JP2001089429A - Cyclobutene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cyclobutene derivative having an excellent ileum type bile acid transporter-inhibiting action, its pharmacologically acceptable salt, its ester or other derivatives. SOLUTION: The cyclobutene derivative of general formula (I) [R1 is a cycloalkyl, an aryl, a heterogeneous ring or the like; R2 is a cycloalkyl, an aryl, a heterogeneous ring or the like; R3 and R4 are each H or the like; A is formula (A-1) (R5 is H or the like; R6 is an amine residue or the like; X and Y are each oxygen atom or the like; Z is a single bond or the like); G is an alkylene or the like; when the broken line is a double bond, D is a carbon atom, and E is a group having =N-0; when the broken line is a single bond, D is a group having CH, and E is a group having NH or the like], its pharmacologically acceptable salt, its ester or other derivatives.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a cyclobutene derivative having an excellent ileal bile acid transporter inhibitory action.

BACKGROUND OF THE INVENTION Hyperlipidemia is one of the three major risk factors for ischemic heart disease. In particular, it is widely known that lowering a high blood cholesterol level is useful for treating or preventing ischemic heart disease. It recognized. As currently available therapeutic agents for hyperlipidemia, for example, HMG-CoA reductase inhibitors and anion exchange resins are known, and these agents treat or prevent hyperlipidemia or arteriosclerosis. [Am. J. Cardiol., 76, 899-905 (199
Five)]. HMG-CoA reductase inhibitors have an effect of inhibiting LDL (low density)
It has the effect of taking up blood cholesterol and promoting excretion into bile by increasing lipoprotein) receptors [Science, 232, 34 (1986)]. The usefulness and safety of these drugs are widely recognized and used by many patients. Anion exchange resins also promote the conversion of cholesterol to bile acids in the liver by adsorbing bile acids and preventing reabsorption of bile acids in the intestine, thereby lowering blood cholesterol levels. [N. Engl. J. Med., 30
2, 1210-1222 (1980)]. As such an anion exchange resin, for example, a method using cholestyramine has already been put to practical use, and since the drug is hardly absorbed into the body, hyperlipidemia in children who are required to be more safe is required. It is regarded as a first-line drug in the treatment of diseases. However,
Cholestyramine has a very high dose per dose,
In addition, there is a drawback in that the rough feeling of the resin when taken is left in the mouth, so that it is very difficult for patients to take the resin. Also, anion exchange resin is a kind of vitamin,
Minerals, drugs and the like are also adsorbed and discharged, so that it is necessary to consider replenishment of vitamins and changes in the administration method of concomitant drugs, and thus there are many problems. Recently, a protein acting in the first step of bile acid reabsorption in the ileum, the ileal bile acid transporter, has been cloned [Wong MH et a.
1, J. Biol. Chem., 269, 1340-1347 (1994)]. It is thought that if the ileal bile acid transporter activity can be inhibited, a pharmacological effect similar to that of cholestyramine can be obtained, and from such a background, it is possible to find an ileal bile acid transporter inhibitor. [Wess G. et al, J. Med. Chem., 37, 873-875 (19
94)]. Prior arts relating to the present invention include the following. (1) Japanese Patent Publication No. 6-509820 (WO93 / 25)
517) In this publication, the following general formula (A)

Embedded image [In the above compound (A), Z is -N (R ³ ) CO
Wherein R ³ is an aryl group, and X is-
An N (R ⁵ ) — group wherein R ⁵ is a hydrogen atom or an alkyl group, R ² is an optionally substituted cycloalkyl or cycloalkenyl group, and R ⁴ is
An aryl group or a heteroaryl group. ] Is disclosed. In the compound (I) of the present invention, a compound having a structure similar to that of the prior art is a compound in which D is a nitrogen atom and E is a group having —CO—, and the cyclobutenyl portion of A is an essential substituent. Has two oxo groups or thioxo groups, whereas the cycloalkenyl group defined for R ² in the above compound (A) is different in that it does not have an oxo group or a thioxo group as a substituent. Further, in this gazette, compounds having a structure similar to that of the compound (I) of the present invention include:
The compound (I) of the present invention is not specifically disclosed at all.
Even if the compound closest to the structure of is selected, at most, only the following compounds are disclosed.

