.72
(2H, br s), 6.80 and 6.85 (total 2H, each d, J = 8.5H
z), 6.94-7.38 (9H, m). Melting point: 191-194 ° C.

Production Example 42 3- (N-methylamino) -4- [3-((4-methoxy
Cyphenyl)-(1- (3,4-difluorophenyl)
Ethylamino) methyl) benzylamino] -3-cyclo
Butene-1,2-dione (Exemplary Compound No. 2-258)
3) The 3-methoxy-4- [3-((4-
Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) benzylamino] -3-
300 mg of cyclobutene-1,2-dione was dissolved in 5 ml of methanol, 5 ml of a 2N methylamine-methanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d).
190 mg of a diastereomer mixture of the title compound was obtained as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.0
Hz), 3.11 (3H, s), 3.42-3.53 (1H, m), 3.68 and 3.72
(total 1H, each s), 4.41 and 4.43 (total 1H, each
s), 4.63 and 4.66 (total 2H, each s), 6.80 and 6.85
(total 2H, each d, J = 8.6Hz), 6.98-7.38 (9H, m). Melting point: 101-103 ° C.

Production Example 43 3-amino-4- [4-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) benzylamino] -3-cyclobutene-1,2
-Dione (Exemplified Compound No. 3-292) (43a) N-[(4-cyanophenyl)-(4- methoate)
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 4-cyano-4′-methoxybenzophenone 1.18 g
And 1.54 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 3.6 ml of triethylamine, 0.4 ml of titanium tetrachloride, 1.25 g of sodium borohydride cyanide, and 0.4 ml of acetic acid. The reaction was carried out in the same manner as in 1a) to obtain 1.76 g of a diastereomer mixture of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 and 1.34 (total
3H, each d, J = 6.5Hz), 3.51-3.67 (1H, m), 3.76 and
3.81 (total3H, each s), 4.55 and 4.59 (total1H, eac
hs), 6.80 and 6.88 (total 2H, each d, J = 8.5Hz), 6.
80-7.18 (3H, m), 7.12 and 7.13 (total 2H, each d, J =
7.9Hz), 7.41 and 7.44 (total 2H, eachd, J = 7.9Hz),
7.54 and 7.62 (total 2H, d, J = 7.9Hz).

(43b) N-[(4-aminomethyl-f
Enyl)-(4-methoxyphenyl) methyl] -N-
[1- (3,4-difluorophenyl) ethyl] amine
1.74 g of dihydrochloride N-[(4-cyanophenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine is dissolved in 40 ml of anhydrous tetrahydrofuran, 700 mg of lithium aluminum hydride was added under cooling, and the mixture was stirred at room temperature for 2 hours. 10 g of sodium sulfate decahydrate was added to the reaction solution, the insolubles were filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a small amount of ether, and 4N hydrochloric acid / ethyl acetate (3 ml) was added.
The resulting precipitate was collected by filtration. The solid was washed with ether and dried to give 2.01 g of a diastereomer mixture of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.71 (3H, d, J = 6.3)
Hz), 3.73 and 3.75 (total 3H, each s), 3.91-4.06 (2
H, m), 4.09-4.22 (1H, m), 5.02-5.18 (1H, m), 6.92 an
d 6.96 (total 2H, each d, J = 8.2Hz), 7.09-7.21 (1H,
m), 7.45-7.81 (2H, m), 7.47 and 7.52 (total 2H, each
d, J = 8.2Hz), 7.58 and 7.62 (total 2H, each d, J = 8.2
Hz), 7.74 and 7.75 (total 2H, each d, J = 8.2Hz).

(43c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(1- (3,4-difur
Orophenyl) ethylamino) methyl) benzylamido
No] -3-cyclobutene-1,2-dione N-[(4-aminomethylphenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine 2HCl To 790 mg of the salt was added 5 ml of a 1 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 670 mg of the obtained yellow oily substance was dissolved in 15 ml of methanol, and 3,4-dimethoxy-3-cyclobutene-1,2-
332 mg of dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to obtain 615 mg of a diastereomer mixture of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.6H)
z), 3.54-3.63 (1H, m), 3.76 and 3.80 (total 3H, each
s), 4.40 and 4.42 (total 3H, each s), 4.41-4.60 (2
H, br), 4.54 (1H, s), 6.79 and 6.87 (total 2H, d, J =
8.7Hz), 6.85-7.35 (9H, m).

(43d) 3-amino-4- [4-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) benzylamino] -3
-Cyclobutene-1,2-dione 3-methoxy-4- [4-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamino) methyl) benzylamino] -3-cyclobutene-
608 mg of 1,2-dione was dissolved in 6 ml of ethanol, and 4 ml of a 2N ammonia-ethanol solution was added.
The reaction was carried out in the same manner as in Production Example (1d) to obtain 450 mg of a diastereomer mixture of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.4
Hz), 3.51 (1H, q, J = 6.4Hz), 3.68 and 3.71 (total 3H,
each s), 4.43 (1H, s), 4.62 and 4.64 (total 2H, eac
hs), 7.19 and 7.23 (total 2H, each d, J = 8.1Hz), 6.
93-7.82 (9H, m). Melting point: 220-225 ° C.

Production Example 44 N- [3- (2-amino-3,4-dioxo-1-cyclyl)
Robutenylamino) phenyl] -N- (4-methoxyphenyl
Enyl) -2-phenylpropionamide (exemplified compound number
No. 2-588) (44a) 3-methoxy-4- [3- (4-methoxyphenyl)
Enylamino) phenyl] amino-3-cyclobutene-
1,2-dione 3-amino-4'-methoxybiphenylamine 508m
g was dissolved in 12 ml of methanol, and 531 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione was added at room temperature. After stirring the reaction solution at 50 ° C. for 1 hour, the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: methylene chloride / ethyl acetate = 1/1)
And purified the title compound as a yellow solid. 589
mg. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.72 (3H, s), 4.35
(3H, s), 6.62 (1H, d, J = 8.1Hz), 6.65-6.80 (1H, m),
6.85-7.18 (2H, m), 6.88 (2H, d, J = 8.7Hz), 7.07 (2H, m
d, J = 8.7Hz).

(44b) N- [3- (2-methoxy-
3,4-dioxo-1-cyclobutenylamino) phenyl
] -N- (4-methoxyphenyl) -2-phenylp
900 mg of ropionamide 2-phenylpropionic acid was added to methylene chloride 1
0 ml, oxalic acid chloride 0.8 ml, N, N
-One drop of dimethylformamide was added and the mixture was stirred at room temperature for 2 hours. The yellow oil obtained after concentration under reduced pressure was dissolved in 4 ml of N, N-dimethylacetamide to give 3-methoxy-4- [3
-(4-methoxyphenylamino) phenyl] amino-
576 mg of 3-cyclobutene-1,2-dione N, N
-Dimethylacetamide (4 ml) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 3 hours. After adding a saturated aqueous solution of sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: methylene chloride / ethyl acetate = 2/1) to obtain 603 mg of the title compound as a purple foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 4.41 (3H, s), 4.61 (3H,
s), 7.08 (1H, d, J = 7.6Hz), 7.22-7.37 (13H, m).

(44c) N- [3- (2-amino-3,
4-dioxo-1-cyclobutenylamino) phenyl]
-N- (4-methoxyphenyl) -2-phenylpropyl
Onamide N- [3- (2-methoxy-3,4-dioxo-1-cyclobutenylamino) phenyl] -N- (4-methoxyphenyl) -2-phenylpropionamide (600 mg) was dissolved in ethanol (4 ml). 6 ml of a normal ammonia-ethanol solution was added, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 521 mg of the title compound as a yellow solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J = 6.6H)
z), 3.57 (1H, q, J = 6.2Hz), 4.49 (3H, s), 6.98 (1H, d,
J = 7.5Hz), 7.15-7.43 (13H, m). Melting point: 168-170 ° C.

Production Example 45 3-amino-4- [3-((3-fluorobenzylamido)
No)-(4-methoxyphenyl) methyl) phenylamido
No] -3-cyclobutene-1,2-dione (exemplary compound
No. 2-813) (45a) N- (3-fluorobenzyl) -N-[(4-
Methoxyphenyl) -3- (nitrophenyl) methyl]
2.57 g of amine 3-nitro-4'-methoxybenzophenone
And 2.35 g of 3-fluorobenzylamine were reacted in the same manner as in Production Example (1a) to obtain 3.29 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.73 (2H, s), 3.78 (3
H, s), 4.89 (1H, s), 6.83-7.12 (5H, m), 7.28-7.34 (3
H, m), 7.47 (1H, t, J = 7.9Hz), 7.77 (1H, d, J = 7.9Hz),
8.06-8.09 (1H, m), 8.33 (1H, t, J = 1.7Hz).

(45b) 3-[(3-fluorobenzyl)
Amino)-(4-methoxyphenyl) methyl] phenyl
Amine (3-fluoro-benzyl)-[(4-methoxyphenyl) -3- (nitrophenyl) methyl] amine 3.27
Using g, the reaction was carried out in the same manner as in Production Example (1b) to obtain 2.74 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.73 (2H, s), 3.77 (3
H, s), 4.71 (1H, s), 6.54 (1H, dd, J = 8.2, 1.9Hz), 6.
74-6.96 (5H, m), 7.06-7.13 (2H, m), 7.23-7.34 (4H,
m).

(45c) 3- [3-((3-fluoro
Benzylamino)-(4-methoxyphenyl) methyl)
Enylamino] -4-methoxy-3-cyclobutene-
409 mg of 1,2-dione 3-[(3-fluorobenzylamino)-(4-methoxyphenyl) methyl] phenylamine and 3,
4-dimethoxy-3-cyclobutene-1,2-dione 1
The reaction was carried out in the same manner as in Production Example (1c) using 73 mg,
490 mg of the title compound was obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.73 (2H, s), 3.79 (3
H, s), 4.42 (3H, s), 4.80 (1H, s), 6.86 (2H, dt, J =
8.7, 2.3Hz), 6.94 (1H, dt, J = 8.6, 2.4Hz), 7.05-7.33
(8H, m), 7.38 (1H, s).

(45d) 3-Amino-4- [3-((3
-Fluorobenzylamino)-(4-methoxyphenyi)
Ru) methyl) phenylamino] -3-cyclobutene-
1,2-dione 3- [3-((3-fluorobenzylamino)-(4-
Methoxyphenyl) methyl) phenylamino] -4-methoxy-3-cyclobutene-1,2-dione 423 mg
Was used in the same manner as in Production Example (1d) to obtain 327 mg of the title compound as a pale yellow solid. Melting point: 209-212 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 3.63 (2H, s), 3.71
(3H, s), 4.69 (1H, s), 6.87 (2H, d, J = 8.5 Hz), 7.00-
7.45 (10H, m).

Production Example 46 N-[(3- (2-amino-3,4-dioxo-cyclo)
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] benzamide (Exemplary Compound No. 2-
565) (46a) azide- (4-methoxyphenyl)-(3-
Nitrophenyl) methane-bromo - (4-methoxyphenyl) - (3-nitro-phenyl) - dimethylformamide 20 methane 25.8g
The solution was dissolved in 0 ml, and 26.1 g of sodium azide was added under ice cooling, followed by stirring for 1 hour. After further stirring at room temperature for 1 hour, dimethylformamide was distilled off under reduced pressure. Water was added to the obtained residue, and extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6/1) to obtain 18.6 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.82 (3H, s), 5.77 (1
H, s), 6.90-6.94 (2H, m), 7.21 (2H, d, J = 8.7Hz), 7.5
3 (1H, t, J = 8.0Hz), 7.65 (1H, d, J = 7.1Hz), 8.15 (1H,
dd, J = 8.0, 1.9Hz), 8.21 (1H, s).

(46b) Amino- (4-methoxyphenyl)
)-(3-nitrophenyl) methane hydrochloride azide- (4-methoxyphenyl)-(3-nitrophenyl) methane 18.5 g in anhydrous tetrahydrofuran 10
0 ml of triphenylphosphine at room temperature.
The mixture was stirred while adding 5 g little by little. After confirming that the triphenylphosphine had dissolved and the generation of nitrogen had ended, 20 ml of water was added, and the mixture was heated under reflux for 6 hours. The tetrahydrofuran of the reaction solution was distilled off, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1) to obtain a colorless oil. The obtained free compound was dissolved in a 4N hydrogen chloride-ethyl acetate solution, the solvent was evaporated, and the obtained residue was suspended in diisopropyl ether and collected by filtration to obtain 13.8 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.75 (3H, s), 5.84 (1
H, s), 7.00 (2H, d, J = 8.7Hz), 7.51 (2H, d, J = 8.8Hz),
7.74 (1H, t, J = 8.0Hz), 8.03 (1H, d, J = 7.8Hz), 8.22 (1
H, dd, J = 8.3, 1.8Hz), 8.47 (1H, t, J = 1.7Hz).

(46c) N-[(4-methoxyphenyi)
3)-(3-nitrophenyl) methyl] benzamidoamino- (4-methoxyphenyl)-(3-nitrophenyl) methane hydrochloride (3.12 g) in acetonitrile 20
The suspension was added to 2.95 ml of triethylamine, and stirred at room temperature for 20 minutes. The reaction solution was ice-cooled, and a solution of 1.49 g of benzoyl chloride dissolved in 10 ml of acetonitrile was added dropwise little by little, followed by stirring at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a light brown solid. This solid was suspended in methanol, collected by filtration, washed with ether, and dried.
3.29 g of the title compound were obtained as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.81 (3H, s), 6.43 (1
H, d, J = 7.0Hz), 6.66 (1H, d, J = 6.8Hz), 6.91 (2H, d,
J = 8.7Hz), 7.18 (1H, d, J = 8.7Hz), 7.44-7.56 (4H, m),
7.67 (1H, d, J = 7.7Hz), 7.82 (1H, d, J = 7.3Hz), 8.19 (1
H, s).

(46d) N-[(3-aminophenyl)
-(4-methoxyphenyl) methyl] benzamide salt
3.24 g of the acid salt N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] benzamide was added little by little to a mixture of ethanol and concentrated hydrochloric acid (1: 1) at room temperature. The reaction solution was ice-cooled, 6.78 g of tin (II) chloride was added little by little, and the mixture was stirred at room temperature for 20 minutes and then refluxed for 2 hours. After cooling, the reaction solution was neutralized by adding an aqueous sodium hydroxide solution,
The precipitated insoluble matter was removed by filtration through Celite. The filtrate was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: n-
Hexane / ethyl acetate = 2/1) for separation and purification to give a colorless oil. The obtained free compound was dissolved in a 4 N hydrogen chloride-ethyl acetate solution, and the solid obtained by evaporating the solvent was suspended in ether and collected by filtration to obtain 2.68 g of the title compound as a white solid. . NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 6.37
(1H, d, J = 8.5Hz), 6.93 (2H, d, J = 8.7Hz), 7.19-7.57
(9H, m), 7.93 (2H, d, J = 8.2Hz).

(46e) N-[(3- (2-methoxy-
3,4-dioxocyclobut-1-enylamino) fe
Nil)-(4-methoxyphenyl) methyl] benzami
555 mg of de- N-[(3-aminophenyl)-(4-methoxyphenyl) methyl] benzamide hydrochloride is dissolved in 15 ml of methanol, and 428 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione is added at room temperature. Was.
After stirring for 10 minutes at room temperature, 153 mg of triethylamine
Was dissolved in 10 ml of methanol dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was made weakly acidic by adding 0.5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 /
The compound was separated and purified in 1) to give the title compound as a white foam.
05 mg was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.74 (3H, s), 4.31 (3
H, s), 6.35 (1H, d, J = 7.3Hz), 6.75-7.62 (11H, m), 7.
86 (2H, d, J = 7.5Hz).

(46f) N-[(3- (2-amino-
3,4-dioxo-1-cyclobutenylamino) phenyl
)-(4-methoxyphenyl) methyl] benzamide Using 489 mg of N-[(3- (2-methoxy-3,4-dioxo-cyclobut-1-enylamino) phenyl)-(4-methoxyphenyl) methyl] benzamide The reaction was carried out in the same manner as in Production Example (1d) to obtain 301 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 6.32
(1H, d, J = 8.5Hz), 6.92 (2H, d, J = 8.7 Hz), 6.98 (1H,
d, J = 7.7Hz), 7.21 (1H, s), 7.27-7.56 (7H, m), 7.94 (2
H, d, J = 7.4Hz).

Production Example 47 N-[(3- (2-amino-3,4-dioxo-cyclo)
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] -3-fluoro-benzamide (eg
Compound No. 2-826) (47a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -3-fluorobenzamidoamino- (4-methoxyphenyl)-(3-nitrophenyl) methane hydrochloride (1.50 g) and 3-fluorobenzoyl chloride (811 mg) were reacted in the same manner as in Production Example (46c). Was performed to obtain 1.73 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.81 (3H, s), 6.41 (1
H, d, J = 7.0 Hz), 6.64 (1H, d, J = 6.9 Hz), 6.89-6.98 (2
H, m), 7.15-7.63 (7H, m), 7.66 (1H, d, J = 8.0Hz), 8.1
8 (1H, s).

(47b) N-[(3-aminophenyl)
-(4-methoxyphenyl) methyl] -3-fluorobe
617 mg of undsamide hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -3-fluorobenzamide is dissolved in 20 ml of ethanol, and tin (II) chloride is added at room temperature.
1.54 g was added little by little and the mixture was refluxed for 1 hour. After cooling down,
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the precipitated insoluble matter was removed by filtration through celite. The filtrate was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the precipitated solid was collected by filtration, and 468 mg of the title compound as a white solid.
Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 6.34
(1H, d, J = 8.2Hz), 6.93 (2H, d, J = 8.6Hz), 7.10-7.35
(5H, m), 7.38-7.43 (2H, m), 7.51-7.57 (1H, m), 7.74
7.80 (2H, m).

(47c) N-[(3- (2-methoxy-
3,4-dioxo-cyclobut-1-enylamino) f
Enyl)-(4-methoxyphenyl) methyl] -3-f
Fluorobenzamide N-[(3-aminophenyl)-(4-methoxyphenyl) methyl] -3-fluorobenzamide hydrochloride 24
4 mg and 3,4-dimethoxy-3-cyclobutene-1,
The same reaction as in Production Example (46e) was carried out using 107 mg of 2-dione, and 285 mg of the title compound was obtained as a white solid.
I got NMR spectrum (CDCl ₃ ) δ ppm: 3.78 (3H, s), 4.31 (3
H, s), 6.31 (1H, d, J = 7.3 Hz), 6.85-7.66 (12H, m).

(47d) N-[(3- (2-amino-
3,4-dioxocyclobut-1-enylamino) fe
Nil)-(4-methoxyphenyl) methyl] -3-fur
Orobenzuamido N - [(3- (2-methoxy-3,4-dioxo-cyclopropyl but-1-enylamino) phenyl) - (4-methoxyphenyl) methyl] -3-fluorobenzamide 269
The reaction was carried out in the same manner as in Production Example (1d) using mg to obtain 230 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 6.31
(1H, d, J = 8.4Hz), 6.97 (2H, d, J = 7.7Hz), 6.93 (1H,
d, J = 8.7Hz), 7.20-7.39 (5H, m), 7.50-7.54 (2H, m), 7.
75-7.81 (2H, m).

Production Example 48 N-[(3- (2-amino-3,4-dioxo-cyclo)
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] -4-fluorobenzamide (exemplary
( Compound No. 2-969) (48a) N-[(4-methoxyphenyl)-(3-ni
Trophenyl) methyl] -4-fluorobenzamidoamino- (4-methoxyphenyl)-(3-nitrophenyl) methane hydrochloride (1.51 g) and 4-fluorobenzoyl chloride (813 mg) were reacted in the same manner as in Production Example (46c). To give 1.72 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.81 (3H, s), 6.41 (1
H, d, J = 7.0Hz), 6.60 (1H, d, J = 7.0Hz), 6.89-6.93 (2
H, m), 7.10-7.25 (4H, m), 7.53 (1H, t, J = 8.0Hz), 7.6
6 (1H, d, J = 8.0Hz), 7.81-7.86 (2H, m), 8.14 (1H, s).

(48b) N-[(3-aminophenyl)
-(4-methoxyphenyl) methyl] -4-fluorobe
Production example (47b) using 1.72 g of dunzamide hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -4-fluorobenzamide and 4.30 g of tin (II) chloride
The title compound was converted to a white solid by 70%.
6 mg were obtained. NMR spectrum _{(CDCl 3) δppm: 3.73 (} 3H, s), 6.17 (1
H, d, J = 8.7Hz), 6.60 (1H, d, J = 7.0Hz), 6.89-6.92 (2
H, m), 7.10-7.25 (4H, m), 7.53 (1H, t, J = 7.9Hz), 7.6
6 (1H, d, J = 8.0Hz), 7.81-7.86 (2H, m), 8.14 (1H, s).

(48c) N-[(3- (2-methoxy-
3,4-dioxo-cyclobut-1-enylamino) f
Enyl)-(4-methoxyphenyl) methyl] -4-f
Fluorobenzamide N-[(3-aminophenyl)-(4-methoxyphenyl) methyl] -4-fluorobenzamide hydrochloride 67
4 mg and 3,4-dimethoxy-3-cyclobutene-1,
The reaction was carried out in the same manner as in Production Example (46e) using 250 mg of 2-dione, and 399 mg of the title compound was converted into a yellow solid.
I got Melting point: 115-116 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 4.28
(3H, s), 6.30 (1H, d, J = 8.4Hz), 6.93 (2H, d, J = 8.7H
z), 7.06 (1H, d, J = 7.7Hz), 7.26-7.34 (7H, m), 8.00-
8.04 (2H, m).

(48d) N-[(3- (2-amino-
3,4-dioxo-cyclobut-1-enylamino) f
Enyl)-(4-methoxyphenyl) methyl] -4-f
Le Oro benzamide N - [(3- (2-methoxy-3,4-dioxo - cyclobut-1-enylamino) phenyl) - (4-methoxyphenyl) methyl] -4-fluorobenzamide 34
The reaction was carried out in the same manner as in Production Example (1d) using 6 mg, to obtain 223 mg of the title compound as a yellow solid. Melting point: 212-213 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 3.74 (3H, s), 6.31
(1H, d, J = 8.5Hz), 6.92 (2H, d, J = 8.7Hz), 6.97 (1H,
d, J = 7.7Hz), 7.20 (1H, s), 7.23-7.48 (5H, m), 7.50-
7.53 (1H, m), 7.96-8.04 (2H, m).

Production Example 49 3-amino-4- [3- (benzyloxyimino- (4
-Methoxyphenyl) -methyl) phenylamino] -3
-Cyclobutene-1,2-dione (Exemplary Compound No. 5-
4) (49a) (4-methoxyphenyl)-(3-nitroph
Dissolve 2.44 g of O-benzyloxime (4-methoxyphenyl)-(3-nitrophenyl) methanone in 40 ml of anhydrous dichloromethane, add 3.02 g of O-benzylhydroxylamine and 7.9 ml of triethylamine, and add 15 minutes. The mixture was stirred under ice cooling. To the reaction solution, 30 ml of an anhydrous dichloromethane solution of 1.51 ml of titanium tetrachloride was slowly added dropwise, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent:
n-hexane / ethyl acetate = 9/1).
1.81 g of a pale yellow oil was obtained. Ethanol was added thereto, and the mixture was allowed to stand. The precipitated solid was collected by filtration to obtain 1.54 g of the isomer (A) of the title compound as a white solid. The filtrate was concentrated to give 764 mg of isomer (B) as a pale yellow oil as a 2: 1 mixture with isomer (A). Isomer (A) Melting point: 100-101 ° C NMR spectrum (CDCl ₃ ) δ ppm: 3.82 (3H, s), 5.21 (2
H, s), 6.86 (2H, d, J = 8.9Hz), 7.27-7.38 (7H, m), 7.5
9 (1H, t, J = 7.9Hz), 7.63-7.66 (1H, m), 8.22-8.27 (2H,
m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 3.82 (1H, s), 3.86
(2H, s), 5.21 (2 / 3H, s), 5.26 (4 / 3H, s), 6.86 (2/3
(H, d, J = 8.9Hz), 6.96 (4 / 3H, d, J = 8.7Hz), 7.27-7.39
(7H, m), 7.49 (2 / 3H, t, J = 8.0Hz), 7.59 (1 / 3H, t,
J = 7.9Hz), 7.63-7.66 (1 / 3H, m), 7.73-7.88 (2 / 3H,
m), 8.22-8.35 (2H, m).

(49b) (3-Aminophenyl)-(4
-Methoxyphenyl) methanone O-benzyloxime (4-methoxyphenyl)-(3-nitrophenyl) methanone isomer of O-benzyl-oxime (A) 974
mg and 2.55 g of tin (II) chloride in 30 ml of ethanol
Was added and heated under reflux for 1 hour. After the ethanol was distilled off, the residue was diluted with ethyl acetate, and the ethyl acetate layer was washed with a 5N aqueous sodium hydroxide solution, water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 893 mg of the title compound isomer (A) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 3.80 (3H, s), 5.20 (2
H, s), 6.57-6.86 (5H, m), 7.20 (1H, t, J = 7.87Hz), 7.
22-7.45 (7H, m). (4-Methoxyphenyl)-(3-nitrophenyl) methanone A mixture of O-benzyl oxime isomers (B) was prepared using 752 mg and 1.97 g of tin (II) chloride. The reaction was carried out in the same manner as in Example (1b) to give 623 mg of a yellow oily product as a 2: 1 mixture of isomer (B) of the title compound with isomer (A). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 3.80 (1H, s), 3.81
(2H, s), 5.20 (2 / 3H, s), 5.23 (4 / 3H, s), 6.55-7.45
(13H, m).

(49c) 3- [3- (benzyloxyi
Mino- (4-methoxyphenyl) -methyl) phenyla
Mino] -4-methoxy-3-cyclobutene-1,2-di
Isomer (A) 886 of on (3-aminophenyl)-(4-methoxyphenyl) methanone O-benzyl-oxime
mg and 3,4-dimethoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 757 mg of -dione to obtain 1.09 g of the isomer (A) of the title compound as a yellow foam. Isomer (A) Melting point: 70-71 ° C NMR spectrum (CDCl ₃ ) δ ppm: 3.81 (3H, s), 4.35 (3
H, s), 5.21 (2H, s), 6.82-6.86 (2H, m), 7.12-7.15 (2
H, m), 7.22-7.45 (9H, m). (3-Aminophenyl)-(4-methoxyphenyl) methanone 593 mg of a mixture of the isomers (B) of O-benzyloxime and 3,4-dimethoxy-3- Cyclobutene
The reaction was carried out in the same manner as in Production Example (1c) using 507 mg of 1,2-dione, and 690 mg of a yellow foam was obtained by converting isomer (B) of the title compound into a 2: 1 mixture with isomer (A)
Obtained. Isomer (B) Melting point: 71-72 ° C NMR spectrum (CDCl ₃ ) δ ppm: 3.81 (1H, s), 3.85
(2H, s), 4.34 (2H, s), 4.35 (1H, s), 5.21 (2 / 3H,
s), 5.25 (4 / 3H, s), 6.82-6.86 (2 / 3H, m), 6.93-6.97
(4 / 3H, m), 7.12-7.15 (2 / 3H, m), 7.22-7.45 (31 / 3H,
m).

(49d) 3-Amino-4- [3- (ben
Jiloxyimino- (4-methoxyphenyl) methyl
Phenylamino] -3-cyclobutene-1,2-dione 3- [3- (benzyloxyimino- (4-methoxyphenyl) methyl) phenylamino] -4-methoxy-3
-Isomer of cyclobutene-1,2-dione (A) 780
The reaction was carried out in the same manner as in Production Example (1d) using mg, to give 869 mg of the title compound isomer (A) as a yellow solid. Isomer (A) Melting point: 245-248 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 3.76 (3H, s), 5.15
(2H, s), 6.90-6.95 (3H, m), 7.22-7.58 (10H, m). 3- [3- (benzyloxyimino- (4-methoxyphenyl) methyl) phenylamino] -4-methoxy- Three
Using 442 mg of a mixture of the isomers (B) of -cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1d).
As one mixture, 190 mg of a yellow foam was obtained. Isomer (B) Melting point: 218-220 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 3.76 (1H, s), 3.8
0 (2H, s), 5.15 (2 / 3H, s), 5.18 (4 / 3H, s), 6.90-6.9
5 (1H, m), 7.00-7.03 (2H, m), 7.22-7.75 (10H, m).

Production Example 50 N-[(3- (2-amino-3,4-dioxocyclobutane)
To-1-enylamino) phenyl)-(4-methoxyphenyl)
Enyl) methyl] -2-phenylpropionamide (eg
Compound No. 2-464) (50a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -2-phenylpropionami
De Amino - (4-methoxyphenyl) - (3-nitrophenyl) methane hydrochloride 2.58g was dissolved in anhydrous dichloromethane 50 ml, and stirred under ice-cooling was added triethylamine 1.77 g. 1.32 g of 2-phenylpropionic acid and 20 ml of dichloromethane were added to the reaction solution, and 10 ml of dimethylformamide anhydride was further added to completely dissolve it. A solution of 2.40 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride suspended in 30 ml of dichloromethane was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane / ethyl acetate = 2/1) to give 2.41 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.53 and 1.56 (total
3H, each d, J = 7.1Hz), 3.63 and 3.68 (total 1H, each
q, J = 7.1Hz), 3.77 and 3.78 (total 3H, eachs), 5.85
and 5.87 (total 1H, each d, J = 7.7Hz), 6.17 and 6.1
9 (total 1H, each d, J = 7.3Hz), 6.69-7.00 (4H, m), 7.
25-7.50 (7H, m), 7.87 and 8.02 (total3H, each s).

(50b) N-[(3-aminophenyl)
-(4-methoxyphenyl) methyl] -2-phenylp
Lopionamide hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -2-phenylpropionamide 2.37
g and 5.76 g of tin (II) chloride.
The reaction was carried out in the same manner as in b) to obtain 1.96 g of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.34 and 1.35 (tot
al 3H, each d, J = 6.9Hz), 3.35-3.55 (1H, m), 3.70 a
nd 3.74 (total 3H, each s), 6.01-6.06 (1H, m), 6.83 (1
H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.06-7.55
(11H, m).

(50c) N-[(3- (2-methoxy-
3,4-dioxocyclobut-1-enylamino) fe
Nyl)-(4-methoxyphenyl) methyl] -2-fe
Sulfonyl propionamide N - [(3- aminophenyl) - (4-methoxyphenyl) methyl] -2-phenylpropionamide hydrochloride 555mg and 3,4-dimethoxy-3-cyclobutene -
The reaction was carried out in the same manner as in Production Example (46e) using 398 mg of 1,2-dione, and the title compound was converted into a yellow solid in an amount of 425 mg.
mg was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.25 and 1.27 (total
3H, each d, J = 7.3Hz), 3.63 and 3.71 (total 1H, each
q, J = 7.1Hz), 3.75 and 3.77 (total 3H, eachs), 4.39
and 4.38 (total 3H, each s), 6.08 and 6.09 (total 1H
H, each d, J = 7.5Hz), 6.72-7.42 (13H, m).

(50d) N-[(3- (2-amino-
3,4-dioxo-cyclobut-1-enylamino) f
Enyl)-(4-methoxyphenyl) methyl] -2-f
Enylpropionamide N-[(3- (2-methoxy-3,4-dioxocyclobut-1-enylamino) phenyl)-(4-methoxyphenyl) methyl] -2-phenylpropionamide 3
The reaction was carried out in the same manner as in Production Example (1d) using 80 mg,
262 mg of the title compound was obtained as a yellow solid. Melting point: 206-209 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.34 and 1.36 (tot
al 3H, each d, J = 7.4Hz), 3.69 and 3.74 (total 3H, e
ach s), 3.818 and 3.824 (total 1H, each q, J = 7.1H
z), 5.98 (1H, d, J = 8.2Hz), 6.74-7.50 (13H, m).

Production Example 51 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione and its hydrochloride (Exemplified Compound No. 2-237) (51a) 3-amino-4- [3-((4-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Lamino) methyl) phenylamino] -3-cyclobute
3-Methoxy-4- [3-((4-methoxyphenyl)-(1- (3,4-difluorophenyl)) of n-1,2-dione Production Example 35
294 mg of isomer (A) of ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione was dissolved in 8 ml of ethanol, and 1.5 ml of a 2N ammonia-ethanol solution was added. The reaction was carried out in the same manner to obtain 202 mg of the isomer (A) of the title compound as a yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.6)
Hz), 3.57 (1H, q, J = 6.6Hz), 3.69 (3H, s), 4.43 (1H,
s), 6.82 (2H, d, J = 8.7Hz), 6.97 (1H, d, J = 7.5Hz), 7.
02-7.40 (6H, m), 7.22 (2H, d, J = 8.7 Hz). Melting point: 163-165 ° C. 3-methoxy-4- [3-((4-methoxyphenyl)-(1 -(3,4-difluorophenyl)
254 mg of the isomer (B) of ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione was dissolved in 6 ml of ethanol, and 1 ml of a 2N ammonia-ethanol solution was added. The reaction was carried out to give the isomer (B) of the title compound as a yellow solid in 16
9 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J = 6.6
Hz), 3.52 (1H, q, J = 6.6Hz), 3.73 (3H, s), 4.40 (1H,
s), 6.88 (2H, d, J = 8.6Hz), 6.91 (1H, d, J = 7.7Hz), 7.
00-7.42 (6H, m), 7.25 (2H, d, J = 8.6 Hz). Melting point: 172-174 ° C.

(51b) 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl)
Enyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione hydrochloride 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
163 mg of dione isomer (B) in 5 ml of methanol
And 1 ml of a 4N hydrochloric acid / ethyl acetate solution was added, followed by concentration under reduced pressure. The residue was solidified by adding methanol / ether to obtain 158 mg of a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J = 6.6)
Hz), 3.77 (3H, s), 4.23 (1H, q, J = 6.6Hz), 5.16 (1H,
s), 7.00 (2H, d, J = 8.6Hz), 7.18-7.62 (7H, m), 7.54 (2
H, d, J = 8.6 Hz). Melting point: 172-175 ° C.

Production Example 52 3-amino-4- [3-((2-hydroxy-2-fe
Nylethylamino)-(4-methoxyphenyl) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-558) (52a) N- [2- (t-butyl-dimethylsilyloxy)
B) -2-Phenylethyl] -N-[(4-methoxy
Nyl)-(3-nitrophenyl) methyl] amine 3-nitro-4'-methoxybenzophenone 2.38 g
And 2- (t-butyl-dimethyl-silyloxy) -2-
4.64 g of phenylethylamine was dissolved in 40 ml of anhydrous dichloromethane, and 5.1 ml of triethylamine was added. The reaction solution was ice-cooled, and a solution of 1.2 ml of titanium tetrachloride in 12 ml of anhydrous dichloromethane was slowly added dropwise.
Stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain 6.88 g of an imine compound as a yellow oil.
The obtained oil was dissolved in 70 ml of ethanol, 2.33 g of sodium borohydride sodium and 0.8 ml of acetic acid.
The reaction was carried out in the same manner as in Production Example (1a) using the above compound, and 4.95 g of the title compound was obtained as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: −0.12 (3H, s), 0.
03 and 0.04 (total 3H, each s), 0.859 and 0.864 (tota
l 9H, each s), 2.68-2.77 (2H, m), 3.76 and 3.78 (tot
al 3H, each s), 4.83-4.87 (2H, m), 6.82 and 6.84 (2
H, each d, J = 6.6Hz), 7.23-7.31 (7H, m), 7.38-7.44 (1
H, m), 7.66-7.69 (1H, m), 8.02-8.06 (1H, m), 8.27 (1H,
d, J = 7.9Hz).

(52b) 2-[((4-methoxyphenyl
)-(3-nitrophenyl) methyl) amino] -1-f
Enylethanol N- [2- (t-butyl-dimethylsilyloxy) -2-
Phenylethyl] -N-[(4-methoxyphenyl)-(3
20 ml of a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution was added to 4.95 g of -nitrophenyl) methyl] amine, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 3/1) to obtain 3.26 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 2.80-2.90 (2H, m),
3.777 and 3.780 (total3H, each s), 4.76-4.83 (1H,
m), 4.91 (1H, s), 6.86 (2H, d, J = 8.6Hz), 7.24-7.45 (7
H, m), 7.46-7.48 (1H, m), 7.71 (1H, d, J = 7.5Hz), 8.0
7 (1H, d, J = 7.9Hz), 8.26 (1H, d, J = 9.2Hz).

(52c) 2-[((3-aminophenyl)
-(4-methoxyphenyl) methyl) -amino] -1-f
E sulfonyl ethanol 2 - [((4-methoxyphenyl) - (3-nitrophenyl) methyl) amino] -1-phenylethanol 3.2
6 g was dissolved in methanol 60 ml, and nickel chloride hexahydrate 4.09 g and sodium borohydride 1.3 g were dissolved.
Was used in the same manner as in Production Example (1b) to give 2.2 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 2.66-2.75 (1H, m),
2.85-2.90 (1H, m), 3.77 (3H, s), 4.70-4.74 (1H, m),
4.71 (1H, s), 6.53 (1H, dd, J = 2.0, 8.3Hz), 6.65-6.67
(1H, m), 6.70-6.74 (1H, m), 6.83 (2H, d, J = 8.4Hz),
7.08 (1H, t, J = 5.2Hz), 7.20-7.36 (7H, m).

(52d) 3- [3-((2-hydroxy
-2-phenylethyl) amino- (4-methoxyphenyl)
L) methyl) phenylamino] -4-methoxy-3-si
Clobutene-1,2-dione 2-[((3-aminophenyl)-(4-methoxyphenyl) methyl) amino] -1-phenylethanol 2.2
g was dissolved in 40 ml of methanol, 940 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to give the title compound as a white foam. 32 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.67-2.80 (1H, m),
2.85-2.93 (1H, m), 3.77 (3H, s), 4.44 (3H, s), 4.74-
4.83 (2H, m), 6.84 (2H, d, J = 8.6Hz), 7.10-7.12 (2H,
m), 7.24-7.37 (9H, m).

(52e) 3-amino-4- [3-((2
-Hydroxy-2-phenylethylamino)-(4-me
Toxiphenyl) methyl) phenylamino] -3-cycl
Lobutene-1,2-dione 3- [3-((2-hydroxy-2-phenylethylamino- (4-methoxyphenyl) methyl) phenylamino)]-4-methoxy-3-cyclobutene-1,2-dione 1.35 g of 2N ammonia-ethanol solution 1
9 ml was added, and the reaction was carried out in the same manner as in Production Example (1d).
1.36 g of the title compound was obtained as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.57 (2H, d, J
= 6.6Hz), 3.695 and 3.704 (total 3H, each s), 4.76-
4.84 (2H, m), 6.84 and 6.86 (total 2H, each d, J = 8.4H
z), 7.04 (1H, t, J = 7.1 Hz), 7.17-7.42 (10H, m). Melting point: 117 ° C (dec).

Production Example 53 3-amino-4- [3-((2- (1H-indole-
3-yl) ethylamino)-(4-methoxyphenyl) meth
Tyl) phenylamino] -3-cyclobutene-1,2-
Dione (Exemplified Compound No. 2-1985) (53a) N- [2- (1H-indol-3-yl) d
Tyl] -N-[(4-methoxyphenyl)-(3-nitroph
[Enyl] methyl] amine 3-nitro-4'-methoxybenzophenone (1.5 g) and tryptamine (1.86 g) in anhydrous dichloromethane (15 ml)
, And 3.22 ml of triethylamine was added. The reaction solution was ice-cooled, and a diluted solution of 0.77 ml of titanium tetrachloride in 8 ml of anhydrous dichloromethane was slowly added dropwise, followed by stirring at room temperature for 2 hours. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the precipitated insolubles were removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the imine compound as a yellow oil (2.63 g). The obtained oil was dissolved in 30 ml of ethanol, and reacted in the same manner as in Production Example (1a) using 1.46 g of sodium borohydride and 0.5 ml of acetic acid. The title compound was converted into a yellow oil. 2.33 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.84-3.04 (4H, m),
3.76 (3H, s), 4.86 (1H, s), 6.81 (2H, d, J = 8.7Hz), 7.
03 (1H, d, J = 2.1Hz), 7.10 (1H, t, J = 7.2Hz), 7.17-7.2
4 (3H, m), 7.34-7.42 (2H, m), 7.55 (1H, d, J = 7.6Hz),
7.68 (1H, d, J = 7.8Hz), 8.02 (1H, d, J = 8.0Hz), 8.27 (1
H, t, J = 1.9Hz).

(53b) 3-[[2- (1H-indole
-3-yl) ethylamino]-(4-methoxyphenyl) meth
Tyl] phenylamine [2- (1H-indol-3-yl) ethyl]-[(4
-Methoxyphenyl)-(3-nitrophenyl) methyl]
2.33 g of the amine was dissolved in 50 ml of ethanol, and the reaction was carried out in the same manner as in Production Example (1b) using 2.76 g of nickel chloride hexahydrate and 878 mg of sodium borohydride, and 484 mg of the title compound was obtained as a pale yellow oil. Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.86-3.03 (4H, m),
3.75 (3H, s), 4.69 (1H, s), 6.49 (1H, d, J = 8.1Hz), 6.
62 (1H, d, J = 1.9Hz), 6.71 (1H, d, J = 7.6Hz), 6.79 (2H,
d, J = 8.7Hz), 7.00-7.25 (6H, m), 7.35 (1H, d, J = 8.1H
z), 7.58 (1H, d, J = 7.7Hz).

(53c) 3- [3-((2- (1H-India
Yl-3-yl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) phenylamino] -4-methoxy-3-cycl
Lobutene-1,2-dione 3-[(2- (1H-indol-3-yl) ethylamino)-(4-methoxyphenyl) methyl] phenylamine 4
80 mg was dissolved in 5 ml of methanol, 193 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c) to give 342 mg of the title compound as a pale yellow foam. Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.28-3.05 (4H, m),
3.75 (3H, s), 4.37 (3H, s), 4.78 (1H, s), 6.79 (2H, d,
J = 8.6Hz), 7.03-7.24 (9H, m), 7.36 (1H, d, J = 8.1Hz),
7.54 (1H, d, J = 7.8Hz).

(53d) 3-amino-4- [3-((2
-(1H-indol-3-yl) ethylamino)-(4
-Methoxyphenyl) methyl) phenylamino] -3-
Cyclobutene-1,2-dione 3- [3-((2- (1H-indol-3-yl) ethylamino)-(4-methoxyphenyl) methyl) phenylamino] -4-methoxy-3-cyclobutene-1 , 2-
1.4 ml of a 2N ammonia-ethanol solution was added to 340 mg of dione, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 257 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.73-2.76 (2H,
m), 2.86-2.91 (2H, m), 3.70 (3H, s), 6.82 and 6.85 (t
otal 1H, each s), 6.84 (2H, d, J = 8.6Hz), 6.92 (1H,
t, J = 7.3Hz), 7.00-7.46 (10H, m). Melting point: 184 ° C (dec) Production Example 54 3-amino-4- [3-((4-methoxyphenyl)-
(2-cyclohexylethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound No. 2-437) (54a) N-[(4-methoxyphenyl)-(3- nitro)
Rophenyl) methyl] -N- [2- (cyclohexene-1
-Yl) ethyl] amine 3-nitro-4'-methoxybenzophenone 2 g and 2-
(Cyclohexen-1-yl) ethylamine 2.17 m
was dissolved in 20 ml of anhydrous dichloromethane, and 4.33 ml of triethylamine was added. The reaction solution was ice-cooled, a solution of titanium tetrachloride (1.03 ml) in anhydrous dichloromethane (10 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution,
The precipitated insoluble matter was removed by filtration through Celite. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.70 g of an imine compound as a brown oil. The obtained oil was dissolved in 60 ml of ethanol, and reacted in the same manner as in Production Example (1a) using 1.96 g of sodium borohydride cyanide and 0.67 ml of acetic acid, and the title compound was converted into a yellow oil. 2.80 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.50-1.63 (4H, m),
1.86-1.87 (2H, m), 2.16 (2H, t, J = 6.8Hz), 2.56-2.67
(2H, m), 3.78 (3H, s), 4.86 (1H, s), 5.45 (1H, br.s),
6.85 (2H, d, J = 8.7Hz), 7.25-7.28 (2H, m), 7.45 (1H ,.
t, J = 7.8Hz), 7.73 (1H, d, J = 8.0Hz), 8.06 (1H, d, J =
7.8Hz), 8.28-8.29 (1H, m).

(54b) 3-[(4-methoxyphenyl)
-(2- (cyclohexen-1-yl) ethylamino)
Methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- [2- (cyclohexen-1-yl)
Ethyl] amine (2.80 g) was dissolved in methanol (60 ml), and the reaction was carried out in the same manner as in Production Example (1b) using nickel chloride hexahydrate (3.61 g) and sodium borohydride (1.15 g). 2.15 g of a mixture of the title compound and 3-[(4-methoxyphenyl)-(2-cyclohexylethylamino) methyl] phenylamine having a reduced cyclohexene ring was obtained as a yellow oil. NMR spectrum _{(CDCl 3) δppm: 1.37-1.42 (} 2H, m),
1.50-1.66 (2H, m), 1.87-1.97 (4H, m), 2.13-2.17 (2H, m
m), 2.54-2.65 (2H, m), 3.77 (3H, s), 4.66 (1H, s), 5.
44-5.47 (1H, m), 6.51-6.53 (1H, m), 6.70-6.84 (4H,
m), 7.06 (1H, t, J = 7.7Hz), 7.26-7.31 (2H, m).

(54c) 3-methoxy-4- [3-
((4-methoxyphenyl)-(2- (cyclohexene
-1-yl) ethylamino) methyl) phenylamino]
-3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(2- (cyclohexen-1-yl) ethylamino) methyl] phenylamine and 3-[(4-methoxyphenyl)-(2 -Cyclohexylethylamino) methyl] phenylamine2.
15 g was dissolved in 40 ml of methanol, and 953 mg of 3,4-dimethoxy-3-cyclobutene-1,2-dione was added, and the reaction was carried out in the same manner as in Production Example (1c). The crude product is subjected to reverse phase medium pressure chromatography (elution solvent: acetonitrile / acetic acid buffer aqueous solution (water: acetic acid: triethylamine =
1000: 2: 2) = 50/50) to give 815 mg of the title compound as a pale orange foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.48-2.70 (12H,
m), 3.77 (3H, s), 4.44 (3H, s), 4.82 (1H, br), 5.44 (1
H, br.s), 6.81-7.30 (8H, m). Also, 3-methoxy-4- [3 derived from 3-[(4-methoxyphenyl)-(2-cyclohexylethylamino) methyl] phenylamine. 632 mg of-((4-methoxyphenyl)-(2-cyclohexylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione were obtained as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 0.81-2.63 (15H,
m), 3.77 (3H, s), 4.45 (3H, s), 4.82 (1H, br), 6.82-
7.38 (8H, m).

(54d) 3-Amino-4- [3-((4
-Methoxyphenyl)-(2-cyclohexylethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione Preparation of (54c) 3- methoxy-4- [3 - ((4-
Methoxyphenyl)-(2-cyclohexylethylamino) methyl) phenylamino] -3-cyclobutene-
To 630 mg of 1,2-dione was added 2.8 ml of a 2N ammonia-ethanol solution, and the reaction was carried out in the same manner as in Production Example (1d) to obtain 536 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δppm: 0.77-1.38 (3H,
m), 2.43-2.49 (2H, m), 3.70 (3H, s), 4.70 (1H, br.s),
6.84 (2H, d, J = 8.6Hz), 7.03 (1H, d, J = 7.6Hz), 7.23
(1H, t, J = 7.7Hz), 7.31-7.40 (4H, m). Melting point: 168-171 ° C.

Production Example 55 3-Hydroxy-4- {3- [phenyl-((R) -1]
-Phenylethylamino) methyl] phenylamino}-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-3) (55a) 3-t-butoxy-4- {3- [phenyl-
((R) -1-phenylethylamino) methyl] phenyl
1.9 g of isomer (A) of 3-amino--3 -cyclobutene-1,2-dione 3- [phenyl-((R) -1-phenylethylamino) methyl] phenylamine, 4-t-
Butoxy-3-methoxy-3-cyclobutene-1,2-
The reaction was carried out in the same manner as in Production Example (1c) using 1.25 g of dione to obtain 2.3 g of the isomer (A) of the title compound as a white solid. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.62-3.71 (1H, m), 4.62 (1H,
s), 7.10-7.36 (14H, m). Melting point: 129-131 ° C 2.3 g of 3- [phenyl-((R) -1-phenylethylamino) methyl] phenylamine isomer (B), 4-g t
-Butoxy-3-methoxy-3-cyclobutene-1,2
Using 1.54 g of -dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.53 g of the isomer (B) of the title compound as a white solid. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.62 (9H, s), 3.66 (1H, q, J = 6.7Hz), 4.61 (1
H, s), 7.00-7.36 (14H, m). Melting point: 137-139 ° C.

(55b) 3-Hydroxy-4- {3-
[Phenyl-((R) -1-phenylethylamino) me
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione 3-t-butoxy-4- {3- [phenyl-((R)-
1-phenylethylamino) methyl] phenylamino}
Isomer (A) of -3-cyclobutene-1,2-dione
1.0 g was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1.5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution is adjusted to pH using diluted hydrochloric acid and aqueous sodium hydroxide solution.
After adjusting to 4.5, the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The solidified target product was suspended in ethyl acetate and collected by filtration to obtain 469 mg of the title compound isomer (A) as a gray solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.5Hz), 4.27 (1H, br), 4.97 (1H, br.s), 6.90 (1H, d,
J = 7.7 Hz), 7.22-7.67 (13H, m). Melting point: 205 ° C. (dec) Optical rotation [α] _D = −359.9 (c = 1.00, AcO
H) 3-t-butoxy-4- {3- [phenyl-((R)-
1-phenylethylamino) methyl] phenylamino}
Isomer (B) of -3-cyclobutene-1,2-dione
Using 1.0 g and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in the above method to obtain the isomer (B) of the title compound.
Was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.59 (3H, br),
4.10-4.17 (1H, br), 4.98-5.03 (1H, br), 6.89-6.99 (1
H, br), 7.18-7.59 (12H, m), 7.72 (1H, s). Melting point: 202 ° C. (dec) Optical rotation [α] _D = + 67.5 (c = 1.00, AcO
H).

Production Example 56 3-Hydroxy-4- {3- [phenyl-((S) -1]
-Phenylethylamino) methyl] phenylamino}-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-3) (56a) 3-t-butoxy-4- {3- [phenyl-
((S) -1-phenylethylamino) methyl] phenyl
1.9 g of the isomer of aminoamino- 3 -cyclobutene-1,2-dione 3- [phenyl-((S) -1-phenylethylamino) methyl] phenylamine (A),
4-t-butoxy-3-methoxy-3-cyclobutene-
Using 1.25 g of 1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.3 g of the isomer (A) of the title compound as a white solid.

Also, isomer (B) of 3- [phenyl-((S) -1-phenylethylamino) methyl] phenylamine (2.3 g) and 4-t-butoxy-3-methoxy-3
Using 1.54 g of -cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 2.53 g of the isomer (B) of the title compound as a white solid.

(56b) 3-Hydroxy-4- {3-
[Phenyl-((S) -1-phenylethylamino) me
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione 3-t-butoxy-4- {3- [phenyl-((S)-
1-phenylethylamino) methyl] phenylamino}
Isomer (A) of -3-cyclobutene-1,2-dione
Using 1.0 g and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to obtain 855 mg of the title compound isomer (A) as a white solid. Isomer (A) Optical rotation [α] _D = + 359.4 (c = 1.00, AcO
H) 3-t-butoxy-4- {3- [phenyl-((S)-
1-phenylethylamino) methyl] phenylamino}
Isomer (B) of -3-cyclobutene-1,2-dione
Using 1.0 g and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to obtain 855 mg of the title compound isomer (B) as a white solid. Isomer (B) Optical rotation [α] _D = −56.4 (c = 1.00, AcO
H).