Embedded image Further, the above compound (A) is disclosed as a selective phosphodiesterase IV inhibitor, and its use as an ileal bile acid transporter inhibitory action is not described or suggested. (2) JP-A-7-309837 (EP 62359)
7A) and JP-A-8-175994.

Embedded image [In the above compound (B), the ring A is a benzene ring which may be further substituted, and Q is OQ ¹ (wherein Q ¹ represents an aliphatic hydrocarbon group which may be substituted). ]
Are disclosed. In the compound (I) of the present invention, as those having a structure similar to the prior art, a broken line indicates a double bond, D is a carbon atom, and E
Is a group having ＝ N—O—, whereas the compound of the present invention has a cyclobutenylamino group substituted with oxo or thioxo as the substituent A of the benzene ring, Are different in that a cyclobutenylamino group is not disclosed as a substituent on the benzene ring.
Furthermore, the present publications do not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resemble the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compounds are disclosed.

Embedded image The compound (B) is disclosed as a calcium channel opening agent in JP-A-7-309837 (EP623597A), and is disclosed in JP-A-8-1759.
No. 94 discloses a lipid metabolism improving agent, and does not describe or suggest its use as an ileal bile acid transporter inhibitory action. (3) JP-A-11-60548 (WO98 / 56)
757) This publication discloses the following general formula (C)

Embedded image [In the above compound (C), R ¹ is a C ₆ -C ₁₀ aryl group substituted with 1 to 3 groups selected from the substituent group α, and 1 to 3 groups selected from the substituent group β. An optionally substituted tetrazolyl group, wherein R ² , R ³ and R
⁴ is a hydrogen atom, and R ⁵ is a C ₇ -C ₁₀ aralkyl group which may be substituted with 1 to 3 groups selected from the substituent group γ. Has been disclosed as an ileal bile acid transporter inhibitor. In the compound (I) of the present invention, as a compound having a structure similar to that of the prior art, a broken line indicates a single bond, D is a carbon atom, and E is a group having -NH-. While the compound of the invention has a cyclobutenylamino group substituted with oxo or thioxo as a substituent A on the benzene ring, the present publication discloses a cyclobutenylamino group as a substituent on the benzene ring. There is no difference. Furthermore, the present publications do not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resemble the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compounds are disclosed.

Embedded image (4) Japanese Patent Application Laid-Open No. 11-199570
The following general formula (D)

Embedded image [In the above compound (D), Ar1 and Ar2 are aromatic groups which may have a substituent, and Q is an oxygen atom,
May be via a divalent group selected from a sulfur atom which may be oxidized and an imino which may have a substituent,
And a divalent linear aliphatic hydrocarbon group which may have a substituent, X is a hydrogen atom, and ring A is a nitrogen-containing 5- to 7-membered ring which may have a substituent. Show. ] Is disclosed. In the compound (I) of the present invention, as a compound having a structure similar to that of the prior art, a broken line indicates a single bond, D is a carbon atom, and E is a group having -NH-. While the compound of the present invention has a cyclobutenylamino group substituted with oxo or thioxo as the substituent A of the benzene ring, the present publication discloses a cyclobutenylamino group as a substituent of Ar1 or Ar2. The difference is that they do not. Further, the present publications do not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention. Further, the above compound (D) is disclosed as a neurodegeneration inhibitor, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted long-term studies on the synthesis of ileal bile acid transporter-inhibiting derivatives and their pharmacological activities. It has been found that it has an excellent inhibitory effect on acid transporters,
The present invention has been completed. Still another object of the present invention is to provide a medicine containing a cyclobutene derivative as an active ingredient.