Production Example 57 4- {3-[(1- (3,4-difluorophenyl) e
Tylamino)-(3-methoxyphenyl) methyl] -4
-Methoxyphenylamino} -3-hydroxy-3-si
Clobutene-1,2-dione (Exemplary Compound No. 2-33)
90) (57a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(2-methoxy-5-nitrophenyl
)-(3-methoxyphenyl) methyl] amine (2-methoxy-5-nitrophenyl)-(3-methoxyphenyl) ketone 600 mg and 1- (3,4-difluorophenyl) ethylamine hydrochloride 809 mg, triethylamine 1 .75ml, titanium tetrachloride 0.28m
1, 583 mg of sodium cyanoborohydride and 0.18 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 830 mg of the title compound as a yellow foam. NMR spectrum (CDCl ₃ ) δppm: 1.31 and 1.35 (t
otal 3H, each d, J = 6.6and 6.6Hz), 3.60 and 3.69 (to
tal 1H, each q, J = 6.6 and 6.6Hz), 3.76 and3.82 (tot
al 3H, each s), 3.80 (3H, s), 4.91 and 4.92 (total 1
H, each s), 6.73-6.94 (5H, m), 7.04-7.27 (3H, m), 8.
10 and 8.18 (total 1H, each dd, J = 2.9, 8.9 and 2.9,
9.2Hz), 8.29 and 8.46 (total 1H, each d, J = 2.8 and
2.8Hz).

(57b) 3-[(1- (3,4-difur
Orophenyl) ethylamino)-(3-methoxyphenyl)
L) Methyl] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
A mixed solution of 810 mg of N-[(2-methoxy-5-nitrophenyl)-(3-methoxyphenyl) methyl] amine and 1.43 g of stannic chloride in a 1: 1 concentrated hydrochloric acid-ethanol mixture 20
Then, the mixture was dissolved in ml and heated under reflux for 2 hours. The reaction solution was adjusted to weak alkaline with excess sodium hydroxide and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Residue in reverse layer HP
LC [acetonitrile: acetic acid buffer (water: acetic acid:
Triethylamine = 1000: 2: 2) = 50: 50] to give 235 mg of the title compound isomer (A) as a yellow oil. Further, the isomer mixture is subjected to silica gel column chromatography (elution solvent: cyclohexane /
Purification with ethyl acetate (1/1) yielded 187 mg of isomer (B) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.8Hz), 3.61-3.69 (1H, m), 3.65 (3H, s), 3.80 (3H,
s), 4.88 (1H, s), 6.50-6.51 (2H, m), 6.65 (1H, d, J = 9.
2Hz), 6.78 (1H, dd, J = 3.0, 7.9Hz), 6.88-6.94 (3H,
m), 7.03-7.10 (1H, m), 7.12-7.18 (1H, m), 7.22 (1H,
isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.30 (3H, d, J =
6.6Hz), 3.60 (3H, s), 3.67 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.77 (1H, s), 6.57-6.59 (1H, m), 6.64 (1H, d, J
= 2.7Hz), 6.71 (2H, d, J = 8.6Hz), 6.87 (1H, d, J = 8.0H
z), 6.93 (1H, d, J = 1.7Hz), 6.98-7.19 (4H, m).

(57c) 3-t-butoxy-4- {3-
[(1- (3,4-difluorophenyl) ethylamido
No)-(3-Methoxyphenyl) methyl] -4-methoxy
Cyphenylamino} -3-cyclobutene-1,2-di
Down 3 - [(1- (3,4-difluorophenyl) ethylamino) - (3-methoxyphenyl) methyl] -4-methoxyphenyl isomer of the amine (A) 220mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using -dione (203 mg) to give 305 mg of the isomer (A) of the title compound as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.68 (1H, q, J = 6.7Hz), 3.73 (3
H, s), 3.81 (3H, s), 4.92 (1H, s), 6.78-6.81 (2H, m),
6.88-6.94 (3H, m), 7.03-7.31 (5H, m). 3-[(1- (3,4-difluorophenyl) ethylamino)-(3-methoxyphenyl) methyl] -4-methoxyphenylamine Isomer (B) 180 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 166 mg of -dione to obtain 210 mg of the isomer (B) of the title compound as a yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 3.69 (3
H, s), 3.76 (3H, s), 4.90 (1H, s), 6.71-6.73 (1H, m),
6.84-6.87 (2H, m), 6.90 (1H, s), 6.96-7.00 (1H, m),
7.05-7.18 (3H, m), 7.29-7.37 (2H, m).

(57d) 4- {3-[(1- (3,4-
Difluorophenyl) ethylamino)-(3-methoxy
Phenyl) methyl] -4-methoxyphenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(3-methoxyphenyl) methyl] -4 -Methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 300 m
g in 5 ml of t-butanol and 3 ml of 1N hydrochloric acid.
Was added and stirred at room temperature for 30 minutes and at 100 ° C. for 30 minutes. After neutralizing the reaction solution with 3 ml of 1 N aqueous sodium hydroxide solution,
Diluted with water. The insolubles precipitated during the dilution were collected by filtration, and the solid was washed with water, diethyl ether and acetone in that order, and dried to obtain 206 mg of the title compound isomer (A) as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.55 (3H, d, J
= 6.7Hz), 3.72 (3H, s), 3.82 (3H, s), 4.22 (1H, br), 5.
27 (1H, br.s), 6.93-7.00 (3H, m), 7.21-7.24 (2H, m),
7.34 (1H, t, J = 8.0Hz), 7.49-7.57 (3H, m), 7.65-7.68
(1H, m). Melting point: 238-241 ° C. 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(3-methoxyphenyl) methyl] -4- Methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 200 m
g in 5 ml of t-butanol and 2 ml of 1N hydrochloric acid.
Was added and stirred at 100 ° C. for 1 hour. After the reaction solution was neutralized with 2 ml of a 1 N aqueous solution of sodium hydroxide, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain 88 mg of the isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.31 (3H, br),
3.24-3.70 (1H, br), 3.57 (3H, s), 3.70 (3H, s), 4.78
(1H, br.s), 6.74-6.84 (4H, m), 7.10-7.15 (2H, m), 7.3
3-7.40 (2H, m), 7.48 (1H, d, J = 8.1 Hz), 7.84 (1H, br). Melting point: 235 ° C (dec).

Production Example 58 4- {3-[(1- (3,4-difluorophenyl) e
Tylamino)-(4-methoxyphenyl) methyl] -4
-Methoxyphenylamino} -3-hydroxy-3-si
Clobutene-1,2-dione (Exemplary Compound No. 2-34)
05) (58a) N- (1- (3,4-difluorophenyl)
Ethyl) -N-[(2-methoxy-5-nitrophenyl
1.)-(4-methoxyphenyl) methyl] amine (2-methoxy-5-nitrophenyl)-(4-methoxyphenyl) ketone 1.5 g and 1- (3,4-difluorophenyl) ethylamine hydrochloride 02g, 4.37 ml of triethylamine, 0.69 ml of titanium tetrachloride,
1.46 g of sodium cyanoborohydride, 0.1% of acetic acid.
The reaction was carried out in the same manner as in Production Example (1a) using 45 ml to obtain 2.10 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.35 (t
otal 3H, each d, J = 6.6and 6.5Hz), 3.59 and 3.65 (to
tal 1H, each q, J = 6.6 and 6.6Hz), 3.76, 3.79, 3.80
and 3.82 (total 6H, each s), 4.88 and 4.90 (total 1
H, each s), 6.78-6.93 (4H, m), 7.04-7.22 (4H, m), 8.
10 and 8.17 (total 1H, each dd, J = 2.8,8.9 and 2.9,
9.3Hz), 8.30 and 8.49 (total 1H, each d, J = 2.8 and
2.8Hz).

(58b) 3-[(1- (3,4-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
L) Methyl] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(2-methoxy-5-nitrophenyl)-(4-
Methoxyphenyl) methyl] amine 2.0 g, stannic chloride 3.54 g, concentrated hydrochloric acid-ethanol 1: 1 mixed solution 40
The reaction was carried out and purified in the same manner as in Production Example (57b) using the same isomer (A) as an yellow oily substance.
70 mg, 591 mg of isomer (B) as a yellow oil
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.59 (3H, s), 3.65 (1H, q, J = 6.6Hz), 3.76 (3H
H, m), 4.74 (1H, s), 6.58 (1H, dd, J = 2.8, 8.5Hz), 6.
64-6.72 (2H, m), 6.74-6.83 (3H, m), 6.97-7.00 (1H,
m), 7.06-7.22 (4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.7Hz), 3.61-3.65 (1H, m), 3.65 (3H, s), 3.80 (3H,
s), 4.85 (1H, s), 6.49-6.52 (2H, s), 6.65 (1H, dd, J =
1.3, 7.5Hz), 6.84-6.90 (3H, m), 7.05-7.16 (2H, m),
7.23-7.27 (3H, m).

(58c) 3-t-butoxy-4- {3-
[(1- (3,4-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] -4-methoxy
C-phenylamino} -3-cyclobutene-1,2-di
On 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-methoxyphenylamine isomer (A) 360 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 333 mg of -dione to obtain 260 mg of the title compound isomer (A) as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.63 (1H, q, J = 6.6Hz), 3.68 (3
H, s), 3.76 (3H, s), 4.87 (1H, s), 6.78 (2H, d, J = 8.7
Hz), 6.84 (1H, d, J = 8.8Hz), 6.95-7.00 (1H, m), 7.05-
7.15 (2H, s), 7.20 (2H, d, J = 8.6Hz), 7.26-7.40 (2H,
m). Isomer of 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-methoxyphenylamine (B) 360 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 333 mg of -dione to obtain 512 mg of the isomer (B) of the title compound as a yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 3.72 (3
H, s), 3.81 (3H, s), 4.89 (1H, s), 6.78 (1H, d, J = 8.8
Hz), 6.86-6.90 (3H, m), 7.03-7.26 (6H, m).

(58d) 4- {3-[(1- (3,4-
Difluorophenyl) -ethylamino)-(4-methoxy)
Cyphenyl) methyl] -4-methoxy-phenylamido
NO -3-Hydroxy-3-cyclobutene-1,2-di
On 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 250 m
g, and reacted and purified in the same manner as in Production Example (57d) to give isomer (A) of the title compound as a pale yellow solid in 115%
mg. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.6Hz), 3.57 (3H, s), 3.73 (3H, s), 4.50 (1H, br), 5.
05 (1H, br.s), 6.91-6.95 (3H, m), 7.03-7.05 (1H, m),
7.32-7.40 (4H, m), 7.45-7.52 (1H, m), 7.65 (1H, d, J =
2.3Hz). Melting point: 252-255 ° C 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-methoxyphenyl Amino｝ -3-
Cyclobutene-1,2-dione isomer (B) 400 m
g and reacted and purified in the same manner as in Production Example (57d) to give the title compound isomer (B) as a pale yellow solid in 230 mg
mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.53 (3H, d, J
= 6.6Hz), 3.71 (3H, s), 3.77 (3H, s), 4.11-4.24 (1H, b
r), 5.24 (1H, br.s), 6.93 (1H, d, J = 9.0Hz), 6.99 (2H,
d, J = 8.7Hz), 7.23-7.25 (1H, m), 7.47 (2H, d, J = 8.6H
z), 7.50-7.65 (4H, m). Melting point: 245-249 ° C.

Production Example 59 4- {5-[(1- (3,4-difluorophenyl) e]
Tylamino)-(4-methoxyphenyl) methyl]-
2,3-dimethoxyphenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione (exemplary compound number
2-3406) (59a) N- (1- (3,4-difluorophenyl)
Ethyl) -N-[(3,4-dimethoxy-5-nitroph
Enyl)-(4-methoxyphenyl) methyl] amine (3,4-dimethoxy-5-nitrophenyl)-(4-
(Methoxyphenyl) ketone 700 mg and 1- (3,4-
Difluorophenyl) ethylamine hydrochloride 854m
g, triethylamine 1.84 ml, titanium tetrachloride 0.
29ml, sodium borohydride 616m
g, acetic acid 0.19 ml, and the reaction was carried out in the same manner as in Production Example (1a) to give 950 mg of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.35 (t
otal 3H, each d, J = 6.4and 6.4Hz), 3.59-3.65 (1H,
m), 3.77, 3.81, 3.82, 3.73, 3.91and 3.96 (total 9H,
each s), 4.49 and 4.52 (total 1H, each s), 6.81-6.
95 (3H, m), 7.00-7.17 (5H, m), 7.03 and 7.31 (total 1
H, each s).

(59b) 5-[(1- (3,4-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
M)]-2,3-Dimethoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(3,4-dimethoxy-5-nitrophenyl)-
The reaction was carried out in the same manner as in Production Example (1b) using 950 mg of (4-methoxyphenyl) methyl] amine, 985 mg of nickel chloride hexahydrate and 330 mg of sodium borohydride. The crude product obtained by the post-treatment is subjected to silica gel column chromatography (ethyl acetate / toluene = 1).
/ 10 mg) to give 215 mg of isomer (A) of the title compound as a yellow oil and 370 mg of isomer (B) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.68 (1H, q, J = 6.6Hz), 3.76 (3H, s), 3.80 (3H
H, s), 3.81 (3H, s), 4.36 (1H, s), 6.25 (1H, d, J = 1.9
Hz), 6.33 (1H, d, J = 1.8Hz), 6.79 (2H, d, J = 8.7Hz),
6.94-6.98 (1H, m), 7.09-7.21 (4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.8Hz), 3.61 (1H, q, J = 6.6Hz), 3.758 (3H, s), 3.764
(3H, s), 3.81 (3H, s), 4.38 (1H, s), 6.25 (1H, d, J = 1.
8Hz), 6.30 (1H, d, J = 1.8Hz), 6.86 (2H, d, J = 8.7Hz),
6.88-6.94 (1H, m), 7.06-7.26 (4H, m).

(59c) 3-t-butoxy-4- {5-
[(1- (3,4-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] -2,3-di
Methoxyphenylamino} -3-cyclobutene-1,2
-Dione 5-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2,3-
360 mg of isomer (B) of dimethoxyphenylamine
4-t-butoxy-3-methoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 310 mg of 1,2-dione to obtain 150 mg of the title compound isomer (B) as a yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.65 (9H, s), 3.64 (1H, q, J = 6.6Hz), 3.78 (3
H, s), 3.80 (3H, s), 3.86 (3H, s), 4.49 (1H, s), 6.55
(1H, br), 6.88 (2H, d, J = 8.7Hz), 6.97-7.00 (1H, m),
7.05-7.12 (2H, m), 7.25-7.31 (2H, m), 7.52-7.70 (1H, b
r).

(59d) 4- {5-[(1- (3,4-
Difluorophenyl) -ethylamino)-(4-methoxy)
Cyphenyl) methyl] -2,3-dimethoxy-phenyl
Amino} -3-hydroxy-3-cyclobutene-1,2
-Dione 3-t-butoxy-4- {5-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2,3-dimethoxyphenylamino}
Isomer (B) 1 of -3-cyclobutene-1,2-dione
The reaction and purification were carried out in the same manner as in Production Example (57d) using 47 mg, and the isomer (B) of the title compound was converted to a yellow solid by the use of 8 mg.
2 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.20-1.45 (3H,
br), 3.35-3.90 (10H, m), 4.25-4.50 (1H, br.), 6.50-
6.70 (1H, d, m), 6.80-7.70 (7H, m), 7.80-8.00 (1H,
m). Melting point: 200-205 ° C.

Production Example 60 4- {5-[(1- (3,5-difluorophenyl) e]
Tylamino)-(4-methoxyphenyl) methyl]-
2,3-dimethoxyphenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione (exemplary compound number
2-3476) (60a) N- [1- (3,5-difluorophenyl)
Ethyl] -N-[(3,4-dimethoxy-5-nitrophene
Nyl)-(4-methoxyphenyl) methyl] amine (3,4-dimethoxy-5-nitrophenyl)-(4-
750 mg of methoxyphenyl) ketone and 1- (3,5-
Difluorophenyl) ethylamine hydrochloride 915m
g, triethylamine 1.98 ml, titanium tetrachloride 0.1 g.
31ml, sodium borohydride 660m
g, acetic acid 0.20 ml, and the reaction was carried out in the same manner as in Production Example (1a) to give 990 mg of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.36 (t
otal 3H, each d, J = 6.5and 6.5Hz), 3.61-3.66 (1H,
m), 3.77, 3.818, 3.82, 3.88, 3.91 and 3.96 (total 9
H, each s), 4.52 and 4.55 (total 1H, each s), 6.66-
6.91 (5H, m) 7.03-7.06 (1H, m), 7.14-7.17 (2H, m), 7.3
0 and 7.37 (total 1H, each d, J = 2.0 and1.9Hz).

(60b) 5-[(1- (3,5-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
M)]-2,3-dimethoxyphenylamine N- [1- (3,5-difluorophenyl) ethyl]-
N-[(3,4-dimethoxy-5-nitrophenyl)-
The same reaction as in Production Example (1b) was carried out using 870 mg of (4-methoxyphenyl) methyl] amine, 1.04 g of nickel chloride hexahydrate and 302 mg of sodium borohydride to obtain 550 mg of the title compound as a colorless oil. Was. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.
6Hz), 3.62 and 3.69 (total 1H, each q, J = 6.7 and 6.
6Hz), 3.76, 3.765, 3.768, 3.80, 3.807 and 3.814 (to
tal 9H, each s), 4.39 and 4.41 (total 1H, each s),
6.25-6.27 (1H, m), 6.31-6.35 (1H, m), 6.65-6.71 (1H, m
m), 6.77-6.89 (4H, m), 7.19-7.22 (2H, m).

(60c) 3-t-butoxy-4- {5-
[(1- (3,5-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] -2,3-di
Methoxyphenylamino} -3-cyclobutene-1,2
-Dione 5-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2,3-
Using 540 mg of dimethoxyphenylamine and 348 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to give 260 mg of the title compound as a colorless foam. Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.38 (3H,
m), 1.63 and 1.65 (total9H, each s), 3.63-3.70 (1H,
m), 3.76, 3.79, 3.80, 3.84, 3.87 and 3.93 (total 9
H, each s), 4.49 and 4.53 (total 1H, each s), 6.59-
6.71 (2H, m), 6.80-6.90 (4H, m), 7.21-7.28 (2H, m),
7.52-7.71 (1H, br).

(60d) 4- {5-[(1- (3,5-
Difluorophenyl) -ethylamino)-(4-methoxy)
Cyphenyl) methyl] -2,3-dimethoxy-phenyl
Amino} -3-hydroxy-3-cyclobutene-1,2
-Dione 3-t-butoxy-4- {5-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2,3-dimethoxyphenylamino}
The reaction and purification were carried out in the same manner as in Production Example (57d) using 247 mg of -3-cyclobutene-1,2-dione to obtain 137 mg of an isomer mixture of the title compound as a yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.48 (3H, d, J
= 6.8Hz), 3.70-3.77 (9H, m), 4.10-4.50 (1H, br), 4.80-
5.20 (1H, br), 6.69-7.90 (9H, m). Melting point: 167-171 ° C.

Production Example 61 4- {3-[(1- (3,5-difluorophenyl) e
Tylamino))-(4-methoxyphenyl) methyl]-
4-methoxyphenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-3
477) (61a) N- (1- (3,5-difluorophenyl)
Ethyl) -N-[(2-methoxy-5-nitrophenyl
1.)-(4-methoxyphenyl) methyl] amine (2-methoxy-5-nitrophenyl)-(4-methoxyphenyl) ketone 1.29 g and 1- (3,5-difluorophenyl) ethylamine hydrochloride. 74g, triethylamine 3.76ml, titanium tetrachloride 0.59m
1, 1.25 g of sodium borohydride and 0.39 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 1.78 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33-1.37 (3H,
m), 3.60 and 3.66 (total1H, each q, J = 6.6, 6.7Hz),
3.76, 3.79, 3.81 and 3.83 (total 6H, each s), 4.91 a
nd 4.93 (total 1H, each s), 6.65-6.90 (6H, m), 7.17
and 7.22 (total2H, each d, J = 8.6 and 8.6Hz), 8.10 a
nd 8.17 (total 1H, each dd, J = 2.9, 8.6 and 2.9, 8.8
Hz), 8.27 and 8.50 (total 1H, each d, J = 2.8 and 2.9
Hz).

(61b) 3-[(1- (3,5-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
L) Methyl] -4-methoxyphenylamine N- [1- (3,5-difluorophenyl) ethyl]-
N-[(2-methoxy-5-nitrophenyl)-(4-
The same reaction as in Production Example (59b) was carried out and purified using 1.75 g of methoxyphenyl) methyl] amine, 2.24 g of nickel chloride hexahydrate and 651 mg of sodium borohydride to give the isomer of the title compound (A ) As a yellow oil and 471 mg of isomer (B) as an orange solid.
0 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.59 (3H, s), 3.67 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.77 (1H, s), 6.58 (1H, J = 2.9, 8.6Hz), 6.63-
6.72 (3H, m), 6.78 (2H, d, J = 8.7Hz), 6.85 (2H, dd, J =
2.1, 8.6 Hz), 7.16-7.23 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.64 (1H, q, J = 6.7Hz), 3.67 (3H, s), 3.81 (3
H, s), 4.88 (1H, s), 6.49-6.52 (2H, m), 6.64-6.70 (2
H, m), 6.80 (2H, dd, J = 2.1, 8.6Hz), 6.86 (2H, d, J =
8.7 Hz), 7.26 (2H, d, J = 8.6 Hz). Melting point: 105-106 ° C.

(61c) 3-t-butoxy-4- {3-
[(1- (3,5-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] -4-methoxy
Cyphenylamino} -3-cyclobutene-1,2-di
Down 3 - [(1- (3,5-difluorophenyl) ethylamino) - (4-methoxyphenyl) methyl] -4-methoxyphenyl isomer of the amine (A) 450mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 416 mg of -dione to obtain 570 mg of the isomer (A) of the title compound as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 3.68 (3
H, s), 3.76 (3H, s), 4.90 (1H, s), 6.64-6.70 (1H, m),
6.77-6.86 (5H, m), 7.21 (2H, d, J = 8.7Hz), 7.26-7.31
(1H, br), 7.40 (1H, br.s). 3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-methoxyphenylamine isomer (B) 630 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 582 mg of -dione to obtain 880 mg of the isomer (B) of the title compound as a yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.8Hz), 1.62 (9H, s), 3.65 (1H, q, J = 6.7Hz), 3.74 (3
H, s), 3.81 (3H, s), 4.92 (1H, s), 6.64-6.70 (1H, m),
6.76-6.80 (3H, m), 6.86-6.89 (2H, m), 7.11 (1H, br),
7.16-7.28 (3H, m).

(61d) 4- {3-[(1- (3,5-
Difluorophenyl) ethylamino)-(4-methoxy
Phenyl) methyl] -4-methoxyphenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4 -Methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 200 m
g and reacted and purified in the same manner as in Production Example (57d) to give the isomer (A) of the title compound as a pale green solid in the form of 118
mg. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.59 (3H, d, J
= 6.4Hz), 3.56 (3H, s), 3.72 (3H, s), 4.47 (1H, br), 5.
07 (1H, br.s), 6.90-6.99 (5H, m), 7.27-7.42 (4H, m),
7.69 (1H, s). Melting point: 258-263C 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4. -Methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 200 m
g, and reacted and purified in the same manner as in Production Example (57d) to give isomer (B) of the title compound as a pale yellow solid in 122%
mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.52 (3H, d, J
= 6.6Hz), 3.71 (3H, s), 3.77 (3H, s), 4.21 (1H, br), 5.
27 (1H, br.s), 6.94 (1H, d, J = 8.9Hz), 7.00 (2H, d, J =
8.7Hz), 7.17-7.39 (3H, m), 7.47 (2H, d, J = 8.5Hz), 7.
55 (1H, d, J = 2.0 Hz), 7.60-7.64 (1H, m). Melting point: 200-204 ° C.

Production Example 62 4- {3-[((S) -1- (3,4-difluorophene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione (Exemplified Compound No. 2-42) (62a) 3-t-butoxy-4- {3-[((S)-
1- (3,4-difluorophenyl) ethylamino)-
(4-methoxyphenyl) methyl] phenylamino}-
3-cyclobutene-1,2-dione 3-[((S) -1- (3,4-difluorophenyl)
Production Example (1c) using 500 mg of isomer (B) of ethylamino)-(4-methoxyphenyl) methyl] phenylamine and 500 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. The reaction was carried out in the same manner as in the above to give the isomer (B) of the title compound as a colorless foam.
05 mg was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.52 (1H, s), 6.88 (2H, d, J = 8.5Hz), 6.94-7.3
1 (9H, m).

(62b) 4- {3-[((S) -1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione hydrochloric acid
Salt 3-t-butoxy-4- {3-[((S) -1- (3,
4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione isomer (B)
To the ethyl acetate solution, 3 ml of a 4N HCl / ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with diethyl ether, and the precipitated solid was collected by filtration and dried to obtain 472 mg of the hydrochloride of the isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.8Hz), 3.77 (3H, m), 4.21 (1H, q, J = 6.7Hz), 5.10 (1
H, s), 7.00 (2H, d, J = 8.7Hz), 7.20-7.21 (1H, m), 7.3
0-7.59 (8H, m). Melting point: 192-195 ° C Optical rotation [α] _D = -0.1 ° (c = 1.00, AcO
H).

Production Example 63 4- {3-[((R) -1- (3,4-difluorophene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione and its hydrochloride (Exemplary Compound No.
2-42) (63a) 3-t-butoxy-4- {3-[((R)-
1- (3,4-difluorophenyl) ethylamino)-
(4-methoxyphenyl) methyl] phenylamino}-
3-cyclobutene-1,2-dione 3-[((R) -1- (3,4-difluorophenyl)
Production Example (1c) using 500 mg of isomer (B) of ethylamino)-(4-methoxyphenyl) methyl] phenylamine and 410 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. The reaction was carried out in the same manner as in the above to give the isomer (B) of the title compound as a colorless foam.
50 mg were obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.5Hz), 3.81 (3
H, s), 4.52 (1H, s), 6.88 (2H, d, J = 8.6Hz), 6.97-7.3
8 (9H, m).

(63b) 4- {3-[((R) -1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione hydrochloric acid
Salt 3-t-butoxy-4- {3-[((R) -1- (3,
4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione isomer (B) 300 mg of 5
To 2 ml of anhydrous methylene chloride solution, 2 ml of trifluoroacetic acid was added and stirred at room temperature for 1 hour. After evaporating the solvent and excess trifluoroacetic acid under reduced pressure, the residue was redissolved in 10 ml of ethyl acetate. 2 ml of 4N HCl was added to this solution.
/ Ethyl acetate solution was added and the mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with diethyl ether, and the precipitated solid was collected by filtration and dried to obtain the hydrochloride of the isomer (B) of the title compound as a pale yellow solid (260 mg). Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 3.77 (3H, s), 4.21 (1H, q, J = 6.6Hz), 5.09 (1
H, s), 6.99 (2H, d, J = 8.7Hz), 7.20-7.22 (1H, m), 7.3
4-7.41 (3H, m), 7.47-7.60 (5H, m). Melting point: 192 to 196 ° C Optical rotation [α] _D = + 11.1 ° (c = 1.00, Ac
OH).

(63c) 4- {3-[((R) -1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[((R) -1- (3,
4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione Using 175 mg of the isomer (B), the reaction was carried out in the same manner as in Production Example (55b). Purification was performed to obtain 129 mg of the isomer (B) of the title compound as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.56 (3H, br),
3.76 (3H, s), 4.19 (1H, br), 5.00 (1H, br), 6.91-7.00
(3H, m), 7.20-7.24 (2H, m), 7.45-7.56 (5H, m), 7.69
(1H, s). Melting point: 193 to 200 ° C. Optical rotation [α] _D = + 102.6 ° (c = 0.76, A
cOH).

Production Example 64 4- {3-[((R) -1- (3,5-difluorophene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione and its hydrochloride (Exemplary Compound No.
2-56) (64a) N-[(R) -1- (3,5-difluorophenyl)
Enyl) ethyl] -N-[(4-methoxyphenyl)-
3.91 g of (3-nitrophenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ketone and 4.42 g of hydrochloride of (R) -1- (3,5-difluorophenyl) ethylamine, triethylamine 11.7 ml, titanium tetrachloride 2.01 ml, sodium cyanoborohydride 4.25 g, acetic acid 1.31
The reaction was carried out in the same manner as in Production Example (1a) using the above-mentioned ml, and purification was performed to obtain 860 mg of an isomer (B) as a yellow oil which eluted later than the title compound. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 3.67 (1H, q, J = 6.6Hz), 3.82 (3H, s), 4.63 (1
H, s), 6.66-6.72 (1H, m), 6.76-6.85 (2H, m), 6.90 (2
H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 7.41 (1H, t,
J = 8.0Hz), 7.61 (1H, d, J = 7.3Hz), 8.04 (1H, dd, J = 2.0,
8.0Hz), 8.22 (1H, d, J = 1.9Hz).

(64b) 3-[((R) -1- (3,5
-Difluorophenyl) ethylamino)-(4-methoxy)
(Ciphenyl) methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl) ethyl] -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine isomer (B ) 820mg
And 1.13 g of nickel chloride hexahydrate and 328 mg of sodium borohydride were reacted in the same manner as in Production Example (1b) to obtain 480 mg of the isomer (B) of the title compound as a yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 3.64 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.47 (1
H, s), 6.51 (1H, dd, J = 2.0, 8.2Hz), 6.62 (1H, d, J = 1.
6Hz), 6.62-6.71 (2H, m), 6.80 (2H, dd, J = 2.1, 8.3H
z), 6.86 (2H, d, J = 8.6Hz), 7.04 (1H, t, J = 7.9Hz), 7.
20 (2H, d, J = 8.7Hz).

(64c) 3-t-butoxy-4- {3-
[((R) -1- (3,5-difluorophenyl) ethyl]
Ruamino)-(4-methoxyphenyl) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
Production Example (1c) using 450 mg of isomer (B) of ethylamino)-(4-methoxyphenyl) methyl] phenylamine and 450 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. The isomer (B) of the title compound was converted into a yellow foam by the reaction as described in 6 above.
10 mg were obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.55 (1H, s), 6.66-6.70 (1H, m), 6.80 (2H, dd,
J = 1.9, 8.1Hz), 6.88 (2H, d, J = 8.7Hz), 7.19-7.31 (6H,
m).

(64d) 4- {3-[((R) -1-
(3,5-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione hydrochloric acid
Salt 3-t-butoxy-4- {3-[((R) -1- (3,
5-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione Using 200 mg of the isomer (B), the reaction was carried out in the same manner as in Production Example (63b). Purification was performed to obtain 175 mg of isomer (B) of the title compound as a brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.8Hz), 3.77 (3H, s), 4.24 (1H, m), 5.13 (1H, s), 6.9
9 (2H, d, J = 8.8Hz), 7.19-7.22 (2H, m), 7.23-7.42 (4H,
m), 7.52-7.57 (3H, m). Melting point: 180-185 ° C Optical rotation [α] _D + 14.7 ° (c = 0.90, Ac
OH).

(64e) 4- {3-[((R) -1-
(3,5-difluorophenyl) -ethylamino)-
(4-methoxyphenyl) -methyl] -phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
On 3-t-butoxy-4- {3-[((R) -1- (3,
5-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione Isomer (B) (340 mg) was reacted in the same manner as in Production Example (55b). Purification was performed to obtain 202 mg of the title compound isomer (B) as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.55 (3H, br),
3.76 (3H, s), 4.20 (1H, br), 5.04 (1H, br.), 6.93-7.0
0 (3H, m), 7.17-7.30 (4H, m), 7.46 (2H, d, J = 8.2Hz),
7.55 (1H, d, J = 8.1 Hz), 7.69 (1H, d, J = 0.5 Hz). Melting point: 195 to 200 ° C. Optical rotation [α] _D = + 117.3 ° (c = 1.03, A
cOH).

Production Example 65 4- {3-[(1- (3,5-difluorophenyl) e
Tylamino)-(4-ethoxyphenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-3485) (65a) N- [1- (3,5-difluorophenyl)
Ethyl] -N-[(4-ethoxyphenyl)-(3-d
Trophenyl) methyl] amine (4-ethoxyphenyl)-(3-nitrophenyl) ketone 1.0 g, 1- (3,5-difluorophenyl) ethylamine 1.16 g, triethylamine 2.01 m
l, 0.49 ml of titanium tetrachloride, 975 mg of sodium borohydride cyanide, and 0.32 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 1.41 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.34-1.44 (6H,
m), 3.61 and 3.67 (total1H, each q, J = 6.6 and 6.7H
z), 3.98 and 4.21 (total 2H, each q, J = 6.9 and6.9H
z), 4.42 and 4.68 (total 1H, each s), 6.66-6.89 (5H,
m), 7.13-7.16 (2H, m), 7.40 and 7.49 (total 1H, eac
ht, J = 7.9 and 7.8Hz), 7.60-7.66 (1H, m), 8.03-8.12
(1H, m), 8.22-8.26 (1H, m).

(65b) 3-[(1- (3,5-difur
Orophenyl) ethylamino)-(4-ethoxyphenyl)
L) methyl] phenylamine N- [1- (3,5-difluorophenyl) ethyl]-
Reaction was performed in the same manner as in Production Example (59b) using 1.39 g of N-[(4-ethoxyphenyl)-(3-nitrophenyl) methyl] amine, 1.84 g of nickel chloride hexahydrate and 537 mg of sodium borohydride. And purified to give 316 m of the isomer (A) of the title compound as a yellow oil.
g, 531 mg of isomer (B) as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.8Hz), 1.38 (3H, t, J = 6.8Hz), 3.68 (1H, q, J = 6.7H
z), 3.98 (2H, q, J = 6.9Hz), 4.46 (1H, s), 6.56-6.70 (4
H, m), 6.76-6.85 (4H, m), 7.11 (1H, t, J = 7.6Hz), 7.1
8 (2H, d, J = 8.7 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.7Hz) .1.41 (3H, t, J = 6.7Hz), 3.63 (1H, q, J = 6.6H)
z), 4.02 (2H, q, J = 6.9Hz), 4.46 (1H, s), 6.51 (1H, dd,
J = 2.0, 8.1Hz), 6.62 (1H, s), 6.62-6.70 (2H, m), 6.7
7-6.87 (4H, m), 7.04 (1H, t, J = 7.7Hz), 7.18 (2H, d, J
= 8.6Hz).

(65c) 3-t-butoxy-4- {3-
[(1- (3,5-difluorophenyl) ethylamido
No)-(4-ethoxyphenyl) methyl] phenylamido
Roh} -3-cyclobutene-1,2-dione 3 - [(1- (3,5-difluorophenyl) ethylamino) - (4-ethoxyphenyl) methyl] isomer phenylamine (A) 288 mg, 4- t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 277
and 393 mg of the title compound isomer (A) as a yellow oil.
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.40 (6H,
m), 1.63 (9H, m), 3.66 (1H, q, J = 6.6Hz), 3.98 (2H, q,
J = 6.9Hz), 4.56 (1H, s), 6.66-6.72 (1H, m), 6.79 (4H,
dd, J = 2.0, 8.6Hz), 7.07-7.08 (1H, m), 7.17 (2H, d,
J = 8.6 Hz), 7.24-7.39 (3H, m). 438 mg of isomer (B) of 3-[(1- (3,5-difluorophenyl) ethylamino)-(4-ethoxyphenyl) methyl] phenylamine , 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 422
and 494 mg of the isomer (B) of the title compound as a yellow foam.
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.41 (3H, t, J = 7.0Hz), 1.63 (9H, s), 3.65 (1
H, q, J = 6.9Hz), 4.03 (2H, q, J = 6.9Hz), 4.54 (1H, s),
6.65-6.70 (1H, m), 6.80 (2H, dd, J = 2.0, 8.4Hz), 6.87
(2H, d, J = 8.6Hz), 7.04-7.41 (6H, m).

(65d) 4- {3-[(1- (3,5-
Difluorophenyl) ethylamino)-(4-ethoxy
Phenyl) methyl] phenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-ethoxyphenyl) methyl] phenylamino} -3-cyclobutene-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 352 mg of 1,2-dione isomer (A) to obtain 299 mg of the title compound isomer (A) as a pale brown solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.30 (3H, t, J
= 6.8Hz), 1.65 (3H, d, J = 6.7Hz), 4.01 (2H, q, J = 6.9H
z), 4.29 (1H, br), 5.13 (1H, s), 6.93 (2H, d, J = 8.7H
z), 7.16 (2H, dd, J = 1.6, 7.9 Hz), 7.26-7.54 (7H, m). Melting point: 185-190 ° C. 3-t-butoxy-4- {3-[(1- (3, 5-difluorophenyl) ethylamino)-(4-ethoxyphenyl) methyl] phenylamino} -3-cyclobutene-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 468 mg of 1,2-dione isomer (B) to obtain 338 mg of the title compound isomer (B) as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.32 (3H, t, J
= 7.1Hz), 1.65 (3H, d, J = 6.8Hz), 4.03 (2H, q, J = 7.1H)
z), 4.23 (1H, br), 5.13 (1H, s), 6.97 (2H, d, J = 8.7H
z), 7.20-7.22 (2H, m), 7.28-7.42 (4H, m), 7.51-7.55
(3H, m). Melting point: 178-182 ° C.

Production Example 66 4- {3-[(1- (3,5-difluorophenyl) e
Tylamino)-(4-propyloxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-34)
89) (66a) N- [1- (3,5-difluorophenyl)
Ethyl] -N-[(3-nitrophenyl)-(4-pro
[ Pyroxyphenyl ) methyl] amine (3-nitrophenyl)-(4-propyloxyphenyl) ketone 790 mg, 1- (3,5-difluorophenyl) ethylamine 870 mg, triethylamine
Using 54 ml, 0.37 ml of titanium tetrachloride, 733 mg of sodium borohydride cyanide, and 0.24 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 1.16 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.01 and 1.04 (t
otal 3H, each t, J = 7.5and 7.4Hz), 1.35 and 1.36 (to
tal 3H, each d, J = 6.5 and 6.5Hz), 1.73-1.86 (2H,
m), 3.61 and 3.67 (total 1H, each q, J = 6.6 and 6.6H
z), 3.87 and 3.92 (total 2H, each t, J = 6.5 and 6.6H
z), 4.62 and 4.68 (total 1H, each s), 6.66-6.91 (5H,
m), 7.14 (2H, d, J = 8.6Hz), 7.40 and 7.49 (total 1H,
each t, J = 8.0 and 7.8Hz), 7.61 and 7.66 (total 1H,
each d, J = 8.0 and 7.9Hz), 8.04 and 8.10 (total 1H,
each dd, J = 1.8, 8.0 and 1.8, 8.0Hz), 8.23-8.26 (1
H, m).

(66b) 3-[(1- (3,5-difur
Orophenyl) ethylamino)-(4-propyloxy
Phenyl) methyl] phenylamine N- [1- (3,5-difluorophenyl) ethyl]-
1.10 g of N-[(3-nitrophenyl)-(4-propyloxyphenyl) methyl] amine and nickel chloride 6
1.41 g of hydrate and sodium borohydride 411
The reaction was carried out in the same manner as in Production Example (1b) using mg to give 915 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.00 and 1.03 (t
otal 3H, each t, J = 7.4and 7.4Hz), 1.31 (3H, d, J = 6.
7Hz), 1.73-1.85 (2H, m), 3.64 and 3.69 (total1H, eac
hq, J = 6.6 and 6.7Hz), 3.87 and 3.91 (total 2H, eac
ht, J = 6.6 and6.5Hz), 4.46 (1H, s), 6.50-6.70 (4H,
m), 6.77-6.87 (4H, m), 7.04 and 7.11 (total 1H, each
dd, J = 7.7, 7.9 and 7.6, 7.9Hz), 7.18 (2H, d, J = 8.6
Hz).

(66c) 3-t-butoxy-4- {3-
[(1- (3,5-difluorophenyl) ethylamido
No)-(4-Propyloxyphenyl) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethylamino)-(4-propyloxyphenyl) methyl] phenylamine 860 mg, 4-t-butoxy-3 The reaction was carried out in the same manner as in Production Example (1c) using 599 mg of -methoxy-3-cyclobutene-1,2-dione. The crude product obtained by the post-treatment was purified by silica gel column chromatography (ethyl acetate / toluene = 1/10) to give the title compound isomer (A) as a pale yellow foam as 457 m
g, 206 mg of isomer (B) as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, t, J =
7.5Hz), 1.35 (3H, d, J = 6.7Hz), 1.63 (9H, s), 1.77 (2
H, m), 3.66 (1H, q, J = 6.6Hz), 3.87 (2H, t, J = 6.6Hz),
4.56 (1H, s), 6.66-6.71 (1H, m), 6.80 (4H, d, J = 8.7H
z), 7.07-7.36 (6H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.04 (3H, t, J =
7.5Hz), 1.33 (3H, d, J = 6.6Hz), 1.63 (9H, s), 1.81 (2
H, m), 3.65 (1H, q, J = 6.6Hz), 3.91 (2H, t, J = 6.5Hz),
4.54 (1H, s), 6.65-6.70 (1H, m), 6.81 (2H, dd, J = 2.
0, 8.4Hz), 6.88 (2H, d, J = 8.5Hz), 7.05-7.29 (6H, m).

(66d) 4- {3-[(1- (3,5-
Difluorophenyl) ethylamino)-(4-propyl
Oxyphenyl) methyl] phenylamino} -3-hydrido
Roxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) -ethylamino)-(4-propyloxyphenyl) methyl] The reaction and purification were carried out in the same manner as in Production Example (63b) using 440 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione to give the isomer (A) of the title compound as a pale yellow solid. 381 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 0.95 (3H, t, J
= 7.4Hz), 1.63 (3H, d, J = 6.8Hz), 1.70 (2H, m), 3.91 (2
H, t, J = 6.6Hz), 4.30 (1H, br), 5.13 (1H, s), 6.94 (2
H, d, J = 8.8Hz), 7.14-7.19 (3H, m), 7.27-7.36 (2H,
m), 7.45 (1H, d, J = 8.1Hz), 7.51 (2H, d, J = 8.7Hz), 7.
56 (1H, s). Melting point: 176-180 ° C 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-propyloxyphenyl) methyl] phenyl Reaction and purification were carried out in the same manner as in Production Example (63b) using 195 mg of the isomer (B) of amino｝ -3-cyclobutene-1,2-dione to obtain 170 mg of the isomer (B) of the title compound as a white solid. Was. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 0.97 (3H, t, J =
7.5Hz), 1.64 (3H, d, J = 6.8Hz), 1.72 (2H, m), 3.93 (2H
H, t, J = 6.6Hz), 4.24 (1H, br), 5.14 (1H, s), 6.98 (2
H, d, J = 8.7Hz), 7.19-7.21 (2H, m), 7.29-7.42 (4H,
m), 7.52-7.54 (3H, m). Melting point: 167-172 ° C.

Production Example 67 4- {3-[(1- (3,5-difluorophenyl) e
Tylamino)-(4-isopropoxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-34)
90) (67a) N- [1- (3,5-difluorophenyl)
Ethyl] -N-[(3-nitrophenyl)-(4-iso
Propoxyphenyl ) methyl] amine (3-nitrophenyl)-(4-isopropoxyphenyl) ketone 850 mg, 1- (3,5-difluorophenyl) ethylamine 936 mg, triethylamine
The reaction was carried out in the same manner as in Production Example (1a) using 66 ml, titanium tetrachloride 0.39 ml, sodium borohydride 788 mg, and acetic acid 0.26 ml to obtain 1.20 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.29-1.37 (9H,
m), 3.61 and 3.68 (total1H, each q, J = 6.6 and 6.6H
z), 4.46-4.57 (1H, m), 4.62 and 4.67 (total 1H, each
s), 6.66-6.83 (4H, m), 6.87 (1H, d, J = 8.5Hz), 7.11-
7.15 (2H, m), 7.40and 7.49 (total 1H, each t, J = 8.0
and 8.0Hz), 7.62 and 7.66 (total 1H, each d, J = 8.0
and 7.5Hz), 8.03-8.12 (1H, m), 8.23-8.26 (1H, m).

(67b) 3-[(1- (3,5-difur
(Orophenyl) ethylamino)-(4-isopropoxy
Phenyl) methyl] phenylamine N- [1- (3,5-difluorophenyl) ethyl]-
1.17 g of N-[(3-nitrophenyl)-(4-isopropoxyphenyl) methyl] amine and nickel chloride 6
1.50 g of hydrate and sodium borohydride 437
The reaction was carried out in the same manner as in Production Example (1b) using 1.0 mg to obtain 1.0 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.29-1.34 (9H,
m), 3.64 and 3.68 (total1H, each q, J = 6.6 and 6.7H
z), 4.45-4.55 (1H, m), 4.45 and 4.46 (total 1H, each
s), 6.50-6.70 (4H, m), 6.75-6.85 (4H, m), 7.02-7.18
(3H, m).

(67c) 3-t-butoxy-4- {3-
[(1- (3,5-difluorophenyl) ethylamido
No)-(4-Isopropoxyphenyl) methyl] phenyl
Lamino {-3-cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethylamino)-(4-isopropoxyphenyl) methyl] phenylamine 930 mg, 4-t-butoxy-3 Using 648 mg of -methoxy-3-cyclobutene-1,2-dione, the reaction was carried out and purified in the same manner as in Production Example (66c) to give the isomer (A) of the title compound as a pale yellow foam in 463 m
g, 407 mg of isomer (B) as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (6H, d, J =
6.1Hz), 1.35 (3H, d, J = 6.7Hz), 1.63 (9H, s), 3.66 (1
H, q, J = 6.6Hz), 4.48 (1H, m), 4.55 (1H, s), 6.66-6.7
1 (1H, m), 6.76-6.82 (4H, m), 7.08-7.37 (6H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.33-1.35 (9H, m
m), 1.63 (9H, s), 3.66 (1H, q, J = 6.6Hz), 4.53 (2H,
m), 6.64-6.70 (1H, m), 6.79-6.87 (4H, m), 7.05-7.40
(6H, m).

(67d) 4- {3-[(1- (3,5-
Difluorophenyl) ethylamino)-(4-isopro
Poxyphenyl) methyl] phenylamino} -3-hydr
Roxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-isopropoxyphenyl) methyl] phenyl The reaction and purification were carried out in the same manner as in Production Example (63b) using 450 mg of the amino｝ -3-cyclobutene-1,2-dione isomer (A) to give 369 mg of the title compound isomer (A) as a pale brown solid. Obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.24 (6H, d, J
= 5.9Hz), 1.64 (3H, d, J = 6.7Hz), 4.25-4.38 (1H, br),
4.60 (1H, m), 5.11 (1H, s), 6.91 (2H, d, J = 8.7Hz), 7.
14-7.37 (5H, m), 7.45 (1H, d, J = 8.0Hz), 7.50 (2H, d,
J = 8.7 Hz), 7.55 (1H, s). Melting point: 194-198 ° C. 3-t-butoxy-4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-iso Propoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione isomer (B) was reacted and purified in the same manner as in Production Example (63b) using 386 mg of isomer (B) of the title compound. Was obtained as a white solid (302 mg). Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (6H, dd,
J = 1.9, 6.0Hz), 1.65 (3H, d, J = 6.7Hz), 4.24 (1H, br),
4.63 (1H, m), 5.13 (1H, s), 6.96 (2H, d, J = 8.7Hz),
7.21 (2H, dd, J = 1.7, 8.0Hz), 7.23-7.43 (4H, m), 7.52
-7.54 (3H, m). Melting point: 176-179 ° C.

Production Example 68 4- {3-[(1- (3,4-difluorophenyl) e
Tylamino)-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-39) (68a) 3-t-butoxy-4- {3-[(1-
(3,4-difluorophenyl) ethylamino)-(4
-Fluorophenyl) methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamine (B) 300 mg, 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 310
and 267 mg of the title compound isomer (B) as a colorless foam.
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.61 (1H, q, J = 6.7Hz), 4.56 (1
H, s), 6.92-7.14 (6H, m), 7.23-7.40 (5H, m).

(68b) 4- {3-[(1- (3,4-
Difluorophenyl) ethylamino)-(4-fluoro
Phenyl) methyl] phenylamino} -3-hydroxy
-3-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 250 mg of 1,2-dione isomer (B) to obtain 158 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.24 (1H, q, J = 6.7Hz), 5.20 (1H, s), 7.20-
7.35 (5H, m), 7.39-7.60 (4H, m), 7.69 (2H, dd, J = 5.3,
8.6 Hz). Melting point: 180-182 ° C.

Production Example 69 4- {3-[((R) -1- (3,5-difluorophene)
Nyl) ethylamino)-(4-fluorophenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione and its hydrochloride (Exemplary Compound No.
2-53) (69a) N-[(R) -1- (3,5-difluorophenyl)
Enyl) ethyl] -N-[(4-fluorophenyl)-
(3-Nitrophenyl) methyl] amine (4-fluorophenyl)-(3-nitrophenyl) ketone (3.0 g) and (R) -1- (3,5-difluorophenyl) ethylamine hydrochloride (3.55 g, triethylamine) 9.38 ml, titanium tetrachloride 1.61 ml, sodium cyanoborohydride 3.08 g, acetic acid 1.05 m
Using l, the reaction was carried out in the same manner as in Production Example (1a) to obtain 4.48 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.7and 6.6Hz), 3.59-3.67 (1H,
m), 4.68 and 4.72 (total 1H, each, s), 6.67-6.81 (3
H, m), 6.96-7.08 (2H, m), 7.21-7.27 (2H, m), 7.43 an
d 7.51 (total 1H, each t, J = 8.0 and 7.8Hz), 7.60 an
d 7.64 (total 1H, each d, J = 8.0 and 7.8Hz), 8.06 an
d 8.13 (total 1H, each dd, J = 1.8, 7.9 and 1.8, 7.9H
z), 8.21-8.25 (1H, m).

(69b) 3-[((R) -1- (3,5
-Difluorophenyl) ethylamino)-(4-fluoro
Rophenyl) methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl) ethyl] -N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine (4.40 g) and chloride 6.54 g of nickel hexahydrate and sodium borohydride
The same reaction as in Production Example (59b) was carried out and purified using 81 g, and 1.24 g of the isomer (A) of the title compound was obtained as a yellow oil, and 1.66 g of the isomer (B) was obtained as a yellow oil.
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.69 (1H, q, J = 6.7Hz), 4.47 (1H, s), 6.59 (2
H, dd, J = 1.9, 4.0Hz), 6.64-6.71 (2H, m), 6.82 (2H, d
d, J = 2.1, 6.6Hz), 6.93 (2H, t, J = 8.6Hz), 7.12 (1H, d
d, J = 7.7, 8.4 Hz), 7.23-7.52 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.58-3.66 (1H, m), 4.50 (1H, s), 6.51-6.83 (6
H, m), 6.91-7.10 (3H, m), 7.23-7.29 (2H, m).

(69c) 3-t-butoxy-4- {3-
[((R) -1- (3,5-difluorophenyl) ethyl]
Ruamino)-(4-fluorophenyl) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
Production Example (1c) using 500 mg of isomer (A) of ethylamino)-(4-fluorophenyl) methyl] phenylamine and 517 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. The reaction was carried out in the same manner as in to give 681 mg of the isomer (A) of the title compound as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 6.66-6.72 (1H, m), 6.77-6.82 (2H, m), 6.95 (2
H, t, J = 8.7Hz), 7.04-7.07 (1H, m), 7.16-7.41 (5H,
m). 3-[((R) -1- (3,5-difluorophenyl)
Production Example (1c) using 500 mg of isomer (B) of ethylamino)-(4-fluorophenyl) methyl] phenylamine and 517 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. 580 mg of the title compound isomer (B) was obtained as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.6Hz), 4.59 (1H
H, s), 6.66-6.71 (1H, m), 6.76-6.81 (2H, m), 7.01-7.
07 (3H, m), 7.16-7.36 (5H, m).

(69d) 4- {3-[((R) -1-
(3,5-difluorophenyl) ethylamino)-(4
-Fluorophenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione hydrochloric acid
Salt 3-t-butoxy-4- {3-[((R) -1- (3,
5-Difluorophenyl) -ethylamino)-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione (627 mg of isomer (A)) was reacted in the same manner as in Production Example (63b). Purification was performed to obtain 542 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.32 (1H, q, J = 6.6Hz), 5.27 (1H, s), 7.17-
7.32 (6H, m), 7.34-7.43 (2H, m), 7.56 (1H, s), 7.71 (2
H, dd, J = 5.4, 8.7 Hz). Melting point: 183-187 ° C. Optical rotation [α] _D = −68.0 ° (c = 0.89, AcO)
H) 3-t-butoxy-4- {3-[((R) -1- (3,
5-Difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione Using 551 mg of the isomer (B), the reaction was carried out in the same manner as in Production Example (63b). Purification was performed to obtain 501 mg of the isomer (B) of the title compound as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.26 (1H, q, J = 6.7Hz), 5.28 (1H, s), 7.19-
7.43 (8H, m), 7.54 (1H, s), 7.72 (2H, dd, J = 5.5,8.6H
z) mp:. 187-190 ° C. Optical rotation _{[α] D = -12.8 ° (} c = 1.00, AcO
H).

(69e) 4- {3-[((R) -1-
(3,5-difluorophenyl) ethylamino)-(4
-Fluorophenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione 4- {3-[((R) -1- (3,5-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamino} -3- Dissolve 300 mg of isomer B of hydroxy-3-cyclobutene-1,2-dione hydrochloride in 5 ml of methanol and add 1N hydrochloric acid and 1N-
After adjusting the pH to 4 with an aqueous sodium hydroxide solution, the mixture was diluted with water. The precipitated solid was collected by filtration, washed with water and diethyl ether, and dried to obtain 164 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.57 (3H, d, J
= 6.7Hz), 4.23 (1H, br), 5.20 (1H, br.s), 6.98 (1H, d,
J = 7.6Hz), 7.17-7.30 (6H, m), 7.51-7.53 (1H, m), 7.62
(2H, dd, J = 5.5 , 8.5Hz), 7.68 (1H, s) mp:. 188~192 ℃ Optical rotation _{[α] D = + 38.2 °} (c = 1.09, AcO
H).

Production Example 70 4- {3-[(4-fluorophenyl)-((R) -1]
-Phenylpropylamino) methyl] phenylamino}
-3-Hydroxy-3-cyclobutene-1,2-dione
Hydrochloride (Exemplified Compound No. 2-3111) (70a) N-[(4-fluorophenyl)-(3-d
Trophenyl) methyl] -N-((R) -1-phenyl
Propyl) amine (4-fluorophenyl)-(3-nitrophenyl) ketone 2.0 g, (R) -1-phenylpropylamine 2.11 g, triethylamine 4.55 ml, titanium tetrachloride 1.08 ml, borocyanoborohydride Production example (1a) using 2.16 g of sodium and 0.70 ml of acetic acid
The reaction was carried out in the same manner as in the above to give 2.85 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 0.83 and 0.87 (t
otal 3H, each t, J = 7.4and 7.4Hz), 1.62-1.86 (2H,
m), 3.31 and 3.36 (total 1H, each q, J = 6.9 and7.0H
z), 4.65 and 4.70 (total 1H, each, s), 6.94 and 7.0
5 (total 2H, eacht, J = 8.7 and 8.7Hz), 7.12-7.67 (8H,
m), 8.01-8.13 (2H, m), 8.18-8.26 (1H, m).

(70b) 3-[(4-Fluorophenyl)
)-((R) -1-phenylpropylamino) methyl
Phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] -N-((R) -1-phenylpropyl)
The reaction was carried out and purified in the same manner as in Production Example (59b) using 2.70 g of an amine, 4.06 g of nickel chloride hexahydrate and 1.18 g of sodium borohydride to give isomer (A) of the title compound in yellow. 778 mg of an oily substance and 615 mg of the isomer (B) were obtained as a yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 0.81 (3H, t, J =
7.4Hz), 1.58-1.80 (2H, m), 3.43 (1H, t, J = 7.0Hz), 4.
46 (1H, s), 6.56-6.59 (1H, m), 6.63 (1H, s), 6.69 (1H,
d, J = 7.5Hz), 6.90 (2H, t, J = 8.7Hz), 7.09-7.34 (8H,
m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 0.83 (3H, t, J =
7.5Hz), 1.57-1.81 (2H, m), 3.32 (1H, t, J = 7.0Hz), 4.
47 (1H, s), 6.50 (1H, dd, J = 2.1, 8.1Hz), 6.57-6.63 (2
H, m), 6.97-7.04 (3H, m), 7.15-7.35 (7H, m).

(70c) 3-t-butoxy-4- {3-
[(4-fluorophenyl)-((R) -1-phenyl
Propylamino) methyl] phenylamino} -3-cycl
Lobutene-1,2-dione 3-[(4-fluorophenyl)-((R) -1-phenylpropylamino) methyl] phenylamine isomer (A) 625 mg, 4-t-butoxy-3-methoxy-
Using 691 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 710 mg of the isomer (A) of the title compound as a colorless foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 0.81 (3H, t, J =
7.5Hz), 1.62 (9H, s), 1.57-1.88 (2H, m), 3.38 (1H, t,
J = 6.9Hz), 4.56 (1H, s), 6.92 (2H, t, J = 8.6Hz), 7.09-
7.35 (11H, m). 3-[((R) -1-phenylpropylamino)-(4
-Fluorophenyl) methyl] phenylamine isomer (B) 534 mg, 4-t-butoxy-3-methoxy-
Using 588 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 760 mg of the isomer (B) of the title compound as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 0.83 (3H, t, J =
7.4Hz), 1.62 (9H, s), 1.62-1.81 (2H, m), 3.34 (1H, t,
J = 7.0Hz), 4.56 (1H, s), 6.99-7.35 (13H, m).

(70d) 4- {3-[(4-fluorofuran)
Enyl)-((R) -1-phenylpropylamino) me
Tyl] phenylamino} -3-hydroxy-3-cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl)-((R) -1-phenylpropylamino) methyl] phenylamino} -3-cyclobutene-1 Production Example (63) using 500 mg of isomer (A) of 2,2-dione.
The reaction and purification were carried out in the same manner as in b) to obtain 436 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 0.58 (3H, t, J
= 7.4Hz), 1.90-2.02 (1H, m), 2.39-2.50 (1H, m), 3.99 (1
H, br), 5.01 (1H, s), 7.18-7.25 (3H, m), 7.32-7.37 (3
H, m), 7.43-7.45 (4H, m), 7.53 (1H, s), 7.61 (2H, dd,
J = 5.3, 8.7 Hz). Melting point: 190-194 ° C. Optical rotation [α] _D = −131.5 (c = 1.13, AcO)
H) Isomer of 3-t-butoxy-4- {3-[(4-fluorophenyl)-((R) -1-phenylpropylamino) methyl] phenylamino} -3-cyclobutene-1,2-dione (B) Production Example (63)
The reaction and purification were carried out in the same manner as in b) to give 427 mg of the title compound isomer (B) as a pale brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 0.56 (3H, t, J
= 7.5Hz), 1.91-2.01 (1H, m), 2.43-2.51 (1H, m), 3.83 (1
H, br), 5.01 (1H, s), 7.26-7.49 (11H, m), 7.65 (2H, d
d, J = 5.3, 8.7 Hz). Melting point: 180-185 ° C. Optical rotation [α] _D = −38.5 (c = 0.50, AcO)
H).

Production Example 71 4- {3-[(4-chlorophenyl)-(1- (3,5
-Difluorophenyl) ethylamino) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobutene-1,
2-dione hydrochloride (Exemplified Compound No. 2-54) (71a) N-[(4-chlorophenyl)-(3-nitto
Rophenyl) methyl] -N- (1- (3,5-difluoro)
2.0 g of (phenyl ) ethyl) amine (4-chlorophenyl)-(3-nitrophenyl) ketone and 2.40 g of 1- (3,5-difluorophenyl) ethylamine, 4.26 ml of triethylamine,
Using 1.01 ml of titanium tetrachloride, 3.02 g of sodium borohydride cyanide and 0.66 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.92 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.6and 6.6Hz), 3.61-3.67 (1H,
m), 4.66 and 4.71 (total 1H, each s), 6.67-6.80 (3H,
m), 7.19-7.28 (3H, m), 7.34 and 7.36 (total 1H, eac
hs), 7.43 and 7.51 (total 1H, each t, J = 8.0 and 8.
0Hz), 7.57-7.64 (1H, m), 8.05-8.14 (1H, m), 8.20-8.2
3 (1H, m). (71b) 3-[(4-chlorophenyl)-(1-
(3,5-difluorophenyl) ethylamino) methyl
L] phenylamine N- [1- (3,5-difluorophenyl) ethyl]-
N-[(4-chlorophenyl)-(3-nitrophenyl)
2.79 g of [methyl] amine and nickel chloride hexahydrate
The reaction was carried out and purified using 79 g and 1.10 g of sodium borohydride in the same manner as in Production Example (59b) to give 808 mg of the title compound isomer (A) as a colorless oil.
572 mg of isomer (B) was obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.69 (1H, q, J = 6.7Hz), 4.47 (1H, s), 6.57-6.
71 (4H, m), 6.78-6.84 (2H, m), 7.10-7.52 (5H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.58-3.63 (1H, m), 4.48 (1H, s), 6.51-6.54 (1
H, m), 6.57-6.58 (1H, m), 6.62-6.71 (2H, m), 6.74-6.
80 (2H, m), 7.05 (1H, dd, J = 7.6, 7.9Hz), 7.24-7.30 (4
H, m).

(71c) 3-t-butoxy-4- {3-
[(4-chlorophenyl)-(1- (3,5-difluoro)
Lphenyl) ethylamino) methyl] phenylamino
562 mg of isomer (A) of -3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl] phenylamine, 4-t-butoxy -3-
Methoxy-3-cyclobutene-1,2-dione 555 m
Using g, the reaction was carried out in the same manner as in Production Example (1c) to obtain 731 mg of the title compound isomer (A) as a colorless foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.58 (1
H, s), 6.66-6.72 (1H, m), 6.79 (2H, dd, J = 2.1, 8.4H
z), 7.03 (1H, d, J = 6.8 Hz), 7.23-7.40 (7H, m). 3-[(4-chlorophenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl] phenyl Amine isomer (B) 479 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 473m
Using g, the reaction was carried out in the same manner as in Production Example (1c) to obtain 644 mg of the title compound isomer (B) as a colorless foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.8Hz), 1.63 (9H, s), 3.62 (1H, q, J = 6.6Hz), 4.57 (1
H, s), 6.66-6.71 (1H, m), 6.76-6.80 (2H, m), 7.00-7.
02 (1H, m), 7.25-7.35 (7H, m).

(71d) 4- {3-[(4-chlorophe
Nyl)-(1- (3,5-difluorophenyl) ethyl
Amino) methyl] phenylamino} -3-hydroxy-
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl] phenylamino} -3 -Cyclobutene-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 300 mg of 1,2-dione isomer (A) to obtain 245 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.32 (1H, br), 5.25 (1H, s), 7.16-7.19 (3H,
m), 7.26-7.36 (2H, m), 7.44-7.47 (3H, m), 7.58 (1H,
s), 7.66 (2H, d, J = 8.6 Hz). Melting point: 182 to 185 ° C. 3-t-butoxy-4- {3-[(4-chlorophenyl)-(1- (3,5-difluorophenyl)] Ethylamino) methyl] phenylamino} -3-cyclobutene-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 300 mg of 1,2-dione isomer (B) to obtain 255 mg of the title compound isomer (B) as a brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.27 (1H, br), 5.26 (1H, s), 7.22 (2H, dd, J =
1.9, 8.2Hz), 7.28-7.45 (4H, m), 7.51-7.54 (3H, m),
7.69 (2H, d, J = 8.6 Hz). Melting point: 180-185 ° C.

Production Example 72 4- {5-[(1- (3,4-difluorophenyl) e]
Tylamino)-(4-methoxyphenyl) methyl)]-
2-fluorophenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride (exemplary compound number
2-3400) (72a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(4-fluoro-3-nitrophenyl
1.)-(4-methoxyphenyl) methyl] amine (4-fluoro-3-nitrophenyl)-(4-methoxyphenyl) ketone (2.0 g) and 1- (3,4-difluorophenyl) ethylamine hydrochloride 81, triethylamine 6.08 ml, titanium tetrachloride 0.96 ml, sodium cyanoborohydride 2.03 g, acetic acid 0.6
The reaction was carried out in the same manner as in Production Example (1a) using 2 ml to obtain 2.63 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.33 and 1.36 (t
otal 3H, each d, J = 6.6and 6.7Hz), 3.58 and 3.64 (to
tal 1H, each q, J = 6.7 and 6.6Hz), 3.77 and3.82 (tot
al 3H, each s), 4.53 and 4.60 (total 1H, each s),
6.77-6.97 (3H, m), 7.02-7.26 (5H, m), 7.49-7.60 (1H,
m), 8.04-8.09 (1H, m).

(72b) 5-[(1- (3,4-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
L) Methyl] -2-fluorophenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(4-fluoro-3-nitrophenyl)-(4-
Using 2.5 g of [methoxyphenyl) methyl] amine, 3.29 g of nickel chloride hexahydrate and 957 mg of sodium borohydride, the reaction was carried out in the same manner as in Production Example (1b) to obtain 1.82 g of the title compound as a yellow oil. Obtained. NMR spectrum (CDCl ₃ ) δppm: 1.30 and 1.31 (t
otal 3H, each d, J = 6.6and 6.6Hz), 3.58-3.66 (1H,
m), 3.76 and 3.80 (total 3H, each s), 4.41 (1H, s),
6.56-6.61 (1H, m), 6.68-6.72 (1H, m), 6.77-6.94 (4H,
m), 7.06-7.18 (4H, m).

(72c) 3-t-butoxy-4- {5-
[(1- (3,4-difluorophenyl) ethylamido
No)-(4-methoxyphenyl) methyl] -2-fluoro
Rophenylamino} -3-cyclobutene-1,2-di
Down 5 - [(1- (3,4-difluorophenyl) ethylamino) - (4-methoxyphenyl) methyl] -2-fluorophenyl amine 500 mg, 4-t-butoxy -3
-Methoxy-3-cyclobutene-1,2-dione 477
The product was purified in the same manner as in Production Example (66c) using the above-mentioned compound to give the isomer (A) of the title compound as a yellow oil in the form of a yellow oil.
25 mg and 256 mg of isomer (B) were obtained as a yellow solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 3.75 (3
H, s), 4.53 (1H, s), 6.80 (2H, d, J = 8.7Hz), 6.94-7.2
8 (8H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.34 (3H, d, J =
6.7Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.6Hz), 3.80 (3H
H, s), 4.51 (1H, s), 6.87-7.00 (5H, m), 7.06-7.27 (5
H, m). Melting point: 142-145 ° C.

(72d) 4- {5-[(1- (3,4-
Difluorophenyl) ethylamino)-(4-methoxy
Phenyl) methyl] -2-fluorophenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione
Hydrochloride 3-t-butoxy-4- {5-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2-fluorophenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 200 m
g, and reacted and purified in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a pale gray solid in 175 g
mg. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 3.74 (3H, s), 4.33 (1H, br), 5.10 (1H, s), 6.
94 (2H, d, J = 8.7Hz), 7.13-7.15 (1H, m), 7.26-7.32 (2
H, m), 7.44-7.57 (4H, m), 7.80 (1H, dd, J = 1.6, 7.7H
z). Melting point: 175-177 ° C 3-t-butoxy-4- {5-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -2-fluorophenylamino ｝ -3-
225 m of cyclobutene-1,2-dione isomer (B)
g, and reacted and purified in the same manner as in Production Example (63b) to give the isomer (B) of the title compound as a white solid in 190 m
g was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J =
6.7Hz), 3.76 (3H, s), 4.23 (1H, br), 5.19 (1H, s), 6.
98 (2H, d, J = 8.7Hz), 7.21-7.23 (1H, m), 7.27-7.32 (1
H, m), 7.44-7.61 (5H, m), 7.76 (1H, dd, J = 2.0, 7.9H
z). Melting point: 175-178 ° C.

Production Example 73 4- {3-[(1- (3,4-difluorophenyl) e]
Tylamino)-(4-methoxyphenyl) methyl] -4
-Fluorophenylamino} -3-hydroxy-3-si
Clobutene-1,2-dione hydrochloride (Exemplary Compound No. 2
-3401) (73a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(2-fluoro-5-nitrophenyl
)-(4-methoxyphenyl) methyl] amine (2-fluoro-5-nitrophenyl)-(4-methoxyphenyl) ketone 828 mg and 1- (3,4-difluorophenyl) ethylamine hydrochloride 1.16 g, 2.52 ml of triethylamine, 0.40 m of titanium tetrachloride
l, 840 mg of sodium cyanoborohydride and 0.62 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 860 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.37 (t
otal 3H, each d, J = 6.6and 6.7Hz), 3.61 and 3.69 (to
tal 1H, each q, J = 6.6 and 6.6Hz), 3.77 and3.80 (tot
al 3H, each s), 4.89 and 4.90 (total 1H, each s),
6.80-6.95 (3H, m), 7.02-7.23 (5H, m), 8.05-8.17 (1H,
m), 8.45 and 8.59 (total 1H, each dd, J = 2.9, 6.3 and
2.9, 6.3Hz).

(73b) 3-[(1- (3,4-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
L) Methyl] -4-fluorophenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(2-fluoro-5-nitrophenyl)-(4-
The same reaction as in Production Example (59b) was carried out and purified using 800 mg of methoxyphenyl) methyl] amine, 1.05 g of nickel chloride hexahydrate and 306 mg of sodium borohydride to give the isomer (A) of the title compound. 330 mg as a yellow oil, isomer (B) 3 as a yellow oil
50 mg were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.68 (1H, q, J = 6.6Hz), 3.76 (3H, s), 4.73 (1
H, s), 6.50-6.54 (1H, m), 6.70 (1H, dd, J = 2.9, 6.0H
z), 6.78-6.83 (3H, m), 6.95-6.99 (1H, m), 7.05-7.27
(4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 3.66 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.83 (1
H, s), 6.43-6.47 (1H, m), 6.64 (1H, dd, J = 2.9, 6.1H
z), 6.70-7.26 (8H, m).

(73c) 3-t-butoxy-4- {3-
[(1- (3,4-difluorophenyl) ethylamido
No)-(4-Methoxyphenyl) methyl] -4-fluoro
Rophenylamino} -3-cyclobutene-1,2-di
Down 3 - [(1- (3,4-difluorophenyl) ethylamino) - (4-methoxyphenyl) methyl] -4-fluorophenyl isomer of amine (A) 268 mg, 4-
t-butoxy-3-methoxy-3-cyclobutene-1,
The reaction was carried out in the same manner as in Production Example (1c) using 255 mg of 2-dione to obtain 348 mg of the isomer (A) of the title compound as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.66 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.85 (1H, s), 6.81 (2H, d, J = 8.7Hz), 6.95-7.5
7 (7H, m), 7.57 (1H, br). 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -4-fluorophenylamine isomer ( B) 316 mg, 4-
t-butoxy-3-methoxy-3-cyclobutene-1,
The reaction was carried out in the same manner as in Production Example (1c) using 301 mg of 2-dione to obtain 476 mg of the title compound isomer (B) as a yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.67 (1H, q, J = 6.6Hz), 3.80 (3H
H, s), 4.87 (1H, s), 6.86-7.27 (9H, m), 7.44 (1H, b
r).

(73d) 4- {3-[(1- (3,4-
Difluorophenyl) ethylamino)-(4-methoxy
Phenyl) methyl] -4-fluorophenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione salt
Salt 3-t-butoxy-4- {3 - [(1- (3,4-difluorophenyl) ethylamino) - (4-methoxyphenyl) methyl] -4-fluorophenyl} -3-
Isomer of cyclobutene-1,2-dione (A) 318 m
g, and reacted and purified in the same manner as in Production Example (63b) to give 258 m of the isomer (A) of the title compound as a white solid.
g was obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 3.74 (3H, s), 4.48 (1H, br), 5.10 (1H, s), 6.
94 (2H, d, J = 8.8Hz), 7.14-7.19 (2H, m), 7.37-7.52 (5
H, m), 7.85 (1H, dd, J = 2.6, 6.3 Hz). Melting point: 190-193 ° C. 3-t-butoxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino) )-(4-Methoxyphenyl) methyl] -4-fluorophenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 444 m
g, and reacted and purified in the same manner as in Production Example (63b) to give 325 of the isomer (B) of the title compound as a pale yellow solid.
mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.8Hz), 3.78 (3H, s), 4.29 (1H, br), 5.24 (1H, s), 7.
01 (2H, d, J = 8.9Hz), 7.18-7.27 (2H, m), 7.39-7.63 (5
H, m), 7.72-7.74 (1H, m). Melting point: 185-190 ° C.

Production Example 74 4- {3-[((S) -1-cyclohexylethylamido)
No)-(4-methoxyphenyl) methyl] phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
On hydrochloride (Exemplified Compound No. 2-2) (74a) 3-t-butoxy-4- {3-[((S)-
1-cyclohexylethylamino)-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
-1,2-dione 3-[((S) -1-cyclohexylethylamino)-
(4-methoxyphenyl) methyl] phenylamine1.
Using 63 g and 1.33 g of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, Production Example (1
The reaction was carried out in the same manner as in c) to obtain 1.89 g of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 0.97-1.41 (9H,
m), 1.52-1.80 (14H, m), 2.35-2.42 (1H, m), 3.77 and
3.78 (total 3H, each s), 4.91 (1H, s), 6.82-6.85 (2H,
m), 7.16-7.36 (6H, m).

(74b) 4- {3-[((S) -1-S
Clohexylethylamino)-(4-methoxyphenyl)
Ru) methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((S) -1-cyclohexylethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene -1,2-
The reaction and purification were carried out in the same manner as in Production Example (63b) using 482 mg of dione to give the title compound as a white solid in 415 m
g was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.95-1.37 (9H,
m), 1.60-1.76 (4H, m), 1.82-1.92 (1H, m), 2.88 (1H, b
r), 3.75 and 3.76 (total 3H, each s), 5.53 (1H, br),
6.98-7.01 (2H, m), 7.36-7.47 (3H, m), 7.60 (1H, d, J
= 7.5Hz), 7.68 (2H, dd, J = 5.5, 8.6Hz). Melting point: 192-195 ° C.

Production Example 75 4- {3-[(1- (2,4-difluorophenyl) e]
Tylamino)-(4-methoxyphenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-49) (75a) N- [1- (2,4-difluorophenyl)
Ethyl] -N-[(4-methoxyphenyl)-(3-d
5. trophenyl ) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ketone 2.0 g, 1- (2,4-difluorophenyl) ethylamine hydrochloride 3.01 g, triethylamine
The reaction was carried out in the same manner as in Production Example (1a) using 5 ml, titanium tetrachloride 1.03 ml, sodium cyanoborohydride 2.06 g, and acetic acid 0.67 ml to obtain 2.90 g of the title compound as a yellow oil. . NMR spectrum (CDCl ₃ ) δ ppm: 1.39-1.43 (3H,
m), 3.76 and 3.80 (total3H, each s), 3.87 and 3.95
(total 1H, each q, J = 6.8 and 6.7Hz), 4.65 (1H, s),
6.75-6.90 (4H, m), 7.14-7.28 (3H, m), 7.39 and 7.48
(total 1H, each t, J = 8.0 and 8.0Hz), 7.61 and 7.69
(total 1H, each d, J = 7.5 and 7.7Hz), 8.03 and 8.09
(total 1H, each dd, J = 2.0, 8.0 and 1.8, 7.8Hz), 8.
23-8.27 (1H, m).

(75b) 3-[(1- (2,4-difur
(Orophenyl) ethylamino)-(4-methoxyphenyl)
L) methyl] phenylamine N- [1- (2,4-difluorophenyl) ethyl]-
As in Production Example (1b) using 2.80 g of N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, 3.34 g of nickel chloride hexahydrate and 1.12 g of sodium borohydride. To give 2.23 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.8Hz), 3.75 and 3.79 (total 3H, each s), 3.91 3.96
(total 1H, each q, J = 6.8 and 6.6Hz), 4.46 and4.64
(total 1H, each d), 6.50 and 6.56 (total 1H, each d
d, J = 2.0, 8.1 and2.0, 8.1Hz), 6.62-6.86 (6H, m), 7.
01 and 7.09 (total 1H, each t, J = 7.8 and 7.9Hz), 7.
18-7.31 (3H, m).

(75c) 3-t-butoxy-4- {3-
[(1- (2,4-difluorophenyl) ethylamido]
No)-(4-methoxyphenyl) methyl] phenylamido
No {-3-cyclobutene-1,2-dione 3-[(1- (2,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamine 2.18 g, 4-t-butoxy- 3-methoxy-3
Using 1.63 g of -cyclobutene-1,2-dione, the reaction was purified in the same manner as in Production Example (66c), and 812 mg of isomer (A) of the title compound was obtained as a yellow oil, and isomer (B) was obtained. 754 mg were obtained as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.75 (3H, s), 3.93 (1H, q, J = 6.
8Hz), 4.56 (1H, s), 6.74-6.88 (4H, m), 7.07-7.45 (7H,
m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.8Hz), 1.63 (9H, s), 3.80 (3H, s), 3.93 (1H, q, J = 6.
8Hz), 4.55 (1H, s), 6.73-6.88 (4H, m), 7.04-7.38 (7H,
m).

(75d) 4- {3-[(1- (2,4-
Difluorophenyl) ethylamino)-(4-methoxy
Phenyl) methyl] phenylamino} -3-hydroxy
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3 - [(1- (2,4-difluorophenyl) ethylamino) - (4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-
Using 395 mg of 1,2-dione isomer (A), the reaction and purification were carried out in the same manner as in Production Example (63b) to obtain 336 mg of the title compound isomer (A) as a pale red solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.69 (3H, d, J
= 6.7Hz), 3.75 (3H, s), 4.45 (1H, br), 5.23 (1H, br s),
6.97 (2H, d, J = 8.7Hz), 7.23-7.41 (5H, m), 7.52 (1H,
s), 7.59 (2H, d, J = 8.7 Hz), 7.84-7.90 (1H, m). Melting point: 182-187 ° C 3-t-butoxy-4- {3-[(1- (2,4- Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-
Using 455 mg of 1,2-dione isomer (B), the reaction and purification were carried out in the same manner as in Production Example (63b) to obtain 314 mg of isomer (B) of the title compound as a pink solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.69 (3H, d, J
= 6.8Hz), 3.76 (3H, s), 4.39 (1H, br), 5.19 (1H, br s),
6.97 (2H, d, J = 8.7Hz), 7.23-7.43 (5H, m), 7.55-7.60
(3H, m), 7.86-7.92 (1H, m). Melting point: 178-185 ° C.

Production Example 76 4- {3-[(1- (3-chlorophenyl) ethylamido]
No)-(4-methoxyphenyl) methyl] phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
On hydrochloride (Exemplified Compound No. 2-31) (76a) N- [1- (3-chlorophenyl) ethyl]
-N-[(4-methoxyphenyl)-(3-nitrophen
Nyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ketone (2.0 g) and 1- (3-chlorophenyl) ethylamine hydrochloride (2.99 g), triethylamine (6.5 ml),
The reaction was carried out in the same manner as in Production Example (1a) using 1.03 ml of titanium tetrachloride, 2.06 g of sodium cyanoborohydride, and 0.67 ml of acetic acid to obtain 2.69 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.6and 6.6Hz), 3.60 and 3.67 (t
otal 1H, each q, J = 6.6 and 6.6Hz), 3.76 and3.81 (to
tal 3H, each s), 4.63 and 4.67 (total 1H, each s),
6.81 and 6.89 (total 2H, each d, J = 8.7 and 8.7Hz),
7.05-7.30 (6H, m), 7.39 and 7.48 (total 1H, each t,
J = 8.0 and 7.9Hz), 7.60 and 7.67 (total 1H, each d,
J = 7.8 and 7.9Hz), 8.01-8.11 (1H, m), 8.22-8.26 (1H,
m).

(76b) 3-[(1- (3-chlorophene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
L] phenylamine N- [1- (3-chlorophenyl) ethyl] -N-
[(4-methoxyphenyl)-(3-nitrophenyl)
2.60 g of [methyl] amine and nickel chloride hexahydrate
The reaction was carried out in the same manner as in Production Example (1b) using 11 g and sodium borohydride (1.04 g) to obtain 2.15 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 3.63 and 3.68 (total 1H, each q, J = 6.7 and
6.6Hz), 3.76 and 3.80 (total 3H, each s), 4.47 (1H,
s), 6.49-6.70 (3H, m), 6.79 and 6.86 (total 2H, each
d, J = 8.7 and 8.5Hz), 7.02-7.35 (7H, m).

(76c) 3-t-butoxy-4- {3-
[(1- (3-chlorophenyl) -ethylamino)-
(4-methoxyphenyl) methyl] phenylamino}-
3-cyclobutene-1,2-dione 3-[(1- (3-chlorophenyl) ethylamino)-
(4-methoxyphenyl) methyl] phenylamine2.
09g and 1.57 g of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione.
The reaction was carried out and purified in the same manner as in 6c), and 481 mg of the isomer (A) of the title compound was obtained as a yellow oil, and the isomer (B)
Was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.7Hz), 3.76 (3
H, s), 4.56 (1H, s), 6.80 (2H, d, J = 8.6Hz), 7.09-7.3
6 (10H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.55 (1H, s), 6.88 (2H, d, J = 8.7Hz), 7.03-7.3
4 (10H, m).

(76d) 4- {3-[(1- (3-chloro
(Rophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1 , 2-
Production Example (63) using 441 mg of dione isomer (A)
The reaction and purification were carried out in the same manner as in b) to give 250 mg of the isomer (A) of the title compound as a yellow foam. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 3.74 (3H, s), 4.24 (1H, br), 5.09 (1H, br s),
6.96 (2H, d, J = 8.7Hz), 7.22 (1H, d, J = 7.6Hz), 7.33-
7.37 (2H, m), 7.43-7.54 (7H, m). IR spectrum (cm ^-1 ): 1800.2, 1703.8, 1582.
3, 1516.7, 1440.6, 1257.4 3-t-butoxy-4- {3-[(1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2 −
Production Example (63) using 474 mg of the dione isomer (B)
The reaction and purification were carried out in the same manner as in b) to give 333 mg of isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, d, J
= 6.7Hz), 3.77 (3H, s), 4.18 (1H, br), 5.07 (1H, br s),
6.99 (2H, d, J = 8.7Hz), 7.35-7.56 (10H, m).
70-173 ° C.

Production Example 77 3-Hydroxy-4- {3-[(4-methoxyphenyl)
)-(1- (3-trifluoromethylphenyl) ethyl
Ruamino) methyl] phenylamino} -3-cyclobute
1,2-dione hydrochloride (Exemplary Compound No. 2-349)
4) (77a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -N- [1- (3-trifluoro)
[ Romethylphenyl ) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ketone (2.0 g) and 1- (3-trifluoromethylphenyl) ethylamine hydrochloride (3.51 g), triethylamine (6.5 ml), tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 1.03 ml of titanium, 2.06 g of sodium borohydride and 0.67 ml of acetic acid to obtain 2.92 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.40 and 1.41 (t
otal 3H, each d, J = 6.7and 6.7Hz), 3.71 and 3.77 (to
tal 1H, each q, J = 6.7 and 6.7Hz), 3.76 and3.82 (tot
al 3H, each s), 4.60 and 4.65 (total 1H, each s),
6.81 and 6.90 (total 2H, each d, J = 8.7 and 8.7Hz),
7.14 and 7.17 (total 2H, each d, J = 8.7and 8.7Hz),
7.36-7.66 (6H, m), 8.00-8.12 (1H, m), 8.20-8.26 (1H, m
m).

(77b) 3-[(4-methoxyphenyi)
)-(1- (3-trifluoromethylphenyl) ethyl
L-amino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- [1- (3-trifluoromethylphenyl) ethyl] amine and nickel chloride hexahydrate 3.15 g and sodium borohydride 1.05
Using g, the reaction was carried out in the same manner as in Production Example (1b) to obtain 2.60 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.8Hz), 3.71-3.84 (1H, m), 3.75 and 3.80 (total 3H,
each s), 4.43 and 4.44 (total 1H, each s), 6.49-6.6
9 (3H, m), 6.78 and 6.86 (total 2H, each d, J = 8.7 an
d 8.7Hz), 7.03 and 7.11 (total 1H, each t, J = 7.8 an
d 7.7Hz), 7.17-7.21 (2H, m), 7.41-7.53 (4H, m).

(77c) 3-t-butoxy-4- {3-
[(4-methoxyphenyl)-(1- (3-trifluoro)
L-methylphenyl) ethylamino) methyl] phenyla
Mino} -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(1- (3-trifluoromethylphenyl) ethylamino) methyl] phenylamine 2.16 g, 4-t-butoxy- Using 1.49 g of 3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out and purified in the same manner as in Production Example (66c) to give 620 m of the title compound isomer (A) as a pale yellow foam.
g, isomer (B) 650 mg as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.75 (3H, s), 3.76 (1H, q, J = 6.
7Hz), 4.54 (1H, s), 6.79 (2H, d, J = 8.7Hz), 7.07 (1H,
m), 7.17 (2H, d, J = 8.6 Hz), 7.24-7.53 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.75 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.52 (1H, s), 6.89 (2H, d, J = 8.7Hz), 7.02 (1H,
m), 7.16-7.28 (5H, m), 7.41 (4H, m).

(77d) 3-hydroxy-4- {3-
[(4-methoxyphenyl)-(1- (3-trifluoro)
L-methylphenyl) ethylamino) methyl] phenyla
Mino} -3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)-(1- (3-trifluoromethylphenyl) ethylamino) methyl] phenyl The reaction and purification were carried out in the same manner as in Production Example (63b) using 610 mg of the isomer (A) of amino｝ -3-cyclobutene-1,2-dione to obtain 522 mg of the isomer (A) of the title compound as a brown solid. Was. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.69 (3H, d, J
= 6.7Hz), 3.73 (3H, s), 4.37 (1H, br), 5.09 (1H, br s),
6.94 (2H, d, J = 8.7Hz), 7.28 (1H, d, J = 7.6Hz), 7.36
(1H, dd, J = 7.8, 8.0Hz), 7.43 (1H, d, J = 8.4Hz), 7.52
-7.54 (3H, m), 7.64-7.68 (1H, m), 7.73-7.77 (3H, m). Melting point: 183-188 ° C.

3-t-butoxy-4- {3-[(4-methoxyphenyl)-(1- (3-trifluoromethylphenyl) ethylamino) methyl] phenylamino} -3
-Isomer (B) 630 of cyclobutene-1,2-dione
The reaction and purification were carried out in the same manner as in Production Example (63b) using mg, to give 45% of the isomer (B) of the title compound as a pale yellow solid.
7 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J
= 6.7Hz), 3.76 (3H, s), 4.32 (1H, br), 5.11 (1H, br s),
6.99 (2H, d, J = 8.4Hz), 7.33-7.41 (3H, m), 7.51-7.54
(3H, m), 7.66-7.70 (1H, m), 7.74-7.79 (3H, m). Melting point: 180-185 ° C.

Production Example 78 4- {3-[(1- (3,4-dimethylphenyl) ethyl]
Ruamino)-(4-methoxyphenyl) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobutene-1,
2-Dione hydrochloride (Exemplified Compound No. 2-3493) (78a) N- [1- (3,4-dimethylphenyl) e
Tyl] -N-[(4-methoxyphenyl)-(3-nitro
( Phenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ketone (1.0 g), 1- (3,4-dimethylphenyl) ethylamine hydrochloride (1.44 g), triethylamine (3.2)
Using 5 ml, titanium tetrachloride 0.51 ml, sodium cyanoborohydride 1.03 g, and acetic acid 0.33 ml, the reaction was carried out in the same manner as in Production Example (1a) to obtain 1.45 g of the title compound as a yellow oil. . NMR spectrum (CDCl ₃ ) δppm: 1.359 and 1.364
(total 3H, each d, J = 6.8 and 6.6Hz), 2.25, 2.26 an
d 2.27 (total 6H, each s), 3.53 and 3.62 (total 1H,
each q, J = 6.7 and 6.7Hz), 3.76 and 3.81 (total 3H,
each s), 4.66 and 4.68 (total 1H, each s), 6.80-7.2
2 (7H, m), 7.37 and 7.49 (total 1H, eacht, J = 7.8 and
7.9Hz), 7.59 and 7.70 (total 1H, each d, J = 7.8 and
7.5Hz), 8.00-8.10 (1H, m), 8.21-8.26 (1H, m).

(78b) 3-[(1- (3,4-dimethyl)
Ruphenyl) ethylamino)-(4-methoxyphenyl)
L) methyl] phenylamine N- [1- (3,4-dimethylphenyl) ethyl] -N
A reaction was carried out in the same manner as in Production Example (1b) using 1.32 g of-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, 1.61 g of nickel chloride hexahydrate and 539 mg of sodium borohydride. Purification gave 1.10 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 2.26 (6H, s), 3.59 and 3.64 (total 1H, each
q, J = 6.7 and 6.7Hz), 3.75 and 3.80 (total 3H, each
s), 4.51 (1H, s), 6.48-6.57 (1H, m), 6.62-6.72 (2H,
m), 6.78 and 6.85 (total 2H, each d, J = 8.7 and 8.6H
z), 6.96-7.11 (4H, m), 7.19 and 7.24 (total 2H, each
d, J = 8.6 and 8.7Hz).

(78c) 3-t-butoxy-4- {3-
[(1- (3,4-dimethylphenyl) -ethylamido
No)-(4-methoxyphenyl) methyl] phenylamido
No.-3-cyclobutene-1,2-dione 3-[(1- (3,4-dimethylphenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamine 1.06 g, 4-t-butoxy- 3-methoxy-3-
The reaction was carried out and purified using 812 mg of cyclobutene-1,2-dione in the same manner as in Production Example (66c). 456 mg of the isomer (A) of the title compound was obtained as a yellow foam, and 428 mg were obtained as a foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.62 (9H, s), 2.31 (6H, s), 3.60 (1H, q, J = 6.
7Hz), 3.75 (3H, s), 4.60 (1H, s), 6.79 (2H, d, J = 8.7H
z), 6.81-6.99 (1H, m), 7.09-7.34 (8H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.62 (9H, s), 2.25 (6H, s), 3.59 (1H, q, J = 6.
7Hz), 3.80 (3H, s), 4.58 (1H, s), 6.87 (2H, d, J = 8.7H
z), 6.96-7.10 (2H, m), 7.14-7.27 (7H, m).

(78d) 4- {3-[(1- (3,4-
Dimethylphenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl] phenylamino} -3-hydroxy-
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,4-dimethylphenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino}- 3-cyclobutene-
Reaction and purification were carried out in the same manner as in Production Example (63b) using 360 mg of 1,2-dione isomer (A) to obtain 289 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 2.19 (3H, s), 2.23 (3H, s), 3.74 (3H, s), 4.0
8 (1H, br), 4.99 (1H, br), 6.96 (2H, d, J = 8.8Hz), 7.0
5 (1H, s), 7.09 (1H, d, J = 7.9Hz), 7.19 (1H, d, J = 7.9H
z), 7.29 (1H, d, J = 7.1Hz), 7.35-7.42 (2H, m), 7.50-7.
52 (3H, m). Melting point: 200-206 ° C 3-t-butoxy-4- {3-[(1- (3,4-dimethylphenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino ｝ -3-cyclobutene-
Reaction and purification were carried out in the same manner as in Production Example (63b) using 350 mg of 1,2-dione isomer (B) to obtain 305 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.8Hz), 2.22 (3H, s), 2.25 (3H, s), 3.78 (3H, s), 4.0
0-4.06 (1H, br), 4.96 (1H, br), 6.99 (2H, d, J = 8.7H
z), 7.08-7.10 (2H, m), 7.20 (1H, d, J = 8.0Hz), 7.35-
7.42 (3H, m), 7.47 (1H, s), 7.51 (2H, d, J = 8.7 Hz). Melting point: 198-203 ° C.

Production Example 79 4- {3-[[(S) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
Ru] phenylamino} -3-hydroxyamino-3-si
Clobutene-1,2-dione (Exemplary Compound No. 2-35)
14) 4- {3-[[(S) -1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-methoxy-3-cyclobutene-1,2 -500 mg of dione isomer (B) and 50 w
After stirring a solution of 0.064 ml of t% -hydroxylamine aqueous solution in 5 ml of methanol for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 50).
/ 1 to 20/1), and isomer (B) of the title compound
Was obtained as a brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.28 (3H, br),
3.54 (1H, br), 3.72 (3H, s), 4.40 (1H, br), 6.86-7.4
6 (11H, m). Melting point: 115-118 ° C Optical rotation [α] _D = -32.0 ° (c = 0.505, E
tOH).

Production Example 80 4- {3-[[(R) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
Ru] phenylamino} -3-hydroxyamino-3-si
Clobutene-1,2-dione (Exemplary Compound No. 2-35)
14) 4- {3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-methoxy-3-cyclobutene-1,2 -300 mg of dione isomer (B) and 50 w
The reaction and purification were conducted in the same manner as in Production Example (79) using 0.038 ml of a t% -hydroxylamine aqueous solution to obtain 270 mg of the title compound isomer (B) as a brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J
= 6.4Hz), 3.54 (1H, br), 3.72 (3H, s), 4.40 (1H, br),
6.87 (2H, d, J = 8.6Hz), 6.94 (1H, d, J = 7.5Hz), 7.06-7.
08 (1H, m), 7.15-7.42 (7H, m). Melting point: 90 ° C. (dec) Optical rotation [α] _D = + 42.8 ° (c = 0.535, Et
OH).

Production Example 81 {2- [3-(((R) -1- (3,4-difluorophenyl)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl) phenylamino] -3,4-dioxo-1-cycl
Lobuten-1-ylamino diacetic acid hydrochloride (exemplary compound
No. 2-3513) (81a) {2- [3-(((R) -1- (3,4-di
Fluorophenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl) phenylamino] -3,4-dioxo
-1-cyclobuten-1-ylamino} -acetic acid t-bu
Tyl ester 4- {3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-methoxy-3-cyclobutene-1,2- To a suspension of 300 mg of dione isomer (B) and 116 mg of glycine t-butyl ester hydrochloride in 5 ml of t-butanol, 0.13 ml of triethylamine was added and reacted at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1/1)
Purification afforded 380 mg of the title compound isomer (B) as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 1.45 (9H, s), 3.63 (1H, q, J = 6.6Hz), 3.79 (3
H, s), 4.33-4.45 (2H, m), 4.54 (1H, s), 6.86 (2H, d, J
= 8.5Hz), 6.95-7.28 (9H, m).

(81b) {2- [3-(((R) -1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl) phenylamino] -3,
4-dioxo-1-cyclobuten-1-ylamino vinegar
Acid hydrochloride {2- [3-(((R) -1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) phenylamino] -3,4-dioxo-1-cyclobutene The reaction and purification were conducted in the same manner as in Production Example (63b) using 280 mg of the isomer (B) of -1-ylamino} acetic acid t-butyl ester to obtain 250 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.64 (3H, br),
3.76 (3H, s), 4.22-4.24 (1H, br), 4.35 (2H, br), 5.1
4 (1H, br), 6.99 (2H, d, J = 8.4Hz), 7.20-7.56 (8H, m),
8.28 (1H, br). Melting point: 168-171 ° C. Optical rotation [α] _D = + 33.8 ° (c = 1.02, AcO)
H).

Production Example 82 2- {2- [3-(((R) -1- (3,4-difluoro)
(Rophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) phenylamino] -3,4-dioxo-1
-Cyclobuten-1-yl-aminodiethanesulfonic acid
(Exemplified Compound No. 2-2937) 4- {3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-methoxy-3 Meta- of 300 mg of isomer (B) of cyclobutene-1,2-dione, 0.26 ml of triethylamine and 157 mg of taurine
The 5 ml solution was stirred at room temperature for 4 hours. The reaction solution was neutralized with 1N-hydrochloric acid and diluted with water and ethyl acetate. The precipitated solid is collected by filtration and subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1).
Then, 205 mg of the isomer (B) of the title compound was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.64 (3H, br),
2.79 (2H, br), 3.77 (3H, s), 3.95 (2H, br), 4.26 (1H,
br), 5.19 (1H, br), 6.86-7.58 (11H, m). Melting point: 212-214 ° C. Optical rotation [α] _D = + 28.5 ° (c = 1.04, AcO
H).

Production Example 83 4- {3-[(4-fluorophenyl)-(1- (thio)
Phen-2-yl) ethylamino) methyl] phenyla
Mino} -3-hydroxy-3-cyclobutene-1,2-
Dione hydrochloride (Exemplified Compound No. 2-81) (83a) N-[(4-fluorophenyl)-(3-ni
Trophenyl) methyl] -N- [1- (thiophene-2
-Yl) ethyl] amine 4-fluoro-3'-nitrobenzophenone 1.80 g
And 2.01 g of 1- (thiophen-2-yl) ethylamine hydrochloride, 6.1 ml of triethylamine and 0.9 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a) to obtain an imine compound. The obtained imine compound was reacted with 1.84 g of sodium cyanoborohydride and 0.6 ml of acetic acid in the same manner as in Production Example (1a) to obtain 2.43 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.50 and 1.51 (t
otal 3H, each d, J = 6.6Hz), 3.90 and 3.94 (total 1H,
each q, J = 6.6Hz), 4.87 and 4.89 (total 1H, each
s), 6.78 and 6.80 (total 1H, each d, J = 3.3Hz), 6.93
-7.09 (3H, m), 7.23-7.34 (3H, m), 7.42 and 7.51 (total
1H, each t, J = 7.9Hz), 7.65 and 7.72 (total 1H, each
d, J = 7.7Hz), 8.05 and 8.13 (total 1H, each dd, J =
2.2, 8.1Hz), 8.23 and 8.28 (total 1H, each t, J = 1.9H
z).

(83b) 3-[(4-Fluorophenyl)
)-(1- (thiophen-2-yl) ethylamino)
2. Methyl] phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] -N- [1- (thiophen-2-yl) ethyl] amine 2.41 g, nickel chloride hexahydrate 2
The reaction was carried out in the same manner as in Production Example (59b) using 2 g and sodium sodium borohydride (1.03 g), and the mixture was separated and purified to give the title compound isomer (A) as a pale yellow oily substance (687).
mg, 552 mg of isomer (B) of the title compound as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (3H, d, J =
6.6Hz), 3.99 (1H q, J = 6.6Hz), 4.69 (1H, s), 6.58 (1H,
dd, J = 1.8, 7.5Hz), 6.68 (1H, t, J = 1.8Hz), 6.73 (1H,
(dd, J = 1.8, 7.5Hz), 6.83 (1H, d, J = 3.4Hz), 6.90-6.9
6 (3H, m), 7.12 (1H, t, J = 7.7Hz), 7.21 (1H, dd, J = 1.
Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.47 (3H, d, J =
6.6Hz), 3.92 (1H, q, J = 6.6Hz), 4.70 (1H, s), 6.51 (1
H, dd, J = 2.0, 7.9Hz), 6.64 (1H, t, J = 1.7Hz), 6.68 (1
H, d, J = 7.7Hz), 6.79 (1H, d, J = 3.4Hz), 6.90-7.06 (4
H, m), 7.22 (1H, dd, J = 1.1, 5.1Hz), 7.34 (2H, dd, J =
5.5, 8.6Hz).

(83c) 3-t-butoxy-4- {3-
[(4-fluorophenyl)-(1- (thiophene-2)
-Yl) ethylamino) methyl] phenylamino} -3
320 mg of isomer (A) of -cyclobutene -1,2-dione 3-[(4-fluorophenyl)-(1- (thiophen-2-yl) ethylamino) methyl] phenylamine and 4-t-butoxy-3 −
Methoxy-3-cyclobutene-1,2-dione 431 m
and 431 mg of the isomer (A) of the title compound as a white foamy solid in the same manner as in Production Example (1c).
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.96 (1H q, J = 6.6Hz), 4.79 (1H,
s), 6.81 (1H, d, J = 3.2Hz), 6.91-6.96 (1H, m), 6.95 (2
H, t, J = 8.3 Hz), 7.12-7.53 (7H, m). An isomer of 3-[(4-fluorophenyl)-(1- (thiophen-2-yl) ethylamino) methyl] phenylamine ( B) A reaction was carried out in the same manner as in Production Example (1c) using 280 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione and 190 mg of the compound to give the isomer (B) of the title compound in white. 317 mg were obtained as a foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.49 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.93 (1H, q, J = 6.6Hz), 4.79 (1
H, s), 6.81 (1H, d, J = 3.3Hz), 6.95 (1H, dd, J = 3.4,
5.0Hz), 7.03 (2H, t, J = 6.5Hz), 7.02-7.48 (7H, m).

(83d) 4- {3-[(4-fluorofuran)
Enyl)-(1- (thiophen-2-yl) ethylamido
No) methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl)-(1- (thiophen-2-yl) ethylamino)
Methyl] phenylamino} -3-cyclobutene-1,2
Using 351 mg of the isomer of dione (A) and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give 28% of the isomer (A) of the title compound as a white solid.
2 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.74 (3H, d, J
= 6.7Hz), 4.59 (1H, q, J = 6.7Hz), 5.15 (1H, s), 7.10 (1
H, dd, J = 3.7, 5.0Hz), 7.15 (1H, d, J = 3.5Hz), 7.23-7.
29 (3H, m), 7.37 (1H, t, J = 8.0Hz), 7.45 (1H, d, J = 8.0
Hz), 7.60-7.66 (2H, m), 7.64 (2H, dd, J = 5.2, 8.8 Hz). Melting point: 183-190 ° C (dec) 3-t-butoxy-4- {3-[(4- Fluorophenyl)-(1- (thiophen-2-yl) ethylamino)
Methyl] phenylamino} -3-cyclobutene-1,2
Using 285 mg of -dione isomer (B) and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give 22% of the isomer (B) of the title compound as a white solid.
5 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.72 (3H, d, J
= 6.7Hz), 4.50 (1H, q, J = 6.7Hz), 5.19 (1H, s), 7.10-
7.16 (2H, m), 7.23-7.43 (4H, m), 7.46 (1H, d, J = 7.5H
z), 7.56 (1H, s), 7.67 (1H, d, J = 5.2Hz), 7.71 (2H, d
d, J = 5.5, 8.7 Hz). Melting point: 195-200 ° C (dec).