Means for Solving the Problems (1) The cyclobutenyl derivative of the present invention has the following general formula (I)

Embedded image [Wherein, R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted with 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 with 1 to 5 substituents, or
A heterocyclic group substituted by 1 to 5 groups selected from substituent groups a and b, and R ² is a cycloalkyl group, an aryl group, a heterocyclic group, a group selected from substituent group a. 1 to 3 substituted cycloalkyl groups, 1 to 3 substituted aryl groups with a group selected from substituent group a, or
A heterocyclic group substituted by 1 to 3 groups selected from a substituent group a, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or a group selected from a substituent group a; A is
The following formula (A-1)

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. , An oxygen atom or a sulfur atom, and Z represents a single bond or a C ₁ -C ₆ alkylene group.)
A group having a single bond, a C ₁ -C ₆ alkylene group or a substituted C ₁ -C ₆ alkylene group (the substituent is
A hydroxy group, an oxo group, a cycloalkyl group, an aryl group, a heterocyclic group, a group selected from substituent groups a and b,
1 to 5 substituted cycloalkyl groups, 1 to 5 substituted aryl groups selected from substituent groups a and b, or 1 to 5 substituted cycloalkyl groups selected from substituent groups a and b It is a substituted heterocyclic group. ), And when the broken line indicates a double bond, D indicates a carbon atom, and E indicates は N
Represents a group having -O-, and when the broken line represents a single bond,
D represents a group having CH or a nitrogen atom, and E represents a group having an oxygen atom, a sulfur atom, -NH-, or a group having -CO-. ], A pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, 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 <substituent group b> a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group, Di-lower alkylcarbamoyl group, nitro group, cycloalkyl group, aryl group, aryloxy group, aralkyloxy group, arylthio group, and substituent group a
A cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio group substituted by 1 to 3 groups selected from Among these, preferred compounds include the following compounds. (2) When the general formula (I) is the general formula (Ia) or (Ib)