Production Example 84 4- {3-[[1- (3,5-dimethoxyphenyl) e]
Tylamino]-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-350
1) (84a) N- [1- (3,5-dimethoxyphenyl)
Ethyl] -N-[(4-fluorophenyl)-(3-d
Trophenyl ) methyl] amine 4-fluoro-3'-nitrobenzophenone 1.72 g
And 2.73 g of 1- (3,5-dimethoxyphenyl) ethylamine hydrochloride, 5.8 ml of triethylamine and 0.9 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a) to obtain an imine compound. The obtained imine compound, 1.76 g of sodium borohydride cyanide, and acetic acid 0.1% were obtained.
The reaction was carried out in the same manner as in Production Example (1a) using 6 ml, to obtain 2.71 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.7Hz), 3.52 and 3.59 (total 1H,
each q, J = 6.7Hz), 3.78 (6H, s), 4.71 and 4.74 (tota
l 1H, each s), 6.33 and 6.37 (total 1H, each d, J =
2.3Hz), 6.39 (2H, d, J = 2.2Hz), 6.96 and 7.04 (total 2
H, each t, J = 8.6Hz), 7.22-7.33 (2H, m), 7.40 and 7.4
9 (total 1H, each t, J = 7.9Hz), 7.56 and 7.67 (total
1H, each d, J = 7.7Hz), 8.10 and 8.12 (total 1H, each
d, J = 7.0Hz), 8.25 and 8.26 (total 1H, each s).

(84b) 3-[[1- (3,5-Dimethoate)
[Xyphenyl) ethylamino]-(4-fluorophenyl
M)] phenylamine N- [1- (3,5-dimethoxyphenyl) ethyl]-
As in Production Example (59b) using 2.70 g of N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine, 3.13 g of nickel chloride hexahydrate and 1.00 g of sodium borohydride. To 892 mg of the title compound isomer (A) as a pale yellow oily substance and 546 mg of the title compound isomer (B) as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.64 (1H, q, J = 6.6Hz), 3.77 (6H, s), 4.53 (1
H, s), 6.36 (1H, t, J = 2.2Hz), 6.43 (2H, d, J = 2.2Hz),
6.57 (1H, d, J = 8.0Hz), 6.64 (1H, s), 6.69 (1H, d, J =
7.5Hz), 6.92 (2H, t, J = 8.7Hz), 7.10 (1H, t, J = 7.7H
z), 7.24-7.28 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.55 (1H, q, J = 6.6Hz), 3.77 (6H, s), 4.54 (1
H, s), 6.36 (1H, t, J = 1.5Hz), 6.37 (2H, d, J = 2.1Hz),
6.50 (1H, d, J = 7.5Hz), 6.59 (1H, s), 6.65 (1H, d, J =
7.7Hz), 6.96-7.06 (3H, m), 7.28-7.32 (2H, m).

(84c) 3-t-butoxy-4- {3-
[[1- (3,5-dimethoxyphenyl) ethylamido]
No]-(4-fluorophenyl) methyl] phenylami
708 mg of isomer (A) of no-3--3 -cyclobutene-1,2-dione 3-[[1- (3,5-dimethoxyphenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine, 4- t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 411
The reaction was carried out in the same manner as in Production Example (1c) using Compound No. mg to give 953 m of the isomer (A) of the title compound as a white foamy solid.
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 1.63 (9H, s). 3.60 (1H, q, J = 6.5Hz), 3.78 (6
H, s), 4.63 (1H, s), 6.37 (1H, t, J = 2.2Hz), 6.40 (2H,
d, J = 2.2Hz), 6.94 (2H, t, J = 8.7Hz), 7.05-7.11 (1H,
m), 7.22-7.49 (5H, m). Isomer of 3-[[1- (3,5-dimethoxyphenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine (B) (526 mg, 4- t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 306
The reaction was carried out in the same manner as in Production Example (1c) using Compound No. mg to give 673 m of the isomer (B) of the title compound as a white foamy solid.
g was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s) .3.56 (1H, q, J = 6.6Hz), 3.77 (6
H, s), 4.63 (1H, s), 6.36 (1H, t, J = 2.3Hz), 6.38 (2H,
d, J = 2.2Hz), 7.00-7.05 (3H, m), 7.22-7.49 (5H, m).

(84d) 4- {3-[[1- (3,5-
Dimethoxyphenyl) ethylamino]-(4-fluoro
Phenyl) methyl] phenylamino} -3-hydroxy
-3-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dimethoxyphenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-
Using 426 mg of 1,2-dione isomer (A) and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a white solid.
71 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 3.72 (6H, s), 4.13-4.18 (1H, m), 5.11 (1H,
s), 6.51 (1H, d, J = 2.0Hz), 6.55 (2H, d, J = 2.0Hz), 7.
17 (1H, d, J = 7.7Hz), 7.24 (2H, t, J = 8.8Hz), 7.34 (1H,
t, J = 7.8Hz), 7.46 (1H, d, J = 7.8Hz), 7.58 (1H, s), 7.
64 (2H, dd, J = 5.6, 8.7 Hz). Melting point: 191-194 ° C. 3-t-butoxy-4- {3-[[1- (3,5-dimethoxyphenyl) ethylamino]-(4- Fluorophenyl) methyl] phenylamino} -3-cyclobutene-
Using 338 mg of 1,2-dione isomer (B) and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 241 mg of the title compound isomer (B) as a white solid. . Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 3.74 (6H, s), 4.05 (1H, q, J = 6.7Hz), 5.13 (1
H, s), 6.53 (1H, d, J = 2.0Hz), 6.57 (2H, d, J = 2.1Hz),
7.29 (2H, t, J = 8.8Hz), 7.29-7.40 (2H, m), 7.41-7.44
(1H, m), 7.52 (1H, s), 7.69 (2H, dd, J = 5.4, 8.6 Hz). Melting point: 189-192 ° C.

Production Example 85 4- {3-[(4-fluorophenyl)-[1- (3,
4,5-trifluorophenyl) ethylamino] methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-3
502) (85a) N-[(4-fluorophenyl)-(3-d
Trophenyl) methyl] -N- [1- (3,4,5-to
Fluorophenyl) ethyl] amine 4-fluoro-3'-nitrobenzophenone 2.14 g
And 3.31 g of 1- (3,4,5-trifluorophenyl) ethylamine hydrochloride, 7.2 ml of triethylamine and 1.1 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a) to give the imine compound. Obtained. The obtained imine compound was reacted with 2.19 g of sodium borohydride cyanide and 0.7 ml of acetic acid in the same manner as in Production Example (1a) to obtain 3.35 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.36 (to
tal 3H, each d, J = 6.8Hz), 3.56-3.64 (1H, m), 4.65 a
nd 4.70 (total 1H, each s), 6.83-6.91 (2H, m), 6.98 a
nd 7.07 (total 2H, each t, J = 8.7Hz), 7.20-7.27 (2H,
m), 7.43 and 7.52 (total 1H, each t, J = 7.9Hz), 7.56
and 7.62 (total1H, each d, J = 7.7Hz), 8.08 and 8.14
(total 1H, each d, J = 7.7Hz), 8.21 and 8.23 (total 1H
H, each s).

(85b) 3-[(4-Fluorophenyl)
)-[1- (3,4,5-trifluorophenyl)-
Ethylamino] -methyl] -phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] -N- [1- (3,4,5-trifluorophenyl) ethyl] amine 3.30 g , Nickel chloride 6
3.96 g of hydrate, 1.25 g of sodium borohydride
The reaction was carried out in the same manner as in Production Example (59b), and the mixture was separated and purified. 1.25 g of isomer (A) of the title compound as a pale yellow oily substance, and 975 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.7Hz), 3.65 (1H, q, J = 6.7Hz), 4.44 (1H, s), 6.65-6.
64 (3H, m), 6.90-7.00 (4H, m), 7.13 (1H, t, J = 7.8Hz),
7.21-7.42 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.30 (3H, d, J =
6.7Hz), 3.57 (1H, q, J = 6.7Hz), 4.47 (1H, s), 6.53 (1
H, dd, J = 1.4, 7.9Hz), 6.58 (1H, d, J = 1.8Hz), 6.63 (1
H, d, J = 7.7Hz), 6.88 (2H, t, J = 7.5Hz), 6.98-7.08 (3
H, m), 7.22-7.31 (2H, m).

(85c) 3-t-butoxy-4- {3-
[(4-fluorophenyl)-[1- (3,4,5-to
Trifluorophenyl) ethylamino] methyl] phenyl
Amino} -3-cyclobutene-1,2-dione 3-[(4-fluorophenyl)-[1- (3,4,5
Same as Production Example (1c) using 450 mg of isomer (A) of -trifluorophenyl) ethylamino] methyl] phenylamine and 266 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. To give the isomer (A) of the title compound as a white foamy solid in 9
53 mg were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.91-7.04 (4H, m), 7.22-7.46 (6H, m). 3-[(4-fluorophenyl)-[1- (3,4,5
Same as Production Example (1c) using 928 mg of isomer (B) of -trifluorophenyl) ethylamino] methyl] phenylamine and 548 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. To give 1.25 g of isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.59 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.90 (2H, dd, J = 6.6, 8.3Hz), 7.04 (2H, t, J = 8.
7Hz), 7.22-7.48 (6H, m).

(85d) 4- {3-[(4-fluorofuran)
Enyl)-[1- (3,4,5-trifluorophenyl)
Ru) ethylamino] methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl)-[1- (3,4,5-trifluorophenyl) ethylamino] methyl Using 473 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 1 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound. Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 4.32 (1H, q, J = 6.5Hz), 5.20 (1H, s), 7.20-
7.26 (3H, m), 7.34-7.46 (4H, m), 7.56 (1H, s), 7.70 (2
H, dd, J = 5.4, 8.5 Hz). Melting point: 189-193 ° C. 3-t-butoxy-4- {3-[(4-fluorophenyl)-[1- (3,4,5-trifluorophenyl) ) Ethylamino] methyl] phenylamino} -3-cyclobutene-1,2-dione Using 509 mg of the isomer (B) and 1 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the title compound. 310 mg of isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.26 (1H, q, J = 6.7Hz), 5.26 (1H, s), 7.24 (2
(H, t, J = 8.8Hz), 7.32-7.46 (5H, m), 7.53 (1H, s), 7.7
1 (2H, dd, J = 5.3, 8.6 Hz). Melting point: 192-197 ° C.

Production Example 86 4- {3-[[1- (3,5-dichlorophenyl) -e]
Tylamino]-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-350
5) (86a) N- [1- (3,5-dichlorophenyl) e
Tyl] -N-[(4-fluorophenyl)-(3-nitto
Rophenyl) methyl] amine 4-fluoro-3'-nitrobenzophenone 2.02 g
And 3.01 g of 1- (3,5-dichlorophenyl) ethylamine hydrochloride, 6.8 ml of triethylamine and 1.0 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a) to obtain an imine compound. Using the obtained imine compound, 2.07 g of sodium cyanoborohydride and 0.7 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 3.40 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.7Hz), 3.50-3.66 (1H, m), 4.67
and 4.71 (total 1H, each s), 6.96-7.17 (5H, m), 7.21-
7.42 (2H, m), 7.42 and 7.52 (total 1H, each t, J = 7.9
Hz), 7.58 and 7.64 (total 1H, each d, J = 7.7Hz), 8.0
6 and 8.13 (total 1H, each d, J = 8.3Hz), 8.20 and 8.
24 (total 1H, each s).

(86b) 3-[[1- (3,5-Dichloro
Rophenyl) ethylamino]-(4-fluorophenyl
M)] phenylamine N- [1- (3,5-dichlorophenyl) ethyl] -N
As in Production Example (59b), using-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine (3.39 g), nickel chloride hexahydrate (3.86 g), and sodium borohydride (1.23 g). Perform the reaction, separate and purify,
The isomer (A) of the title compound was converted into a pale yellow oily substance by 97%.
0 mg, 5% of the isomer (B) of the title compound as a white solid.
67 mg were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.66 (1H, q, J = 6.5Hz), 4.47 (1H, s), 6.58-6.
60 (2H, m), 6.66 (1H, d, J = 7.6Hz), 6.93 (2H, t, J = 8.7H
z), 7.10-7.15 (2H, m), 7.16 (2H, d, J = 1.8Hz), 7.22-
7.39 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.32 (3H, d, J =
6.7Hz), 3.58 (1H, q, J = 6.7Hz), 4.49 (1H, s), 6.52 (1
H, dd, J = 2.4, 8.0Hz), 6.59 (1H, d, J = 2.0Hz), 6.64 (1
H, d, J = 7.6Hz), 6.90-7.14 (3H, m), 7.21 (2H, d, J = 1.
9Hz), 7.23-7.31 (3H, m).

(86c) 3-t-butoxy-4- {3-
[[1- (3,5-dichlorophenyl) ethylamino]
-(4-fluorophenyl) methyl] phenylamino}
491 mg of isomer (A) of -3-cyclobutene-1,2-dione 3-[[1- (3,5-dichlorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine, 4-t-butoxy -3-
Methoxy-3-cyclobutene-1,2-dione 279m
Using g, the reaction was carried out in the same manner as in Production Example (1c) to obtain 400 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.64 (9H, s). 3.64 (1H, q, J = 6.8Hz), 4.58 (1
H, s), 6.95 (2H, t, J = 8.6Hz), 7.04 (1H, d, J = 7.3Hz),
7.13 (2H, d, J = 1.9 Hz), 7.22-7.44 (6H, m). Isomerism of 3-[[1- (3,5-dichlorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine Body (B) 535 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 304m
and 646 mg of the isomer (B) of the title compound as a white foamy solid in the same manner as in Production Example (1c).
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.64 (9H, s) .3.61 (1H, q, J = 6.7Hz), 4.59 (1
H, s), 7.00-7.06 (1H, m), 7.04 (2H, t, J = 8.7Hz), 7.12
(2H, d, J = 1.8Hz), 7.21-7.38 (6H, m).

(86d) 4- {3-[[1- (3,5-
Dichlorophenyl) ethylamino]-(4-fluorophenyl
Enyl) methyl] phenylamino} -3-hydroxy-
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dichlorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3 -Cyclobutene-
Using 391 mg of 1,2-dione isomer (A) and 1 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a white solid.
26 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 4.32 (1H, q, J = 6.8Hz), 5.31 (1H, s), 7.21-
7.25 (3H, m), 7.35 (1H, d, J = 7.8Hz), 7.42-7.45 (1H,
m), 7.47 (2H, d, J = 1.5 Hz), 7.58-7.70 (4H, m). Melting point: 189-192 ° C 3-t-butoxy-4- {3-[[1- (3,5- Dichlorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-
Using 605 mg of 1,2-dione isomer (B) and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 498 mg of the title compound isomer (B) as a white solid. . Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.28 (1H, q, J = 6.7Hz), 5.34 (1H, s), 7.27-
7.42 (5H, m), 7.48-7.56 (3H, m), 7.64 (1H, t, J = 1.9H
z), 7.70 (2H, dd, J = 5.3, 8.7 Hz). Melting point: 193-198 ° C.

Production Example 87 4- {3-[[1- (3,4-difluorophenyl) p]
Propylamino]-(4-methoxyphenyl) methyl] f
Phenylamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-42) (87a) N- [1- (3,4-difluorophenyl)
Propyl] -N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] amine 4-methoxy-3'-nitrobenzophenone 2.00 g
And 2.75 g of 1- (3,4-difluorophenyl) propylamine hydrochloride, 6.5 ml of triethylamine and 1.0 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a) to obtain an imine compound. . Using the obtained imine compound, 1.97 g of sodium cyanoborohydride and 0.7 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 3.18 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 0.80 and 0.86 (t
otal 3H, each t, J = 7.4Hz), 1.55-1.82 (2H, m), 3.31
and 3.38 (total 1H, each t, J = 6.9Hz), 3.76 and 3.82
(total 3H, each s), 4.57 and 4.62 (total 1H, each s)
s), 6.80 and 6.90 (total 2H, each d, J = 8.7Hz), 6.82
-7.17 (5H, m), 7.38 and 7.48 (total 1H, each t, J = 7.
9Hz), 7.57 and 7.64 (total1H, each d, J = 7.8Hz), 8.0
3 and 8.09 (total 1H, each d, J = 8.3Hz), 8.20 and 8.
25 (total 1H, each s).

(87b) 3-[[1- (3,4-difur
Orophenyl) propylamino]-(4-methoxyfe
Nyl) methyl] phenylamine N- [1- (3,4-difluorophenyl) propyl]
Production Example (1b) was obtained using 3.17 g of -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, 3.66 g of nickel chloride hexahydrate, and 1.17 g of sodium borohydride. The reaction was carried out in the same manner to obtain 2.76 g of the title compound as a pale yellow oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 0.89 (3H, t, J =
6.6Hz), 1.51-1.76 (2H, m), 3.34 and 3.41 (total 1H,
each t, J = 6.6Hz), 3.75 and 3.80 (total 3H, each s),
4.40 (1H, s), 6.48-6.68 (3H, m), 6.77 and 6.86 (tota
l 2H, each d, J = 8.8Hz), 6.83-6.94 (1H, m), 7.00-7.1
9 (5H, m).

(87c) 3-t-butoxy-4- {3-
[[1- (3,4-difluorophenyl) propylamido]
No]-(4-methoxyphenyl) methyl] phenylami
No-3--3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) propylamino]-(4-methoxyphenyl) methyl] phenylamine 2.70 g, 4-t-butoxy- Using 1.56 g of 3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (66c), and the mixture was separated and purified to give the isomer (A) of the title compound as a white foam.
52 mg, 657 mg of the isomer (B) of the title compound were obtained as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 0.88 (3H, t, J =
6.8Hz), 1.51-1.90 (2H, m), 1.63 (9H, s), 3.38 (1H, t,
J = 6.7Hz), 3.75 (3H, s), 4.50 (1H, s), 6.79 (2H, d,
J = 8.4Hz), 6.85-7.03 (1H, m), 7.16 (2H, d, J = 8.5Hz),
7.03-7.36 (6H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 0.86 (3H, t, J =
7.5Hz), 1.51-1.83 (2H, m), 1.68 (9H, s), 3.41 (1H, t,
J = 6.8Hz), 3.86 (3H, s), 4.53 (1H, s), 6.93 (2H, d, J =
8.7Hz), 6.90-6.98 (1H, m), 7.24 (2H, d, J = 8.6Hz), 7.
04-7.37 (6H, m).

(87d) 4- {3-[[1- (3,4-
Difluorophenyl) propylamino]-(4-methoxy
[Ciphenyl) methyl] phenylamino} -3-hydroxy
Ci-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) propylamino]-(4-methoxyphenyl) methyl] phenylamino Using 622 mg of isomer (A) of ３−-3-cyclobutene-1,2-dione and 1.5 ml of trifluoroacetic acid, a reaction was carried out in the same manner as in Production Example (63b) to give isomer (A) of the title compound. 482 mg were obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 0.60 (3H, t, J
= 7.4Hz), 1.87-1.99 (1H, m), 2.32-2.38 (1H, m), 3.73 (3
H, s), 4.03-4.13 (1H, m), 4.98 (1H, s), 6.93 (2H, d,
J = 8.7Hz), 7.07-7.09 (2H, m), 7.31 (1H, t, J = 7.9Hz),
7.43-7.54 (4H, m), 7.46 (2H, d, J = 8.6 Hz). Melting point: 185-188 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,4- Production example (63b) using 626 mg of isomer (B) of difluorophenyl) propylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione and 1.5 ml of trifluoroacetic acid. And 498 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 0.57 (3H, t, J
= 7.4Hz), 1.88-1.98 (1H, m), 2.34-2.42 (1H, m), 3.77 (3
H, s), 3.92 (1H, d, J = 10.5Hz), 5.00 (1H, s), 6.99 (2H,
d, J = 8.7Hz), 7.14-7.16 (1H, m), 7.32-7.56 (6H, m),
7.52 (2H, d, J = 8.9 Hz). Melting point: 188-192 ° C (dec).

Production Example 88 4- {3-[[1- (3,4-difluorophenyl) e]
Tylamino]-(4-fluorophenyl) methyl] -4
-Methoxyphenylamino} -3-hydroxy-3-si
Clobutene-1,2-dione (Exemplary Compound No. 2-33)
76) (88a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(4-fluorophenyl)-(2-meth
Toxi-5-nitrophenyl) methyl] amine 3.11 g of 4-fluoro-2'-methoxy-5'-nitrobenzophenone, 2.73 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, 5.8 ml of triethylamine The reaction was carried out in the same manner as in Production Example (1a) using 0.9 ml of titanium tetrachloride to obtain an imine compound. Using the obtained imine compound, 1.76 g of sodium borohydride cyanide, and 0.6 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a), and the mixture was separated and purified to give the isomer (A) of the title compound in white 1.62 g as a solid and 2.19 g of the isomer (B) of the title compound as a white solid were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 3.60 (1H, q, J = 6.6Hz), 3.79 (3H, s), 4.89 (1
H, s), 6.90-6.95 (3H, m), 7.05-7.15 (2H, m), 7.20-7.
33 (3H, m), 8.20 (1H, dd, J = 2.9, 7.8Hz), 8.48 (1H, d,
J = 2.8 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.63 (1H, q, J = 6.6Hz), 3.81 (3H, s), 4.91 (1
H, s), 6.83 (1H, d, J = 9.0Hz), 6.87-6.92 (1H, m), 6.98
-7.11 (4H, m), 7.24-7.28 (2H, m), 8.12 (1H, dd, J = 2.
9, 9.1Hz), 8.30 (1H, d, J = 2.8Hz).

(88b) 3-[[1- (3,4-difur
Orophenyl) ethylamino]-(4-fluorophenyl
L) Methyl] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(4-fluorophenyl)-(2-methoxy-5
-Nitrophenyl) methyl] amine isomer (A) 70
The reaction was carried out in the same manner as in Production Example (1b) using 0 mg, 800 mg of nickel chloride hexahydrate and 258 mg of sodium borohydride to obtain 532 mg of the isomer (A) of the title compound as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.58 (3H, s), 3.66 (1H, q, J = 6.6Hz), 4.72 (1
H, s), 6.59-6.68 (2H, m), 6.72 (1H, d, J = 8.4Hz), 6.91
(2H, t, J = 8.7Hz), 6.96-7.18 (3H, m), 7.24-7.38 (2H,
m). N- [1- (3,4-difluorophenyl) ethyl]-
N-[(4-fluorophenyl)-(2-methoxy-5
-Nitrophenyl) methyl] amine isomer (B) 66
Using 0 mg, 762 mg of nickel chloride hexahydrate, and 243 mg of sodium borohydride, the reaction was carried out in the same manner as in Production Example (1b) to obtain 332 mg of the title compound isomer (B) as a pale yellow oily substance. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.60-3.71 (1H, m), 3.64 (3H, s), 4.88 (1H,
s), 6.50-6.67 (2H, m), 6.65 (1H, d, J = 8.0Hz), 6.85-
6.92 (1H, m), 6.95-7.18 (4H, m), 7.28-7.35 (2H, m).

(88c) 3-t-butoxy-4- {3-
[[1- (3,4-difluorophenyl) ethylamido]
No]-(4-Fluorophenyl) methyl] -4-methoxy
Cyphenylamino} -3-cyclobutene-1,2-di
Down 3 - [[1- (3,4-difluorophenyl) ethylamino] - (4-fluorophenyl) methyl] -4-methoxyphenyl isomer of the amine (A) 526mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 351 mg of -dione to obtain 588 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s). 3.64 (1H, q, J = 6.5Hz), 3.68 (3
H, s), 4.86 (1H, s), 6.85 (1H, d, J = 8.7Hz), 6.92 (2H,
t, J = 8.8Hz), 6.93-6.99 (1H, m), 7.08-7.42 (6H, m). 3-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) Methyl] -4-methoxyphenylamine (B) (324 mg) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione (232 mg) were reacted in the same manner as in Production Example (1c) to give the title. The compound isomer (B) was converted to a white foamy solid by 4
07 mg were obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s) .3.62 (1H, q, J = 6.0Hz), 3.72 (3
H, s), 4.92 (1H, s), 6.79 (1H, d, J = 8.6Hz), 6.86-6.9
3 (1H, m), 7.01 (2H, t, J = 8.4Hz), 7.01-7.37 (6H, m).

(88d) 4- {3-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-fluoro
Phenyl) methyl] -4-methoxyphenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] -4 -Methoxyphenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 560 m
g, 1.5 ml of trifluoroacetic acid, and the production example (55
The reaction was carried out in the same manner as in b) to give the isomer (A) of the title compound.
Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.35 (3H, br),
3.34-3.75 (1H, m), 3.55 (3H, s), 4.80 (1H, br), 6.84
(1H, d, J = 8.8Hz), 7.05-7.15 (3H, m), 7.25-7.41 (4H,
m), 7.47 (1H, d, J = 8.8 Hz), 7.83 (1H, s). Melting point: 191 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,4-difluoro Phenyl) ethylamino]-(4-fluorophenyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 402m
g, 1 ml of trifluoroacetic acid, Production Example (55b)
153 mg of the title compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.31 (3H, br),
3.34-3.64 (1H, m), 3.62 (3H, s), 4.89 (1H, br), 6.78
-6.80 (1H, m), 7.05-7.18 (3H, m), 7.31-7.58 (5H, m),
7.63 (1H, s). Melting point: 230 ° C (dec).

Production Example 89 4- {5-[[1- (3,4-difluorophenyl) e]
Tylamino]-(4-fluorophenyl) methyl]-
2,3-dimethoxyphenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione (exemplary compound number
2-3377) (89a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(4-fluorophenyl)-(3,4
-Dimethoxy-5-nitrophenyl) methyl] amine 2.47 g of 4-fluoro-3 ', 4'-dimethoxy-5'-nitrobenzophenone and 2.83 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride, triethylamine Using 5.6 ml and 1.0 ml of titanium tetrachloride, the reaction was carried out in the same manner as in Production Example (1a) to obtain an imine compound. Production Example (1) using the obtained imine compound, 2.04 g of sodium cyanoborohydride, and 0.7 ml of acetic acid.
The reaction was carried out in the same manner as in a) to obtain 3.42 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.36 (t
otal 3H, each d, J = 6.7Hz), 3.58-3.67 (1H, m), 3.82,
3.88,3.92 and 3.97 (total 6H, each s), 4.54 (1H, s),
6.85-7.39 (9H, m).

(89b) 5-[[1- (3,4-difur
Orophenyl) ethylamino]-(4-fluorophenyl
M)]-2,3-Dimethoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
3.42 g of N-[(4-fluorophenyl)-(3,4-dimethoxy-5-nitrophenyl) methyl] amine,
The reaction was carried out in the same manner as in Production Example (59b) using 3.65 g of nickel chloride hexahydrate and 1.17 g of sodium borohydride. And 1.39 g of the isomer (B) of the title compound as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.68 (1H, q, J = 6.6Hz), 3.80 (3H, s), 3.82 (3
H, s), 4.38 (1H, s), 6.22 (1H, d, J = 1.8Hz), 6.30 (1H,
d, J = 1.9Hz), 6.93 (2H, t, J = 8.8Hz), 6.90-6.97 (1H,
m), 7.07-7.18 (2H, m), 7.22-7.28 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.58 (1H, q, J = 6.7Hz), 3.76 (6H, s), 4.41 (1
H, s), 6.22 (1H, d, J = 1.4Hz), 6.28 (1H, d, J = 1.4Hz),
6.88-6.92 (1H, m), 7.01 (2H, t, J = 8.7Hz), 7.05-7.11
(2H, m), 7.24-7.28 (2H, m).

(89c) 3-t-butoxy-4- {5-
[[1- (3,4-difluorophenyl) ethylamido]
No]-(4-fluorophenyl) methyl] -2,3-di
Methoxyphenylamino} -3-cyclobutene-1,2
-Dione 5-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] -2,3-
637 mg of isomer (A) of dimethoxyphenylamine,
4-t-butoxy-3-methoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 338 mg of 1,2-dione to obtain 690 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
4.7Hz), 1.63 (9H, s) .3.65-3.74 (1H, m), 3.84 (3H,
s), 3.94 (3H, s), 4.49 (1H, s), 6.73-6.78 (1H, m), 6.9
2-7.01 (3H, m), 7.08-7.16 (2H, m), 7.21-7.39 (3H, m). 5-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl ) Methyl] -2,3-
660 mg of isomer (B) of dimethoxyphenylamine,
4-t-butoxy-3-methoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 350 mg of 1,2-dione to obtain 602 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.7Hz), 1.68 (9H, s). 3.64 (1H, q, J = 6.8Hz), 3.81 (3
H, s), 3.90 (3H, s), 4.55 (1H, s), 6.53 (1H, br), 6.94
-7.00 (1H, m), 7.03-7.13 (2H, m), 7.05 (2H, t, J = 8.7H
z), 7.31-7.38 (2H, m), 7.60-7.71 (1H, m).

(89d) 4- {5-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-fluoro
Phenyl) methyl] -2,3-dimethoxyphenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
On 3-t-butoxy-4- {5-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] -2,3-dimethoxyphenylamino}
Isomer (A) 6 of -3-cyclobutene-1,2-dione
Using 88 mg and 1 ml of trifluoroacetic acid, the production example (5
The reaction was carried out in the same manner as in 5b) to obtain 350 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.30 (3H, br),
3.33 (1H, br), 3.76 (6H, s), 4.38 (1H, br), 6.63 (1H,
s), 7.02-7.13 (3H, m), 7.31-7.51 (4H, m), 7.94 (1H,
s). Melting point: 188 DEG C. (dec) 3-t-butoxy-4- {5-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] -2,3- Dimethoxyphenylamino｝
Isomer (B) 5 of -3-cyclobutene-1,2-dione
Production Example (5) using 95 mg and 1 ml of trifluoroacetic acid
The reaction was carried out in the same manner as in 5b) to obtain 360 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.30 (3H, br),
3.33 (1H, br), 3.71 (6H, s), 4.44 (1H, br), 6.57 (1H,
s), 7.06-7.18 (3H, m), 7.28-7.51 (4H, m), 7.93 (1H,
s). Melting point: 195 ° C (dec).

Production Example 90 4- {3-[[1- (3,4-difluorophenyl) e]
Tylamino]-(4-methoxyphenyl) methyl] ben
Ziramino {-3-hydroxy-3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-117) (90a) 3-t-butoxy-4- {3-[[1-
(3,4-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] benzylamino} -3-
1.47 g of cyclobutene-1,2-dione N-[(3-aminomethylphenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine dihydrochloride, 4-t-amine in 0.8 ml of triethylamine and 30 ml of methanol
Butoxy-3-methoxy-3-cyclobutene-1,2-
684 mg of dione was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with hydrochloric acid and concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (elution solvent: hexane / ethyl acetate = 2
/ 1) to give the title compound as a white foamy solid.
09 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 1.59 (9H, s) .3.54-3.67 (1H, m), 3.76 and 3.
81 (total 3H, each s), 4.52 and 4.56 (total 1H, each
s), 4.58, 4.74 and 4.81 (total 2H, each br), 6.79 a
nd 6.87 (total 2H, each d, J = 8.7Hz), 6.85-6.93 (1H,
m), 7.05-7.38 (8H, m).

(90b) 4- {3-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] benzylamino} -3-hydroxy
-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] benzylamino} -3 -Cyclobutene-
Using 1.08 g of 1,2-dione, the reaction was carried out in the same manner as in Production Example (55b) to give the title compound as a white solid in the form of 889
mg. NMR spectrum (DMSO-d ₆ ) δppm: 1.49 (3H, br),
3.70−4.08 (1H, m), 3.72 and 3.74 (total 3H, each
s), 4.59 and 4.61 (total 1H, each s), 4.71 and5.00
(total 2H, each br), 6.90 and 6.94 (total 2H, each
d, J = 8.7Hz), 7.04-7.16 (1H, m), 7.23-7.82 (6H, m),
7.41 and 7.45 (total 2H, each d, J = 8.8 Hz). Melting point: 180-184 ° C.

Production Example 91 4- {4-[[1- (3,4-difluorophenyl) e]
Tylamino]-(4-methoxyphenyl) methyl] ben
Ziramino {-3-hydroxy-3-cyclobutene-
1,2-dione (Exemplified Compound No. 3-47) (91a) 3-t-butoxy-4- {4-[[1-
(3,4-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] benzylamino} -3-
1.88 g of cyclobutene-1,2-dione N-[(4-aminomethylphenyl)-(4-methoxyphenyl) methyl] -N- [1- (3,4-difluorophenyl) ethyl] amine dihydrochloride, The reaction was carried out in the same manner as in Production Example (90a) using 3.3 ml of triethylamine and 883 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione. 6) (A) as white foam
45 mg, 712 mg of isomer (B) of the title compound were obtained as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 1.59 (9H, s). 3.60 (1H, q, J = 6.7Hz), 3.75 (3
H, s), 4.55 (1H, s), 4.62 (1H, br), 4.82 (1H, br), 6.
79 (2H, d, J = 8.6Hz), 6.90-6.97 (1H, m), 7.08-7.36 (8
H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 1.57 (9H, s). 3.64 (1H, q, J = 6.6Hz), 3.80 (3
H, s), 4.54 (1H, s), 4.65 (1H, br), 4.76 (1H, br), 6.
87 (2H, d, J = 8.6Hz), 6.92-6.98 (1H, m), 7.08-7.42 (8
H, m).

(91b) 4- {4-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] benzylamino} -3-hydroxy
-3-cyclobutene-1,2-dione 3-t-butoxy-4- {4-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] benzylamino} -3 -Cyclobutene-
The same reaction as in Production Example (55b) was carried out using 622 mg of 1,2-dione isomer (A) to obtain 168 mg of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.43 (3H, br),
3.53-3.70 (1H, m), 3.80 (3H, s), 4.42-4.58 (2H, br),
4.55 (1H, s), 6.82 (2H, d, J = 7.0Hz), 7.00-7.08 (1H,
m), 7.18-7.48 (8H, m). Melting point: 188 DEG C. (dec) 3-t-butoxy-4- {4-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxy Phenyl) methyl] benzylamino} -3-cyclobutene-
Using 705 mg of 1,2-dione isomer (B), the reaction was carried out in the same manner as in Production Example (55b) to obtain 266 mg of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.46 (3H, br),
3.73 (3H, s), 3.75-4.03 (1H, m), 4.52 (1H, s), 4.60-
5.08 (2H, br), 6.92 (2H, d, J = 8.3Hz), 7.08-7.16 (1H,
m), 7.21-7.60 (8H, m). Melting point: 193 ° C (dec).

Production Example 92 4- {3-[[1- (3,4-difluorophenyl) e]
Tylamino]-(4-methoxyphenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione and its hydrochloride (Exemplary Compound No. 2
-42) (92a) 3-t-butoxy-4- {3-[[1-
(3,4-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine 396 mg, 4-t-butoxy-3-methoxy-
Isomer (A) 23 of 3-cyclobutene-1,2-dione
Using 7 mg, a reaction was conducted in the same manner as in Production Example (1c).
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, t, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.54 (1H, s), 6.80 (2H, d, J = 8.8Hz), 6.92-6.9
7 (1H, m), 7.05-7.14 (3H, m), 7.17 (2H, d, J = 8.7Hz),
7.31-7.40 (3H, m). Isomer of 3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine (B) 340 mg, 4-t-butoxy -3
-Methoxy-3-cyclobutene-1,2-dione 339
The reaction was carried out in the same manner as in Production Example (1c) using 4 mg of the isomer (B) of the title compound as a white foam.
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, t, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.7Hz), 3.81 (3
H, s), 4.52 (1H, s), 6.88 (2H, d, J = 8.6Hz), 6.92-6.9
7 (1H, m), 7.06-7.17 (3H, m), 7.19 (2H, d, J = 8.7Hz),
7.17-7.32 (3H, m).

(92b) 4- {3-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] phenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3 -Cyclobutene-
Using 511 mg of 1,2-dione isomer (A), the reaction was carried out in the same manner as in Production Example (55b) to obtain 257 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.29 (3H, br),
3.58 (1H, br), 3.70 (3H, s), 4.35 (1H, br), 6.74-6.9
3 (3H, m), 7.10-7.55 (7H, m), 7.64 (1H, s). Melting point: 198 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,4- Using 774 mg of the isomer (B) of difluorophenyl) -ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione and 4 ml of trifluoroacetic acid, The reaction was carried out in the same manner to obtain 642 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.29 (3H, br),
3.30-3.61 (1H, m), 3.73 (3H, s), 4.35 (1H, br), 6.63
-7.48 (8H, m), 7.51 (2H, d, J = 7.4Hz), 7.64 (1H, s). Melting point: 183 ° C (dec).

(92c) 4- {3-[[1- (3,4-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] phenylamino} -3-hydroxy
-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-
To 462 mg of 1,2-dione isomer (B) and 2 ml of ethyl acetate, 2 ml of 4N hydrochloric acid / ethyl acetate was added and stirred for 1.5 hours. The resulting solid was collected and washed with ethyl acetate-diethyl ether to give 120 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 3.76 (3H, s), 4.23 (1H, q, J = 6.8Hz) 5.03 (1H,
s), 6.98 (2H, d, J = 8.7Hz), 7.18 (1H, d, J = 7.6Hz),
7.21-7.24 (1H, m), 7.28 (1H, t, J = 7.7Hz), 7.48-7.58
(5H, m), 7.61 (1H, d, J = 1.4 Hz). Melting point: 193-195C.

Production Example 93 4- {3-[[1- (3,5-difluorophenyl) e]
Tylamino]-(4-methoxyphenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-56) (93a) 3-[[1- (3,5-difluorophenyl)
Ru) ethylamino]-(4-methoxyphenyl) methyl
L] phenylamine [1- (3,5-difluorophenyl) ethyl]-
[(4-methoxyphenyl)-(3-nitrophenyl)
7.59 g of [methyl] amine, nickel chloride hexahydrate 9.
The reaction was carried out in the same manner as in Production Example (59b) using 05 g and 2.89 g of sodium borohydride, and the mixture was separated and purified to give the isomer (A) of the title compound as a pale yellow oil (1.18)
g, 1.17 g of the isomer (B) of the title compound as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.71 (1H, q, J = 6.7Hz), 3.79 (3H, s), 4.49 (1
H, s), 6.60 (1H, d, J = 7.9Hz), 6.64 (1H, s), 6.57-6.6
8 (2H, m), 6.75-6.86 (2H, m), 6.82 (2H, d, J = 8.7Hz),
7.14 (1H, t, J = 7.7 Hz), 7.22 (2H, d, J = 8.7 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 3.63 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.47 (1
H, s), 6.51 (1H, dd, J = 2.3, 8.0Hz), 6.62 (1H, d, J = 1.
9Hz), 6.65-6.71 (2H, m), 6.79 (2H, dd, J = 2.0, 8.4H
z), 6.86 (2H, d, J = 8.7Hz), 7.04 (1H, t, J = 7.8Hz), 7.
20 (2H, d, J = 8.6Hz).

(93b) 3-t-butoxy-4- {3-
[[1- (3,5-difluorophenyl) ethylamido
No]-(4-methoxyphenyl) methyl] phenylami
552 mg of isomer (A) of 4-{- 3-cyclobutene-1,2-dione 3-[[1- (3,5-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine and 4- t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 3
Using 31 mg, the reaction was carried out in the same manner as in Production Example (1c).
Isomer (A) of the title compound as a white foam, 740
mg. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.64 (9H, s), 3.67 (1H, q, J = 6.5Hz), 3.77 (3
H, s), 4.58 (1H, s), 6.67-6.73 (1H, m), 6.79-6.84 (2
H, m), 6.82 (2H, d, J = 8.8Hz), 6.96-7.01 (1H, m), 7.2
0 (2H, d, J = 8.6 Hz), 7.29-7.40 (3H, m). Of 3-[[1- (3,5-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine 570 mg of isomer (B) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 3
Using 42 mg, a reaction was carried out in the same manner as in Production Example (1c).
Isomer (B) of the title compound as a white foam, 808
mg. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.8Hz), 1.64 (9H, s), 3.65 (1H, q, J = 6.7Hz), 3.81 (3
H, s), 4.54 (1H, s), 6.66-6.71 (1H, m), 6.80 (2H, d, J
= 7.1Hz), 6.88 (2H, d, J = 8.6Hz), 7.01-7.08 (1H, m),
7.20 (2H, d, J = 8.7Hz), 7.23-7.33 (3H, m).

(93c ) 4- {3-[[1- (3,5-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] phenylamino {3-hydroxy-
3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,5-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3- Cyclobutene
Using 738 mg of 1,2-dione isomer (A), the reaction was carried out in the same manner as in Production Example (55b) to obtain 489 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.48 (3H, br),
3.33-3.70 (1H, br), 3.70 (3H, s), 4.40 (1H, br), 6.8
2-7.35 (8H, m), 7.53 (2H, d, J = 8.0 Hz), 7.65 (1H, s). Melting point: 183 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,5-difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-
Using 807 mg of 1,2-dione isomer (B), the reaction was carried out in the same manner as in Production Example (55b) to obtain 510 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.53 (3H, br),
3.76 (3H, s), 4.17 (1H, br), 5.01 (1H, br), 6.91 (1H,
d, J = 7.3Hz), 6.98 (2H, d, J = 8.3Hz), 7.12-7.32 (4H,
m), 7.44 (2H, d, J = 8.0Hz), 7.55 (1H, d, J = 8.1Hz), 7.
68 (1H, s). Melting point: 195 ° C (dec).

Production Example 94 3-hydroxy-4- {3-[(4-methoxyphenyl)
)-((R) -1- (p-tolyl) ethylamino)
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione hydrochloride (Exemplified Compound No. 2-3491) (94a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (p-to
[ Ryl ) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 10.79 g and (R) -1- (p-tolyl) ethylamine 5.67 g were reacted in the same manner as in Production Example (1a). 7.78 g of the title compound as a pale yellow oil
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.7Hz), 2.35 and 2.37 (total 3H, each s), 3.58 and
3.66 (total 1H, each q, J = 6.7 and 6.8Hz), 3.76 and
3.81 (total 3H, each s), 4.64 and 4.67 (total 1H, e
ach s), 6.80 and6.89 (total 2H, each d, J = 8.7 and
8.6Hz), 7.06-7.21 (6H, m), 7.38 and 7.47 (total 1H,
each t, J = 7.9 and 8.0Hz), 7.61 and 7.70 (total 1H,
each d, J = 7.7 and 7.8Hz), 8.00-8.10 (1H, m), 8.21 a
nd 8.25 (total 1H, each s).

(94b) 3-[(4-methoxyphenyi)
)-((R) -1- (p-tolyl) ethylamino)
7.72 g of tyl ] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (p-tolyl) ethyl] amine was dissolved in 150 ml of ethanol, 15.6 g of anhydrous tin (II) (II) chloride was added, and the mixture was heated under reflux for 3 hours. After cooling, ethanol was distilled off, the residue was dissolved in ethyl acetate, and the organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained yellow oil was purified using silica gel column chromatography (elution solvent, toluene / THF = 8/1),
Isomer (A) and isomer (B) of the title compound were obtained as pale yellow oils, 1.43 g and 0.78 g, respectively. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 2.35 (3H, s), 3.66 (1H, q, J = 6.7Hz), 3.74 (3
H, s), 4.48 (1H, s), 6.56 (1H, dd, J = 2.0, 8.2Hz), 6.
65-6.88 (4H, m), 7.07-7.30 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.8Hz), 2.35 (3H, s), 3.61 (1H, q, J = 6.8Hz), 3.80 (3H
H, s), 4.48 (1H, s), 6.49 (1H, dt, J = 1.1, 7.0Hz), 6.
61-6.62 (1H, m), 6.65 (1H, d, J = 7.6Hz), 6.85 (2H, d,
J = 8.7Hz), 7.02 (1H, t, J = 7.8Hz), 7.10-7.30 (6H, m).

(94c) 3-t-butoxy-4- {3-
[(4-methoxyphenyl)-((R) -1- (p-to
Lyl) ethylamino) methyl] phenylamino} -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (p
-Tolyl) ethylamino) methyl] phenylamine isomer (A) (1.41 g) was dissolved in methanol (25 ml),
3-tert-butoxy-4-methoxy-3-cyclobutene-
After adding 1.12 g of 1,2-dione and stirring for 1 hour at room temperature, the solvent was distilled off under reduced pressure. The obtained pale yellow foam was purified by silica gel column chromatography (elution solvent, toluene / THF = 10/1) to obtain 780 mg of the title compound isomer (A) as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.61 (9H, s), 2.35 (3H, s), 3.63 (1H, q, J =
6.7Hz), 3.74 (3H, s), 4.57 (1H, s), 6.58 (2H, d, J = 8.7
Hz), 7.05-7.40 (10H, m). 3-[(4-methoxyphenyl)-((R) -1- (p
-Tolyl) ethylamino) methyl] phenylamine isomer (B) (750 mg), 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione (598 mg) and methanol (10 ml) were used to give the isomer of the title compound. (A)
The reaction was carried out in the same manner as in the preparation of, and 990 mg of the isomer (B) of the title compound was obtained as a pale yellow oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 1.61 (9H, s), 2.35 (3H, s), 3.63 (1H, q, J =
6.7Hz), 3.74 (3H, s), 4.57 (1H, s), 6.78 (2H, d, J = 8.7
Hz), 7.05-7.40 (10H, m).

(94d) 3-hydroxy-4- {3-
[(4-methoxyphenyl)-((R) -1- (p-to
Lyl) ethylamino) methyl] phenylamino} -3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (p-tolyl) ethylamino) methyl] phenylamino} -3 -Cyclobutene-1,2-
Using 768 mg of dione isomer (A), Production Example (63
The reaction was carried out in the same manner as in b) to obtain 584 mg of the isomer (A) of the title compound as a pale yellow-white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.67 (3H, br),
2.33 (3H, br), 3.74 (3H, br), 4.14 (1H, br), 4.95 (1
H, brs), 6.95 (2H, d, J = 8.8Hz), 7.19-7.29 (4H, br),
7.34-7.42 (3H, br), 7.48 (1H, br), 7.51-7.54 (2H, b
r). Melting point: 196-202 ° C. (dec) Optical rotation [α] _D = -42.4 (c = 1.00, AcO
H) 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (p-tolyl) ethylamino) methyl] phenylamino} -3-cyclobutene-1,2-
Production Example (63) using 970 mg of dione isomer (B)
The reaction was carried out in the same manner as in b) to obtain 652 mg of the isomer (B) of the title compound as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.6Hz), 2.34 (3H, s), 3.77 (3H, s), 4.06 (1H, br), 4.
92 (1H, brs), 6.99 (2H, d, J = 8.8Hz), 7.08-7.26 (4H, b
r), 7.30-7.41 (4H, m), 7.47 (1H, br), 7.53 (1H, d, J =
8.1Hz). Melting point: 199-203 ° C (dec) Optical rotation [α] _D = -16.9 (c = 1.00, AcO
H).

Production Example 95 3-Hydroxy-4- (3-{(4-methoxyphenyl)
)-[(R) -1- (4-methoxyphenyl) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
-1,2-dione hydrochloride (Exemplified Compound No. 2-74) (95a) N-[(R) -1- (4-methoxyphenyl)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
Production Example (1a) using 6.00 g of (-nitrophenyl ) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone and 5.32 g of (R) -1- (4-methoxyphenyl) ethylamine The reaction was carried out in the same manner to obtain 8.83 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.37 (t
otal 3H, each d, J = 6.61 and 6.62Hz), 3.55 and 3.64
(total 1H, each q, J = 6.61 and 6.63Hz), 3.76, 3.81
and 3.83 (total 6H, each s), 4.63 and 4.66 (total 1
H, each s), 6.77-6.93 (4H, m), 7.09-7.24 (4H, m), 7.
37 and 7.47 (total 1H, each t, J = 7.90 and 7.91Hz),
7.58 and 7.68 (total 1H, each d, J = 7.93 and 7.94H
z), 8.01 and 8.08 (total 1H, each dd, J = 2.0, 7.9 and
2.0, 8.0Hz), 8.22 and 8.27 (total1H, each d, J = 1.8
6 and 1.91Hz).

(95b) 3-{(4-methoxyphenyi)
)-[(R) -1- (4-methoxyphenyl) ethyl
Amino] methyl} phenylamine N-[(R) -1- (4-methoxyphenyl) ethyl]
8.83 g of -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, anhydrous tin chloride (I
I) The reaction was carried out in the same manner as in Production Example (94b) using 17.6 g of (II) and 50 ml of ethanol to give the isomers (A) and (B) of the title compound as pale yellow oils each as 1 0.02 g and 1.06 g were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.61 (1H, q, J = 6.6Hz), 3.75 (3H, s), 3.81 (3
H, s), 4.47 (1H, s), 6.51 (1H, dd, J = 2.0, 7.1Hz), 6.
66 (1H, d, J = 2.0Hz), 6.70 (1H, d, J = 7.5Hz), 6.78 (2H,
d, J = 8.7Hz), 6.87 (2H, d, J = 8.7Hz), 7.10 (1H, t, J =
7.9 Hz), 7.13-7.20 (4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.60 (1H, q, J = 6.6Hz), 3.80 (3H, s), 3.81 (3
H, s), 4.47 (1H, s), 6.49 (1H, dd, J = 2.0, 8.1Hz), 6.
61 (1H, d, J = 2.0Hz), 6.65 (1H, d, J = 2.0Hz), 6.82-6.8
8 (4H, m), 7.02 (1H, t, J = 7.8 Hz), 7.15-7.35 (4H, m).

(95c) 3-t-butoxy-4- (3-
{(4-methoxyphenyl)-[(R) -1- (4-meth
Toxiphenyl) ethylamino] methyl @ phenylami
D ) -3-cyclobutene-1,2-dione 3-{(4-methoxyphenyl)-[(R) -1- (4
-Methoxyphenyl) ethylamino] methyl} phenylamine isomer (A) 990 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 65
Production Example (1c) using 5 mg and 25 ml of methanol
The reaction was carried out in the same manner as described above to obtain 1.29 g of the isomer (A) of the title compound as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.62 (1H, q, J = 6.6Hz), 3.75 (3
H, s), 3.82 (3H, s), 4.57 (1H, s), 6.79 (2H, d, J = 8.7
Hz), 6.88 (2H, d, J = 8.4Hz), 7.05-7.20 (4H, m), 7.25-
7.40 (4H, m) .3-{(4-methoxyphenyl)-
Isomer of [(R) -1- (4-methoxyphenyl) ethylamino] methyldiphenylamine (B) 1.03
g, 3-tert-butoxy-4-methoxy-3-cyclobutene-1,2-dione (787 mg) and methanol (25 ml) were reacted in the same manner as in Production Example (1c) to give the isomer (B) of the title compound. 1.17 g were obtained as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.61 (1H, q, J = 6.6Hz), 3.80 (3H
H, s), 3.81 (3H, s), 4.55 (1H, s), 6.86-6.89 (4H, m),
7.03 (1H, d, J = 7.5Hz), 7.10-7.35 (7H, m).

(95d) 3-Hydroxy-4- (3-
{(4-methoxyphenyl)-[(R) -1- (4-meth
Toxiphenyl) ethylamino] methyl @ phenylami
No) -3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- (3-{(4-methoxyphenyl)-[(R) -1- (4-methoxyphenyl) ethylamino] methyl Using 1.25 g of the isomer (A) of {phenylamino) -3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (63b), and the isomer (A) of the title compound was pale yellow-white. 831 mg was obtained as a solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.6Hz), 3.74 (3H, s), 3.78 (3H, s), 4.14 (1H, br), 4.
94 (1H, brs), 6.94-6.99 (4H, d, J = 8.8Hz), 7.20-7.30
(3H, m), 7.36 (1H, t, J = 8.1Hz), 7.43 (1H, d, J = 8.1H
z), 7.49-7.51 (3H, m). Melting point: 191-195 (dec) Optical rotation [α] _D = -82.6 (c = 1.00, AcO
H) 3-t-butoxy-4- (3-{(4-methoxyphenyl)-[(R) -1- (4-methoxyphenyl) ethylamino] methyl} phenylamino) -3-cyclobutene-1,2 Using 1.11 g of isomer (B) of -dione, the reaction was carried out in the same manner as in Production Example (63b) to obtain 911 mg of isomer (B) of the title compound as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.6Hz), 3.77 (3H, s), 3.79 (3H, s), 4.06 (1H, br), 4.
92 (1H, brs), 6.99 (4H, dd, J = 2.9, 8.8Hz), 7.39 (2H,
d, J = 8.8Hz), 7.34-7.42 (3H, m), 7.47 (1H, s), 7.58 (1
H, d, J = 8.8 Hz). Melting point: 194-198 ° C. (dec) Optical rotation [α] _D = −1.79 (c = 1.01, AcO
H).