Embedded image(3) A compound represented by the general formula (I)
(4) Z is a single bond or C₁-C_Two
A compound which is an alkylene group, (5) Z is a single bond or
A compound which is a methylene group, (6) Z is a single bond
Compound, (7) R^FiveIs a hydrogen atom or a lower alkyl group
(8) R^FiveIs a hydrogen atom or a methyl group
(9) R^FiveIs a hydrogen atom
Object, (10) R⁶Is a hydroxy group or an amine residue
Certain compounds, (11) R⁶Is a hydroxy group, hydro
A compound which is a xyamino group or an amino group, (12) R
⁶Is a hydroxy group, (13) X and Y
Is an oxygen atom, (14) D has CH
(15) wherein D is C
(16) a compound which is a group having H, wherein E is an oxygen atom
A compound having a substituent, a sulfur atom or -NH-,
(17) a compound wherein E is a group having -NH-,
(18) G is C₁-C₆Alkylene group or substituted
C₁-C₆A compound which is an alkylene group, (19) G is
C₁-C₆Alkylene group or substituted C₁-C₆Archire
Group (the substituent is a hydroxy group, an oxo group, an aryl
1 to 3 substituents selected from a group or a group selected from substituent group a
Aryl group. (20) G
But C₁-C₆A compound which is an alkylene group, (21) G
But C₁-C_FourA compound which is an alkylene group, (22) G
Is a methylene, methylmethylene or ethylmethylene group
Certain compounds, (23) G is a methylmethylene group
Compound, (24) R¹Is a cycloalkyl group, aryl
Group, heterocyclic group, a group selected from substituent groups a and b
1 to 3 substituted aryl groups or substituent groups a and
1 to 3 heterocyclic groups substituted by a group selected from b and b
(25) R¹Is an aryl group, benze
5- or 6-membered aromatic heterocyclic group which may be condensed with
1 to 3 substituted with groups selected from groups a and b
A substituent which may be condensed with an aryl group or a benzene ring
5 substituted with 1 to 3 groups selected from groups a and b
A compound which is a 6- to 6-membered aromatic heterocyclic group, (26) R¹
May be condensed with an aryl group or a benzene ring.
Membered aromatic heterocyclic group or 1 to 3 substituted aryl
5- or 6-membered aromatic that may be condensed with a group or a benzene ring
Group heterocyclic group (the substituent is a substituent group a, cycloalkyl
Group, aryl group, aryloxy group, aralkyloxy
Group, arylthio group, and substituent group a.
Cycloalkyl, aryl substituted with 1 to 3 groups
, Aryloxy, aralkyloxy and arylthio
A group selected from the group consisting of: ) Is a compound
Object, (27) R¹Is fused with an aryl group or benzene ring
A 5- or 6-membered aromatic heterocyclic group which may be
Condensed with individually substituted aryl group or benzene ring
A 5- or 6-membered aromatic heterocyclic group (the substituent may be
Atom, hydroxy group, lower alkyl group, halogeno lower
Alkyl group, lower alkoxy group, nitro group, cycloal
Kill, aryl, aryloxy and arylthio
A group selected from the group consisting of: ) Is a compound
Object, (28) R¹But C₆-C_TenAryl group, Thieni
, Furyl, pyrrolyl, thiazolyl, oxazo
Ryl, imidazolyl, pyridyl, and benzene rings
Combined, thienyl, furyl, pyrrolyl, thiazolyl, o
A xazolyl, imidazolyl or pyridyl group, or
1 to 3 substituted C₆-C_TenAryl group (the substituent
Represents a halogen atom, a hydroxy group, a lower alkyl group,
Logeno lower alkyl group, lower alkoxy group and nitro group
Is a group selected from the group consisting of ) Is a compound
(29) R¹Is phenyl, 1-naphthyl, 2-naph
Tyl, 3-fluorophenyl, 4-fluorophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-di
Fluorophenyl, 3,5-difluorophenyl, 3,
4-dichlorophenyl, 3,5-dichlorophenyl, 3
-Hydroxyphenyl, 4-hydroxyphenyl, 3-
Methylphenyl, 4-methylphenyl, 3,4-dimethyl
Phenyl, 3-methoxyphenyl, 4-methoxyphenyl
Nil, 3,4-dimethoxyphenyl, 3,4,5-tri
Methoxyphenyl, 3,4,5-trifluorophenyl
(30) a compound which is a phenyl, thienyl or pyridyl group;
R¹Is phenyl, 3-fluorophenyl, 3-chloro
Phenyl, 3,4-difluorophenyl, 3,5-diph
Fluorophenyl, 3,4-dichlorophenyl, 3,5-
Dichlorophenyl, 2-thienyl or 4-pyridyl group
Certain compounds, (31) R^TwoIs a cycloalkyl group,
A group selected from a reel group, a heterocyclic group, and a substituent group a;
From 3 to 3 substituted aryl groups or substituent groups a
A heterocyclic group substituted by 1 to 3 groups with a selected group
Compound, (32) R^TwoIs condensed with an aryl group or benzene ring
A 5- or 6-membered aromatic heterocyclic group which may be
Fused with a 3-substituted aryl group or benzene ring
A 5- or 6-membered aromatic heterocyclic group which may be