Production Example 96 3- {3-[[(R) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-fluorophenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
Ten-1,2-dione and its hydrochloride (exemplary compound
No. 2-39) (96a) N-[(R) -1- (3,4-difluorophenyl)
Enyl) ethyl] -N-[(4-fluorophenyl)-
(3-Nitrophenyl) methyl] amine (4-fluorophenyl)-(3-nitrophenyl) methanone 12.91 g and (R) -1- (3,4-difluorophenyl) ethylamine hydrochloride 10.19 g The reaction was carried out in the same manner as in Production Example (1a) to obtain 18.47 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.37 (t
otal 3H, each d, J = 6.60 and 6.64Hz), 3.60 and 3.64
(total 1H, each q, J = 6.69 and 6.60Hz), 4.65and 4.6
9 (total 1H, each s), 6.85-7.30 (7H, m), 7.41 and 7.
51 (total 1H, each t, J = 7.99 and 7.94Hz), 7.57 and
7.63 (total 1H, each d, J = 7.82 and 7.84Hz), 8.05 an
d 8.12 (total 1H, each dd, J = 1.6, 8.0 and 1.8, 8.0H
z), 8.21and 8.23 (total 1H, each t, J = 1.87 and 1.90
Hz).

(96b) 3-[[(R) -1- (3,4
-Difluorophenyl) ethylamino]-(4-fluoro
L-phenyl) methyl] phenylamine N-[(R) -1- (3,4-difluorophenyl) ethyl] -N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine 18.44 g, chloride Nickel hexahydrate 22.69 g, sodium borohydride 7.
Production Example (59) using 22 g and 150 ml of methanol
The reaction was carried out in the same manner as in b), followed by separation and purification to obtain 1.27 g and 2.79 g of the title compound as a pale yellow oil, respectively, as isomers (A) and (B). Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 3.67 (1H, q, J = 6.6Hz), 4.45 (1H, s), 6.57-6.
65 (3H, m), 6.89-6.97 (3H, m), 7.00-7.27 (5H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 3.68 (1H, q, J = 6.6Hz), 4.47 (1H, s), 6.50-6.
53 (1H, m), 6.57 (1H, dd, J = 1.6, 1.9Hz), 6.63 (1H, d,
J = 7.3hz), 6.87-6.95 (1H, m), 6.97-7.15 (5H, m), 7.
23-7.30 (2H, m).

(96c) 3-t-butoxy-4- {3-
[[(R) -1- (3,4-difluorophenyl) ethyl]
Ruamino]-(4-fluorophenyl) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[[(R) -1- (3,4-difluorophenyl)
Using 1.24 g of isomer (A) of ethylamino]-(4-fluorophenyl) methyl] phenylamine, 963 mg of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 15 ml of methanol. The reaction was carried out in the same manner as in Production Example (94c) to obtain 597 mg of the title compound isomer (A) as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.66 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.91-6.96 (3H, m), 6.98-7.14 (3H, m), 7.20-7.
41 (5H, m). 3-[[(R) -1- (3,4-difluorophenyl)
1.31 g of isomer (B) of ethylamino]-(4-fluorophenyl) methyl] phenylamine, 1.01 g of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 16 ml of methanol were added. The reaction was carried out in the same manner as in Production Example (1c) to obtain 997 mg of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.61 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.90-7.15 (6H, m), 7.20-7.45 (5H, m).

(96d) 3- {3-[[(R) -1-
(3,4-difluorophenyl) ethylamino]-(4
-Fluorophenyl) methyl] phenylamino} -4-
Hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[(R) -1- (3,
4-Difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione Isomer (A) (585 mg) was reacted in the same manner as in Production Example (55b). This gave 516 mg of the isomer (A) of the title compound as a pale yellow-white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.59 (3H, d, J
= 5.7Hz), 4.30 (1H, br), 5.05 (1H, brs), 6.98-7.00 (3H,
d, J = 7.5Hz), 7.25-7.35 (2H, m), 7.42-7.65 (5H, m).
7.77 (1H, d, J = 1.7 Hz) Melting point: 195-198 ° C. (dec) Optical rotation [α] _D = −398.8 (c = 1.00, A
cOH) 3-t-butoxy-4- {3-[[(R) -1- (3,
Using 979 mg of the isomer (B) of 4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (55b). This gave 868 mg of the title compound isomer (B) as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.38 (3H, d, J
= 6.7Hz), 3.50 (1H, br), 4.41 (1H, brs), 6.71 (1H, d, J
= 7.48Hz), 7.03-7.14 (4H, m), 7.28-7.43 (4H, m), 7.51
(1H, d, J = 1.8 Hz), 7.63 (1H, s). Melting point: 130-132 ° C. (dec) Optical rotation [α] _D = −33.8 (c = 0.10, D
MSO).

(96e ) 3- {3-[[(R) -1-
(3,4-difluorophenyl) ethylamino]-(4
-Fluorophenyl) methyl] phenylamino} -4-
Hydroxy-3-cyclobutene-1,2-dione hydrochloric acid
Salt 3- {3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2- 337 mg of dione isomer (A) was suspended in 5 ml of methanol, and 4N hydrochloric acid-ethyl acetate solution 3 was added.
ml was added to dissolve. The solvent was distilled off under reduced pressure, and the obtained pale yellow foam was suspended in ether and collected by filtration to obtain 337 mg of the isomer (A) of the title compound as a pale yellowish white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J
= 6.8Hz), 4.31 (1H, q, J = 6.4Hz), 5.07 (1H, s), 7.10-
7.25 (3H, m), 7.34 (1H, dd, J = 7.9, 8.1Hz), 7.42 (2H,
d, J = 7.3Hz), 7.46-7.55 (2H, m), 7.57-7.66 (1H, m),
7.72 (2H, dd, J = 5.4, 8.4Hz) melting point:. 195-200 ℃ (dec) optical rotation _{[α] D = -50.6 (c} = 1.00, AcO
H) 3- {3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2 Using 404 mg of the dione isomer (B) in 4 ml of methanol and 3 ml of a 4N hydrochloric acid-ethyl acetate solution, a reaction was carried out in the same manner as in the case of producing the isomer (A) of the title compound. 338 mg of B) was obtained as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.71 (3H, d, J)
= 6.7Hz), 4.03 (1H, br), 5.12 (1H, s), 7.18-7.30 (3H,
m), 7.32-7.51 (4H, m), 7.56 (1H, d, J = 7.5Hz), 7.63
7.68 (1H, m), 7.76 (2H, dd, J = 5.3, 8.7 Hz). Melting point: 172 to 180 ° C. (dec) Optical rotation [α] _D = 17.1 (c = 1.01, AcO
H).

Production Example 97 3- {3-[[(R) -1- (3-fluorophenyl)]
Ethylamino]-(4-methoxyphenyl) methyl] F
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione and its hydrochloride (Exemplary Compound No. 2
-21) (97a) N-[(R) -1- (3-fluorophenyl)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl ) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 11.16 g and (R) -1- (3-fluorophenyl) ethylamine hydrochloride 7.62 g were prepared using Production Example (1a). ) To give 15.11 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.38 (t
otal 3H, each d, J = 6.7and 6.6Hz), 3.61 and 3.69 (to
tal 1H, each q, J = 6.6 and 6.7Hz), 3.76 and3.81 (tot
al 3H, each s), 4.63 and 4.68 (total 1H, each s),
6.78-7.05 (5H, m), 7.13-7.33 (3H, m), 7.39 and 7.48
(total 1H, each t, J = 8.0 and 7.8Hz), 7.60-7.67 (tot
al 1H, each d, J = 7.3, 7.9Hz), 8.07-8.11 (1H, m), 8.
22-8.26 (1H, m).

(97b) 3-[[(R) -1- (3-F
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamine N-[(R) -1- (3-fluorophenyl) ethyl]
-N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine 15.08 g, nickel chloride hexahydrate 18.84 g, sodium borohydride 6.0 g,
The reaction was carried out in the same manner as in Production Example (59b) using 150 ml of methanol, and the isomers (A) and (B) of the title compound were converted into pale yellow oily substances (787 mg, 6 mg).
05 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.70 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.47 (1
H, s), 6.55-6.58 (1H, m), 6.63-6.64 (1H, m), 6.69 (1
H, d, J = 7.5Hz), 6.78 (2H, d, J = 8.7Hz), 6.91-6.98 (1
H, m), 6.97-7.30 (6H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.47 (1
H, s), 6.50 (1H, dd, J = 2.1, 8.1Hz), 6.61-6.62 (1H,
m), 6.66 (1H, d, J = 7.5Hz), 6.86 (2H, d, J = 8.7Hz), 6.
94-7.05 (3H, m), 7.15-7.30 (4H, m).

(97c) 3-t-butoxy-4- {3-
[[(R) -1- (3-fluorophenyl) ethylamido
No]-(4-methoxyphenyl) methyl] phenylami
765 mg of the isomer (A) of no {-3-cyclobutene-1,2-dione 3-[[(R) -1- (3-fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine; 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 60
Production Example (94) using 3 mg and 10 ml of methanol.
The reaction was carried out in the same manner as in c) to obtain 767 mg of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.7Hz), 3.76 (3
H, s), 4.57 (1H, s), 6.80 (2H, d, J = 8.7Hz), 6.92-7.0
4 (2H, m), 7.06-7.40 (8H, m). An isomer of 3-[[(R) -1- (3-fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamine ( B) 582 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 45
Production example (94c) using 9 mg and 8 ml of methanol
And 792 mg of the title compound isomer (B) was obtained as a pale yellow foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.66 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.55 (1H, s), 6.75-7.10 (4H, m), 7.13-7.40 (8
H, m).

(97d) 3- {3-[[(R) -1-
(3-Fluorophenyl) ethylamino]-(4-metho
Xyphenyl) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[(R) -1- (3-
Production Example (55b) using 772 mg of the isomer (A) of fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione, 3 ml of trifluoroacetic acid, and 10 ml of dichloromethane. ), To give 635 mg of isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.29 (3H, d, J
= 6.6Hz), 3.57-3.62 (1H, br), 3.68 (3H, s), 4.35 (1H, b
rs), 6.75-6.81 (3H, m), 7.02 (1H, dt, J = 2.5,8.5Hz),
7.08-7.23 (5H, m), 7.30-7.38 (1H, m), 7.54 (1H, d, J
= 8.0 Hz), 7.63 (1H, s) Melting point: 114-117 ° C (dec) Optical rotation [α] _D = -196 (c = 1.00, AcOH) 3-t-butoxy-4- {3- [ [(R) -1- (3-
Production example using 476 mg of isomer (B) of fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione using 3 ml of trifluoroacetic acid and 10 ml of dichloromethane. The reaction was carried out in the same manner as (55b) to give 232 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.30 (3H, br),
3.74 (3H, s), 3.74 (1H, q, J = 6.7Hz), 3.60-3.80 (1H, b
r), 4.00-4.20 (1H, br), 6.80-7.75 (12H, m). Melting point: 114-117 ° C (dec) Optical rotation [α] _D = +44.7 (c = 1.01, AcO
H).

(97e) 3- {3-[[(R) -1-
(3-Fluorophenyl) ethylamino]-(4-metho
Xyphenyl) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3- {3-[[(R) -1- (3-fluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl] phenylamino {-4-hydroxy-3-cyclobutene-
133 mg of 1,2-dione isomer (A) was used in 3 ml of methanol and 3 ml of a 4N hydrochloric acid-ethyl acetate solution,
The reaction was carried out in the same manner as in Production Example (96e) to obtain 122 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, d, J
= 6.8Hz), 3.74 (3H, s), 4.15-4.30 (1H, br), 5.03 (1H, b
rs), 6.94-6.96 (2H, m), 7.12-7.60 (10H, m). Melting point: 175-180 (dec) Optical rotation [α] _D = -112 (c = 0.46, AcOH) 3- ｛ Isomer of 3-[[(R) -1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2-dione (B) 404 mg was reacted in the same manner as in Production Example (96e) using 4 ml of methanol and 2 ml of a 4N hydrochloric acid-ethyl acetate solution to obtain 146 mg of the isomer (B) of the title compound as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J
= 6.9Hz), 3.73 (3H, s), 4.16-4.25 (1H, br), 4.96 (1H, b
r), 6.92 (2H, d, J = 7.6Hz), 7.13-7.26 (3H, m), 7.31-7.
47 (5H, m), 7.56-7.62 (2H, m). Melting point: 164-168 ° C (dec) Optical rotation [α] _D = -3.8 (c = 0.42, AcO
H).

Production Example 98 3- (3-{(4-fluorophenyl)-[(R) -1]
-(3-Fluorophenyl) -ethylamino] methyl}
Phenylamino) -4-hydroxy-3-cyclobutene
-1,2-dione and its trifluoroacetate and salt
Acid salt (Exemplified Compound No. 2-18) (98a) N-[(R) -1- (3-fluorophenyl)
Ru) ethyl] -N-[(4-fluorophenyl)-(3
-Nitrophenyl ) methyl] amine (4-fluorophenyl)-(3-nitrophenyl) methanone 8.03 g and (R) -1- (3-fluorophenyl) ethylamine hydrochloride 5.75 g were prepared using Production Example (1).
The reaction was carried out in the same manner as in a), and the isomer (A) of the title compound,
Isomer (B) was converted to 2.85 each as a pale yellow oil.
g, 1.67 g. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J =
6.8Hz), 3.61 (1H, q, J = 6.7Hz), 4.70 (1H, s), 6.91-
7.00 (5H, m), 7.19-7.33 (3H, m), 7.51 (1H, t, J = 7.9H
z), 7.65 (1H, d, J = 7.5Hz), 8.12 (1H, dd, J = 1.9, 8.0
Hz), 8.24 (1H, dd, J = 1.3, 1.9 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 3.66 (1H, q, J = 6.7Hz), 4.68 (1H, s), 6.90-
7.09 (5H, m), 7.18-7.32 (3H, m), 7.41 (1H, t, J = 8.0H
z), 7.58 (1H, d, J = 8.0 Hz), 8.03-8.06 (1H, m), 8.24
(1H, dd, J = 1.6, 1.9Hz).

(98b) 3-{(4-Fluorophenyl)
)-[(R) -1- (3-fluorophenyl) ethyl
Amino] methyl} phenylamine N-[(R) -1- (3-fluorophenyl) ethyl]
2.82 g of isomer (A) of -N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine, 3.64 g of nickel chloride hexahydrate, 1.16 g of sodium borohydride, 30 ml of methanol Production Example (1)
The reaction was carried out in the same manner as in b), and the isomer (A) of the title compound was obtained.
Was obtained as a colorless oil (2.52 g). Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.70 (1H, q, J = 6.6Hz), 4.48 (1H, s), 6.59-
6.61 (2H, m), 6.67 (1H, d, J = 7.4Hz), 6.89-6.96 (3H,
m), 7.00-7.03 (2H, m), 7.14 (1H, t, J = 7.7Hz), 7.23-
7.30 (3H, m). N-[(R) -1- (3-fluorophenyl) ethyl]
1.63 g of isomer (B) of -N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] amine, 2.11 g of nickel chloride hexahydrate, 6.74 g of sodium borohydride, 20 ml of methanol Production Example (1)
The reaction was carried out in the same manner as in b), and the isomer (B) of the title compound was obtained.
Was obtained as a colorless oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 3.62 (1H, q, J = 6.7Hz), 4.50 (1H, s), 6.50-
6.53 (1H, m), 6.59 (1H, dd, J = 1.5, 1.9Hz), 6.64 (1H, m
d, J = 8.0Hz), 6.90-7.06 (6H, m), 7.26-7.33 (3H, m).

(98c) 3-t-butoxy-4- (3-
{(4-fluorophenyl)-[(R) -1- (3-f
Fluorophenyl) ethylamino] methyl @ phenylami
No.) Isomer of 3 -cyclobutene-1,2-dione 3-{(4-fluorophenyl)-[1- (3-fluorophenyl) ethylamino] methyl} phenylamine (A) 2.48 g, 3- 2.02 g of t-butoxy-4-methoxy-3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (94c) using 35 ml of methanol to obtain 3.49 g of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.68 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 6.91-7.10 (6H, m), 7.22-7.39 (6H, m) .3-
1.46 g of {(4-fluorophenyl)-[(R) -1- (3-fluorophenyl) ethylamino] methyl} phenylamine isomer (B), 3-t-butoxy-4-
Methoxy-3-cyclobutene-1,2-dione 1.19
g, and 30 ml of methanol, and reacted in the same manner as in Production Example (94c) to obtain 2.04 g of the isomer (B) of the title compound as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 6.92-7.06 (6H, m), 7.21-7.32 (6H, m).

(98d) 3- (3-{(4-fluorofuran)
Enyl)-[(R) -1- (3-fluorophenyl) e
Tylamino] methyl @ phenylamino) -4-hydroxy
C-3-cyclobutene-1,2-dione trifluoro
Acetate 3-tert-butoxy-4- (3-{(4-fluorophenyl)-[(R) -1- (3-fluorophenyl) ethylamino] methyl} phenylamino) -3-cyclobutene-1,2 1.29 g of the dione isomer (A) was dissolved in 13 ml of dichloromethane and 1 ml of trifluoroacetic acid was added. After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure.
Toluene was added and azeotroped twice. Ether was added to the obtained white solid, which was collected by filtration to obtain 1.34 g of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.7Hz), 4.31 (1H, q, J = 6.7Hz), 5.25 (1H, s), 7.05
(1H, d, J = 7.7Hz), 7.17 (1H, d, J = 7.6Hz), 7.24-7.28
(4H, m), 7.34 (1H, t, J = 7.9Hz), 7.44-7.48 (2H, m),
7.60-7.65 (3H, m). Melting point: 190-194 ° C (dec) Optical rotation [α] _D = -56.2 (c = 1.07, Ac
OH) 3-t-butoxy-4- (3-{(4-fluorophenyl)-[(R) -1- (3-fluorophenyl) ethylamino] methyl} phenylamino) -3-cyclobutene-1,2 The reaction was carried out in the same manner as in the case of the isomer (A) using 2.00 g of the isomer of the dione (B), 4 ml of trifluoroacetic acid and 8 ml of dichloromethane to obtain the isomer (B) of the title compound as a pale yellow solid. 0.68 g was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.7Hz), 4.24 (1H, q, J = 6.7Hz), 5.25 (1H, s), 7.06
(1H, d, J = 7.7Hz), 7.21 (1H, d, J = 7.8Hz), 7.25-7.33
(5H, m), 7.45-7.54 (2H, m), 7.61-7.66 (3H, m). Melting point: 187-189 ° C (dec) Optical rotation [α] _D = +37.1 (c = 1.01, AcO
H).

(98e) 3- (3-{(4-fluorofuran)
Enyl)-[(R) -1- (3-fluorophenyl) e
Tylamino] methyl @ phenylamino) -4-hydroxy
C - 3 -cyclobutene-1,2-dione 3- (3-{(4-fluorophenyl)-[(R) -1
-(3-Fluorophenyl) ethylamino] methyl @ phenylamino) -4-hydroxy-3-cyclobutene-
Isomer (B) 5 of 1,2-dione trifluoroacetate
13 mg was dissolved in 5 ml of methanol, and 80 ml of a phthalate standard solution (pH 4.01) was added. The resulting white precipitate was collected by filtration and sufficiently washed with water to obtain 453 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.59 (3H, d, J =
6.6Hz), 4.10-4.30 (1H, br), 5.16 (1H, s), 6.97 (1H,
d, J = 7.7Hz), 7.20-7.31 (6H, m), 7.44-7.66 (4H, m),
7.70 (1H, s). Melting point: 186 ° C. (dec) Optical rotation [α] _D = + 39.4 (c = 1.01, AcO
H).

(98f) 3- (3-{(4-fluorofuran)
Enyl)-[(R) -1- (3-fluorophenyl) e
Tylamino] methyl @ phenylamino) -4-hydroxy
Ci-3-cyclobutene-1,2-dione hydrochloride 3- (3-{(4-fluorophenyl)-[(R) -1
-(3-Fluorophenyl) ethylamino] methyl @ phenylamino) -4-hydroxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (63b) using 500 mg of 1,2-dione trifluoroacetate to obtain 410 mg of the title compound as a pale yellow solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.68 (3H, d, J =
6.6Hz), 4.13-4.28 (1H, br), 5.17 (1H, s), 7.20 (1H,
d, J = 7.5Hz), 7.24-7.51 (8H, m), 7.53 (1H, s), 7.71 (2
H, dd, J = 5.3, 8.5 Hz). Melting point: 180 ° C. (dec) Optical rotation [α] _D = −22.3 (c = 0.99, AcO
H).

Production Example 99 3- (3-{[1- (3,4-difluorophenyl) e]
Tylamino]-(thiophen-2-yl) methyldiphenyl
Nylamino) -4-hydroxy-3-cyclobutene-
1,2-dione trifluoroacetate (exemplified compound number
2-45) (99a) N- [1- (3,4-difluorophenyl)
Ethyl] -N-[(3-nitrophenyl)-(thiophene
Production Example (1a) using 3.03 g of (2--2 -yl) methyl] amine (3-nitrophenyl)-(thiophen-2-yl) methanone and 2.52 g of 1- (3,4-difluorophenyl) ethylamine The reaction was carried out in the same manner as described above to give 4.62 g of the title compound as a red-orange oil. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.37 (t
otal 3H, each d, J = 6.61 and 6.63Hz), 3.59 and 3.81
(total 1H, each q, J = 6.58 and 6.60Hz), 4.88and 4.9
5 (total 1H, each s), 6.63-7.03 (3H, m), 7.05-7.33 (3
H, m), 7.44 and 7.54 (total 1H, each t, J = 7.97 and
7.93Hz), 7.64-7.97 (1H, m), 8.07-8.19 (1H, m), 8.21-
8.27 (1H, m).

(99b) 3-{[1- (3,4-difur
Orophenyl) ethylamino]-(thiophen-2-i
M) methyl @ phenylamine N- [1- (3,4-difluorophenyl) ethyl]-
Production example using 4.60 g of N-[(3-nitrophenyl)-(thiophen-2-yl) methyl] amine, 5.84 g of nickel chloride hexahydrate, 1.86 g of sodium borohydride and 100 ml of methanol ( The reaction was carried out in the same manner as in 59b) and the mixture was separated and purified to give the isomers (A) and (B) of the title compound as pale yellow oils each in 1.025%.
g, 495 mg. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (3H, d, J =
6.6Hz), 3.67 (1H, q, J = 6.5Hz), 4.59 (1H, s), 6.60-6.
66 (4H, m), 6.89 (1H, dd, J = 3.7, 5.1Hz), 7.02-7.26
(5H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.77 (1H, q, J = 6.6Hz), 4.77 (1H, s), 6.54-6.
56 (1H, m), 6.60 (1H, t, J = 2.0Hz), 6.70 (1H, d, J = 7.5H
z), 6.82 (1H, d, J = 3.7Hz), 6.87-6.99 (2H, m), 7.05-
7.16 (3H, m), 7.23 (1H, dd, J = 1.2, 5.1Hz).

(99c) 3-t-butoxy-4- (3-
{[1- (3,4-difluorophenyl) ethylamido]
No]-(thiophen-2-yl) methyldiphenylamido
No.) 3-cyclobutene-1,2-dione 3-{[1- (3,4-difluorophenyl) ethylamino]-(thiophen-2-yl) methyl} phenylamine isomer (A) 1.03 g , 3-t-butoxy-4
-Methoxy-3-cyclobutene-1,2-dione 809
Production Example (94c) using mg and 15 ml of methanol
The reaction was carried out in the same manner as in the above to give 932 mg of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 4.72 (1
H, s), 6.63 (1H, d, J = 3.6Hz), 6.87 (1H, dd, J = 3.4,
5.0Hz), 7.01-7.27 (5H, m), 7.34-7.37 (3H, m). 3-{[1- (3,4-difluorophenyl) ethylamino]-(thiophen-2-yl) methyl} phenyl 495 mg of amine isomer (B), 3-t-butoxy-4
-Methoxy-3-cyclobutene-1,2-dione 391
Production Example (94c) using 10 mg of methanol and 10 ml of methanol
And 709 mg of the title compound isomer (B) was obtained as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.79 (1H, q, J = 6.6Hz), 4.86 (1
H, s), 6.87 (1H, d, J = 3.3Hz), 6.97 (1H, dd, J = 3.5,
5.0Hz), 6.99-7.01 (1H, m), 7.07-7.16 (3H, m), 7.25-
7.35 (4H, m).

(99d) 3- (3-{[1- (3,4-
Difluorophenyl) ethylamino]-(thiophene-
2-yl) methyl @ phenylamino) -4-hydroxy
-3-cyclobutene-1,2-dionetrifluoroacetic acid
The salt 3-t-butoxy-4- (3-{[1- (3,4-difluorophenyl) ethylamino]-(thiophen-2-
Yl) methyl @ phenylamino) -3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (98d) using 906 mg of 1,2-dione isomer (A), 3 ml of trifluoroacetic acid, and 10 ml of dichloromethane to obtain 851 mg of isomer (A) of the title compound as a white solid. . Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.59 (3H, d, J
= 6.6Hz), 4.27 (1H, br), 5.37 (1H, br.s), 7.05-7.18 (3
H, m), 7.32-7.38 (2H, m), 7.43-7.52 (2H, m), 7.55-7.
60 (3H, m). Melting point: 177-181 ° C (dec) 3-t-butoxy-4- (3-{[1- (3,4-difluorophenyl) ethylamino]-(thiophen-2-
Yl) methyl @ phenylamino) -3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (98d) using 699 mg of 1,2-dione isomer (B), 3 ml of trifluoroacetic acid, and 10 ml of dichloromethane to obtain 666 mg of the isomer (B) of the title compound as a white solid. . Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.57 (3H, d, J
= 6.7Hz), 4.27 (1H, q, J = 4.2Hz), 5.49 (1H, s), 7.12 (1
H, dd, J = 3.7, 5.0Hz), 7.16 (1H, d, J = 7.7Hz), 7.26-7.
36 (2H, m), 7.44 (1H, d, J = 3.0 Hz), 7.48-7.87 (5H, m). Melting point: 181-182 ° C (dec).

Production Example 100 3- {5-[[(R) -1- (3,5-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
2-fluorophenylamino} -4-hydroxy
-3-cyclobutene-1,2-dione trifluorovinegar
Acid salt (Exemplified Compound No. 2-3400) (100a) N-[(R) -1- (3,5-difluoro)
Phenyl) ethyl] -N-[(4-fluoro-3-nitto
Rophenyl)-(4-methoxyphenyl) methyl] ami
Down (4-fluoro-3-nitrophenyl) - (4-methoxyphenyl) methanone 2.53g, (R) -1- (3 ,
5-Difluorophenyl) ethylamine hydrochloride 1.78
Using g, the reaction was carried out in the same manner as in Production Example (1a) to obtain 3.62 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.37 (t
otal 3H, each d, J = 6.64 and 6.65Hz), 3.65 and 3.66
(total 1H, each q, J = 6.6 and 6.5Hz), 3.77 and 3.82
(total 3H, each s), 4.55 and 4.63 (total 1H, each s)
s), 6.66-6.92 (5H, m), 7.11-7.24 (3H, m), 7.53 and 7.
59 (total 1H, each ddd, J = 2.4, 4.2, 8.5and 2.3, 4.
3, 8.6Hz), 8.05 and 8.19 (total 1H, each dd, J = 2.3,
7.1 and 2.2, 7.2Hz).

(100b) 5-[[(R) -1- (3,
5-difluorophenyl) ethylamino]-(4-metho
Xyphenyl) methyl] -2-fluoro-phenylamido
Emissions N - [(R) -1- ( 3,5- difluorophenyl) ethyl] -N - [(4- fluoro-3-nitrophenyl)
-(4-methoxyphenyl) methyl] amine 3.60
g, 4.11 g of nickel chloride hexahydrate, 1.30 g of sodium borohydride, and 50 ml of methanol, and the reaction was carried out in the same manner as in Production Example (1b) to obtain 3.27 g of the title compound as a yellow oil. . NMR spectrum (CDCl ₃ ) δppm: 1.31 and 1.32 (t
otal 3H, each d, J = 6.67 and 6.62Hz), 3.55-3.75 (1H,
m), 3.76 and 3.81 (total 3H, each s), 4.44 (1H, s),
6.55-6.97 (8H, m), 7.17 (2H, d, J = 8.6Hz).

(100c) 3-t-butoxy- 4-−5
-[[(R) -1- (3,5-difluorophenyl) e
Tylamino]-(4-methoxyphenyl) methyl] -2
-Fluorophenylamino} -3-cyclobutene-1,
2-dione 5-[[(R) -1- (3,5-difluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl]-
Using 3.24 g of 2-fluorophenylamine, 2.32 g of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 30 ml of methanol, the reaction was carried out in the same manner as in Production Example (66c) and separated. Purification gave 1.01 g and 817 mg of isomer (A) and isomer (B) of the title compound as pale yellow foams, respectively. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.66 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.56 (1H, s), 6.66-6.71 (1H, m), 6.78-6.82 (4
H, m), 7.00 (1H, br), 7.04-7.09 (1H, m), 7.15-7.30 (3
H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.64 (9H, s), 3.65 (1H, q, J = 6.7Hz), 3.80 (3H
H, s), 4.54 (1H, s), 6.64-6.69 (1H, m), 6.81 (2H, dd,
J = 2.0, 8.1Hz), 6.88 (2H, d, J = 8.5Hz), 6.92-7.02 (2H,
m), 7.10-7.30 (3H, m).

(100d) 3- {5-[[(R) -1-
(3,5-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] -2-fluorophenyl
Amino} -4-hydroxy-3-cyclobutene-1,2
-Dione trifluoroacetate 3-t-butoxy-4- {5-[[(R) -1- (3,
5-Difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] -2-fluorophenylamino} -3-cyclobutene-1,2-dione isomer (A) (539 mg), trifluoroacetic acid (3 ml) and dichloromethane (10 ml) were added. The reaction was carried out in the same manner as in Production Example (98d) using the isomer (A) of the title compound as a white solid to give 3
58 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60 (3H, d, J
= 6.7Hz), 3.76 (3H, s), 4.39-4.47 (1H, br), 5.15 (1H, b
rs), 6.94-6.99 (3H, m), 7.11 (2H, d, J = 6.3Hz), 7.21-
7.35 (2H, m), 7.54 (2H, d, J = 7.6Hz), 7.57-7.85 (1H,
m). Melting point: 184-186 ° C. (dec) Optical rotation [α] _D = −373 (c = 1.00, AcOH) 3-t-butoxy-4- {5-[[(R) -1- ( 3,
5-Difluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] -2-fluorophenylamino} -3-cyclobutene-1,2-dione isomer (B) 360 mg, trifluoroacetic acid 3 ml, dichloromethane 10 ml The reaction was carried out in the same manner as in Production Example (98d), using isomer (B) of the title compound as a white solid to give 3
20 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.59 (3H, d, J
= 6.7Hz), 3.78 (3H, s), 4.37 (1H, q, J = 6.6Hz), 5.30 (1
H, s), 6.99 (2H, d, J = 8.8Hz), 7.10-7.33 (5H, m), 7.5
4 (2H, d, J = 8.7 Hz), 7.85 (1H, dd, J = 2.0, 8.0 Hz). Melting point: 180-182 ° C. (dec) Optical rotation [α] _D = + 56.0 (c = 1. 04, DM
SO).

Production Example 101 3- {3-[[1- (3,4-Difluorophenyl) e]
Tylamino]-(4-methylthiophenyl) methyl]
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione trifluoroacetate (exemplified compound number
2-3486) (101a) N- [1- (3,4-difluorophenyl)
Ru) ethyl] -N-[(4-methylthiophenyl)-
(3-Nitrophenyl) methyl] amine (4-methylthiophenyl)-(3-nitrophenyl)
Production Example (1) using 2.73 g of methanone and 1.94 g of 1- (3,4-difluorophenyl) ethylamine hydrochloride.
The reaction was carried out in the same manner as in a) to give 3.77 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.32 and 1.36 (t
otal 3H, each d, J = 6.4and 6.0 Hz), 2.44 and 2.49 (t
otal 3H, each s), 3.60 and 3.66 (total 1H, each q,
J = 6.63 and 6.60Hz), 4.61 and 4.67 (total 1H, each
s), 6.88-6.91 (1H, m), 7.03-7.18 (5H, m), 7.23-7.26
(1H, m), 7.40 and 7.48 (total 1H, each t, J = 8.01 an
d 7.98Hz), 7.58 and 7.64 (total 1H, each d, J = 8.2 an
d 7.7Hz), 8.04 and 8.11 (total 1H, each dd, J = 1.9,
7.9 and 2.0, 8.0Hz), 8.22-8.24 (1H, m).

(101b) 3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methylthiophene
Enyl) methyl] phenylamine N- [1- (3,4-difluorophenyl) ethyl]-
Production example (59b) using 3.74 g of N-[(4-methylthiophenyl)-(3-nitrophenyl) methyl] amine, 4.29 g of nickel chloride hexahydrate, 1.37 g of sodium borohydride and 80 ml of methanol The reaction was carried out in the same manner as in the above) and the mixture was separated and purified to give the isomers (A) and (B) of the title compound as colorless oils each as a colorless oil (7).
96 mg and 400 mg were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 2.43 (3H, s), 3.68 (1H, q, J = 6.5Hz), 4.48 (1
H, s), 6.56-6.59 (2H, m), 6.65 (1H, d, J = 7.5Hz), 6.94
-6.97 (1H, m), 7.05-7.29 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.31 (3H, d, J =
6.7Hz), 2.48 (3H, s), 3.62 (1H, q, J = 6.7Hz), 4.44 (1H,
s), 6.51 (1H, dd, J = 2.1, 8.1Hz), 6.59 (1H, dd, J = 1.
6, 1.8Hz), 6.65 (1H, d, J = 7.4Hz), 6.91-6.95 (1H, m),
7.00-7.13 (3H, m), 7.19-7.34 (4H, m).

(101c) 3-t-butoxy-4- {3
-[[1- (3,4-difluorophenyl) ethylamido
No]-(4-methylthiophenyl) methyl] phenyla
775 mg of isomer (A) of mino} -3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methylthiophenyl) methyl] phenylamine, 3- t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 54
Production Example (94) using 9 mg and 20 ml of methanol.
The reaction was carried out in the same manner as in c) to obtain 1.04 g of the isomer (A) of the title compound as a white foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.64 (9H, s), 2.43 (3H, s), 3.67 (1H, q, J = 6.
6Hz), 4.56 (1H, s), 6.92-6.98 (1H, m), 7.03-7.43 (10
H, m). 387 mg of 3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methylthiophenyl) methyl] phenylamine isomer (B), 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 27
Production Example (94)
The reaction was carried out in the same manner as in c), and the isomer (B) of the title compound was obtained.
Was obtained as a white foam in an amount of 516 mg. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.49 (3H, s), 3.64 (1H, q, J = 6.
6Hz), 4.52 (1H, s), 6.93-7.14 (4H, m), 7.16-7.37 (7H,
m).

(101d) 3- {3-[[1- (3,4
-Difluorophenyl) ethylamino]-(4-methyl
Thiophenyl) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione trifluoro
Loacetate 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methylthiophenyl) methyl] phenylamino} -3-cyclobutene-1,2- The reaction was carried out in the same manner as in Production Example (98d) using 614 mg of the dione isomer (A), 3 ml of trifluoroacetic acid, and 15 ml of dichloromethane to obtain 543 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.61 (3H, d, J
= 6.7Hz), 2.46 (3H, s), 4.34 (1H, q, J = 6.6Hz), 5.10 (1
H, s), 6.99 (1H, d, J = 7.5Hz), 7.17-7.19 (1H, m), 7.2
4-7.62 (9H, m). Melting point: 191-192 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-methylthiophenyl) ) Methyl] phenylamino} -3-cyclobutene-1,2-dione (472 mg), 3 ml of trifluoroacetic acid and 12 ml of dichloromethane were reacted in the same manner as in Production Example (98d) to give the isomer of the title compound. 435 mg of the compound (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60 (3H, d, J
= 6.6Hz), 2.48 (3H, s), 4.26 (1H, q, J = 6.6Hz), 5.12 (1
H, s), 7.06 (1H, d, J = 7.9Hz), 7.21-7.37 (4H, m), 7.4
0-7.62 (5H, m), 7.64 (1H, s). Melting point: 194-196 ° C (dec).

Production Example 102 3- {3-[[1- (3,4-Difluorophenyl) e]
Tylamino]-(2,4-dimethoxyphenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
Ten-1,2-dione (Exemplified Compound No. 2-3439) (102a) N- [1- (3,4-difluorophenyl)
Ru) ethyl] -N-[(2,4-dimethoxyphenyl)
Production Example using 3.32 g of- (3-nitrophenyl) methyl] amine (2,4-dimethoxyphenyl)-(3-nitrophenyl) methanone and 2.24 g of 1- (3,4-difluorophenyl) ethylamine ( 1
The reaction was carried out in the same manner as in a), followed by separation and purification to obtain 940 mg and 740 mg of isomers (A) and (B) of the title compound as yellow oils, respectively. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.62-6.72 (4H, m), 3.83 (3H, s), 4.75 (1H,
s), 6.48-6.54 (2H, m), 6.95-7.23 (4H, m), 7.36 (1H,
t, J = 8.0Hz), 7.59 (1H, d, J = 7.4Hz), 8.00 (1H, d, J =
8.3Hz), 8.24 (1H, s). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 3.61 (1H, q, J = 6.6Hz), 3.71 (3H, s), 3.77 (3
H, s), 5.01 (1H, s), 6.40-6.43 (2H, m), 6.86-6.89 (1
H, m), 7.03-7.14 (3H, m), 7.45 (1H, dd, J = 7.3, 8.1H
z), 7.67 (1H, d, J = 7.3Hz), 8.07 (1H, dd, J = 1.5, 8.1H
z), 8.26 (1H, s).

(102b) 3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(2,4-dimethoxy)
[Ciphenyl) methyl] phenylamine N- [1- (3,4-difluorophenyl) ethyl]-
920 mg of isomer (A) of N-[(2,4-dimethoxyphenyl)-(3-nitrophenyl) methyl] amine;
The reaction was carried out in the same manner as in Production Example (1b) using 1.02 g of nickel chloride hexahydrate, 325 mg of sodium borohydride, and 50 ml of methanol to obtain 543 mg of the isomer (A) of the title compound as a colorless oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (3H, d, J =
6.6Hz), 3.61 (1H, q, J = 6.6Hz), 3.66 (3H, s), 3.81 (3
H, s), 4.72 (1H, s), 6.45 (1H, d, J = 2.3Hz), 6.47-6.5
0 (2H, m), 6.60-6.69 (2H, m), 6.96-7.20 (5H, m). N- [1- (3,4-difluorophenyl) ethyl]-
720 mg of isomer (B) of N-[(2,4-dimethoxyphenyl)-(3-nitrophenyl) methyl] amine,
The reaction was carried out in the same manner as in Production Example (1b) using 799 mg of nickel chloride hexahydrate, 254 mg of sodium borohydride and 80 ml of methanol to obtain 580 mg of the title compound isomer (B) as a colorless oil. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 3.68 (1H, q, J = 6.6Hz), 3.72 (3H, s), 3.75 (3
H, s), 4.82 (1H, s), 6.35-6.40 (2H, m), 6.56 (1H, dd,
J = 2.0, 8.1Hz), 6.68 (1H, t, J = 1.7Hz), 6.71 (1H, d,
J = 7.9Hz), 6.89-6.92 (1H, m) 7.00 (1H, d, J = 8.3,
8.1Hz), 7.03-7.20 (3H, m).

(102c) 3-t-butoxy-4- {3
-[[1- (3,4-difluorophenyl) ethylamido
No]-(2,4-dimethoxyphenyl) methyl] phenyl
522 mg of an isomer (A) of ruamino} -3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethylamino]-(2,4-dimethoxyphenyl) methyl] phenylamine Production Example (9) using 362 mg of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 25 ml of methanol.
The reaction was carried out in the same manner as in 4c), and the isomer (A) of the title compound was obtained.
Was obtained as a white foam, 727 mg. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.63 (1H, q, J = 6.6Hz), 3.67 (3
H, s), 3.82 (3H, s), 4.75 (1H, s), 6.46 (1H, d, J = 2.3
Hz), 6.51 (1H, dd, J = 2.4, 8.5Hz), 6.98-7.37 (8H,
m). 549 mg of 3-[[1- (3,4-difluorophenyl) ethylamino]-(2,4-dimethoxyphenyl) methyl] phenylamine isomer (B), 3-t-butoxy-4-methoxy Production Example (9) using 380 mg of -3-cyclobutene-1,2-dione and 25 ml of methanol.
The reaction was carried out in the same manner as in 4c), and the isomer (B) of the title compound was obtained.
Was obtained as a white foam. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.67 (1H, q, J = 6.7Hz), 3.72 (3
H, s), 3.76 (3H, s), 4.93 (1H, s), 6.37-6.40 (2H, m),
6.89-6.92 (1H, m), 7.00-7.18 (4H, m), 7.21-7.35, 3H.
m).

(102d) 3- {3-[[1- (3,4
-Difluorophenyl) ethylamino]-(2,4-di
Methoxyphenyl) methyl] phenylamino} -4-h
Droxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(2,4-dimethoxyphenyl) methyl] phenylamino The reaction was carried out in the same manner as in Production Example (55b) using 707 mg of ３−-3-cyclobutene-1,2-dione isomer (A), 4 ml of trifluoroacetic acid, and 12 ml of dichloromethane to give the isomer (A) of the title compound. 543 mg were obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.05-1.70 (3H,
br), 3.65 (3H, s), 3.77 (3H, s), 4.22 (1H, br), 4.60
-5.25 (1H, br), 6.30-7.20 (5H, br), 7.30-7.75 (5H, b
r). Melting point: 195-215 ° C (dec) 3-t-butoxy-4- {3-[[1- (3,4-difluorophenyl) ethylamino]-(2,4-dimethoxyphenyl) methyl] phenyl The reaction was carried out in the same manner as in Production Example (55b) using 659 mg of the isomer (B) of amino｝ -3-cyclobutene-1,2-dione, 4 ml of trifluoroacetic acid, and 12 ml of dichloromethane to give the isomer (B) of the title compound. Was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.10-1.75 (3H,
br), 3.45-4.45 (7H, br), 4.60-5.30 (1H, br), 6.35-
7.70 (10H, m). Melting point: 200-220 ° C (dec). Production Example 103 4- {3-[(4-chlorophenyl)-((R) -1-]
(3-Fluorophenyl) ethylamino) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplified Compound No. 2-19) (103a) N-[(4-chlorophenyl)-(3-ni
Trophenyl) methyl] -N-[(R) -1- (3-f
Fluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) ketone 880 mg and (R) -1- (3-fluorophenyl)
Using 886 mg of ethylamine hydrochloride, 2.58 ml of triethylamine, 0.44 ml of titanium tetrachloride, 890 mg of sodium borohydride cyanide and 0.29 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil. As a result, 1.25 g was obtained. NMR spectrum (CDCl ₃ ) δppm: 1.38 and 1.39 (t
otal 3H, each d, J = 6.6and 6.8Hz), 3.61 and 3.65 (to
tal 1H, each q, J = 6.9 and 6.7Hz), 4.66 and 4.69 (tot
al 1H, each s), 6.91-7.00 (3H, m), 7.18-7.35 (5H, m),
7.41 and 7.50 (total 1H, each t, J = 8.0 and 7.9Hz),
7.58 and 7.64 (total 1H, each d, J = 8.0 and 7.6Hz),
8.04-8.14 (1H, m), 8.20-8.23 (1H, m).

(103b) 3-[(4-Chlorophenyl)
)-((R) -1- (3-fluorophenyl) ethyl
Amino) methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3-fluorophenyl) ethyl] amine 1.23 g and nickel chloride 6 water 1.52 g of the sum and 509 mg of sodium borohydride
Was used in the same manner as in Production Example (1b) to give 1.12 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.62 and 3.70 (total 1H, each q, J = 6.7 and
6.6Hz), 4.47 and 4.48 (total 1H, each s), 6.50-6.66
(3H, m), 6.91-7.06 (4H, m), 7.09-7.32 (5H, m).

(103c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-((R) -1- (3-f
Fluorophenyl) ethylamino) methyl] phenylami
No-3--3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3-
Fluorophenyl) ethylamino) methyl] phenylamine 1.0 g, 4-t-butoxy-3-methoxy-3-
The reaction was carried out and purified using 779 mg of cyclobutene-1,2-dione in the same manner as in Production Example (66c). 732 mg were obtained as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.68 (1H, q, J = 6.6Hz), 4.58 (1
H, s), 6.93-7.06 (4H, m), 7.10-7.46 (8H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.63 (1H, q, J = 6.7Hz), 4.57 (1
H, s), 6.92-7.00 (4H, m), 7.14-7.39 (8H, m).

(103d) 4- {3-[(4-chlorofu
Enyl)-((R) -1- (3-fluorophenyl) e
Tylamino) methyl] phenylamino} -3-hydroxy
Ci-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3-fluorophenyl) ethylamino) methyl] phenyl The reaction and purification were carried out in the same manner as in Production Example (63b) using the isomer (A) of amino） -3-cyclobutene-1,2-dione (410 mg) to obtain 166 mg of the title compound isomer (A) as a white solid. Was. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 4.30 (1H, br), 5.18 (1H, s), 7.17-7.36 (5H,
m), 7.43-7.48 (4H, m), 7.57 (1H, s), 7.64 (2H, d, J = 8.
Melting point: 191 to 196 ° C. Optical rotation [α] D = + 154.0 ° (c = 0.50, A
cOH) 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3-fluorophenyl) ethylamino) methyl] phenylamino} -3-cyclobutene-1,2- The reaction and purification were carried out in the same manner as in Production Example (63b) using 470 mg of the dione isomer (B) to obtain 362 mg of the title compound isomer (B) as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, d, J
= 6.7Hz), 4.22 (1H, br), 5.19 (1H, s), 7.20 (1H, d, J =
7.7Hz), 7.24-7.29 (1H, m), 7.33-7.54 (8H, m), 7.66 (2
H, d, J = 8.5 Hz). Melting point: 169 ° C .- (dec) Optical rotation [α] D = −0.7 ° (c = 0.50, AcO)
H).

Production Example 104 4- {3-[(4-chlorophenyl)-((R) -1-)
(3,5-difluorophenyl) ethylamino) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-5
4) (104a) N-[(4-chlorophenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (3,5
-Difluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) ketone (1.0 g) and (R) -1- (3,5-difluorophenyl) ethylamine hydrochloride 1.11 g, triethylamine 2.93 ml , Titanium tetrachloride 0.50 ml, sodium cyanoborohydride 1.01 g, acetic acid 0.33 ml
Was used in the same manner as in Production Example (1a) to give 1.45 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.37 (t
otal 3H, each d, J = 6.7and 6.6Hz), 3.60-3.66 (1H,
m), 4.66 and 4.71 (total 1H, each s), 6.67-6.81 (3H,
m), 7.19-7.28 (3H, m), 7.34 and 7.36 (total 1H, eac
h, s), 7.43 and 7.51 (total 1H, each t, J = 7.9 and
7.9Hz), 7.59 and 7.63 (total 1H, each d, J = 7.6 and
7.9Hz), 8.05-8.14 (1H, m), 8.20-8.23 (1H, m).

(104b) 3-[(4-Chlorophenyi)
)-((R) -1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] amine (1.41 g) and chloride 1.66 g of nickel hexahydrate and sodium borohydride 55
The reaction was carried out in the same manner as in Production Example (1b) using 8 mg to give 1.29 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.60 and 3.69 (total 1H, each q, J = 6.6 and
6.6Hz), 4.47 and 4.48 (total 1H, each s), 6.51-6.84
(6H, m), 7.05 and 7.12 (total 1H, each t, J = 7.8 and
7.7Hz), 7.20-7.31 (4H, m).

(104c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-((R) -1- (3,5
-Difluorophenyl) ethylamino) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3,
5-Difluorophenyl) ethylamino) methyl] phenylamine (1.17 g) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione (867 mg) were reacted in the same manner as in Production Example (66c). Purification afforded isomer (A) of the title compound as a pale yellow oil in 241 m
g, 365 mg of isomer (B) as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.58 (1
H, s), 6.67-6.72 (1H, m), 6.79 (2H, dd, J = 2.1, 8.5H
z), 7.03 (1H, d, J = 6.9 Hz), 7.14-7.40 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.64 (9H, s), 3.61 (1H, q, J = 6.7Hz), 4.57 (1
H, s), 6.66-6.72 (1H, m), 6.76-6.81 (2H, m), 7.00-7.
02 (1H, m), 7.14-7.35 (7H, m).

(104d) 4- {3-[(4-chlorofu
Enyl)-((R) -1- (3,5-difluorophenyl)
Ru) ethylamino) methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclobutene-1,2-dione (230 mg) is reacted and purified in the same manner as in Production Example (63b) using 230 mg of the isomer (A) of the title compound. Was obtained as a light brown solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.32 (1H, br), 5.25 (1H, s), 7.17-7.21 (3H,
m), 7.26-7.37 (2H, m), 7.43-7.47 (3H, m), 7.58 (1H,
s), 7.66 (2H, d, J = 8.6 Hz). Melting point: 184-187 ° C Optical rotation [α] D = -130.7 ° (c = 0.56, A
cOH) 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclobutene-1,2-dione Isomer (B) was reacted and purified in the same manner as in Production Example (63b) using 351 mg of isomer (B). Was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 4.27 (1H, br), 5.26 (1H, s), 7.22 (2H, dd, J =
1.7, 8.0Hz), 7.28-7.42 (4H, m), 7.51-7.55 (3H, m),
7.68 (2H, d, J = 8.4 Hz). Melting point: 182 to 189 ° C. Optical rotation [α] D = + 11.1 ° (c = 0.52, Ac
OH).

Production Example 105 4- {3-[(4-Chlorophenyl)-((R) -1-]
(3,4-difluorophenyl) ethylamino) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-4)
0) (105a) N-[(4-chlorophenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (3,4
-Difluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) ketone (1.0 g) and (R) -1- (3,4-difluorophenyl) ethylamine hydrochloride 1.11 g, triethylamine 2.93 ml , Titanium tetrachloride 0.50 ml, sodium cyanoborohydride 1.01 g, acetic acid 0.33 ml
And the reaction was carried out in the same manner as in Production Example (1a) to give 1.42 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.37 (t
otal 3H, each d, J = 6.8and 6.8Hz), 3.59 and 3.63 (to
tal 1H, each q, J = 6.6 and 6.7Hz), 4.63 and 4.68 (tot
al 1H, each s), 6.87-6.95 (1H, m), 7.03-7.22 (4H,
m), 7.24-7.27 (1H, m), 7.33 and 7.35 (total 1H, eac
h, s), 7.42 and 7.51 (total 1H, each t, J = 8.0 and 8.
0Hz), 7.56 and 7.62 (total 1H, each d, J = 8.0 and 7.
9Hz), 8.05-8.14 (1H, m), 8.20-8.22 (1H, m).

(105b) 3-[(4-Chlorophenyl)
)-((R) -1- (3,4-difluorophenyl)
1.30 g of ethylamino) methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3,4-difluorophenyl) ethyl] amine and chloride 1.53 g of nickel hexahydrate and sodium borohydride 51
The reaction was carried out in the same manner as in Production Example (1b) using 4 mg to obtain 1.20 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.7Hz), 3.59 and 3.67 (total 1H, each q, J = 6.6 and
6.7Hz), 4.44 and 4.45 (total 1H, each s), 6.51-6.67
(3H, m), 6.89-6.97 (1H, m), 7.02-7.15 (3H, m), 7.19-
7.32 (4H, m).

(105c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-((R) -1- (3,4
-Difluorophenyl) ethylamino) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3,
4-Difluorophenyl) ethylamino) methyl] phenylamine (1.15 g) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione (852 mg) were reacted in the same manner as in Production Example (66c). Then, 308 mg of isomer (A) of the title compound was obtained as a pale yellow oil, and 800 mg of isomer (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.65 (1H, q, J = 6.6Hz), 4.55 (1
H, s), 6.93-6.96 (1H, m), 7.02 (1H, d, J = 6.8Hz), 7.07
. -7.40 (9H, m) isomer (B) NMR spectrum _{(CDCl 3) δppm: 1.34 (} 3H, d, J =
6.6Hz), 1.64 (9H, s), 3.61 (1H, q, J = 6.6Hz), 4.54 (1
H, s), 6.92-7.00 (2H, m), 7.06-7.35 (9H, m).

(105d) 4- {3-[(4-chlorofu
Enyl)-((R) -1- (3,4-difluorophenyl)
Ru) ethylamino) methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3,4-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclobutene-1,2-dione isomer (A) 280 mg, reacted and purified in the same manner as in Production Example (63b) to give the title compound isomer (A) Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 4.31 (1H, br), 5.19 (1H, s), 7.18-7.25 (2H,
m), 7.34-7.59 (7H, m), 7.65 (2H, d, J = 8.6Hz).
190-196 ° C. Optical rotation [α] D = −58.6 ° (c = 0.575, A
cOH) 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (3,4-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclobutene-1,2-dione Isomer (B) was reacted and purified in the same manner as in Production Example (63b) using 340 mg of isomer (B) of the title compound. Was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.8Hz), 4.24 (1H, br), 5.20 (1H, s), 7.20-7.22 (1H,
m), 7.30-7.63 (8H, m), 7.68 (2H, d, J = 8.5 Hz). Melting point: 190 ° C. (dec) Optical rotation [α] D = −4.6 ° (c = 0.49, AcO
H).

Production Example 106 4- {3-[[1- (3,5-Dinitrophenyl) ethyl ]
Ruamino]-(4-fluorophenyl) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobutene-1,
2-dione hydrochloride (Exemplified Compound No. 2-3506) (106a) N- {3-[[1- (3,5-dinitroph)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] phenyl} acetamide N- [3- (4-fluorofubenzoyl) phenyl} acetamide 830 mg, 1- (3,5-dinitrophenyl) ethylamine hydrochloride 1.19 g, triethylamine 2.7 ml and titanium tetrachloride 0.4 ml Was used in the same manner as in Production Example (1a) to give an imine compound. Using the obtained imine compound, 806 mg of sodium cyanoborohydride and 0.3 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 1.16 g of the title compound as a pale brown foam. NMR spectrum (CDCl ₃ ) δppm: 1.46 and 1.47 (t
otal 3H, each d, J = 6.7Hz), 2.14 and 2.18 (total 3H,
each s), 3.95-4.01 (1H, m), 4.59 and 4.68 (total 1
H, each s), 6.90-7.35 (7H, m), 7.51 and 7.56 (total
1H, each s), 8.44and 8.48 (total 2H, each d, J = 2.1H
z), 8.84 and 8.91 (total 1H, each t, J = 2.1Hz).

(106b) 3-[[1- (3,5-dini)
Trophenyl) ethylamino]-(4-fluorophenyl
L) Methyl] phenylamine N- {3-[[1- (3,5-dinitrophenyl) ethylamino]-(4-fluorophenyl) methyl] phenyl} acetamide (1.15 g) was dissolved in methanol (16 ml), and concentrated hydrochloric acid was added. 4 ml was added and the mixture was stirred at 70 ° C. for 3 hours. After adding a saturated aqueous sodium hydrogen carbonate solution and concentrating under reduced pressure, the residue was extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain 442 mg of the title compound isomer (A) as red crystals and the title compound isomer (B). 235 mg were obtained as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.45 (3H, d, J =
6.7Hz), 3.96 (1H q, J = 6.7Hz), 4.57 (1H, s), 6.43 (1H,
dd, J = 2.4, 8.0Hz), 6.52 (1H, t, J = 2.0Hz), 6.58 (1H,
d, J = 7.6Hz), 6.97 (1H, t, J = 7.8Hz), 7.04 (2H, t, J =
8.6Hz), 7.30 (2H, dd, J = 5.4, 8.7Hz), 8.45 (2H, d, J =
2.1Hz), 8.87 (1H, t, J = 2.1Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.44 (3H, d, J =
6.7Hz), 3.99 (1H, q, J = 6.6Hz), 4.48 (1H, s), 6.56 (1
H, t, J = 2.0Hz), 6.60-6.65 (2H, m), 6.91 (2H, t, J = 8.7
Hz), 7.15 (1H, t, J = 7.7Hz), 7.24 (2H, dd, J = 5.6, 8.5
Hz), 8.50 (2H, d, J = 2.1Hz), 8.90 (1H, t, J = 2.1Hz).

(106c) 3-t-butoxy-4- {3
-[[1- (3,5-dinitrophenyl) ethylamido
No]-(4-fluorophenyl) methyl] phenylami
414 mg of isomer (A) of 4-{- 3-cyclobutene-1,2-dione 3-[[1- (3,5-dinitrophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 221 m
g, and reacted in the same manner as in Production Example (1c) to give 394 mg of the title compound isomer (A) as a yellow foam.
Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.48 (3H, d, J =
6.7Hz), 1.66 (9H, s) .4.01 (1H, q, J = 6.6Hz), 4.67 (1H
H, s), 6.90 (1H, d, J = 7.2Hz), 7.04-7.10 (3H, m), 7.14
(1H, t, J = 7.8Hz), 7.33 (2H, dd, J = 5.4, 8.6Hz), 7.48
-7.60 (1H, br), 8.46 (2H, d, J = 2.1Hz), 8.84 (1H, t, J
= 2.0 Hz). Isomer of 3-[[1- (3,5-dinitrophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamine (B) 230 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 124m
g, and reacted in the same manner as in Production Example (1c) to give 284 mg of the title compound isomer (B) as a yellow foamy solid
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.49 (3H, d, J =
6.6Hz), 1.65 (9H, s), 3.99 (1H, q, J = 6.6Hz), 4.61 (1
H, s), 6.93 (2H, t, J = 8.7Hz), 7.00 (1H, d, J = 7.8Hz),
7.21-7.26 (3H, m), 7.35 (1H, t, J = 7.7Hz), 7.50-7.60
(1H, br), 8.49 (2H, d, J = 2.0Hz), 8.91 (1H, t, J = 2.0H
z).

(106d) 4- {3-[[1- (3,5
-Dinitrophenyl) ethylamino]-(4-fluoro
Phenyl) methyl] phenylamino} -3-hydroxy
-3-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dinitrophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (63b) using 378 mg of 1,2-dione isomer (A) and 2 ml of trifluoroacetic acid to obtain 338 mg of isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J
= 6.6Hz), 4.66 (1H, q, J = 6.6Hz), 5.36 (1H, s), 7.26-
7.31 (5H, m), 7.47 (1H, s), 7.67 (2H, dd, J = 5.3,8.6H
z), 8.73 (2H, d, J = 2.0 Hz), 8.80 (1H, t, J = 2.0 Hz). Melting point: 188 ° C. (dec) 3-t-butoxy-4- {3-[[1- ( 3,5-Dinitrophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -3-cyclobutene-
Using 277 mg of 1,2-dione isomer (B) and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 220 mg of isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.76 (3H, d, J
= 6.6Hz), 4.65 (1H, br), 5.21 (1H, s), 7.18-7.26 (1H,
m), 7.21 (2H, t, J = 8.8Hz), 7.36 (1H, t, J = 8.9Hz), 7.
44 (1H, d, J = 8.3Hz), 7.50 (1H, s), 7.66 (2H, dd, J = 5.
5, 8.2Hz), 8.69 (2H, d, J = 1.9Hz), 8.83 (1H, t, J = 1.9
Melting point: 190 ° C (dec) Production Example 107 4- {3-[(4-methoxyphenyl)-[1- (3,
4,5-trifluorophenyl) ethylamino] methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-3
504) (107a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N- [1- (3,4,5-
Trifluorophenyl) ethyl] amine 4-methoxy-3'-nitrobenzophenone 2.19
g, 1- (3,4,5-trifluorophenyl) ethylamine hydrochloride 3.25 g, triethylamine 7.1 ml
The reaction was carried out in the same manner as in Production Example (1a) using 1.0 ml of titanium tetrachloride to obtain an imine compound. 2.14 g of the obtained imine compound and sodium cyanoborohydride,
The reaction was carried out in the same manner as in Production Example (1a) using 0.7 ml of acetic acid to obtain 3.35 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.33 and 1.35 (t
otal 3H, each d, J = 6.5Hz), 3.58 and 3.63 (total 1H,
each q, J = 6.6Hz), 3.77 and 3.82 (total 3H, each
s), 4.59 and 4.67 (total 1H, each s), 6.81-6.95 (2H,
m), 6.82 and 6.90 (total 2H, each d, J = 8.8Hz), 7.1
4 and 7.15 (total 2H, each d, J = 8.7Hz), 7.41 and 7.
50 (total 1H, each t, J = 7.9Hz), 7.59 and 7.63 (total
1H, each dd, J = 1.8, 7.8Hz), 8.05 and 8.11 (total 1
H, each dd, J = 1.8, 7.7Hz), 8.23 and 8.24 (total 1H,
each t, J = 1.8Hz).

(107b) 3-[(4-methoxyphenyi)
)-[1- (3,4,5-trifluorophenyl) e
3.34 g of [ tylamino] methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- [1- (3,4,5-trifluorophenyl) ethyl] amine, nickel chloride 6
3.81 g of hydrate, 1.22 g of sodium borohydride
Was used in the same manner as in Production Example (1b) to give 2.83 g of the title compound as a pale yellow oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (3H, d, J =
6.6Hz), 3.60 and 3.64 (total 1H, each q, J = 6.6Hz),
3.76 and 3.80 (total 3H, each s), 4.43 and 4.44 (tot
al 1H, each s), 6.50-6.67 (3H, m), 6.79 and 6.86 (to
tal 2H, each d, J = 8.8Hz), 6.83-6.95 (2H, m), 7.04 a
nd 7.11 (total 1H, each t, J = 7.6Hz), 7.18 and 7.19
(total 2H, each d, J = 8.7Hz).

(107c) 3-t-butoxy-4- {3
-[(4-methoxyphenyl)-[1- (3,4,5-
Trifluorophenyl) ethylamino] methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-[1- (3,4,5
-Trifluorophenyl) ethylamino] methyl] phenylamine (2.81 g) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione (1.61 g) were reacted in the same manner as in Production Example (66c). To give the isomer (A) of the title compound as a white foamy solid.
13 mg and 403 mg of the title compound isomer (B) were obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.5Hz), 3.76 (3
H, s), 4.54 (1H, s), 6.81 (2H, d, J = 8.6Hz), 6.90 (2H,
dd, J = 6.7,8.3Hz), 7.04 (1H, d, J = 7.0Hz), 7.18 (2H,
d, J = 8.6 Hz), 7.23-7.42 (3H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.65 (9H, s), 3.63 (1H, q, J = 6.7Hz), 3.82 (3
H, s), 4.52 (1H, s), 6.88-6.96 (2H, m), 6.90 (2H, d, J
= 8.6Hz), 7.02-7.08 (1H, br), 7.20 (2H, d, J = 8.7Hz),
7.17-7.42 (3H, m).

(107d) 4- {3-[(4-methoxy)
Phenyl)-[1- (3,4,5-trifluorophenyl)
Ru) ethylamino] methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)-[1- (3,4,5-trifluorophenyl) ethylamino] methyl Using 828 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound. Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.7Hz), 3.74 (3H, s), 4.31 (1H, q, J = 6.2Hz), 5.12 (1
H, s), 6.94 (2H, d, J = 8.9Hz), 7.15 (1H, d, J = 7.5Hz),
7.32-7.40 (3H, m), 7.44 (1H, d, J = 8.0Hz), 7.52 (2H,
d, J = 8.8 Hz), 7.56 (1H, s). Melting point: 185 ° C. (dec) 3-t-butoxy-4- {3-[(4-methoxyphenyl)-[1- (3,4,5) The reaction was carried out in the same manner as in Production Example (63b) using 392 mg of the isomer (B) of -trifluorophenyl) ethylamino] methyl] phenylamino} -3-cyclobutene-1,2-dione and 1.5 ml of trifluoroacetic acid. This gave 265 mg of isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 3.77 (3H, s), 4.24 (1H, q, J = 6.7Hz), 5.15 (1
H, s), 7.00 (2H, d, J = 8.9Hz), 7.33 (1H, d, J = 7.0Hz),
7.36-7.44 (4H, m), 7.52 (1H, s), 7.55 (2H, d, J = 8.7H
z). Melting point: 188 ° C (dec).

Production Example 108 4- {3-[(4-chlorophenyl)-[1- (3,3-
4,5-trifluorophenyl) ethylamino] methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione hydrochloride (Exemplary Compound No. 2-3
503) (108a) N - [(4-chlorophenyl) - (3-D
Trophenyl) methyl] -N- [1- (3,4,5-to
Fluorophenyl) ethyl] amine 4-chloro-3'-nitrobenzophenone 1.82 g,
The reaction was carried out in the same manner as in Production Example (1a) using 2.65 g of 1- (3,4,5-trifluorophenyl) ethylamine hydrochloride, 5.7 ml of triethylamine and 0.9 ml of titanium tetrachloride to obtain an imine compound. Was. The obtained imine compound was reacted with 1.74 g of sodium cyanoborohydride and 0.7 ml of acetic acid in the same manner as in Production Example (1a) to obtain 2.74 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.35 and 1.36 (t
otal 3H, each d, J = 6.6Hz), 3.56-3.63 (1H, m), 4.63
and 4.69 (total 1H, each s), 6.82-6.91 (2H, m), 7.20
(2H, d, J = 7.4Hz), 7.27 and 7.35 (total 2H, each d,
J = 8.4Hz), 7.43 and 7.52 (total 1H, each t, J = 7.9H
z), 7.57 and 7.61 (total 1H, each d, J = 7.7Hz), 8.07
and 8.14 (total 1H, each d, J = 8.1Hz), 8.21 (1H,
s).

(108b) 3-[(4-Chlorophenyi)
)-[1- (3,4,5-trifluorophenyl) e
2.71 g of tylamino] methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N- [1- (3,4,5-trifluorophenyl) ethyl] amine, nickel chloride 6
Hydrate 3.06 g, sodium borohydride 973 mg
The reaction was carried out in the same manner as in Production Example (59b), and separation and purification were carried out to obtain 946 mg of the title compound isomer (A) as a colorless oily substance and 691 mg of the title compound isomer (B) as a white solid. . Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 4.43 (1H, s), 6.58 (1
H, t, J = 1.5Hz), 6.59-6.64 (2H, m), 6.89-6.95 (2H,
m), 7.12 (1H, t, J = 7.7 Hz), 7.22 (4H, s). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.59 (1H, q, J = 6.7Hz), 4.45 (1H, s), 6.52-6.
56 (2H, m), 6.62 (1H, d, J = 7.9Hz), 6.85-6.92 (2H, m),
7.05 (1H, t, J = 7.8Hz), 7.23 (2H, d, J = 8.4Hz), 7.30
(2H, d, J = 8.4Hz).

(108c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-[1- (3,4,5-to
Trifluorophenyl) ethylamino] methyl] phenyl
Amino} -3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-[1- (3,4,5-
923 mg of isomer (A) of trifluorophenyl) ethylamino] methyl] phenylamine, 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 5
Using 21 mg, the reaction was carried out in the same manner as in Production Example (1c).
The isomer (A) of the title compound was converted to a 834 as a white foamy solid.
mg. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.5Hz), 4.55 (1
H, s), 6.89-6.94 (2H, m), 7.00 (1H, d, J = 7.3Hz), 7.20
-7.44 (7H, m). 3-[(4-chlorophenyl)-[1- (3,4,5-
595 mg of isomer (B) of trifluorophenyl) ethylamino] methyl] phenylamine, 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 3
Using 36 mg, a reaction was carried out in the same manner as in Production Example (1c).
Isomer (B) of the title compound as a white foamy solid 583
mg. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.59 (1H, q, J = 6.6Hz), 4.55 (1
H, s), 6.87-6.92 (2H, m), 6.98 (1H, d, J = 6.9Hz), 7.16
-7.42 (3H, m), 7.24 (2H, d, J = 8.6Hz), 7.33 (2H, d, J =
8.5Hz).

(108d) 4- {3-[(4-chlorofu
Enyl)-[1- (3,4,5-trifluorophenyl)
Ru) ethylamino] methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-[1- (3,4,5-trifluorophenyl) ethylamino] methyl] Using 774 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer of the title compound (A ) Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.61 (3H, d, J
= 6.6Hz), 4.31 (1H, q, J = 5.4Hz), 5.19 (1H, s), 7.11 (1
H, d, J = 7.6Hz), 7.30-7.39 (3H, m), 7.43-7.47 (1H,
m), 7.46 (2H, d, J = 8.4Hz), 7.59 (1H, s), 7.62 (2H, d,
J = 8.8 Hz). Melting point: 187 ° C. (dec) 3-t-butoxy-4- {3-[(4-chlorophenyl)-[1- (3,4,5-trifluorophenyl) ethylamino] methyl] Using 510 mg of the isomer (B) of phenylamino} -3-cyclobutene-1,2-dione and 1.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer of the title compound (B ) Was obtained as a white solid, 354 mg. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.26 (1H, q, J = 6.6Hz), 5.25 (1H, s), 7.33-
7.53 (6H, m), 7.52 (2H, d, J = 8.5Hz), 7.69 (2H, d, J =
8.6 Hz). Melting point: 190 ° C (dec).

Production Example 109 3-Hydroxy-4- {3-[(4-methoxyphenyl)
)-(1-methyl-1-phenyl-ethylamino) methyl
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione (Exemplified Compound No. 2-3136) (109a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N- (1-methyl-1-f
Dissolve 2.57 g of ( enylethyl) amine (4-methoxyphenyl)-(3-nitrophenyl) methanone, 1.35 g of cumylamine and 1.35 g of triethylamine in 50 ml of dichloromethane and, under ice-cooling, a solution of 1.65 ml of titanium tetrachloride in dichloromethane. 30 ml was added dropwise. After stirring at room temperature for 2 hours, the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was diluted with 150 ml of ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with a saturated sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained brown oil was washed with ethanol 100m
l, 2.51 g of sodium cyanoborohydride and 2.58 ml of acetic acid were reacted in the same manner as in Production Example (1a), separated and purified to give the title compound as a yellow oil.
43 g were obtained. NMR spectrum (CDCl ₃ ) δppm: 1.34 (3H, s), 1.
40 (3H, s), 3.75 (3H, s), 4.64 (1H, s), 6.77 (2H, d,
J = 8.8Hz), 7.03 (2H, d, J = 8.8Hz), 7.21-7.40 (6H, m),
7.66 (1H, d, J = 7.3Hz), 7.99 (1H, dd, J = 1.5, 8.1Hz),
8.27 (1H, s).

(109b) 3-[(4-methoxyphenyi)
)-(1-methyl-1-phenylethylamino) methyl
L] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N- (1-methyl-1-phenylethyl) amine 1.39 g, nickel chloride hexahydrate 1.76
g, sodium borohydride 559 mg, methanol 1
The reaction was carried out in the same manner as in Production Example (94b) using 00 ml, and 1.21 g of the title compound was obtained as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.34 (3H, s), 1.
35 (3H, s), 3.80 (3H, s), 4.46 (1H, s), 6.65 (1H, d,
J = 2.2, 7.3Hz), 6.60 (1H, s), 6.65 (1H, d, J = 8.1Hz),
6.76 (2H, d, J = 8.8Hz), 7.00 (1H, dd, J = 7.3, 8.1Hz),
7.17 (2H, d, J = 8.8Hz), 7.21-7.26 (1H, m), 7.33 (1H, d
d, J = 7.3, 8.1 Hz), 7.41 (2H, d, J = 7.4 Hz).

(109c) 3-t-butoxy-4- {3
-[(4-methoxyphenyl)-(1-methyl-1-f
Enylethylamino) methyl] phenylamino} -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(1-methyl-1-
Phenylethylamino) methyl] phenylamine 1.1
9 g, 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione 886 mg, methanol 40 ml
Was used and the reaction was carried out in the same manner as in (94c), to obtain 1.42 g of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, s), 1.
37 (3H, s), 1.63 (9H, s), 3.75 (3H, s), 4.56 (1H, s),
6.77 (2H, ddd, J = 2.2, 2.9, 8.8Hz), 7.07-7.12 (3H,
m), 7.20-7.34 (6H, m), 7.40 (2H, d, J = 7.3Hz).

(109d) 3-Hydroxy-4- {3-
[(4-methoxyphenyl)-(1-methyl-1-fe
Nylethylamino) methyl] phenylamino} -3-ci
Clobutene-1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)-(1-methyl-1-phenylethylamino) methyl] phenylamino} -3-cyclobutene-1,2 The reaction was carried out in the same manner as in Production Example (55b) using 1.40 g of -dione, 10 ml of trifluoroacetic acid, and 35 ml of dichloromethane to obtain 1.24 g of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δppm: 1.61 (3H, s),
1.67 (3H, s), 3.76 (3H, s), 4.78 (1H, s), 6.81 (1H, d,
J = 8.1Hz), 6.86 (2H, d, J = 8.8Hz), 7.15 (1H, t, J = 8.1H
z), 7.32-7.46 (6H, m), 7.49-7.54 (2H, m), 7.65-7.68
(1H, m). Melting point: 197 ° C (dec).

Production Example 110 3- (3-{(4-chlorophenyl)-[1- (2,2-
3,4-trifluorophenyl) -ethylamino] -me
Tyl {-phenylamino) -4-hydroxy-3-cycl
Lobutene-1,2-dione hydrochloride (Exemplary Compound No. 2
-3,507) (110a) N - [(4-chlorophenyl) - (3-D
Trophenyl) methyl] -N- [1- (2,3,4-to
Trifluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) methanone 2.62 g, (1- (2,3,4-trifluorophenyl) ethylamine hydrochloride 2.12 g, triethylamine 6.97 ml) The reaction was carried out in the same manner as in Production Example (1a) using 1.6 ml of titanium tetrachloride to obtain an imine compound, using the obtained imine compound, 2.51 g of sodium cyanoborohydride, and 2.6 ml of acetic acid. Production example (1
The reaction was carried out in the same manner as in a) to obtain 4.06 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.43 and 1.44 (t
otal 3H, each d, J = 6.6Hz), 3.90 and 3.94 (total 1H,
each q, J = 6.6Hz), 4.67 and 4.69 (total 1H, each
s), 6.91-7.05 (2H, m), 7.19-7.26 (3H, m), 7.32 and
7.34 (total 1H, eacht, J = 2.2Hz), 7.41 and 7.49 (tota
l 1H, each d, J = 8.1Hz), 8.06 and 8.21 (total 1H, ea
ch dd, J = 2.2, 8.1Hz), 8.21-8.28 (1H, m).

(110b) 3-{(4-chlorophenyi)
)-[1- (2,3,4-trifluorophenyl)-
3.96 g of ethylamino] -methyl} -phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N- [1- (2,3,4-trifluorophenyl) ethyl] amine; Nickel chloride 6
4.47 g of hydrate, 1.42 g of sodium borohydride
The reaction was carried out in the same manner as in Production Example (59b), followed by separation and purification. 1.05 g of isomer (A) of the title compound as a pale yellow oily substance and isomer (B) of the title compound as a pale yellow oily substance 720 mg was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.6Hz), 3.99 (1H, q, J = 6.6Hz), 4.47 (1H, s), 6.56-6.
60 (2H, m), 6.65 (1H, d, J = 8.1Hz), 6.89-6.95 (1H, m),
7.01-7.29 (6H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.6Hz), 3.90 (1H, q, J = 6.6Hz), 4.46 (1H, s), 6.51 (1
H, dd, J = 1.5, 7.3Hz), 6.57 (1H, s), 6.63 (1H, d, J =
7.3Hz), 6.90-7.18 (3H, m), 7.20-7.34 (4H, m).

(110c) 3-t-butoxy-4- (3
-{(4-chlorophenyl)-[1- (2,3,4-to
Trifluorophenyl) ethylamino] methyldiphenyl
Amino) -3-cyclobutene-1,2-dione 3-{(4-chlorophenyl)-[1- (2,3,4-
1.01 g of isomer of (trifluorophenyl) ethylamino] methyl} phenylamine (A), 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 6
Using 68 mg, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (A) of the title compound as a white foamy solid.
60 mg were obtained. Isomer (A) NMR spectrum _{(CDCl 3) δppm: 1.42 (} 3H, d, J =
6.6Hz), 1.63 (9H, s), 3.97 (1H, q, J = 6.6Hz), 4.58 (1
H, s), 6.91-7.09 (3H, m), 7.12-7.47 (7H, m). 3-{(4-chlorophenyl)-[1- (2,3,4-
(Trifluorophenyl) ethylamino] methyl} phenylamine isomer (B) 700 mg, 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 4
Using 62 mg, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (B) of the title compound as a white foamy solid.
00 mg was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.90-3.98 (1H, m), 4.57 (1H,
s), 6.90-7.08 (3H, m), 7.20-7.42 (7H, m).

(110d) 3- (3-{(4-chlorofu
Enyl)-[1- (2,3,4-trifluorophenyl)
Ru) ethylamino] methyl @ phenylamino) -4-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- (3-{(4-chlorophenyl)-[1- (2,3,4-trifluorophenyl) ethylamino] methyl} Using 520 mg of the isomer (A) of (phenylamino) -3-cyclobutene-1,2-dione and 6 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound. 225 mg were obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J
= 6.6Hz), 4.49 (1H, q, J = 6.6Hz), 5.31 (1H, s), 7.24 (1
H, d, J = 7.3Hz), 7.34 (1H, t, J = 8.1Hz), 7.41 (1H, d,
J = 8.1Hz), 7.43-7.52 (3H, m), 7.56-7.59 (1H, m), 7.60
-7.69 (3H, m). Melting point: 176 ° C (dec) 3-t-butoxy-4- (3-{(4-chlorophenyl)-[1- (2,3,4-trifluorophenyl) ethylamino] Using 460 mg of isomer (B) of methyl {phenylamino) -3-cyclobutene-1,2-dione and 5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give an isomer of the title compound (B ) Was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62-1.75 (3H,
br), 4.41 (1H, q, J = 6.6Hz), 5.36 (1H, s), 7.25-7.74
(10H, m). Melting point: 191 ° C (dec).

Production Example 111 3- {3-[[(R) -1- (4-fluorophenyl)]
Ethylamino]-(4-methoxyphenyl) methyl] F
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplified Compound No. 2-28) (111a) N-[(R) -1- (4-fluorophenyl)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl ) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 5.14 g, (R) -1- (4-fluorophenyl) ethylamine hydrochloride 4.24 g, triethylamine 13.9 ml The reaction was carried out in the same manner as in Production Example (1a) using 3.3 ml of titanium chloride to obtain an imine compound. Production Example (1a) using the obtained imine compound, 5.03 g of sodium cyanoborohydride, and 5.15 ml of acetic acid.
The reaction was conducted in the same manner as in, and 7.60 g of the title compound was obtained as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.39 (t
otal 3H, each d, J = 6.6Hz), 3.56-3.72 (1H, m), 3.76
and 3.81 (total 3H, each s), 4.60 and 4.64 (total 1
H, each s), 6.81 and 6.89 (total 2H, each d, J = 8.7H
z), 7.00 and 7.04 (total 2H, each d, J = 8.7Hz), 7.12
-7.25 (4H, m), 7.38 and 7.48 (total 1H, each t, J = 8.
0Hz), 7.57 and 7.66 (total 1H, each d, J = 7.6Hz), 8.
02-8.10 (total 1H, m), 8.22-8.28 (total 1H, m).

(111b) 3-[[(R) -1- (4-
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamine N-[(R) -1- (4-fluorophenyl) ethyl]
Production Example (59b) using 7.60 g of -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, 9.51 g of nickel chloride hexahydrate, and 3.03 g of sodium borohydride The reaction was carried out in the same manner, followed by separation and purification to obtain 1.52 g of the title compound isomer (A) as a pale yellow oily substance and 1.39 g of the title compound isomer (B) as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 3.69 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.44 (1
H, s), 6.57 (1H, dd, J = 2.2, 8.1Hz), 6.63 (1H, s), 6.
68 (1H, d, J = 7.3Hz), 6.77-6.80 (2H, m), 6.98-7.02 (2
H, m), 7.08-7.12 (1H, m), 7.17-7.29 (4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.44 (1
H, s), 6.49-6.51 (1H, m), 6.61 (1H, s), 6.65 (1H, d, J
= 7.3Hz), 6.86 (2H, d, J = 8.8Hz), 6.98-7.05 (3H, m),
7.19-7.22 (4H, m).

(111c) 3-t-butoxy-4- {3
-[[(R) -1- (4-fluorophenyl) ethyla
Mino]-(4-methoxyphenyl) methyl] phenyla
Isomer (A) 1 of mino} -3-cyclobutene-1,2-dione 3-[[(R) -1- (4-fluorophenyl) -ethylamino]-(4-methoxyphenyl) methyl] phenylamine .50 g and 1.10 g of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (A) of the title compound. 1.95 g were obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 3.75 (3
H, s), 4.54 (1H, s), 6.77-6.81 (2H, m), 6.99-7.08 (3
H, m), 7.15-7.23 (4H, m), 7.29-7.36 (3H, m). 3-[[(R) -1- (4-fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl 1.35 g of isomer of phenylamine (B), 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 99
Using 3 mg, the reaction was carried out in the same manner as in Production Example (1c).
Isomer (B) of the title compound as a white foamy solid 2.1
4 g were obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.66 (1H, q, J = 6.6Hz), 3.81 (3
H, s), 4.53 (1H, s), 6.89 (2H, d, J = 8.1Hz), 6.99-7.0
4 (3H, m), 7.20-7.27 (7H, m).

(111d) 3- {3-[[(R) -1-
(4-Fluorophenyl) ethylamino]-(4-metho
Xyphenyl) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[(R) -1- (4-
Production example (63b) using 1.92 g of isomer (A) of fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione and 8 ml of trifluoroacetic acid. The reaction was carried out in the same manner as in 1. to obtain 1.85 g of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65-1.68 (3H,
m), 3.74 (3H, s), 4.15-4.33 (1H, br), 5.00 (1H, s),
6.95-6.98 (2H, m), 7.25-7.57 (10H, m). Melting point: 176 ° C (dec) Optical rotation [α] D = -44.5 (c = 1.00, Ac
OH) 3-t-butoxy-4- {3-[[(R) -1- (4-
Production Example (63b) using 2.12 g of isomer (B) of fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione and 10 ml of trifluoroacetic acid. The reaction was carried out in the same manner as in to give 1.81 g of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.65-1.69 (3H,
m), 3.77 (3H, s), 4.10-4.22 (1H, br), 4.90-5.05 (1H,
br), 6.97-7.00 (2H, m), 7.26-7.56 (10H, m). Melting point: 173 ° C (dec) Optical rotation [α] D = -16.0 (c = 1.00, Ac
OH).

Production Example 112 3- (3-{[(R) -1- (3,4-difluorophene)
Nylamino) ethylamino]-(p-tolyl) methyl
Phenylamino) -4-hydroxy-3-cyclobutene
-1,2-dione (Exemplified Compound No. 2-3386) (112a) N-[(R) -1- (3,4-difluoro)
Phenyl) ethyl] -N-[(3-nitrophenyl)-
(P-tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone
23 g and (R) -1- (3,4-difluorophenyl)
3.39 g of ethylamine hydrochloride, triethylamine 1
The reaction was carried out in the same manner as in Production Example (1a) using 2.2 ml and 2.8 ml of titanium tetrachloride to obtain an imine compound. Production example (1a) using the obtained imine compound, 4.41 g of sodium cyanoborohydride and 4.52 ml of acetic acid.
The reaction was carried out in the same manner as in to give 5.92 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.36 (t
otal 3H, each d, J = 6.6Hz), 2.23 and 2.35 (total 3H,
each s), 3.60 and 3.66 (total 1H, each q, J = 6.6H
z), 4.11 and 4.13 (total 1H, each s), 6.87-6.90 (1H,
m), 7.02-7.20 (7H, m), 7.39 and 7.48 (total 1H, each
dd, J = 7.3, 8.1Hz), 7.58 and 7.65 (total1H, each d,
J = 7.3 and 8.1Hz), 8.02-8.04 (total 1H, m), 8.21-8.
27 (total 1H, m).

(112b) 3-{[(R) -1- (3,
4-difluorophenyl) ethylamino]-(p-tri
5.) g ) methyl} phenylamine N-[(R) -1- (3,4-difluorophenyl) ethyl] -N-[(3-nitrophenyl)-(p-tolyl) methyl] amine 5.88 g, nickel chloride The reaction was carried out in the same manner as in Production Example (59b) using 7.31 g of hexahydrate and 2.33 g of sodium borohydride, and the mixture was separated and purified.
The isomer (A) of the title compound was converted into a colorless oily substance by 0.9
335 mg of 1 g of the title compound isomer (B) was obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
7.3Hz), 2.29 (3H, s), 3.65-3.80 (1H, m), 4.45 (1H,
s), 6.55-6.72 (3H, m), 6.93-7.00 (1H, s), 7.04-7.20
(7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 2.34 (3H, s), 3.63 (1H, q, J = 6.6Hz), 4.45 (1
H, s), 6.50 (1H, dd, J = 2.2, 8.1Hz), 6.61 (1H, s), 6.
66 (1H, d, J = 8.1Hz), 6.91-6.97 (1H, m), 6.98-7.22 (7
H, m).

(112c) 3-t-butoxy-4- (3
-｛[(R) -1- (3,4-difluorophenyl) e
Tylamino]-(p-tolyl) methyldiphenylamido
No) isomer of (A ) -3-cyclobutene-1,2-dione- 3-{[(R) -1- (3,4-difluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamine .90 g, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 65
Using 8 mg, a reaction was carried out in the same manner as in Production Example (1c).
Isomer (A) of the title compound as a white foamy solid 230
mg. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.29 (3H, s), 3.66 (1H, q, J = 6.
6Hz), 4.56 (1H, s), 6.92-6.98 (1H, m), 7.03-7.18 (7H,
m), 7.28-7.40 (3H, m). 3-{[(R) -1- (3,4-difluorophenyl)
Ethylamino]-(p-tolyl) methyl} phenylamine isomer (B) 305 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 224 m
and 460 mg of isomer (B) of the title compound as a white foamy solid by carrying out a reaction in the same manner as in Production Example (1c).
Obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.34 (3H, s), 3.64 (1H, q, J = 6.
6Hz), 4.53 (1H, s), 6.92-6.99 (1H, m), 7.00-7.38 (10
H, m).

(112d) 3- (3-{[(R) -1-
(3,4-difluorophenylamino) ethylamino]
-(P-tolyl) methyldiphenylamino) -4-hydr
Roxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- (3-{[(R) -1- (3,
4-difluorophenyl) ethylamino]-(p-tolyl) methyl {phenylamino) -3-cyclobutene-
Using 220 mg of 1,2-dione isomer (A) and 3 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a white solid.
07 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.6Hz), 2.28 (3H, s), 4.25-4.35 (1H, br), 5.09 (1H,
s), 7.12-7.24 (4H, m), 7.31-7.38 (1H, m), 7.41-7.57
(6H, m). Melting point: 187 ° C. (dec) Optical rotation [α] D = −93.5 (c = 1.01, Ac
OH) 3-t-butoxy-4- (3-{[(R) -1- (3,
4-difluorophenyl) ethylamino]-(p-tolyl) methyl {phenylamino) -3-cyclobutene-
Using 509 mg of 1,2-dione isomer (B) and 3 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to give the isomer (B) of the title compound as a white solid.
02 mg was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.6Hz), 2.31 (3H, s), 4.15-4.24 (1H, br), 5.08 (1H,
s), 7.16-7.23 (1H, m), 7.25 (2H, d, J = 8.1Hz), 7.28-7.
62 (8H, m). Melting point: 185 ° C (dec) Optical rotation [α] D = -12.5 (c = 1.01, Ac
OH).

Production Example 113 4- {3-[(4-methoxyphenyl)-[(R) -1]
-(3,4,5-trifluorophenyl) ethylami
[N] methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride (exemplified compound number
No. 2-3504) (113a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (3,
4,5-trifluorophenyl) ethyl] amine 4-methoxy-3'-nitrobenzophenone 1.73
g, 2.28 g of (R) -1- (3,4,5-trifluorophenyl) ethylamine hydrochloride, 5.6 ml of triethylamine and 0.8 ml of titanium tetrachloride were reacted in the same manner as in Production Example (1a). Performed to obtain an imine compound. Using the obtained imine compound, 1.69 g of sodium cyanoborohydride and 0.6 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.63 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.33 and 1.35 (t
otal 3H, each d, J = 6.6Hz), 3.58 and 3.63 (total 1H,
each q, J = 6.6Hz), 3.77 and 3.82 (total 3H, each
s), 4.59 and 4.67 (total 1H, each s), 6.81-6.94 (2H,
m), 6.82 and 6.90 (total 2H, each d, J = 8.8Hz), 7.1
4 and 7.15 (total 2H, each d, J = 8.7Hz), 7.41 and 7.
56 (total 1H, each t, J = 7.8Hz), 7.59 and 7.63 (total
1H, each d, J = 7.7Hz), 8.05 and 8.11 (total 1H, each
dd, J = 1.2, 7.4Hz), 8.23 and 8.24 (total 1H, each
t, J = 1.9Hz).

(113b) 3-[(4-methoxyphenyi)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3,4,5-trifluorophenyl) ethyl] 2.61 g of amine, 3.00 g of nickel chloride hexahydrate, 9 sodium borohydride
The reaction was carried out in the same manner as in Production Example (1b) using 58 mg,
2.33 g of the title compound were obtained as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (3H, d, J =
6.6Hz), 3.60 and 3.65 (total 1H, each q, J = 6.6Hz),
3.76 and 3.80 (total 3H, each s), 4.43 and 4.44 (tot
al 1H, each s), 6.50-6.61 (2H, m), 6.66 (1H, d, J = 7.
5Hz), 6.79 and 6.86 (total 2H, each d, J = 8.7Hz), 6.
89-6.96 (2H, m), 7.04 and 7.11 (total 1H, each t, J =
7.8Hz), 7.18 and 7.19 (total 2H, each d, J = 8.8Hz).

(113c) 3-t-butoxy-4- {3
-[(4-methoxyphenyl)-[(R) -1- (3,
4,5-trifluorophenyl) ethylamino] methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
On 3-[(4-methoxyphenyl)-[(R) -1-
(3,4,5-trifluorophenyl) ethylamino]
Methyl] phenylamine (2.31 g) and 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione (1.32 g) were reacted and separated and purified in the same manner as in Production Example (66c). 950 mg of the isomer (A) of the compound was obtained as a white foamy solid, and 793 mg of the isomer (B) of the title compound were obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 3.76 (3
H, s), 4.54 (1H, s), 6.81 (2H, d, J = 8.7Hz), 6.90 (2H,
dd, J = 6.7, 8.3Hz), 7.04 (1H, d, J = 6.9Hz), 7.18 (2H,
d, J = 8.7 Hz), 7.23-7.40 (3H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.62 (1H, q, J = 6.7Hz), 3.81 (3
H, s), 4.51 (1H, s), 6.88-6.94 (2H, m), 6.89 (2H, d, J
= 8.7Hz), 7.00-7.06 (1H, br), 7.19 (2H, d, J = 8.6Hz),
7.20-7.40 (3H, m).

(113d) 4- {3-[(4-methoxy)
Phenyl)-[(R) -1- (3,4,5-trifluoro)
Lphenyl) ethylamino] methyl] phenylamino
-3-Hydroxy-3-cyclobutene-1,2-dione
Hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 916 m
g, 2 ml of trifluoroacetic acid, Production Example (63b)
628 mg of the title compound isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 3.73 (3H, s), 4.30 (1H, q, J = 5.8Hz), 5.12 (1
H, s), 6.94 (2H, d, J = 8.7Hz), 7.24 (1H, d, J = 7.5Hz),
7.34-7.43 (4H, m), 7.53 (1H, s), 7.54 (2H, d, J = 8.6
Hz). Melting point: 188 ° C. (dec) Optical rotation: [α] D = −154 (c = 0.91, AcO
H) 3-t-butoxy-4- {3-[(4-methoxyphenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 689 m
g, 2 ml of trifluoroacetic acid, Production Example (63b)
616 mg of the title compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.8Hz), 3.77 (3H, s), 4.25 (1H, q, J = 6.8Hz), 5.15 (1
H, s), 7.00 (2H, d, J = 8.8Hz), 7.33 (1H, d, J = 7.0Hz),
7.36-7.44 (4H, m), 7.52 (1H, s), 7.55 (2H, d, J = 8.8H
z). Melting point: 183 ° C. (dec) Optical rotation: [α] D = + 23.6 (c = 0.82, Ac
OH).

Production Example 114 4- {3-[(4-chlorophenyl)-[(R) -1-]
(3,4,5-trifluorophenyl) ethylamino]
Methyl] phenylamino} -3-hydroxy-3-cycl
Lobutene-1,2-dione hydrochloride (Exemplary Compound No. 2
-3503) (114a) N-[(4-chlorophenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (3,
4,5-trifluorophenyl) ethyl] amine 4-chloro-3'-nitrobenzophenone 1.68 g,
(R) -1- (3,4,5-trifluorophenyl) ethylamine hydrochloride (2.21 g), triethylamine (5.3)
Example (1a) using 0.8 ml of titanium tetrachloride and 0.8 ml of titanium tetrachloride
The reaction was carried out in the same manner as in the above to obtain an imine compound. The resulting imine compound and sodium cyanoborohydride 1.61
g, acetic acid 0.5 ml, and the reaction was carried out in the same manner as in Production Example (1a).
Obtained. NMR spectrum (CDCl ₃ ) δppm: 1.35 and 1.36 (t
otal 3H, each d, J = 6.6Hz), 3.56-3.64 (1H, m), 4.63
and 4.69 (total 1H, each s), 6.83-6.91 (2H, m), 7.20
(2H, d, J = 8.3Hz), 7.27 and 7.35 (total 2H, each d,
J = 7.7Hz), 7.43 and 7.52 (total 1H, each t, J = 8.0H
z), 7.57 and 7.61 (total 1H, each d, J = 7.8Hz), 8.07
and 8.14 (total 1H, each ddd, J = 1.0, 2.2, 8.1Hz),
8.21 (1H, t, J = 1.8Hz).

(114b) 3-[(4-chlorophenyi)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3,4,5-trifluorophenyl) ethyl] amine 2.38 g, nickel chloride hexahydrate 2.69 g, sodium borohydride 8
The reaction was carried out in the same manner as in Production Example (59b) using 66 mg, followed by separation and purification. 942 mg of the isomer (A) of the title compound as a colorless oily substance, and 663 mg of the isomer of the title compound (B) as a colorless oily substance. Obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 4.43 (1H, s), 6.54 (1
H, t, J = 1.9Hz), 6.58-6.63 (2H, m), 6.92 (2H, d, J = 6.
6, 8.5 Hz), 7.12 (1H, t, J = 7.7 Hz), 7.22 (4H, s). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.30 (3H, d, J =
6.6Hz), 3.57 (1H, q, J = 6.6Hz), 4.45 (1H, s), 6.52-6.
60 (2H, m), 6.62 (1H, d, J = 7.9Hz), 6.87 (2H, dd, J = 6.
8, 8.1Hz), 7.05 (1H, t, J = 7.8Hz), 7.23 (2H, d, J = 8.4
Hz), 7.30 (2H, d, J = 8.4Hz).

(114c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-[(R) -1- (3,
4,5-trifluorophenyl) ethylamino] methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
On 3-[(4-chlorophenyl)-[(R) -1- (3,
Isomer (A) of 4,5-trifluorophenyl) ethylamino] methyl] phenylamine (865 mg, 4-t)
-Butoxy-3-methoxy-3-cyclobutene-1,2
Using 488 mg of -dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 947 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.63 (1H, q, J = 6.5Hz), 4.55 (1
H, s), 6.90 (2H, dd, J = 6.7, 8.1Hz), 7.00 (1H, d, J = 7.
2Hz), 7.21-7.42 (7H, m). 3-[(4-chlorophenyl)-[(R) -1- (3,
624 mg of isomer (B) of 4,5-trifluorophenyl) ethylamino] methyl] phenylamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
The reaction was carried out in the same manner as in Production Example (1c) using 353 mg of -dione to obtain 797 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.59 (1H, q, J = 6.6Hz), 4.55 (1
H, s), 6.89 (2H, dd, J = 6.7, 8.1Hz), 6.98 (1H, d, J = 6.
9Hz), 7.16-7.42 (3H, m), 7.24 (2H, d, J = 8.3Hz), 7.33
(2H, d, J = 8.4Hz).

(114d) 4- {3-[(4-chlorofu
Enyl)-[(R) -1- (3,4,5-trifluoro
Phenyl) ethylamino] methyl] phenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione
Hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 840 m
g, 2 ml of trifluoroacetic acid, Production Example (63b)
The reaction was carried out in the same manner as in, to obtain 744 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.6Hz), 4.32 (1H, q, J = 6.5Hz), 5.23 (1H, s), 7.25 (1
H, d, J = 7.2Hz), 7.26-7.44 (4H, m), 7.46 (2H, d, J = 8.
6Hz), 7.55 (1H, s), 7.67 (2H, d, J = 8.4Hz). Melting point: 188 ° C (dec) Optical rotation: [α] D = -117 (c = 0.82, AcO
H) 3-t-butoxy-4- {3-[(4-chlorophenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 757m
g, 2 ml of trifluoroacetic acid, Production Example (63b)
The reaction was carried out in the same manner as in, to obtain 662 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 4.26 (1H, q, J = 6.7Hz), 5.24 (1H, s), 7.33-
7.53 (5H, m), 7.52 (2H, d, J = 8.5Hz), 7.54 (1H, s), 7.
68 (2H, d, J = 8.5 Hz). Melting point: 190 ° C. (dec) Optical rotation: [α] D = + 17.6 (c = 0.92, AcO)
H).

Production Example 115 4- {3-[(4-fluorophenyl)-[(R) -1]
-(3,4,5-trifluorophenyl) ethylami
[N] methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride (exemplified compound number
No. 2-3502) (115a) N-[(4-fluorophenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (3,
4,5-trifluorophenyl) ethyl] amine 4-fluoro-3'-nitrobenzophenone 1.59 g
And (R) -1- (3,4,5-trifluorophenyl)
2.20 g of ethylamine hydrochloride, 5.
Production example using 4 ml and 0.8 ml of titanium tetrachloride (1
The reaction was carried out in the same manner as in a) to obtain an imine compound. The obtained imine compound and sodium cyanoborohydride
The reaction was carried out in the same manner as in Production Example (1a) using 64 g and 0.6 ml of acetic acid.
0 g was obtained. NMR spectrum (CDCl ₃ ) δppm: 1.35 and 1.36 (t
otal 3H, each d, J = 6.6Hz), 3.56-3.63 (1H, m), 4.65
and 4.70 (total 1H, each s), 6.83-6.91 (2H, m), 6.98
and 7.07 (total 2H, each t, J = 8.6Hz), 7.20-7.26 (2
H, m), 7.43 and 7.52 (total 1H, each t, J = 7.8Hz),
7.58 and 7.62 (total 1H, each d, J = 7.7Hz), 8.07 and
8.14 (total 1H, each dd, J = 2.0, 8.0Hz), 8.21 and
8.23 (total 1H, each d, J = 1.9Hz).

(115b) 3-[(4-Fluorophenyl)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (3,4,5-trifluorophenyl) ethyl] Amine 2.46 g, nickel chloride hexahydrate 2.90 g, sodium borohydride 9
The reaction was carried out in the same manner as in Production Example (59b) using 27 mg, and the mixture was separated and purified to give 760 mg of the title compound isomer (A) as a colorless oil and 716 mg of the title compound isomer (B) as a colorless oil. Was. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 4.44 (1H, s), 6.56 (1
H, d, J = 1.8Hz), 6.58-6.64 (2H, m), 6.89-6.98 (4H,
m), 7.12 (1H, t, J = 7.8 Hz), 7.21-7.26 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.30 (3H, d, J =
6.6Hz), 3.58 (1H, q, J = 6.6Hz), 4.47 (1H, s), 6.53 (1
H, dd, J = 1.6, 8.0Hz), 6.58 (1H, s), 6.63 (1H, dd, J =
0.6, 7.7Hz), 6.86-6.89 (2H, m), 7.01 (2H, t, J = 8.6H
z), 7.05 (1H, t, J = 7.8Hz), 7.24-7.27 (2H, m).

(115c) 3-t-butoxy-4- {3
-[(4-fluorophenyl)-[(R) -1- (3,
4,5-trifluorophenyl) ethylamino] methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
On 3-[(4-fluorophenyl)-[(R) -1-
(3,4,5-trifluorophenyl) ethylamino]
738 mg of isomer (A) of methyl] phenylamine, 4
-T-butoxy-3-methoxy-3-cyclobutene-
The reaction was carried out in the same manner as in Production Example (1c) using 434 mg of 1,2-dione to obtain 800 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.90 (2H, dd, J = 6.7, 8.2Hz), 6.95 (2H, t, J = 8.
7Hz), 7.22-7.36 (5H, m), 7.43 (1H, br). 3-[(4-fluorophenyl)-[(R) -1-
(3,4,5-trifluorophenyl) ethylamino]
Methyl) phenylamine isomer (B) 677 mg, 4
-T-butoxy-3-methoxy-3-cyclobutene-
Using 400 mg of 1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 824 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 1.64 (9H, s), 3.60 (1H, q, J = 6.6Hz), 4.56 (1
H, s), 6.89 (2H, dd, J = 6.6, 8.4Hz), 7.04 (2H, t, J = 8.
6Hz), 7.21-7.35 (5H, m), 7.40 (1H, br).

(115d) 4- {3-[(4-fluoro
Phenyl)-[(R) -1- (3,4,5-trifluoro)
Lphenyl) ethylamino] methyl] phenylamino
-3-Hydroxy-3-cyclobutene-1,2-dione
Hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 759 m
g, 3 ml of trifluoroacetic acid, Production Example (63b)
The reaction was carried out in the same manner as in, to obtain 635 mg of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.32 (1H, q, J = 6.7Hz), 5.22 (1H, s), 7.21-
7.25 (1H, m), 7.23 (2H, t, J = 8.7Hz), 7.34-7.44 (4H,
m), 7.56 (1H, s), 7.68 (2H, dd, J = 5.3, 8.6 Hz). Melting point: 186 ° C. (dec) Optical rotation: [α] D = −66.5 (c = 0.90, Ac
OH) 3-t-butoxy-4- {3-[(4-fluorophenyl)-[(R) -1- (3,4,5-trifluorophenyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 740 m
g, 3 ml of trifluoroacetic acid, Production Example (63b)
And 590 mg of the title compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 4.26 (1H, q, J = 6.7Hz), 5.26 (1H, s), 7.29 (2
(H, t, J = 8.8Hz), 7.34-7.46 (5H, m), 7.53 (1H, s), 7.7
1 (2H, dd, J = 5.3, 8.6 Hz). Melting point: 191 ° C. (dec) Optical rotation: [α] D = + 19.1 (c = 0.36, Ac
OH).

Production Example 116 4- {3-[(R) -1- (3,5-difluorophenyl)
Ru) ethylamino]-(4-methylphenyl) methyl]
Phenylamino} -3-hydroxy-3-cyclobutene
-1,2-dione hydrochloride (Exemplary Compound No. 2-345)
7) (116a) N-[(R) -1- (3,5-difluoro)
Phenyl) ethyl] -N-[(4-methylphenyl)-
(3-Nitrophenyl) methyl] amine 4-methyl-3'-nitrobenzophenone 1.69 g, (R) -1- (3,5-difluorophenyl) ethylamine hydrochloride 2.19 g, triethylamine 5.9 ml and tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 0.9 ml of titanium to obtain an imine compound. The obtained imine compound was reacted with 1.79 g of sodium borohydride cyanide and 0.6 ml of acetic acid in the same manner as in Production Example (1a) to obtain 2.62 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.35 and 1.37 (t
otal 3H, each d, J = 6.7Hz), 2.30 and 2.35 (total 3H,
each s), 3.62 and 3.68 (total 1H, each q, J = 6.7H
z), 4.64 and 4.70 (total 1H, each s), 6.66-6.81 (3H,
m), 7.09-7.19 (4H, m), 7.40 and 7.49 (total 1H, each
t, J = 8.0Hz), 7.61 and 7.66 (total 1H, each d, J = 7.
7Hz), 8.04 and 8.10 (total 1H, each d, J = 8.1Hz), 8.
23 and 8.26 (total 1H, each s).

(116b) 3-[[(R) -1- (3,
5-difluorophenyl) ethylamino]-(4-methyl
Phenyl) methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl) ethyl] -N-[(4-methylphenyl)-(3-nitrophenyl) methyl] amine 2.59 g, chloride Nickel 6
Hydrate 3.23 g, sodium borohydride 1.03 g
The reaction was carried out in the same manner as in Production Example (59b), followed by separation and purification. 1.02 g of the isomer (A) of the title compound as a colorless oily substance and 1 0.08 g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 2.29 (3H, s), 3.69 (1H, q, J = 6.6Hz), 4.48 (1
H, s), 6.57 (1H, ddd, J = 0.9, 2.4, 7.9Hz), 6.62 (1H,
t, J = 2.0Hz), 6.64-6.70 (2H, m), 6.82 (2H, dd, J = 2.2,
8.5Hz), 7.06 (2H, d, J = 8.0Hz), 7.10 (1H, t, J = 7.7H
z), 7.17 (2H, d, J = 8.1 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J =
6.7Hz), 2.34 (3H, s), 3.64 (1H, q, J = 6.6Hz), 4.48 (1
H, s), 6.51 (1H, ddd, J = 0.9, 2.4, 8.0Hz), 6.62 (1H,
t, J = 2.0Hz), 6.65-6.70 (2H, m), 6.80 (2H, dd, J = 2.2,
8.5Hz), 7.04 (1H, t, J = 7.8Hz), 7.13 (2H, d, J = 8.0H
z), 7.17 (2H, d, J = 8.2Hz).

(116c) 3-t-butoxy-4- {3
-[(R) -1- (3,5-difluorophenyl) ethyl
Lamino]-(4-methylphenyl) methyl] phenyl
Amino} -3-cyclobutene-1,2-dione 3-[[(R) -1- (3,5-difluorophenyl)
Production Example (1c) using 940 mg of isomer (A) of ethylamino]-(4-methylphenyl) methyl] phenylamine and 590 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione The reaction was carried out in the same manner as in to give 1.20 g of the title compound isomer (A) as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.29 (3H, s), 3.67 (1H, q, J = 6.
6Hz), 4.58 (1H, s), 6.66-6.72 (1H, m), 6.79 (2H, dd, J
= 2.0, 8.5Hz), 7.06-7.12 (1H, m), 7.08 (2H, d, J = 8.0H
z), 7.16 (2H, d, J = 8.0 Hz), 7.26-7.38 (3H, m). 3-[[(R) -1- (3,5-difluorophenyl)
Production Example (1c) using 990 mg of isomer (B) of ethylamino]-(4-methylphenyl) methyl] phenylamine and 618 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione The reaction was carried out in the same manner as in 1. to obtain 1.09 g of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 1.63 (9H, s), 2.35 (3H, s), 3.66 (1H, q, J = 6.
6Hz), 4.55 (1H, s), 6.65-6.70 (1H, m), 6.81 (2H, dd, J
= 1.9, 8.0Hz), 7.04-7.07 (1H, m), 7.15 (2H, d, J = 8.9H
z), 7.17 (2H, d, J = 8.8Hz), 7.22-7.36 (3H, m).

(116d) 4- {3-[(R) -1-
(3,5-difluorophenyl) ethylamino]-(4
-Methylphenyl) methyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(R) -1- (3,5
Preparation Example (63b) using 1.10 g of isomer (A) of -difluorophenyl) ethylamino]-(4-methylphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione and 3 ml of trifluoroacetic acid. ), To give 712 mg of the title compound isomer (A) as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J
= 6.7Hz), 2.28 (3H, s), 4.30 (1H, br), 5.15 (1H, s), 7.
17 (2H, dd, J = 1.8, 8.0Hz), 7.21 (2H, d, J = 8.1Hz), 7.
27-7.43 (4H, m), 7.51 (2H, d, J = 8.2 Hz), 7.53 (1H, s). Melting point: 193 ° C. (dec) Optical rotation: [α] D = −25.9 (c = 0.55, Ac
OH) 3-t-butoxy-4- {3-[(R) -1- (3,5
-Difluorophenyl) ethylamino]-(4-methylphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione isomer (B) (990 mg) and trifluoroacetic acid (3 ml) were used. The same reaction was carried out to obtain 708 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 2.31 (3H, s), 4.25 (1H, q, J = 6.7Hz), 5.14 (1
H, s), 7.19 (2H, dd, J = 1.9, 8.3Hz), 7.25 (2H, d, J = 8.
0Hz), 7.28-7.37 (3H, m), 7.40-7.42 (1H, m), 7.51 (2H,
d, J = 8.1 Hz), 7.54 (1H, s). Melting point: 190 ° C. (dec) Optical rotation: [α] D = + 2.1 (c = 0.65, AcO)
H).

Production Example 117 3- (3-{[1- (3,4-Difluorophenylamido)
No) Ethylamino]-(p-tolyl) methyldiphenyl
Amino) -4-hydroxy-3-cyclobutene-1,2
-Dione and its triethylammonium salt, nato
Lithium salt (Exemplary Compound No. 2-3386) (117a) N- [1- (3,4-difluorophenyl)
Ru) ethyl] -N-[(3-nitrophenyl)-(p-
5. ( tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone
A reaction was carried out in the same manner as in Production Example (1a) using 02 g, 3.92 g of 1- (3,4-difluorophenyl) ethylamine, 13.9 ml of triethylamine and 4.0 ml of titanium tetrachloride to obtain an imine compound. The obtained imine compound was reacted with 6.27 g of sodium cyanoborohydride and 6.5 ml of acetic acid in the same manner as in Production Example (1a) to give 7.79 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.36 (t
otal 3H, each d, J = 6.6Hz), 2.23 and 2.35 (total 3H,
each s), 3.60 and 3.66 (total 1H, each q, J = 6.6H
z), 4.11 and 4.13 (total 1H, each s), 6.87-6.90 (1H,
m), 7.02-7.20 (7H, m), 7.39 and 7.48 (total 1H, each
dd, J = 7.3, 8.1Hz), 7.58 and 7.65 (total1H, each d,
J = 7.3 and 8.1Hz), 8.02-8.04 (total 1H, m), 8.21-8.
27 (total 1H, m).

(117b) 3-{[1- (3,4-diph
Fluorophenyl) ethylamino]-(p-tolyl) methyl
Ruphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
7.76 g of N-[(3-nitrophenyl)-(p-tolyl) methyl] amine, nickel chloride hexahydrate 9.65
g, 3.07 g of sodium borohydride, and the reaction was carried out in the same manner as in Production Example (59b), and the mixture was separated and purified to give 1.67 g of the title compound isomer (A) as a pale yellow oil.
Isomer (B) of the title compound as a pale yellow oil 2.3.
7 g were obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
7.3Hz), 2.29 (3H, s), 3.65-3.80 (1H, m), 4.45 (1H,
s), 6.55-6.72 (3H, m), 6.93-7.00 (1H, m), 7.04-7.20
(7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 2.34 (3H, s), 3.63 (1H, q, J = 6.6Hz), 4.45 (1
H, s), 6.50 (1H, dd, J = 2.2, 8.1Hz), 6.61 (1H, s), 6.
66 (1H, d, J = 8.1Hz), 6.91-6.97 (1H, m), 6.98-7.22 (7
H, m).

(117c) 3-t-butoxy-4- (3
-{[1- (3,4-difluorophenyl) ethylamido]
No]-(p-tolyl) methyl @ phenylamino) -3-
1.64 g of isomer (A) of cyclobutene-1,2-dione 3-{[1- (3,4-difluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamine, 4-t-butoxy- Using 1.29 g of 3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 1.98 g of the isomer (A) of the title compound as a white foamy solid. Was. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.29 (3H, s), 3.66 (1H, q, J = 6.
6Hz), 4.56 (1H, s), 6.92-6.98 (1H, m), 7.03-7.18 (7H,
m), 7.28-7.40 (3H, m). 2.34 g of isomer of 3-{[1- (3,4-difluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamine (B), 4 Using 1.83 g of -t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (B) of the title compound as a white foamy solid 1.98 g was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.6Hz), 1.63 (9H, s), 2.34 (3H, s), 3.64 (1H, q, J = 6.
6Hz), 4.53 (1H, s), 6.92-6.99 (1H, m), 7.00-7.38 (10
H, m).

(117d) 3- (3-{[1- (3,4
-Difluorophenylamino) ethylamino]-(p-
Tolyl) methyl @ phenylamino) -4-hydroxy-
3-cyclobutene-1,2-dione 3-t-butoxy-4- (3-{[1- (3,4-difluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamino) -3-cyclobutene 1.95 g of isomer (A) of -1,2-dione, 4 m of trifluoroacetic acid
Using l, the reaction was carried out in the same manner as in Production Example (55b) to obtain 1.50 g of the isomer (A) of the title compound as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60 (3H, d, J
= 6.6Hz), 2.28 (3H, s), 4.27-4.40 (1H, br), 5.02 (1H,
s), 6.91 (1H, d, J = 7.7Hz), 7.16-7.26 (4H, m), 7.41-7.
57 (5H, m), 7.65 (1H, s). Melting point: 240 ° C (dec) 3-t-butoxy-4- (3-{[1- (3,4-difluorophenyl) ethylamino]-(p 1.96 g of isomer (B) of -tolyl) methyl @ phenylamino) -3-cyclobutene-1,2-dione, 4 m of trifluoroacetic acid
Using l, the reaction was carried out in the same manner as in Production Example (55b) to obtain 402 mg of the isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.58 (3H, d, J
= 6.7Hz), 2.31 (3H, s), 4.15-4.30 (1H, br), 5.05 (1H,
s), 6.95 (1H, d, J = 7.7Hz), 7.20-7.26 (4H, m), 7.43 (1
H, d, J = 8.1 Hz), 7.45-7.57 (3H, m), 7.70 (1H, s). Melting point: 216 ° C (dec).

(117e) 3-hydroxy-4- {3-
[(1- (3,4-difluorophenyl) ethylamido
No)-(p-tolyl) methyl] phenylamino} -3-
Cyclobutene-1,2-dione triethylammonium
Unsalted 3-hydroxy-4-isomer of {3 - - [(1- (3,4-difluorophenyl) ethylamino) (p-tolyl) methyl] phenylamino} -3-cyclobutene-1,2-dione (B) 418 mg of a suspension was suspended in 5 ml of acetone, and triethylamine was added to completely dissolve the suspension. After that, the solvent and excess triethylamine were distilled off under reduced pressure. The obtained white solid was suspended in diisopropyl ether, collected and dried to obtain 463 mg of the isomer (B) of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.19 (9H, t, J
= 7.2Hz), 1.33 (3H, d, J = 6.6Hz), 2.27 (3H, s), 3.11 (6
(H, q, J = 7.3Hz), 3.60-3.75 (1H, br), 4.52 (1H, s), 6.
72 (1H, d, J = 7.6Hz), 7.03-7.13 (4H, m), 7.25 (2H, d,
J = 7.9Hz), 7.30-7.39 (2H, m), 7.48 (1H, dd, J = 1.8, 8.
0 Hz), 7.65 (1H, s). Melting point: 106 ° C (dec).

(117f) 3-Hydroxy-4- {3-
[(1- (3,4-difluorophenyl) ethylamido
No)-(p-tolyl) methyl] phenylamino} -3-
Cyclobutene-1,2-dione sodium salt 3-hydroxy-4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(p-tolyl) methyl] phenylamino} -3-cyclobutene-1 888 mg of 2,2-dione isomer (B) were suspended in 5 ml of acetone, and 185 mg of sodium hydrogen carbonate and 3 ml of distilled water were added. The solution was distilled off under reduced pressure, and the obtained residue was dissolved by adding ethyl acetate, and the insoluble matter was removed by filtration. The filtrate was evaporated under reduced pressure,
The obtained white powder was dissolved in ethyl acetate, and the insoluble matter was removed by filtration. This was repeated three times, and the obtained white powder was suspended in n-hexane and collected by filtration to obtain 652 mg of the title compound. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (3H, d, J
= 6.6Hz), 2.26 (3H, s), 3.51 (1H, q, 6.6Hz), 4.34. (1H,
d, J = 5.9Hz), 6.70 (1H, d, J = 7.3Hz), 7.01-7.11 (4H,
m), 7.21 (2H, d, J = 8.1Hz), 7.30-7.41 (2H, m), 7.50 (1
H, dd, J = 2.2, 8.1 Hz), 7.62 (1H, s). Melting point: 156 ° C. (dec).

Production Example 118 3-Hydroxy-4- {3-
[(4-methoxyphenyl)-((R) -1- (naphtha
Len-1-yl) ethylamino) methyl] phenylami
No｝ -3-cyclobutene-1,2-dione (exemplary compound
No. 2-13) (118a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (naph
[Talen-1-yl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 5.32 g, (R) -1- (1-naphthyl) ethylamine 3.54 g, triethylamine 11.5 ml and tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 3.4 ml of titanium to obtain an imine compound. The obtained imine compound was reacted with 5.20 g of sodium cyanoborohydride and 5.53 ml of acetic acid in the same manner as in Production Example (1a) to obtain 8.34 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.526 and 1.534
(total 3H, each d, J = 6.6Hz), 3.77 and 3.81 (total 3H
H, each s), 4.53 and 4.58 (total 1H, each q, J = 6.6H
z), 4.74 and 4.78 (total 1H, each s), 6.82 and 6.85
(total 2H, eachd, J = 8.8Hz), 7.12 and 7.20 (total 2H
, each d, J = 8.8Hz), 7.32-7.85 (9H, m), 8.01 and 8.
08 (total 1H, each dd, J = 2.2 and 8.1Hz), 8.22 and
8.28 (total1H, each s).

(118b) 3-[(4-methoxyphenyi)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamine N - [(4-methoxyphenyl) - (3-nitrophenyl) methyl] -N - [(R) -1- (naphthalene-1
The same reaction as in Production Example (59b) was carried out using 8.32 g of yl) ethyl] amine, 9.51 g of nickel chloride hexahydrate and 3.03 g of sodium borohydride, and the mixture was separated and purified to give the isomer of the title compound. 1.15 g of (A) was obtained as a colorless oil, and 462 mg of isomer (B) of the title compound was obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (3H, d, J =
6.6Hz), 3.76 (3H, s), 4.57-4.60 (2H, m), 6.54-6.66 (2
H, m), 6.65 (1H, d, J = 7.6Hz), 6.80 (2H, d, J = 8.7Hz),
7.05-7.30 (3H, m), 7.36-7.55 (3H, m), 7.69 (1H, d, J
= 7.0Hz), 7.76 (1H, d, J = 8.1Hz), 7.86 (1H, d, J = 7.9H
z), 7.94 (1H, d, J = 8.4 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (3H, d, J =
6.6Hz), 3.80 (3H, s), 4.54 (1H, q, J = 6.6Hz), 4.60 (1
H, s), 6.52-6.54 (1H, m), 6.70 (1H, d, J = 1.5Hz), 6.71
(1H, d, J = 7.3Hz), 6.82 (2H, d, J = 8.8Hz), 7.05 (1H,
t, J = 8.1Hz), 7.17 (2H, d, J = 8.8Hz), 7.37-7.52 (3H,
m), 7.67 (1H, d, J = 7.3Hz), 7.76 (1H, d, J = 8.1Hz), 7.
87 (1H, d, J = 8.1Hz), 7.90 (1H, d, J = 8.8Hz).

(118c) 3-t-butoxy-4- {3
-[(4-methoxyphenyl)-((R) -1- (naph
Taren-1-yl) ethylamino) methyl] phenyla
Isomer (A) 1 of mino} -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamine .11 g, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 74
Using 8 mg, a reaction was carried out in the same manner as in Production Example (1c).
Isomer (A) of the title compound as a white foamy solid, 1.3
0 g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, d, J =
6.6Hz), 1.58 (9H, s), 3.78 (3H, s), 4.56 (1H, q, J = 6.
6Hz), 4.68 (1H, s), 6.83 (2H, d, J = 8.8Hz), 7.01-7.10
(1H, m), 7.20-7.54 (8H, m), 7.66 (1H, d, J = 7.3Hz),
7.78 (1H, d, J = 7.8 Hz), 7.84-7.90 (2H, m). 3-[(4-methoxyphenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] 449 mg of isomer (B) of phenylamine, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 32
Using 4 mg, a reaction was carried out in the same manner as in Production Example (1c).
Isomer (B) of the title compound as a white foamy solid 452
mg. NMR spectrum (CDCl ₃ ) δ ppm: 1.49 (3H, d, J =
6.6Hz), 1.59 (9H, s), 3.79 (3H, s), 4.55 (1H, q, J = 6.
6Hz), 4.67 (1H, s), 6.85 (2H, d, J = 8.8Hz), 7.07-7.52
(9H, m), 7.67 (1H, d, J = 7.7Hz), 7.76 (1H, d, J = 8.1H
z), 7.87 (1H, d, J = 8.1Hz), 7.91 (1H, d, J = 8.1Hz).

(118d) 3-Hydroxy-4- {3-
[(4-methoxyphenyl)-((R) -1- (naphtha
Len-1-yl) ethylamino) methyl] phenylami
No} -3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] Using 1.24 g of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give the isomer of the title compound (A ) Was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.76 (3H, d, J
= 6.6Hz), 3.77 (3H, s), 5.23 (1H, s), 5.25-5.38 (1H, b
r), 6.71 (1H, d, J = 7.3Hz), 7.00 (2H, d, J = 8.8Hz), 7.
08-7.12 (1H, m), 7.32-7.56 (6H, m), 7.60-7.72 (2H,
m), 7.90-8.05 (3H, m). Optical rotation [α] D = −311.5 (c = 1.07,
AcOH) 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -3-cyclobutene-1, Using 434 mg of 2-dione isomer (B) and 3 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 317 mg of the hydrochloride of isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.80 (3H, d, J
= 6.6Hz), 3.74 (3H, s), 4.95-5.10 (1H, br), 5.30 (1H,
s), 6.89 (2H, d, J = 8.8Hz), 7.28-7.48 (7H, m), 7.50-7.
55 (1H, m), 7.59 (1H, s), 7.65-7.69 (1H, m), 7.90-8.1
7 (3H, m). Melting point: 179 ° C. (dec) Optical rotation [α] D = −83.1 (c = 1.01, Ac
OH).

Production Example 119 3-Hydroxy-4- {3-[(4-methoxyphenyl)
)-((R) -1- (naphthalen-2-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
-1,2-dione (Exemplified Compound No. 2-14) (119a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (naph
Taren-2-yl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 4.45 g, (R) -1- (2-naphthyl) ethylamine 2.96 g, triethylamine 9.6 ml and tetrachloride The reaction was carried out in the same manner as in Production Example (1a) using 2.9 ml of titanium to obtain an imine compound. Using the obtained imine compound, 4.34 g of sodium cyanoborohydride and 4.45 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 6.15 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.52 and 1.53 (t
otal 3H, each d, J = 6.6Hz), 3.77 and 3.79 (total 3H,
each s), 4.52-4.60 (2H, m), 6.51-6.72 (3H, m), 6.79
-6.87 (2H, m), 7.03-7.09 (1H, m), 7.16-7.19 (1H, m),
7.23-7.29 (1H, m), 7.35-7.53 (3H, m), 7.66-7.70 (1H, m
m), 7.74 and 7.68 (total 1H, each s), 7.85-7.95 (2H,
m).

(119b) 3-[(4-methoxyphenyi)
)-((R) -1- (naphthalen-2-yl) ethyl
Amino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (naphthalene-2-
Il) ethyl] amine 6.13 g, nickel chloride hexahydrate 7.06 g, and sodium borohydride 2.25 g were reacted in the same manner as in Production Example (1b) to give the title compound as a pale yellow oil. .23 g were obtained. NMR spectrum (CDCl ₃ ) δppm: 1.46 and 1.48 (t
otal 3H, each d, J = 6.6Hz), 3.77 and 3.81 (total 3H,
each s), 4.51 and 4.56 (total 1H, each q, J = 6.6H
z), 4.73 and 4.77 (total 1H, each s), 6.83 and 6.86
(total 2H, each d, J = 8.8Hz), 7.12 and 7.20 (total 2H
H, each d, J = 8.6Hz), 7.33-8.09 (10H, m), 8.02 and 8.
28 (total 1H, each s).

(119c) 3-t-butoxy-4- {3
-[(4-methoxyphenyl)-((R) -1- (naph
Taren-2-yl) ethylamino) methyl] phenyla
Mino} -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (naphthalen-2-yl) ethylamino) methyl] phenylamine 5.21 g, 4-t -Butoxy-3-methoxy-
Using 3.53 g of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (66c), followed by separation and purification.
The isomer (A) of the title compound was converted to a white foamy solid by 170
mg, 176 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.495 (3H, d, J =
6.6Hz), 1.58 (9H, s), 3.77 (3H, s), 4.55 (1H, q, J = 6.
6Hz), 4.67 (1H, s), 6.79 (2H, d, J = 1.5, 7.3Hz), 7.02
-7.06 (1H, m), 7.17-7.31 (5H, m), 7.35-7.52 (3H, m),
7.65 (1H, d, J = 6.6Hz), 7.77 (1H, d, J = 8.1Hz), 7.84-
7.88 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.502 (3H, d, J =
6.6Hz), 1.61 (9H, s), 3.81 (3H, s), 4.55 (1H, q, J = 6.
6Hz), 4.68 (1H, s), 6.85 (2H, dd, J = 1.5, 7.3Hz), 7.0
8 (1H, d, J = 7.3Hz), 7.17 (2H, d, J = 7.3Hz), 7.23-7.30
(3H, m), 7.36-7.51 (3H, m), 7.67 (1H, d, J = 6.6Hz),
7.76 (1H, d, J = 8.1Hz), 7.87 (1H, d, J = 8.1Hz), 7.91 (1
H, d, J = 8.8Hz).

(119d) 3-Hydroxy-4- {3-
[(4-methoxyphenyl)-((R) -1- (naphtha
Len-2-yl) ethylamino) methyl] phenylami
No} -3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (naphthalen-2-yl) ethylamino) methyl] Using 155 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 2.5 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give the isomer of the title compound (A ) Was obtained as a white solid (113 mg). Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.75 (3H, d, J
= 5.9Hz), 3.77 (3H, s), 5.20 (1H, br s), 5.32 (1H, s),
6.67 (1H, d, J = 7.3Hz), 6.99 (2H, d, J = 8.8Hz), 7.08 (1
H, dd, J = 7.3, 8.1Hz), 7.33-7.68 (8H, m), 7.95-7.80
(3H, m) Melting point: 194 ° C. (dec) Optical rotation [α] D = −324.5 (c = 0.57,
AcOH) 3-t-butoxy-4- {3-[(4-methoxyphenyl)-((R) -1- (naphthalen-2-yl) ethylamino) methyl] phenylamino} -3-cyclobutene-1, The reaction was carried out in the same manner as in Production Example (55b) using 170 mg of 2-dione isomer (A) and 2.5 ml of trifluoroacetic acid to obtain 141 mg of isomer (B) of the title compound as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.77 (3H, d, J
= 5.9Hz), 3.75 (3H, s), 5.00-5.12 (1H, m), 5.28 (1H, br
s), 6.99 (2H, d, J = 7.3Hz), 7.01 (1H, d, J = 7.3Hz),
7.29 (1H, dd, J = 7.3, 8.8Hz), 7.36-7.46 (4H, m), 7.50
-7.71 (3H, m), 7.82 (1H, s), 7.93 (1H, d, J = 7.3Hz),
7.99-8.01 (2H, m). Melting point: 195 ° C. (dec) Optical rotation [α] D = + 85.3 (c = 1.03, Ac
OH).

Production Example 120 3- (3-{[1- (3,4-difluorophenyl) e]
Tylamino]-(pyridin-4-yl) methyldiphenyl
Ruamino) -4-hydroxy-3-cyclobutene-1,
2-dione dihydrochloride (Exemplified Compound No. 2-46) (120a) N- [1- (3,4-difluorophenyl)
Ru) ethyl] -N-[(3-nitrophenyl)-(pyri
(Gin-4-yl) methyl] amine (3-nitrophenyl)-(pyridin-4-yl) methanone (2.81 g) and 1- (3,4-difluorophenyl)
1.94 g of ethylamine, 6.9 ml of triethylamine
And 2.0 ml of titanium tetrachloride were used to carry out a reaction in the same manner as in Production Example (1a) to obtain an imine compound. 3.19 g of the obtained imine compound and sodium cyanoborohydride,
The reaction was carried out in the same manner as in Production Example (1a) using 3.2 ml of acetic acid to obtain 2.10 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.376 and 1.382
(total 3H, each d, J = 6.6Hz), 3.60 and 3.63 (total 1
H, each q, J = 6.6Hz), 4.65 and 4.68 (total 1H, each
s), 6.88-6.95 (1H, m), 7.04-7.17 (2H, m), 7.19 and
7.25 (2H, m), 7.42and 7.62 (2H, m), 8.07-8.21 (2H, m
m), 8.52-8.62 (2H, m).

(120b) 3-{[1- (3,4-diph
Fluorophenyl) ethylamino]-(pyridine-4-i
M) methyl @ phenylamine N- [1- (3,4-difluorophenyl) ethyl]-
As in Production Example 1b using 2.07 g of N-[(3-nitrophenyl)-(pyridin-4-yl) methyl] amine, 2.66 g of nickel chloride hexahydrate and 848 mg of sodium borohydride. The reaction was performed and the mixture was separated and purified to give 684 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δppm: 1.32 and 1.34 (t
otal 3H, each d, J = 6.6Hz), 3.59-3.69 (total 1H, m),
4.42 and 4.46 (total 1H, each s), 6.51-6.63 (3H,
m), 6.88-7.00 (1H, m), 7.04-7.17 (3H, m), 7.21-7.27
(2H, m), 8.47 and 8.55 (total 2H, each dd, J = 1.5,
4.4Hz).

(120c) 3-t-butoxy-4- (3
-{[1- (3,4-difluorophenyl) ethylamido]
No]-(pyridin-4-yl) methyldiphenylamido
G) -3-cyclobutene-1,2-dione 3-{[1- (3,4-difluorophenyl) ethylamino]-(pyridin-4-yl) methyl} phenylamine 280 mg, 4-t-butoxy-3 -Methoxy-3-
Using 213 mg of cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to obtain 292 mg of the title compound as a white foamy solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.61 and 3.67 (total 1H, each
q, J = 6.6Hz), 4.54 and 4.56 (total 1H, each s), 6.90-
7.02 (2H, m), 7.05-7.16 (2H, m), 7.22-7.46 (5H, m),
8.48 and 8.57 (total 2H, each dd, J = 2.2, 4.4Hz).

(120d) 3- (3-{[1- (3,4
-Difluorophenyl) ethylamino]-(pyridine-
4-yl) methyl @ phenylamino) -4-hydroxy
-3-cyclobutene-1,2-dione dihydrochloride 3-t-butoxy-4- (3-{[1- (3,4-difluorophenyl) ethylamino]-(pyridin-4-yl) methyl} phenyl Amino) -3-cyclobutene-
Using 270 mg of 1,2-dione and 3 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 143 mg of the title compound as a pale yellow solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, m),
4.10-4.35 (1H, br), 5.32 (1H, s), 7.24-7.74 (7H, m),
8.04 and 8.08 (total 2H, each s), 8.75 and 8.83 (tot
al 2H, each d, J = 5.1Hz). Melting point: 182 ° C (dec).

Production Example 121 3- {3-[(3,4-difluorobenzylamino)-
(4-methoxyphenyl) methyl] phenylamino}-
4-hydroxy-3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-42) (121a) N- (3,4-difluorobenzyl) -N
-[(4-methoxyphenyl)-(3-nitrophenyl
M) ] Methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone and 8.96 g of 3,4-difluorobenzylamine were reacted in the same manner as in Production Example (1a) to give the title compound Was obtained as a pale yellow oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 3.69 (2H, d, J =
3.8Hz), 3.79 (3H, s), 4.88 (1H, s), 6.87 (2H, d, J = 8.
6Hz), 6.96-7.32 (5H, m), 7.47 (1H, t, J = 7.9Hz), 7.76
(1H, d, J = 8.7Hz), 8.07-8.09 (1H, m), 8.32 (1H, dd,
J = 1.6, 1.9Hz).

(121b) 3-[(3,4-difluoro
Benzylamino)-(4-methoxyphenyl) methyl]
12.68 g of phenylamine N- (3,4-difluorobenzyl) -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, anhydrous tin (II) chloride 25.03
Production Example (94b) using g and 120 ml of ethanol
The reaction was carried out in the same manner as in to give 13.32 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.67 (2H, s), 3.
88 (3H, s), 4.67 (1H, s), 6.52-6.55 (1H, m), 6.715-6.
724 (1H, m), 6.77-6.79 (1H, m), 6.82-6.87 (2H, m), 6.9
3-7.11 (3H, m), 7.15-7.22 (2H, m), 7.30 (2H, d, J = 8.
1Hz).

(121c) 3-t-butoxy-4- {3
-[(3,4-difluorobenzylamino)-(4-meth
Toxiphenyl) methyl] phenylamino} -3-cycl
Lobutene-1,2-dione 3-[(3,4-difluorobenzylamino)-(4-
Methoxyphenyl) methyl] phenylamine 1.32
g, 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione (1.11 g) and methanol (30 ml) were reacted in the same manner as in Production Example (1c) to give the title compound as a pale yellow foam. 1.11 g was obtained as a product. NMR spectrum (CDCl ₃ ) δppm: 1.63 (9H, s), 3.
69 (2H, s), 3.78 (3H, s), 4.78 (1H, s), 6.85 (2H, d, J
= 8.6Hz), 7.00-7.55 (10H, m).

(121d) 3- {3-[(3,4-diph
(Fluorobenzylamino)-(4-methoxyphenyl) meth
Tyl] phenylamino} -4-hydroxy-3-cyclo
Butene-1,2-dione trifluoroacetate 3-t-butoxy-4- {3-[(3,4-difluorobenzylamino)-(4-methoxyphenyl) methyl]
1.09 g of phenylamino} -3-cyclobutene-1,2-dione was dissolved in 30 ml of dichloromethane, and 2 ml of trifluoroacetic acid was added. After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, and toluene was added and azeotroped twice. The obtained white solid was suspended in ether and collected by filtration to obtain 830 mg of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.75 (3H, s),
4.02-4.23 (2H, m), 5.42 (1H, s), 6.99 (2H, d, J = 8.8H
z), 7.13-7.30 (4H, m), 7.40-7.70 (6H, m). Melting point: 206-208 ° C.

Production Example 122 3-hydroxy-4- {3-[((R) -1- (3- meth
Toxiphenyl) ethylamino)-(4-methoxyphen)
Nyl) methyl] phenylamino} -3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-349)
7) (122a) N-[(R) -1- (3-methoxyphenyl)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl ) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) methanone 9.91 g, (R) -1- (3-methoxyphenyl) ethylamine 5.83 g, triethylamine 21.
Production example using 5 ml and 6.15 ml of titanium tetrachloride (1
The reaction was carried out in the same manner as in a) to obtain an imine compound. 8. The resulting imine compound and sodium borohydride cyanide
The reaction was carried out in the same manner as in Production Example (1a) using 68 g and acetic acid (10 ml) to give the title compound as a yellow oil (9.07).
g was obtained. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.38 (t
otal 3H, each d, J = 6.6Hz), 3.57 and 3.66 (total 1H,
each q, J = 6.7 and 6.6Hz), 3.76, 3.80 and 3.81 (tot
al 6H, each s), 4.66 and 4.69 (total 1H, each s),
6.72-6.79 (5H, m), 7.25-7.32 (3H, m), 7.38 and 7.47 (1
H, each t, J = 7.9Hz), 7.59 and 7.62 (1H, each d, J = 7.
6 and 7.5Hz), 8.00-8.10 (1H, m), 8.23-8.27 (1H, m).

(122b) 3-{(4-methoxyphenyi)
)-[(R) -1- (3-methoxyphenyl) ethyl
Amino] methyl} phenylamine N-[(R) -1- (3-methoxyphenyl) ethyl]
9.04 g of -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine, anhydrous tin chloride (I
I) A reaction was carried out in the same manner as in Production Example (94b) using 17.5 g and 150 ml of ethanol, and the reaction was separated and purified to give the isomer (A) of the title compound as a pale yellow oil (1.48).
g, 1.28 g of the isomer (B) of the title compound as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 3.68 (1H, q, J = 6.6Hz), 3.75 (3H, s), 3.80 (3H
H, s), 4.50 (1H, s), 6.55-6.57 (1H, m), 6.67-6.86 (6
H, m), 7.07-7.14 (1H, m), 7.16-7.28 (4H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.7Hz), 3.62 (1H, q, J = 6.7Hz), 3.80 (6H, s), 4.50 (1
H, s), 6.50-6.51 (1H, m), 6.62 (1H, s), 6.67 (1H, d, J
= 7.6Hz), 6.75-6.89 (5H, m), 7.03 (1H, t, J = 7.9Hz),
7.15-7.28 (3H, m).

[0797] (122c) 3-t-butoxy-4- {3
-[((R) -1- (3-methoxyphenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] phenyla
180 mg of isomer (B) of mino} -3-cyclobutene-1,2-dione 3-[((R) -1- (3-methoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamine, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 18
Using 3 mg, the reaction was carried out in the same manner as in Production Example (1c).
The isomer (B) of the title compound was converted into a colorless foam by 185m.
g was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.5Hz), 3.80 (3H
H, s), 3.81 (3H, s), 4.58 (1H, s), 6.78-6.89 (6H, m),
7.05 (1H, d, J = 7.7Hz), 7.17-7.36 (5H, m).

(122d) 3-Hydroxy-4- {3-
[((R) -1- (3-methoxyphenyl) ethylamido]
No)-(4-methoxyphenyl) methyl] phenylamido
No {-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3-
Reaction and purification were carried out in the same manner as in Production Example (63b) using 180 mg of the isomer (B) of methoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-cyclobutene-1,2-dione. This gave 149 mg of isomer (B) of the title compound as a pale brown solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 3.76 (3H, s), 3.77 (3H, s), 4.09 (1H, br), 5.
01 (1H, s), 6.90-7.02 (5H, m), 7.31-7.44 (4H, m), 7.50
-7.52 (3H, m). Melting point: 180-183 ° C Optical rotation [α] D = +16.0 (c = 0.60, AcO
H).

Production Example 123 3- (3-{(4-chlorophenyl)-[(R) -1-]
Phenylethylamino] -methyl @ phenylamino)-
4-hydroxy-3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-6) (123a) N-[(4-chlorophenyl)-(3-ni
Trophenyl) methyl] -N-[(R) -1-phenyl
Ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) methanone (2.00 g), (R) -1-phenylethylamine (1.16 ml), triethylamine (4.24 ml) and titanium tetrachloride (1.26 ml). The reaction was carried out in the same manner as in the above) to obtain an imine compound. The obtained imine compound was reacted with 1.92 g of sodium borohydride cyanide and 0.66 ml of acetic acid in the same manner as in Production Example (1a) to give the isomer (A) of the title compound as a yellow oily substance in an amount of 7%.
60 mg and 720 mg of the isomer (B) of the title compound were obtained as a yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.7Hz), 3.65 (1H, q, J = 6.6Hz), 4.66 (1H, s), 7.20-7.
41 (10H, m), 7.56 (1H, d, J = 7.49Hz), 8.02-8.05 (1H,
m), 8.19-8.21 (1H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, d, J =
6.6Hz), 3.60 (1H, q, J = 6.7Hz), 4.69 (1H, s), 7.15-7.
39 (9H, m), 7.49 (1H, t, J = 8.0Hz), 7.65 (1H, d, J = 7.8H
z), 8.05-8.13 (1H, m), 8.22-8.24 (1H, m).

(123b) 3-{(4-chlorophenyl)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1-phenylethyl] amine isomer (A) 750 mg, nickel chloride hexahydrate 972 mg, hydrogen The reaction was carried out in the same manner as in Production Example (1b) using 309 mg of sodium borohydride, and the mixture was separated and purified to give the isomer (A) of the title compound as a colorless oily substance (640 m).
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 3.69 (1H, q, J = 6.7Hz), 4.48 (1H, s), 6.50-6.
70 (3H, m), 7.11 (1H, t, J = 7.7 Hz), 7.13-7.40 (9H, m). N-[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[( The reaction was carried out in the same manner as in Production Example (1b) using 710 mg of the isomer (B) of R) -1-phenylethyl] amine, 920 mg of nickel chloride hexahydrate and 293 mg of sodium borohydride, and the mixture was separated and purified. The compound isomer (B) was converted into a colorless oily substance in an amount of 620 m
g was obtained. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 3.61 (1H, q, J = 6.7Hz), 4.48 (1H, s), 6.45-6.
65 (3H, m), 7.03 (1H, t, J = 7.7Hz), 7.16-7.40 (9H,
m).

(123c) 3-t-butoxy-4- (3
-{(4-chlorophenyl)-[(R) -1-phenyl
Ethylamino] methyl @ phenylamino) -3-cyclo
630 mg of isomer (A) of butene-1,2-dione 3-{(4-chlorophenyl)-[(R) -1-phenylethylamino] methyl} phenylamine, 4-t-butoxy-3-methoxy-
Using 689 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 430 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 7.03-7.07 (1H, m), 7.20-7.37 (12H, m). 610 mg of isomer (B), 4-t-butoxy-3-methoxy-
Using 667 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 794 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.62 (1H, q, J = 6.7Hz), 4.57 (1
H, s), 6.98-7.03 (1H, m), 7.15-7.38 (12H, m).

(123d) 3- (3-{(4-chlorofu
Enyl)-[(R) -1-phenylethylamino] methyl
(Ruphenylamino) -4-hydroxy-3-cyclobu
Ten-1,2-dione 3-t-butoxy-4- (3-{(4-chlorophenyl)-[(R) -1-phenylethylamino] methyl}
Using 430 mg of isomer (A) of phenylamino) -3-cyclobutene-1,2-dione and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give isomer (A) of the title compound. 292 mg were obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.7Hz), 4.27 (1H, q, J = 6.7Hz), 5.13 (1H, s), 6.94 (1
H, d, J = 7.7Hz), 7.28 (1H, t, J = 8.1Hz), 7.35-7.68 (11
H, m). Melting point: 205 ° C. (dec) Optical rotation [α] D = −275 (c = 1.00, AcO
H) 3-t-butoxy-4- (3-{(4-chlorophenyl)-[(R) -1-phenylethylamino] methyl}
Using 324 mg of the isomer (B) of phenylamino) -3-cyclobutene-1,2-dione and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give the isomer (B) of the title compound. 210 mg were obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.7Hz), 4.18 (1H, q, J = 6.7Hz), 5.14 (1H, s), 7.02 (1
H, d, J = 7.7Hz), 7.30 (1H, t, J = 7.9Hz), 7.32-7.65 (10
H, m), 7.67 (1H, s). Melting point: 208 ° C. (dec) Optical rotation [α] D = −27.0 (c = 1.00, DM
SO).

Production Example 124 3-hydroxy-4- (3-{(4-methoxyphenyi)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamino) -3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-8) (124a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-((R) -1-phenyl)
Ruechiru) amine (4-methoxyphenyl) - (3-nitrophenyl) methanone 2.00g and (R)-1-phenylethylamine 1.18 ml, prepared with triethylamine 4.31ml titanium tetrachloride 1.28ml example ( The reaction was carried out in the same manner as in 1a) to obtain an imine compound. Using the obtained imine compound, 1.95 g of sodium cyanoborohydride and 0.67 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 2.08 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.38 and 1.39 (t
otal 3H, each d, J = 6.6Hz), 3.60 and 3.68 (total 1H,
each q, J = 6.7Hz), 3.76 and 3.81 (total 3H, each
s), 4.64 and 4.67 (total 1H, each s), 6.80 and 6.89
(total 2H, each d, J = 8.7Hz), 7.10-7.50 (8H, m), 7.59
and 7.68 (total 1H, each d, J = 7.8Hz), 7.95-8.13 (1
H, m), 8.20-8.30 (1H, m).

(124b) 3-{(4-methoxyphenyi)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] -N-[(R) -1-phenylethyl] amine 2.06 g, nickel chloride hexahydrate 2.70 g, hydrogenation Production Example (59 mg) using 860 mg of sodium boron
The reaction was carried out in the same manner as in b), and the mixture was separated and purified to obtain 510 mg of the isomer (A) of the title compound as a yellow oily substance and 672 mg of the isomer (B) of the title compound as a yellow oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.7Hz), 3.70 (1H, q, J = 6.6Hz), 3.75 (3H, s), 4.48 (1
H, s), 6.53-6.60 (1H, m), 6.65-6.70 (1H, m), 6.70 (1
H, d, J = 7.4Hz), 6.75-6.80 (2H, m), 7.10 (1H, t, J = 7.
7Hz), 7.15-7.38 (7H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, d, J =
6.6Hz), 3.65 (1H, q, J = 6.6Hz), 3.80 (3H, s), 4.48 (1
H, s), 6.45-6.51 (1H, m), 6.52-6.62 (1H, m), 6.66 (1
H, d, J = 7.9Hz), 6.82-6.87 (2H, m), 7.03 (1H, t, J = 7.
8Hz), 7.15-7.36 (7H, m).

(124c) 3-t-butoxy-4- (3
-{(4-methoxyphenyl)-[(R) -1-phenyl]
Ruethylamino] methyl @ phenylamino) -3-cycl
500 mg of isomer of lobutene-1,2-dione 3-{(4-methoxyphenyl)-[(R) -1-phenylethylamino] methyl} phenylamine (A), 4-t-butoxy-3-methoxy-
Using 554 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 633 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, d, J =
6.3Hz), 1.62 (9H, s), 3.71 (4H, br), 4.60 (1H, s), 6.
77 (2H, d, J = 8.7Hz), 7.05-7.56 (11H, m) .3-｛(4-
Methoxyphenyl)-[(R) -1-phenylethylamino] methyl @ phenylamine isomer (B) 660 m
g, using 731 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, Production Example (1c)
And 389 mg of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.45 (3H, br),
1.61 (9H, s), 3.65-3.80 (1H, m), 3.81 (3H, s), 4.59 (1
H, s), 6.90 (2H, d, J = 8.5Hz), 7.00 (1H, d, J = 6.4Hz),
7.13-7.50 (10H, m).

(124d) 3-Hydroxy-4- (3-
｛(4-methoxyphenyl)-[(R) -1-phenyl
Ethylamino] methyl @ phenylamino) -3-cyclo
Butene-1,2-dione 3-t-butoxy-4- (3-{(4-methoxyphenyl)-[(R) -1-phenylethylamino] methyl}
Using 620 mg of isomer (A) of phenylamino) -3-cyclobutene-1,2-dione and 3 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give isomer (A) of the title compound. 181 mg were obtained as a pale green solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64 (3H, d, J
= 6.7Hz), 3.74 (3H, s), 4.24 (1H, q, J = 6.7Hz), 4.97 (1
H, s), 6.97 (2H, d, J = 8.7Hz), 7.00 (1H, d, J = 8.2Hz),
7.27 (1H, t, J = 7.9Hz), 7.33-7.52 (7H, m), 7.53 (1H,
d, J = 8.1 Hz), 7.59 (1H, s). Melting point: 195 ° C. (dec) Optical rotation [α] D = −52.0 (c = 1.00, DM
SO) 3-t-butoxy-4- (3-{(4-methoxyphenyl)-[(R) -1-phenylethylamino] methyl}
Using 324 mg of the isomer (B) of phenylamino) -3-cyclobutene-1,2-dione and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (55b) to give the isomer (B) of the title compound. 164 mg were obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.8Hz), 3.77 (3H, s), 4.13 (1H, q, J = 6.6Hz), 4.96 (1
H, s), 6.95-7.05 (3H, m), 7.27 (1H, t, J = 7.9Hz), 7.3
5-7.50 (7H, m), 7.57 (1H, dd, J = 1.6Hz, 8.1Hz), 7.67
(1H, s). Melting point: 195 ° C. (dec) Optical rotation [α] D = -40.3 (c = 1.00, DM
SO).

Production Example 125 3- (3-{[(R) -1- (3-fluorophenyl)]
Ethylamino]-(p-tolyl) methyldiphenylamido
No) 4-Hydroxy-3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-3197) (125a) N-[(R) -1- (3-fluorophenyl)
Ru) ethyl] -N-[(3-nitrophenyl)-(p-
2. ( tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone
00g, 2.62 g of (R) -1- (3-fluorophenyl) ethylamine hydrochloride, 8.6 ml of triethylamine
And 2.1 ml of titanium tetrachloride, and the reaction was carried out in the same manner as in Production Example (1a) to obtain an imine compound. 3.13 g of the obtained imine compound and sodium cyanoborohydride,
The reaction was carried out in the same manner as in Production Example (1a) using 1.1 ml of acetic acid to obtain 3.59 g of the title compound as a brown oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.38 (t
otal 3H, each d, J = 6.7Hz), 2.29 and 2.36 (total 3H,
each s), 3.60-3.77 (1H, m), 4.66 and 4.70 (total 1
H, each s), 6.90-7.75 (10H, m), 8.00-8.13 (1H, m),
8.22 and 8.26 (total 1H, each s).

(125b) 3-{[(R) -1- (3-
Fluorophenyl) ethylamino]-(p-tolyl) meth
Tyl @ phenylamine N-[(R) -1- (3-fluorophenyl) ethyl]
3.59 g of -N-[(3-nitrophenyl)-(p-tolyl) methyl] amine, nickel chloride hexahydrate 4.68
g, 1.49 g of sodium borohydride, and the reaction was carried out in the same manner as in Production Example (59b), and the mixture was separated and purified. ) As a yellow oily material (649 m)
g was obtained. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J =
6.7Hz), 2.28 (3H, s), 3.71 (1H, q, J = 6.7Hz), 4.49 (1
H, s), 6.56 (1H, dd, J = 2.0, 8.1Hz), 6.64 (1H, d, J = 2.
0Hz), 6.69 (1H, d, J = 7.5Hz), 6.88-6.98 (1H, m), 7.00
-7.30 (8H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.33 (3H, d, J =
6.6Hz), 2.33 (3H, s), 3.66 (1H, q, J = 6.7Hz), 4.48 (1
H, s), 6.50 (1H, dd, J = 2.0, 8.2Hz), 6.62 (1H, d, J = 1.
9Hz), 6.66 (1H, d, J = 7.5Hz), 6.90-7.35 (9H, m).

(125c) 3-t-butoxy-4- (3
-｛[(R) -1- (3-fluorophenyl) ethyla
Mino]-(p-tolyl) methyl @ phenylamino) -3
-Isomer of cyclobutene-1,2-dione 3-{[(R) -1- (3-fluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamine (A) 500 mg, 4-t-butoxy The reaction was carried out in the same manner as in Production Example (1c) using 554 mg of -3-methoxy-3-cyclobutene-1,2-dione to obtain 633 mg of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.62 (9H, s), 2.29 (3H, s), 3.68 (1H, q, J = 6.
6Hz), 4.59 (1H, s), 6.90-7.40 (12H, m). Isomerism of 3-{[(R) -1- (3-fluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamine Using 660 mg of the isomer (B) and 731 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, the reaction was carried out in the same manner as in Production Example (1c) to give the isomer (B) of the title compound. Was obtained as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 1.62 (9H, s), 2.34 (3H, s), 3.67 (1H, q, J = 6.
6Hz), 4.56 (1H, s), 6.90-7.35 (12H, m).

(125d) 3- (3-{[(R) -1-
(3-Fluorophenyl) ethylamino]-(p-tri
Ru) methyl @ phenylamino) -4-hydroxy-3-
Cyclobutene-1,2-dione 3-t-butoxy-4- (3-{[(R) -1- (3-
Fluorophenyl) ethylamino]-(p-tolyl) methyl @ phenylamino) -3-cyclobutene-1,2-
620 mg of dione isomer (A), trifluoroacetic acid 3
The reaction was carried out in the same manner as in Production Example (55b) using
181 m of the isomer (A) of the title compound as a pale green solid
g was obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.62 (3H, d, J
= 6.7Hz), 2.28 (3H, s), 4.31 (1H, q, J = 6.6Hz), 5.04 (1
H, s), 6.93 (1H, d, J = 7.7Hz), 7.17 (1H, d, J = 7.8Hz),
7.18-7.30 (8H, m), 7.55 (1H, dd, J = 1.5, 8.1Hz), 7.6
5 (1H, s). Melting point: 200 ° C. (dec) Optical rotation [α] D = −392.2 (c = 1.00,
AcOH) 3-t-butoxy-4- (3-{[(R) -1- (3-
Fluorophenyl) ethylamino]-(p-tolyl) methyl @ phenylamino) -3-cyclobutene-1,2-
324 mg of dione isomer (B), trifluoroacetic acid 2
and the reaction was carried out in the same manner as in Production Example (55b).
The isomer (B) of the title compound was converted into a pale yellow solid by 164m.
g was obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.61 (3H, d, J
= 6.8Hz), 2.31 (3H, s), 4.22 (1H, q, J = 6.7Hz), 5.04 (1
H, s), 6.99 (1H, d, J = 7.7Hz), 7.20 (1H, d, J = 7.6Hz),
7.23-7.35 (5H, m), 7.42 (1H, s), 7.44 (1H, s), 7.45-
7.55 (1H, m), 7.56 (1H, dd, J = 1.7, 8.1Hz), 7.69 (1H,
s). Melting point: 198 ° C. (dec) Optical rotation [α] D = + 74.9 (c = 1.00, DM
SO).

Production Example 126 4- {3-[((R) -1- (3-fluorophenyl)]
Ethylamino) -phenylmethyl] phenylamino}-
3-hydroxy-3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-16) (126a) N-[(3-nitrophenyl) -phenyl
Methyl] -N-[(R) -1- (3-fluorophenyl
) Ethyl] amine (3-nitrophenyl) - phenyl ketone 1.0g and (R)-1-(3-fluorophenyl) ethylamine hydrochloride 1.12 g, triethylamine 3.27 ml, titanium tetrachloride 0.56 ml, Production Example (1) using 1.13 g of sodium borohydride cyanide and 0.37 ml of acetic acid
The reaction was carried out in the same manner as in a) to give 1.45 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.37 and 1.39 (t
otal 3H, each d, J = 6.5and 6.5Hz), 3.63 and 3.69 (to
tal 1H, each q, J = 6.7 and 6.6Hz), 4.68 and4.72 (tot
al 1H, each s), 6.92-7.03 (3H, m), 7.20-7.51 (7H,
m), 7.60 and 7.68 (total 1H, each d, J = 8.0 and 8.0H
z), 8.02-8.12 (1H, m), 8.23-8.28 (1H, m).

(126b) 3-[((R) -1- (3-
Fluorophenyl) ethylamino) -phenylmethyl]
Phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
Production Example (1) using 1.37 g of [(R) -1- (3-fluorophenyl) ethyl] amine, 2.14 g of nickel chloride hexahydrate and 623 mg of sodium borohydride.
The reaction was carried out in the same manner as in b) to give 1.16 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.34 and 1.34 (t
otal 3H, each d, J = 6.6and 6.6Hz), 3.66 and 3.72 (to
tal 1H, each q, J = 6.7 and 6.7Hz), 4.52 (1H, s), 6.51
and 6.57 (total 1H, each dd, J = 2.0, 8.1 and 2.0,
8.2Hz), 6.63-6.71 (2H, m), 6.91-7.34 (10H, m).

(126c) 3-t-butoxy-4- {3
-[((R) -1- (3-fluorophenyl) ethyla
Mino) -phenylmethyl] phenylamino} -3-cycl
Lobutene-1,2-dione 3-[((R) -1- (3-fluorophenyl) ethylamino) -phenylmethyl ] phenylamine 1.14
g, using 983 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione.
The reaction was carried out in the same manner as in c) to give the isomer (A) of the title compound.
As a yellow foam, and 660 mg of isomer (B) as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.69 (1H, q, J = 6.7Hz), 4.62 (1
H, s), 6.92-7.02 (3H, m), 7.06-7.37 (10H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.60 (1
H, s), 6.91-7.06 (4H, m), 7.14-7.37 (9H, m).

(126d) 4- {3-[((R) -1-
(3-Fluorophenyl) ethylamino) -phenylmeth
Tyl] phenylamino} -3-hydroxy-3-cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3-
Fluorophenyl) ethylamino) -phenylmethyl]
Using 360 mg of phenylamino} -3-cyclobutene-1,2-dione isomer (A), the reaction and purification were carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a pale brown solid. 301 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J
= 6.7Hz), 4.28 (1H, br), 5.09 (1H, s), 7.18 (1H, d, J =
7.8Hz), 7.24-7.50 (9H, m), 7.53 (1H, s), 7.63-7.65 (2
H, m). Melting point: 255 ° C. (dec) Optical rotation [α] D = −51.0 ° (c = 0.53, Ac
OH) 3-t-butoxy-4- {3-[((R) -1- (3-
Fluorophenyl) ethylamino) -phenylmethyl]
The reaction and purification were carried out in the same manner as in Production Example (63b) using 340 mg of the isomer (B) of phenylamino} -3-cyclobutene-1,2-dione to give the isomer (B) of the title compound as a pale yellow solid. 301 mg were obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J
= 6.7Hz), 4.21 (1H, br), 5.14 (1H, s), 7.18 (1H, d, J =
7.8Hz), 7.24-7.51 (9H, m), 7.55 (1H, s), 7.63 (2H, d,
J = 7.0 Hz). Melting point: 177-182 ° C. (dec) Optical rotation [α] D = −31.7 ° (c = 0.59, Ac)
OH).

Production Example 127 4- {3-[((R) -1- (3,4-difluorophene)
Nyl) ethylamino) -phenylmethyl] phenylami
NO-3-Hydroxy-3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-37) (127a) N-[(3-nitrophenyl) -phenyl
Methyl] -N-[(R) -1- (3,4-difluorophenyl
[Enyl] ethyl] amine (3-nitrophenyl) -phenylketone (1.0 g) and (R) -1- (3,4-difluorophenyl) ethylamine hydrochloride 1.24 g, triethylamine 3.27 m
l, 0.56 ml of titanium tetrachloride, 1.13 g of sodium borohydride, and 0.37 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 1.41 g of the title compound as a yellow oil. . NMR spectrum (CDCl ₃ ) δppm: 1.35 and 1.37 (t
otal 3H, each d, J = 6.5and 6.5Hz), 3.61 and 3.67 (to
tal 1H, each q, J = 6.6 and 6.9Hz), 4.65 and4.71 (tot
al 1H, each s), 6.88-6.98 (1H, m), 7.04-7.16 (2H,
m), 7.21-7.52 (6H, m), 7.59 and 7.66 (total 1H, eac
h, d, J = 7.4 and 7.9Hz), 8.03-8.13 (1H, m), 8.24 and
8.26 (total 1H, each t, J = 1.7 and 1.8Hz).

(127b) 3-[((R) -1- (3,
4-difluorophenyl) ethylamino) -phenylmeth
Tyl] phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
1.36 g of [(R) -1- (3,4-difluorophenyl) ethyl] amine and nickel chloride hexahydrate 2.02
g and sodium borohydride (588 mg) to carry out a reaction in the same manner as in Production Example (1b) to give 1.17 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (3H, d, J =
6.6Hz), 3.63 and 3.69 (total 1H, each q, J = 6.6 and
6.6Hz), 4.48 and 4.49 (total 1H, each s), 6.50-6.69
(3H, m), 6.92-7.34 (9H, m).

(127c) 3-t-butoxy-4- {3
-[((R) -1- (3,4-difluorophenyl) e
Tylamino) -phenylmethyl] phenylamino} -3
-Cyclobutene-1,2-dione 3-[((R) -1- (3,4-difluorophenyl)
Ethylamino) -phenylmethyl] phenylamine1.
Production Example (6) using 939 mg of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in 6c) to obtain 442 mg of the isomer (A) of the title compound as a pale yellow foam, and the isomer (B)
Was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 6.94-6.97 (1H, m), 7.07-7.38 (11H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.64 (1H, q, J = 6.6Hz), 4.57 (1
H, s), 6.94-6.97 (1H, m), 7.02-7.37 (11H, m).

(127d) 4- {3-[((R) -1-
(3,4-difluorophenyl) ethylamino) -fe
Nylmethyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
4-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-cyclobutene-1,2-
Production Example (63) using 300 mg of dione isomer (A)
The reaction and purification were carried out in the same manner as in b) to give 174 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.8Hz), 4.32 (1H, br), 5.10 (1H, s), 7.17-7.19 (1H,
m), 7.27 (1H, d, J = 7.6Hz), 7.33-7.56 (8H, m), 7.62 (2
H, d, J = 7.0 Hz). Melting point: 184-187 ° C. Optical rotation [α] D = −70.9 ° (c = 0.59, Ac)
OH) 3-t-butoxy-4- {3-[((R) -1- (3,
4-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-cyclobutene-1,2-
Production Example (63) using 195 mg of dione isomer (B)
The reaction and purification were carried out in the same manner as in b) to obtain 152 mg of the isomer (B) of the title compound as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.24 (1H, br), 5.16 (1H, s), 7.18-7.20 (1H,
m), 7.32-7.57 (9H, m), 7.64 (2H, d, J = 7.4 Hz). Melting point: 180 ° C. (dec) Optical rotation [α] D = −22.7 ° (c = 0.49, Ac
OH).

Production Example 128 4- {3-[((R) -1- (3,5-difluorophene)
Nyl) ethylamino) -phenylmethyl] phenylami
NO-3-Hydroxy-3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-51) (128a) N-[(3-nitrophenyl) -phenyl
Methyl] -N-[(R) -1- (3,5-difluorophenyl
Eniru) ethyl] amine (3-nitrophenyl) - phenyl ketone 1.0g and (R)-1-(3,5-difluorophenyl) hydrochloride ethylamine 1.24 g, triethylamine 3.27m
l, 0.56 ml of titanium tetrachloride, 1.13 g of sodium cyanoborohydride and 0.37 ml of acetic acid were reacted in the same manner as in Production Example (1a) to obtain 1.51 g of the title compound as a yellow oil. . NMR spectrum (CDCl ₃ ) δppm: 1.36 and 1.38 (t
otal 3H, each d, J = 6.6and 6.7Hz), 3.63 and 3.68 (to
tal 1H, each q, J = 6.6 and 6.6Hz), 4.68 and4.74 (tot
al 1H, each s), 6.66-6.83 (3H, m), 7.22-7.52 (6H,
m), 7.61 and 7.67 (total 1H, each d, J = 7.3 and 7.8H
z), 8.03-8.13 (1H, m), 8.24 and 8.27 (total 1H, each
t, J = 1.9 and 1.8Hz).

(128b) 3-[((R) -1- (3,
5-difluorophenyl) ethylamino) -phenylmeth
Tyl] phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
1.36 g of [(R) -1- (3,5-difluorophenyl) ethyl] amine and nickel chloride hexahydrate 2.02
g and sodium borohydride (588 mg), and the reaction was carried out in the same manner as in Production Example (1b) to obtain 1.25 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δppm: 1.322 and 1.325
(total 3H, each d, J = 6.6 and 6.6Hz), 3.64 and 3.71
(total 1H, each q, J = 6.7 and 6.7Hz), 4.51 and 4.52
(total 1H, each d), 6.52 and 6.58 (total 1H, each d
d, J = 2.0, 8.0 and 2.1, 7.2Hz), 6.63 (1H, s), 6.65-
6.71 (2H, m), 6.76-7.85 (2H, m), 7.05 and7.12 (total
1H, each t, J = 7.8 and 7.8Hz), 7.17-7.35 (5H, m).

(128c ) 3-t-butoxy-4- {3
-[((R) -1- (3,5-difluorophenyl) e
Tylamino) -phenylmethyl] phenylamino} -3
-Cyclobutene-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
Ethylamino) -phenylmethyl] phenylamine1.
Using 25 g, 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione 1.02 g, Production Example (6
The reaction was carried out in the same manner as in 6c), and 733 mg of isomer (A) of the title compound was obtained as a pale yellow foam, and isomer (B)
To give 715 mg as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J =
6.7Hz), 1.63 (9H, s), 3.69 (1H, q, J = 6.6Hz), 4.62 (1
H, s), 6.66-6.72 (1H, m), 6.80 (2H, dd, J = 2.0, 8.1H
z), 7.07-7.39 (9H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, d, J =
6.6Hz), 1.63 (9H, s), 3.66 (1H, q, J = 6.6Hz), 4.60 (1
H, s), 6.65-6.71 (1H, m), 6.80 (2H, dd, J = 2.1, 8.4H
z), 7.05-7.38 (9H, m).

(128d) 4- {3-[((R) -1-
(3,5-difluorophenyl) ethylamino) -fe
Nylmethyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-cyclobutene-1,2-
Production Example (63) using 325 mg of dione isomer (A)
The reaction and purification were carried out in the same manner as in b) to obtain 251 mg of the isomer (A) of the title compound as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.32 (1H, br), 5.18 (1H, s), 7.17 (2H, dd, J =
1.8, 8.0Hz), 7.26-7.43 (7H, m), 7.56 (1H, s), 7.65 (2
H, d, J = 7.1 Hz). Melting point: 184-187 ° C. Optical rotation [α] D = -47.2 ° (c = 0.475, A
cOH) 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-cyclobutene-1,2-
Production Example (63) using 353 mg of dione isomer (B)
The reaction and purification were carried out in the same manner as in b) to give 158 mg of the title compound isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J
= 6.7Hz), 4.27 (1H, br), 5.22 (1H, s), 7.17-7.19 (2H,
m), 7.28-7.47 (7H, m), 7.57 (1H, s), 7.65 (2H, d, J = 7.
Melting point: 180-185 ° C (dec) Optical rotation [α] D = -10.2 ° (c = 0.59, Ac
OH).

Production Example 129 3- {3-[(4-fluorophenyl)-((R) -1]
-(Naphthalen-1-yl) ethylamino) methyl] f
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-316)
2) (129a) N-[[(4-fluorophenyl)-(3
-Nitrophenyl) methyl] -N-[(R) -1- (na
[Phthalen-1-yl) ethyl] amine (4-fluorophenyl)-(3-nitrophenyl) methanone 3.68 g, (R) -1- (naphthalen-1-yl) ethylamine 2.57 g, triethylamine 8.3
Production example (1) using 6 ml and 2.47 ml of titanium tetrachloride.
The reaction was carried out in the same manner as in a) to obtain an imine compound. 2. The obtained imine compound and sodium cyanoborohydride
The reaction was carried out in the same manner as in Production Example (1a) using 77 g and 3.86 ml of acetic acid, and the title compound was obtained as a yellow oil in the form of a yellow oil.
41 g were obtained. NMR spectrum (CDCl ₃ ) δppm: 1.52 and 1.53
(total 3H, each d, J = 6.6Hz), 4.51 and 4.54 (total 1
H, each q, J = 6.6Hz), 4.76 and 4.79 (total 1H, each
s), 6.95-7.04 (2H, m), 7.16-7.27 (2H, m), 7.36-7.64
(6H, m), 7.75-7.93 (3H, m), 8.03 and 8.10 (total 1H,
each dd, J = 2.2 and 8.1Hz), 8.21 and 8.26 (total 1
H, each s).

(129b) 3-[(4-Fluorophenyl)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamine N-[[(4-fluorophenyl)-(3-nitrophenyl) -methyl] -N-[(R) -1- (naphthalene-
1-yl) ethyl] amine 5.38 g, nickel chloride 6
6.39 g of hydrate, 2.03 g of sodium borohydride
The reaction was carried out in the same manner as in Production Example (1b) and the mixture was separated and purified to give 4.46 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.48 (3H, d, J =
6.6Hz), 4.52 and 4.58 (total 1H, each q, J = 6.6Hz),
4.59 and 4.62 (total 1H, each s), 6.52-6.69 (3H, m),
6.91-7.10 (3H, m), 7.22-7.31 (2H, m), 7.37-7.51 (3H, m
m), 7.62-7.69 (1H, m), 7.75 and 7.77 (total 1H, eac
hs), 7.83-7.95 (2H, m).

(129c) 3-t-butoxy-4- {3
-[(4-fluorophenyl)-((R) -1- (naph
Taren-1-yl) ethylamino) methyl] phenyla
Mino} -3-cyclobutene-1,2-dione 3-[(4-fluorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamine 2.43 g, 4-t -Butoxy-3-methoxy-
Using 1.64 g of 3-cyclobutene-1,2-dione,
The reaction was performed and purified in the same manner as in Production Example (66c) to give 0.62 g of the isomer (A) of the title compound as a white foamy solid.
0.20 g of isomer (B) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, d, J =
6.6Hz), 1.58 (9H, s), 4.55 (1H, q, J = 6.6Hz), 4.68 (1
H, s), 6.92-7.03 (3H, m), 7.13-7.22 (3H, m), 7.23-7.
42 (3H, m), 7.42-7.53 (2H, m), 7.65 (1H, d, J = 7,3Hz),
7.77 (1H, d, J = 8.1 Hz), 7.84-7.88 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, d, J =
6.6Hz), 1.62 (9H, s), 4.53 (1H, q, J = 6.6Hz), 4.71 (1
H, s), 6.96-7.08 (3H, m), 7.13-7.35 (5H, m), 7.37-7.
54 (3H, m), 7.65 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 8.1
Hz), 7.84-7.90 (2H, d, J = 8.1Hz).

(129d) 3- {3-[(4-fluoro
Phenyl)-((R) -1- (naphthalen-1-yl)
Ethylamino) methyl] phenylamino} -4-hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl Using 0.61 g of isomer (A) of phenylamino} -3-cyclobutene-1,2-dione and 4 ml of trifluoroacetic acid, a reaction was carried out in the same manner as in Production Example (63b) to give an isomer of the title compound ( A) was converted to a white solid and 28
5 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.81 (3H, d, J
= 6.6Hz), 5.10-5.30 (2H, br), 7.09 (1H, d, J = 8.1Hz),
7.17-7.43 (7H, m), 7.47 (1H, dd, J = 7.3, 8.1Hz), 7.66
(1H, dd, J = 7.3, 8.1Hz), 7.70 (1H, d, J = 5.1Hz), 7.72
(1H, d, J = 5.9Hz), 7.95 (1H, d, J = 8.8Hz), 7.98 (1H,
d, J = 8.1 Hz), 8.05-8.18 (1H, br). Melting point: 173 ° C. (dec) Optical rotation [α] D = −48.0 (c = 1.04, DM
SO) 3-t-butoxy-4- {3-[(4-fluorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -3-cyclobutene-1, Using 0.19 g of the 2-dione isomer (B) and 2 ml of trifluoroacetic acid, the reaction was carried out in the same manner as in Production Example (63b) to obtain 147 mg of the hydrochloride of the isomer (B) of the title compound as a white solid. Was. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.81 (3H, d, J
= 6.6Hz), 5.00-5.10 (1H, br), 5.45 (1H, s), 7.16-7.24
(2H, m), 7.29-7.71 (10H, m), 7.97-8.04 (3H, m). Melting point: 178 ° C (dec) Optical rotation [α] D = -92.9 (c = 1.01, DM
SO).

Production Example 130 3- {3-[(4-Chlorophenyl)-((R) -1-)
(Naphthalen-1-yl) ethylamino) methyl] fe
Nilamino} -4-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-313
6) (130a) N-[[(4-chlorophenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (naph
[Talen-1-yl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) methanone 3.93 g, (R) -1- (naphthalen-1-yl) ethylamine 2.57 g, triethylamine 8.3
Production example (1) using 6 ml and 2.47 ml of titanium tetrachloride.
The reaction was carried out in the same manner as in a) to obtain an imine compound. 2. The obtained imine compound and sodium cyanoborohydride
The reaction was carried out in the same manner as in Production Example (1a) using 77 g and 3.86 ml of acetic acid, and the title compound was obtained as a yellow oil in the form of a yellow oil.
42 g were obtained. NMR spectrum (CDCl ₃ ) δppm: 1.52 and 1.53
(total 3H, each d, J = 6.6Hz), 4.48-4.56 (1H, m), 4.7
5 and 4.78 (total 1H, each s), 7.15-7.31 (4H, m), 7.
36-7.63 (6H, m), 7.75-7.94 (3H, m), 8.02-8.12 (1H,
m), 8.20 and 8.26 (total 1H, each s).

(130b) 3-[(4-Chlorophenyi)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamine N-[[(4-chlorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1- (naphthalene-1-
Yl) ethyl] amine 5.38 g, nickel chloride hexahydrate 6.15 g, and sodium borohydride 1.98 g, and the reaction was carried out in the same manner as in Production Example (1b) to separate and purify.
4.30 g of the title compound were obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.48 (3H, d, J =
6.6Hz), 4.49-4.60 (2H, m), 6.52-6.70 (3H, m), 7.03-
7.10 (1H, m), 7.20-7.29 (4H, m), 7.37-7.51 (3H, m),
7.62-7.68 (1H, m), 7.76 and 7.77 (total 1H, each s),
7.84-7.96 (2H, m).

(130c) 3-t-butoxy-4- {3
-[(4-chlorophenyl)-((R) -1- (naphtha
Len-1-yl) ethylamino) methyl] phenylami
4-{- 3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamine 4.29 g, 4-t- Butoxy-3-methoxy-3
The reaction was carried out and purified using 2.45 g of -cyclobutene-1,2-dione in the same manner as in Production Example (66c) to give 1.49 g of the isomer (A) of the title compound as a white foamy solid, 1.81 g of B) were obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.52 (3H, d, J =
6.6Hz), 1.58 (9H, s), 4.55 (1H, q, J = 6.6Hz), 4.68 (1
H, s), 6.99 (1H, d, J = 6.6Hz), 7.13-7.20 (2H, m), 7.22
-7.42 (6H, m), 7.43-7.53 (2H, m), 7.65 (1H, d, J = 7,3H
z), 7.78 (1H, d, J = 8.8 Hz), 7.87 (2H, d, J = 8.1 Hz). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J =
6.6Hz), 1.77 (9H, s), 4.52 (1H, q, J = 6.6Hz), 4.67 (1
H, s), 7.03 (1H, d, J = 7.3Hz), 7.13-7.34 (7H, m), 7.37
-7.51 (3H, m), 7.64 (1H, d, J = 6.6Hz), 7.77 (1H, d, J =
(8.1Hz), 7.87 (2H, d, J = 8.1Hz). (130d) 3- {3-[(4-chlorophenyl)-
((R) -1- (naphthalen-1-yl) ethylamido
No) methyl] phenylamino} -4-hydroxy-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamino}- Using 0.80 g of 3-cyclobutene-1,2-dione isomer (A) and 5 ml of trifluoroacetic acid, a reaction was carried out in the same manner as in Production Example (63b) to give the isomer (A) of the title compound as a white solid And 47
0 mg was obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δppm: 1.79 (3H, d, J
= 5.9Hz), 5.18-5.24 (1H, br), 5.33 (1H, s), 6.98 (1H,
d, J = 7.3Hz), 7.21 (1H, t, J = 8.1Hz), 7.28-7.44 (3H,
m), 7.45-7.55 (4H, m), 7.59-7.70 (3H, m), 7.92-8.04
(3H, m). Melting point: 167 ° C. (dec) Optical rotation [α] D = −71.9 (c = 1.02, DM
SO) 3-t-butoxy-4- {3-[(4-chlorophenyl)-((R) -1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -3-cyclobutene-1,2 The reaction was carried out in the same manner as in Production Example (63b) using 0.68 g of the isomer (B) of -dione and 5 ml of trifluoroacetic acid to obtain 477 mg of the hydrochloride of the isomer (B) of the title compound as a white solid. . Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.82 (3H, d, J
= 6.6Hz), 5.00-5.12 (1H, br), 5.43 (1H, s), 7.26-7.61
(10H, m), 7.63-7.71 (2H, m), 7.97-8.09 (3H, m). Melting point: 176 ° C. (dec) Optical rotation [α] D = −93.7 (c = 1.01, DM
SO).

Production Example 131 3- (3-{(4-fluorophenyl)-[(R) -1]
-Phenylethylamino] methyl @ phenylamino)-
4-hydroxy-3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-5) (131a) N-[(4-fluorophenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1-phenyi
[Ethyl] amine (4-fluorophenyl)-(3-nitrophenyl) methanone 3.00 g, (R) -1-phenylethylamine 1.85 ml, triethylamine 6.78 ml and titanium tetrachloride 2.02 ml (Production Example) The reaction was carried out in the same manner as in 1a) to obtain an imine compound. Using the obtained imine compound, 3.08 g of sodium cyanoborohydride, and 1.05 ml of acetic acid, the reaction was carried out in the same manner as in Production Example (1a) to obtain 3.93 g of the title compound as a yellow oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.39 and 1.40 (to
tal 3H, each d, J = 6.6Hz), 3.60 and 3.65 (total 1H,
each q, J = 6.6Hz), 4.67 and 4.69 (total 1H, each s),
6.96 and 7.04 (total 2H, each t, J = 8.7Hz), 7.10-7.
41 (7H, m), 7.39and 7.49 (total 1H, each t, J = 7.8H
z), 7.57 and 7.67 (total 1H, each d, J = 7.8Hz), 8.00
-8.15 (1H, m), 8.20 and 8.24 (total 1H, each t, J = 1.
9Hz).

(131b) 3-{(4-Fluorophenyl)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl) methyl] -N-[(R) -1-phenylethyl] amine 3.90 g, nickel chloride hexahydrate 5.29 g, hydrogenated Production Example (59) using 1.68 g of sodium boron
The reaction was carried out in the same manner as in b), and the mixture was separated and purified to obtain 1.24 g of the isomer (A) of the title compound as a colorless oily substance and 848 mg of the isomer (B) of the title compound as a colorless oily substance. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 3.70 (1H, q, J = 6.7Hz), 4.49 (1H, s), 6.57 (1
H, dd, J = 2.0Hz, 7.8Hz), 6.63 (1H, t, J = 1.8Hz), 6.68
(1H, d, J = 7.8Hz), 6.91 (2H, t, J = 8.7Hz), 7.11 (1H,
t, J = 7.8Hz), 7.20-7.30 (5H, m), 7.33 (2H, t, J = 7.8H
z). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J =
6.6Hz), 3.61 (1H, q, J = 6.7Hz), 4.50 (1H, s), 6.50 (1H
H, dd, J = 2.0Hz, 8.0Hz), 6.59 (1H, t, J = 1.7Hz), 6.63
(1H, d, J = 7.9Hz), 6.95-7.07 (3H, m), 7.15-7.40 (7H,
m).

(131c) 3-t-butoxy-4- (3
-{(4-fluorophenyl)-[(R) -1-phenyl]
Ruethylamino] methyl @ phenylamino) -3-cycl
1.24 g of isomer of lobutene-1,2-dione 3-{(4-fluorophenyl)-[(R) -1-phenyl-ethylamino] methyl} phenylamine (A), 4-t-butoxy-3 -Methoxy-
Using 1.43 g of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 1.22 g of the isomer (A) of the title compound as a white foamy solid. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.67 (1H, q, J = 6.6Hz), 4.60 (1
H, s), 6.93 (2H, t, J = 8.8 Hz), 7.04-7.40 (11H, m). 3-{(4-fluorophenyl)-[(R) -1-phenylethylamino] methyl} phenyl Amine isomer (B) 848 mg, 4-t-butoxy-3-methoxy-
Using 975 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Production Example (1c) to obtain 1.03 g of the isomer (B) of the title compound as a white foamy solid. Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.63 (1H, q, J = 6.6Hz), 4.59 (1
H, s), 7.02 (3H, t, J = 8.8Hz), 7.12-7.37 (10H, m).

(131d) 3- (3-{(4-Fluoro)
Phenyl)-[(R) -1-phenylethylamino] meth
Tyl @ phenylamino) -4-hydroxy-3-cyclo
Butene-1,2-dione 3-t-butoxy-4- (3-{(4-fluorophenyl)-[(R) -1-phenylethylamino] methyl}
Using 830 mg of isomer (A) of phenylamino) -3-cyclobutene-1,2-dione and 4 ml of trifluoroacetic acid, a reaction was carried out in the same manner as in Production Example (63b) to give isomer (A) of the title compound. 610 mg were obtained as a pale green solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.63 (3H, d, J
= 6.8Hz), 4.28 (1H, br), 5.10 (1H, s), 6.91 (1H, d, J =
(7.8Hz), 7.22-7.46 (8H, m), 7.53 (1H, d, J = 7.8Hz), 7.56
-7.62 (2H, m), 7.65 (1H, s). Melting point 198 ° C (dec) Optical rotation [α] D = -62.6 (c = 1.00, DM
SO) 3-t-butoxy-4- (3-{(4-fluorophenyl)-[(R) -1-phenylethylamino] methyl}
Using 618 mg of isomer (B) of phenylamino) -3-cyclobutene-1,2-dione and 3 ml of trifluoroacetic acid, a reaction was carried out in the same manner as in Production Example (62b) to give isomer (B) of the title compound. 484 mg were obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60 (3H, d, J
= 5.9Hz), 4.14 (1H, br), 5.09 (1H, s), 6.95 (1H, d, J =
7.8 Hz), 7.23-7.63 (11 H, m), 7.70 (1 H, s). Melting point: 209 ° C. (dec) Optical rotation [α] D = -20.5 (c = 1.00, DM
SO).

Production Example 132 3- (3-{[(R) -1- (3,4-difluorophene)
Nylamino) ethylamino]-(p-tolyl) methyl
Phenylamino) -4-hydroxy-3-cyclobutene
-1,2-dione hydrochloride (Exemplary Compound No. 2-338)
6) (3-nitrophenyl)-(p-tolyl) methanone
23 g and (R) -1- (3,4-difluorophenyl)
Using 3.39 g of ethylamine, the reaction and purification were carried out in the same manner as in Production Example 117 to give 20% of isomer (A) of the title compound.
7 mg and 403 mg of isomer (B) were obtained. Isomer (A) Optical rotation [α] D = −93.5 (c = 1.01, A
cOH) Isomer (B) Optical rotation [α] D = -12.5 (c = 1.01, A
cOH).

Production Example 133 3-Hydroxy-4- {3-[((R) -1- (naphtha)
Len-1-yl) ethylamino) -phenylmethyl] f
Phenylamino} -3-cyclobutene-1,2-dione
(Exemplified Compound No. 2-3316) (133a) N-[(R) -1- (naphthalene-1-i)
Ru) ethyl] -N-[(3-nitrophenyl) -phenyl
[Methyl] amine (Exemplified Compound No. 2-) 1.0 g of (3-nitrophenyl) -phenyl ketone and 1.09 of (R) -1- (1-naphthyl) ethylamine
g, triethylamine 2.68 ml, titanium tetrachloride 0.
56 ml, sodium cyanoborohydride 1.13
g, acetic acid 0.37 ml, and the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil (1.63 g).
Obtained. NMR spectrum (CDCl ₃ ) δppm: 1.52 and 1.53 (t
otal 3H, each d, J = 6.6and 6.8Hz), 4.50-4.59 (1H, ea
ch m), 4.78 and 4.82 (total 1H, each s), 7.21-7.97
(14H, m), 8.00-8.10 (1H, m), 8.25-8.30 (1H, m).

(133b) 3-[((R) -1- (naph
Taren-1-yl) ethylamino) -phenylmethyl]
Phenylamine N-[(R) -1- (naphthalen-1-yl) ethyl]
Production Example (1) using 1.56 g of -N-[(3-nitrophenyl) -phenylmethyl] amine, 2.23 g of nickel chloride hexahydrate and 650 mg of sodium borohydride.
The reaction was carried out in the same manner as in b) to give 1.35 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.479 and 1.482
(total 3H, each d, J = 6.6 and 6.6Hz), 4.55 and 4.60
(total 1H, each q, J = 6.7 and 6.6Hz), 4.63 and 4.65
(total 1H, each s), 6.51-6.73 (3H, m), 7.04-7.09 (1
H, m), 7.17-7.51 (8H, m), 7.69 (1H, t, J = 7.5Hz), 7.7
5-7.95 (3H, m).

(133c) 3-t-butoxy-4- {3
-[((R) -1- (naphthalen-1-yl) ethyla
Mino) -phenylmethyl] phenylamino} -3-cycl
Lobutene-1,2-dione 3-[((R) -1- (naphthalen-1-yl) ethylamino) -phenylmethyl ] phenylamine 1.28
g, using 1.0 g of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, Production Example (66c)
The reaction was carried out and purified in the same manner as described above to obtain 680 mg of the isomer (A) of the title compound as a yellow foam and 670 mg of the isomer (B) as a pale yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, d, J =
6.6Hz), 1.57 (9H, s), 4.57 (1H, q, J = 6.6Hz), 4.72 (1
H, s), 6.99-7.08 (1H, m), 7.14-7.53 (11H, m), 7.67 (1
H, d, J = 7.0Hz), 7.77 (1H, d, J = 8.1Hz), 7.82-7.88 (2
H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J =
6.6Hz), 1.61 (9H, s), 4.55 (1H, q, J = 6.6Hz), 4.73 (1
H, s), 7.08 (1H, d, J = 7.4Hz), 7.12-7.51 (11H, m), 7.
68 (1H, d, J = 7.1Hz), 7.76 (1H, d, J = 8.2Hz), 7.86-7.9
0 (2H, m).

(133d) 3-Hydroxy-4- {3-
[((R) -1- (naphthalen-1-yl) ethylamido]
No) -Phenylmethyl] phenylamino} -3-cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (naphthalen-1-yl) ethylamino) -phenylmethyl]
The reaction and purification were carried out in the same manner as in Production Example (63b) using 400 mg of the isomer (A) of phenylamino} -3-cyclobutene-1,2-dione to give the isomer (A) of the title compound as a pale yellow solid. 315 mg were obtained. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.81 (3H, d, J
= 6.6Hz), 5.19 (1H, br), 5.25 (1H, br), 7.09 (1H, d, J =
7.7Hz), 7.21-7.25 (1H, m), 7.32-7.50 (8H, m), 7.65-7.
69 (3H, m), 7.95-8.05 (3H, m). Melting point: 202-206 ° C Optical rotation [α] D = -122.9 ° (c = 0.5, Ac
OH) 3-t-butoxy-4- {3-[((R) -1- (naphthalen-1-yl) ethylamino) -phenylmethyl]
The reaction and purification were carried out in the same manner as in Production Example (63b) using 240 mg of the isomer (B) of phenylamino} -3-cyclobutene-1,2-dione to give 195 mg of the isomer (B) of the title compound as a white solid. Obtained. Isomer (B) NMR spectrum (DMSO-d ₆ ) δppm: 1.83 (3H, d, J
= 6.7Hz), 5.06 (1H, br), 5.36 (1H, s), 7.22-7.46 (8H,
m), 7.49-7.55 (3H, m), 7.62 (1H, s), 7.67 (1H, dd, J =
7.7, 7.8Hz), 7.97-8.04 (3H, m). Melting point: 206 ° C Optical rotation [α] D = -117.6 ° (c = 0.5, Ac
OH).

Production Example 134 3-Hydroxy-4- {3-[((R) -1- (naphtha)
Len-1-yl) ethylamino)-(p-tolyl) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-3164) (134a) N-[(R) -1- (naphthalene-1-i)
L) ethyl] -N-[(3-nitrophenyl)-(p-to
(Lyl) methyl] amine (Exemplary Compound No. 2-) (3-nitrophenyl)-(p-tolyl) ketone 1.0
g and (R) -1- (1-naphthyl) ethylamine 1.0
6g, triethylamine 2.60ml, titanium tetrachloride 0.55ml, sodium cyanoborohydride 1.1
Using 0 g and acetic acid 0.36 ml, the reaction was carried out in the same manner as in Production Example (1a) to give the title compound as a yellow oil (1.60).
g was obtained. NMR spectrum (CDCl ₃ ) δppm: 1.51 and 1.52 (t
otal 3H, each d, J = 6.6and 6.8Hz), 2.31 and 2.35 (to
tal 3H, each s), 4.52 and 4.57 (total 1H, each q, J
= 6.7 and 6.6Hz), 4.74 and 4.79 (total 1H, each s),
7.09-7.19 (4H, m), 7.33-8.09 (10H, m), 8.25 and 8.30
(1H, m).

(134b) 3-[((R) -1- (naph
Taren-1-yl) ethylamino)-(p-tolyl) me
[ Tyl] phenylamine N-[(R) -1- (naphthalen-1-yl) ethyl]
1.51 g of -N-[(3-nitrophenyl)-(p-tolyl) methyl] amine and 2.08 of nickel chloride hexahydrate
g and sodium borohydride (607 mg) were reacted in the same manner as in Production Example (1b) to obtain 1.40 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (3H, d, J =
6.6Hz), 2.30 and 2.33 (total 3H, each s), 4.53 and
4.61 (1H, m), 4.60 and 4.61 (total 1H, each s), 6.50-
6.72 (3H, m), 7.03-7.10 (3H, m), 7.15 (1H, d, J = 8.0H
z), 7.22 (1H, d, J = 8.0Hz), 7.35-7.51 (3H, m), 7.69 (1
H, dd, J = 4.3, 6.2Hz), 7.76 (1H, d J = 8.2Hz), 7.86 (1
H, d J = 8.0Hz), 7.90-7.95 (1H, m).

(134c) 3-t-butoxy-4- {3
-[((R) -1- (naphthalen-1-yl) ethyla
Mino)-(p-tolyl) methyl] phenylamino} -3
-Cyclobutene-1,2-dione 3-[((R) -1- (naphthalen-1-yl) ethylamino)-(p-tolyl) methyl] phenylamine
40 g and 1.06 g of 4-t-butoxy-3-methoxy-3-cyclobutene-1,2-dione, using a production example (6
The reaction was carried out and purified in the same manner as in 6c), and 780 mg of the isomer (A) of the title compound was obtained as a yellow foam,
Was obtained as a yellow foam. Isomer (A) NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J =
6.6Hz), 1.57 (9H, s), 2.31 (3H, s), 4.56 (1H, q, J = 6.
6Hz), 4.68 (1H, s), 7.00-7.52 (11H, m), 7.66 (1H, d,
J = 7.1Hz), 7.77 (1H, d, J = 8.4Hz), 7.82-7.88 (2H, m). Isomer (B) NMR spectrum (CDCl ₃ ) δppm: 1.49 (3H, d, J =
6.7Hz), 1.60 (9H, s), 2.34 (3H, s), 4.55 (1H, q, J = 6.
6Hz), 4.69 (1H, s), 7.07-7.27 (8H, m), 7.37-7.50 (3H,
m), 7.68 (1H, d, J = 7.1Hz), 7.75 (1H, d, J = 8.1Hz),
7.86 (1H, d, J = 8.0Hz), 7.92 (1H, d, J = 8.5Hz).

(134d) 3-hydroxy-4- {3-
[((R) -1- (naphthalen-1-yl) ethylamido]
No)-(p-tolyl) methyl] phenylamino} -3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (naphthalen-1-yl) ethylamino)-(p-tolyl) methyl] -phenylamino} -3-cyclobutene-1,2
Production Example (6) using 400 mg of -dione isomer (A)
The reaction and purification were carried out in the same manner as in 3b) to give 343 mg of the title compound isomer (A) as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.80 (3H, d, J
= 6.6Hz), 2.31 (3H, s), 5.16 (1H, br), 5.23 (1H, br),
7.08 (1H, d, J = 7.7Hz), 7.22-7.35 (6H, m), 7.40 (1H,
s), 7.46-7.53 (3H, m), 7.67 (1H, t, J = 7.7Hz), 7.95-
8.03 (3H, m). Melting point: 203 ° C. (dec) Optical rotation [α] D = −84.2 ° (c = 0.5, AcO
H) 3-t-butoxy-4- {3-[((R) -1- (naphthalen-1-yl) ethylamino)-(p-tolyl) methyl] phenylamino} -3-cyclobutene-1,2 −
Production Example (63) using 300 mg of dione isomer (B)
The reaction and purification were carried out in the same manner as in b) to obtain 218 mg of the isomer (B) of the title compound as a yellow solid. Isomer (B) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.81 (3H, d, J
= 6.6Hz), 2.28 (3H, s), 5.05 (1H, br), 5.31 (1H, s), 7.
15 (2H, d, J = 8.1Hz), 7.29-7.47 (7H, m), 7.52 (1H, dd,
J = 7.7, 7.9Hz), 7.61 (1H, s), 7.67 (1H, dd, J = 7.7,
7.8Hz), 7.98-8.02 (3H, m). Melting point: 210-215 ° C Optical rotation [α] D = -96.0 ° (c = 0.54, Ac
OH).

Production Example 135 3-Hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino) phenylmethyl
Ru] phenylamino} -3-cyclobutene-1,2-di
On (exemplified compound number 2-3508) When the reaction and purification are carried out in the same manner as in Production Example 55 using 3-nitrobenzophenone and (R) -1- (2,3-difluorophenyl) ethylamine, the title compound is obtained.

Production Example 136 3-Hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(p-tri
Ru) methyl] phenylamino} -3-cyclobutene-
1,2-dione (Exemplified Compound No. 2-3511) Same as in Production Example 55 using (3-nitrophenyl)-(p-tolyl) methanone and (R) -1- (2,3-difluorophenyl) ethylamine. The title compound is obtained by reaction and purification.

Production Example 137 3-Hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(4-fluoro
Lphenyl) methyl] phenylamino} -3-cyclobut
Ten-1,2-dione (Exemplary Compound No. 2-3509) (3-Nitrophenyl)-(4-fluorophenyl) methanone and (R) -1- (2,3-difluorophenyl)
The title compound is obtained by carrying out the reaction and purification in the same manner as in Production Example 55 using ethylamine.

Production Example 138 3-Hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(4-chloro
Phenyl) methyl] phenylamino} -3-cyclobute
Down-1,2-dione (Compound No. 2-3510) (3-nitrophenyl) - (4-chlorophenyl) methanone and (R)-1-(2,3-difluorophenyl) Preparation 55 using ethylamine When the reaction and purification are carried out in the same manner as in the above, the title compound is obtained.

Production Example 139 3-Hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(4-methoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
Ten-1,2-dione (Exemplified Compound No. 2-351) (3-Nitrophenyl)-(4-methoxyphenyl) methanone and (R) -1- (2,3-difluorophenyl)
The title compound is obtained by carrying out the reaction and purification in the same manner as in Production Example 55 using ethylamine.

Example 1 HDL-C (high density lipoprotein-cholesterol)
Measurements Male Syrian golden hamsters were used in the experiments. Animals were housed in metal cages and had free access to a powdered diet containing 0.3% cholesterol and 10% coconut oil and water. Pravastatin, the compound of Production Example 64, and both agents (combination use) were administered at a dose of 0.01% (w / w), respectively, for 2 weeks. The HDL-C measurement was performed using a commercially available measurement kit. Table 5 shows the results.

[0849] From the following results, pravastatin and Production Example 6
By synergistically using HDL-C
It is evident that

[0850]

[Table 5] Test compound HDL-C value Pravastatin 26% Compound of Production Example 64 0% .................. Pavastatin + Compound of Production Example 64 41% Formulation Example 1 Tablet Pravastatin sodium salt (10.0 mg), Production Example 6
Compound 4 (30.0 mg), lactose (408.0 mg), corn starch (50.0 mg) and magnesium stearate (2.0 mg) were mixed, and the mixture was tableted with a tablet machine to give one tablet of 500 mg. And The tablet can be coated (preferably sugar-coated) as necessary.

[0851]

According to the present invention, there is provided a pharmaceutical composition comprising a cyclobutene derivative having the above general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, and an HMG-CoA reductase inhibitor. It has an excellent lipid-lowering effect, has an excellent inhibitory effect on arteriosclerosis in the aorta, has an excellent inhibitory effect on xanthomas that develop in the limb joints, and has low toxicity Therefore, it is useful as a preventive or therapeutic agent (particularly a therapeutic agent) for hyperlipidemia, arteriosclerosis or xanthoma in warm-blooded animals (particularly humans).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/44 A61K 31/44 31/47 31/47 31/505 31/505 45/00 45/00 A61P 3/06 A61P 3/06 9/10 101 9/10 101 35/00 35/00 43/00 111 43/00 111 (72) Inventor Koji Kurata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo F-term within the company (reference) 4C084 AA17 MA01 NA14 ZA452 ZB262 ZC202 ZC332 4C086 AA01 AA02 BA17 BC05 BC13 BC17 BC28 BC42 MA02 MA04 NA14 ZA45 ZB26 ZC20 ZC33 ZC75 4C206 AA01 AA02 DB02 DB52 FA08 ZA04 Z0433

Claims (44)

[Claims] 1. An HMG-CoA reductase inhibitor and a compound represented by the general formula (I): [Wherein, R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1 to 5 groups selected from substituent groups a and b, and a substituent group selected from substituent groups a and b] An aryl group substituted by 1 to 5 groups or a heterocyclic group substituted by 1 to 5 groups selected from substituent groups a and b, wherein R ² is a cycloalkyl group, an aryl group, Heterocyclic group, cycloalkyl group substituted by 1 to 3 groups selected from substituent group a, 1 to 3 groups selected from substituent group a
A substituted or unsubstituted aryl group or a heterocyclic group substituted by 1 to 3 groups selected from a substituent group a, wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom or a substituent group a; A represents a group selected, wherein A is a group represented by the formula (A-1): (Wherein, R ⁵ represents a hydrogen atom, a hydroxy group or a lower alkyl group, R ⁶ represents a hydroxy group, a lower alkoxy group, a lower alkylthio group or an amine residue, and X and Y are the same or different. , An oxygen atom or a sulfur atom; Z represents a single bond or a C ₁ -C ₆ alkylene group); and G represents a single bond, a C ₁ -C ₆ alkylene group or a substituted C ₁ -C ₆ alkylene group.
_1- C ₆ alkylene group (the substituent is a cycloalkyl substituted with 1 to 5 groups selected from a hydroxy group, an oxo group, a cycloalkyl group, an aryl group, a heterocyclic group, a group of substituents a and b) Group, an aryl group substituted by 1 to 5 groups with a group selected from substituent groups a and b, or substituent group a
And a heterocyclic group substituted by 1 to 5 groups selected from b and b. ), And when the broken line indicates a double bond, D indicates a carbon atom;
E represents a group having ＮN—O—, and when the broken line represents a single bond, D represents a group having CH or a nitrogen atom; and E represents an oxygen atom, a sulfur atom, and —NH—.
Or a group having -CO-, wherein the substituent group a is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group,
A lower alkylthio group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a cyano group and a nitro group; and the substituent group b is a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, A lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and 1 to 3 substituents selected from a group selected from the substituent group a , Cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio groups. Or a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof having the above-mentioned formula (I) or separately at an interval. 2. The compound having the general formula (I) is a compound represented by the general formula (Ia) or (Ib): The pharmaceutical composition according to claim 1, which is a compound having the following formula: 3. The pharmaceutical composition according to claim 2, wherein the compound having the general formula (I) is a compound having the general formula (Ia). 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein Z is a single bond or a C ₁ -C ₂ alkylene group. 5. The pharmaceutical composition according to any one of claims 1 to 3, wherein Z is a single bond or a methylene group. 6. The pharmaceutical composition according to any one of claims 1 to 3, wherein Z is a single bond. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein R ⁵ is a hydrogen atom or a lower alkyl group. 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein R ⁵ is a hydrogen atom or a methyl group. 9. The method according to claim 1, wherein R ⁵ is a hydrogen atom.
Item 7. The pharmaceutical composition according to any one of Items 6 to 6. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein R ⁶ is a hydroxy group or an amine residue. 11. The pharmaceutical composition according to any one of claims 1 to 9, wherein R ⁶ is a hydroxy group, a hydroxyamino group or an amino group. 12. The pharmaceutical composition according to any one of claims 1 to 9, wherein R ⁶ is a hydroxy group. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein X and Y are oxygen atoms. 14. The pharmaceutical composition according to any one of claims 1 to 13, wherein D is a group having CH or a nitrogen atom. 15. The pharmaceutical composition according to any one of claims 1 to 13, wherein D is a group having CH. 16. E is an oxygen atom, a sulfur atom or -NH-
The pharmaceutical composition according to any one of claims 1 to 15, which is a group having the formula: 17. The pharmaceutical composition according to any one of claims 1 to 15, wherein E is a group having -NH-. 18. The method according to any one of claims 1 to 17, wherein G is a C ₁ -C ₆ alkylene group or a substituted C ₁ -C ₆ alkylene group. Pharmaceutical composition. 19. G is a C ₁ -C ₆ alkylene group or a substituted C ₁ -C ₆ alkylene group, wherein said substituent is a hydroxy group, an oxo group, an aryl group or a group selected from a substituent group a. 18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the composition is an aryl group substituted with 1 to 3 groups. 20. The pharmaceutical composition according to any one of claims 1 to 17, wherein G is a C ₁ -C ₆ alkylene group. 21. The pharmaceutical composition according to any one of claims 1 to 17, wherein G is a C ₁ -C ₄ alkylene group. 22. The pharmaceutical composition according to any one of claims 1 to 17, wherein G is a methylene, methylmethylene or ethylmethylene group. 23. The pharmaceutical composition according to any one of claims 1 to 17, wherein G is a methylmethylene group. 24. R ¹ is a group selected from a cycloalkyl group, an aryl group, a heterocyclic group, a substituent group a and b.
24 selected from claims 1 to 23, which is an aryl group substituted with 1 to 3 or a heterocyclic group substituted 1 to 3 with a group selected from substituent groups a and b. The pharmaceutical composition according to any one of the preceding claims. 25. An aryl group wherein R ¹ is an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or an aryl group substituted by 1 to 3 groups selected from substituent groups a and b. 4. A 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring or substituted with 1 to 3 groups selected from substituent groups a and b. 24. The pharmaceutical composition according to any one of items 23. 26. R ¹ may be condensed with an aryl group or a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or may be condensed with 1 to 3 substituted aryl groups or a benzene ring. To a 6-membered aromatic heterocyclic group (the substituent is a group selected from a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and a group selected from the substituent group a; 24 to 3 substituted groups selected from the group consisting of cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio groups.) The pharmaceutical composition according to claim 1. 27. R ¹ may be condensed with an aryl group or a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or may be condensed with 1 to 3 substituted aryl groups or a benzene ring. 6-membered aromatic heterocyclic group (the substituent comprises a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a nitro group, a cycloalkyl group, an aryl group, an aryloxy group and an arylthio group 24. The pharmaceutical composition according to any one of claims 1 to 23, which is a group selected from the group :). 28. A thienyl, furyl, pyrrolyl, thiazolyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl or benzene ring fused to R ¹
An oxazolyl, imidazolyl or pyridyl group, or a 1 to 3 substituted phenyl or naphthyl group (the substituent is a group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group) The pharmaceutical composition according to any one of claims 1 to 23, which is a group selected from the group consisting of: 29. R ¹ is phenyl, 1-naphthyl, 2-
Naphthyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4
-Difluorophenyl, 3,5-difluorophenyl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methylphenyl, 4-methylphenyl, 3,4
-Dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,
The pharmaceutical composition according to any one of claims 1 to 23, which is a 5-trimethoxyphenyl, 3,4,5-trifluorophenyl, thienyl or pyridyl group. 30. R ¹ is phenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-thienyl or 24. The pharmaceutical composition according to any one of claims 1 to 23, which is a 4-pyridyl group. 31. R ² is a group selected from the group consisting of a cycloalkyl group, an aryl group, a heterocyclic group and a substituent a.
31. Any one selected from claims 1 to 30 which is a monosubstituted aryl group or a heterocyclic group substituted by 1 to 3 groups selected from a substituent group a. A pharmaceutical composition according to claim 1. 32. R ² is an aryl group, a benzene ring condensed with 5 to be 6-membered aromatic heterocyclic group, or 1 to 3
A 5- or 6-membered aromatic heterocyclic group which may be condensed with an individually substituted aryl group or a benzene ring (the substituent comprises a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group) 31. The method according to claim 1, wherein the group is a group selected from the group.)
The pharmaceutical composition according to any one of the above items. 33. A thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl group wherein R ² is condensed with an aryl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl or benzene ring. Or a pyridyl group or a single-substituted aryl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group). 31. The pharmaceutical composition according to any one of items 30 to 30. (34) R ² is a phenyl group, a naphthyl group, 2-
A thienyl group, a 4-pyridyl group, or a single-substituted phenyl or naphthyl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group); 31. The pharmaceutical composition according to any one of claims 1 to 30. 35. R ² is a phenyl group or a monosubstituted phenyl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group). 31. The pharmaceutical composition according to any one of claims 1 to 30. 36. When R ² is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 4-methylphenyl,
4. The method according to claim 1, which is a methoxyphenyl group.
The pharmaceutical composition according to any one of items 0 to 10. 37. The method according to claim 1, wherein R ³ and R ⁴ are the same or different and each is a hydrogen atom, a hydroxy group, a halogen atom, a lower alkoxy group, an amino group or a di-lower alkylamino group. 37. The pharmaceutical composition according to any one of items 36. 38. The method according to any one of claims 1 to 36, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxy group or a lower alkoxy group. Pharmaceutical composition. 39. The pharmaceutical composition according to any one of claims 1 to 36, wherein R ³ and R ⁴ are a hydrogen atom. 40. The cyclobutene derivative having the general formula (I) is 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3 -Hydroxy-3-cyclobutene-
1,2-dione, 4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-
1,2-dione and 3- {3-[(4-fluorophenyl)-(1- (3-fluorophenyl) ethylamino)
The pharmaceutical composition according to claim 1, which is any one compound selected from methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2-dione or a pharmacologically acceptable salt thereof. object. 41. The method according to claim 1, wherein the HMG-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin or rosuvastatin. The pharmaceutical composition according to item. 42. The pharmaceutical composition according to any one of claims 1 to 40, wherein the HMG-CoA reductase inhibitor is pravastatin, atorvastatin or pitavastatin. 43. The pharmaceutical composition according to any one of claims 1 to 40, wherein the HMG-CoA reductase inhibitor is pravastatin or atorvastatin. 44. The pharmaceutical composition according to any one of claims 1 to 40, wherein the HMG-CoA reductase inhibitor is pravastatin.