Gen atom, hydroxy group, lower alkyl group, halogeno low
Selected from the group consisting of lower alkyl groups and lower alkoxy groups
Group. (33) R^TwoBut,
Aryl group, thienyl group, furyl group, pyrrolyl group, thia
Zolyl, oxazolyl, imidazolyl, pyridyl
Group, thienyl, furyl, pyrrolyl condensed with benzene ring
, Thiazolyl, oxazolyl, imidazolyl or
A pyridyl group or a monosubstituted aryl group (the substituted
The group is a halogen atom, a hydroxy group, a lower alkyl group,
A halogeno lower alkyl group or a lower alkoxy group;
You. (34) R^TwoBut C₆-C_TenA
A reel group, a 2-thienyl group, a 4-pyridyl group, or 1
Replaced C₆-C_TenAn aryl group (the substituent is a halo
Gen atom, hydroxy group, lower alkyl group, halogeno low
A lower alkyl group or a lower alkoxy group. )
Compound, (35) R^TwoIs a phenyl group or one-substituted
A phenyl group (the substituent is a halogen atom, a hydro
A xy group, a lower alkyl group, a halogeno lower alkyl group or
It is a lower alkoxy group. (36)
R^TwoIs phenyl, 4-fluorophenyl, 4-chloro
Phenyl, 4-methylphenyl, or 4-methoxyphenyl
A compound which is a phenyl group, (37) R^ThreeAnd R^FourBut the same
Or differently, a hydrogen atom, a hydroxy group, a halogen atom
, Lower alkoxy group, amino group or di-lower alkyl
A compound which is an amino group, (38) R^ThreeAnd R^FourBut the same
One or different, a hydrogen atom, a hydroxy group or a lower
A compound which is a oxy group, (39) R^ThreeAnd R^FourBut water
A compound that is an elementary atom, (40) selected from the following:
At least one compound. 3- (3-{(4-fluorophenyl)-[1-phenyl
Ruethylamino] methyl @ phenylamino) -4-hydr
Roxy-3-cyclobutene-1,2-dione, 3- (3
-{(4-chlorophenyl)-[1-phenylethyla
Mino] -methyldiphenylamino) -4-hydroxy-
3-cyclobutene-1,2-dione, 3-hydroxy-
4- (3-{(4-methoxyphenyl)-[1-phenyl
Ruethylamino] methyl @ phenylamino) -3-cycl
Lobutene-1,2-dione, 3-hydroxy-4- {3
-[(4-methoxyphenyl)-(1- (naphthalene-
1-yl) ethylamino) methyl] phenylamino}-
3-cyclobutene-1,2-dione, 4- {3-[(1
-(3-fluorophenyl) ethylamino) -phenyl
Methyl] phenylamino} -3-hydroxy-3-cycl
Lobutene-1,2-dione, 3- (3-{(4-fluoro
L-phenyl)-[1- (3-fluorophenyl) -ethyl
Ruamino] methyl @ phenylamino) -4-hydroxy
-3-cyclobutene-1,2-dione, 4- {3-
[(4-chlorophenyl)-(1- (3-fluorophene
Nyl) ethylamino) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione, 3-
{3-[[1- (3-fluorophenyl) ethylamido]
No]-(4-methoxyphenyl) methyl] phenylami
No-4--4-hydroxy-3-cyclobutene-1,2-di
On, 4- {3-[(1- (3,4-difluorophenyl)
Ru) ethylamino) -phenylmethyl] phenylami
NO-3-Hydroxy-3-cyclobutene-1,2-di
On, 3- {3-[[1- (3,4-difluorophenyl)
Ru) ethylamino]-(4-fluorophenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
Ten-1,2-dione, 4- {3-[(4-chlorophen
Nyl)-(1- (3,4-difluorophenyl) ethyl
Amino) 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,
4- {3-[(1- (3,5-difluorophenyl) e
Tylamino)-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione, 4- {3-[(4-chlorophenyl)
-(1- (3,5-difluorophenyl) ethylamido
No) methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione, 4- {3-[(1-
(3,5-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino} -3-
Hydroxy-3-cyclobutene-1,2-dione, 4-
{3-[(1- (3,5-difluorophenyl) ethyl]
Amino) -phenylmethyl] phenylamino} -3-h
Droxy-3-cyclobutene-1,2-dione, 3-a
Mino-4- [3-((4-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
On, 3-amino-4- [3-((4-fluorophenyl
)-(1-phenylethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione, 3-a
Mino-4- [3-((4-methoxyphenyl)-(1-
Phenylethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, 3-amino-4-
[3- (4-pyridyl- (1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, 3-amino-4- [3-((4-methoxy
Enyl)-(1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione, 3-amino-4- [3-((4-fur
Orophenyl)-(1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-si
Clobutene-1,2-dione, 3-amino-4- [3-
(4-methoxyphenyl- (1- (3,4-difluoro
Phenyl) ethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione, 3-amino-4-
[3- (4-pyridyl- (1- (3,4-difluorofuran)
Enyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, 3-amino-4-
[3- (phenyl- (1- (3,5-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-si
Clobutene-1,2-dione, 3-amino-4- [3-
((4-fluorophenyl)-(1- (3,5-difur
Orophenyl) ethylamino) methyl) phenylami
No] -3-cyclobutene-1,2-dione, 3-amino
-4- [3-((4-methoxyphenyl)-(1-
(3,5-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
On, 3-amino-4- [3-((4-methoxyphenyl
)-(1- (4-pyridyl) ethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-di
3-amino-4- [3-((4-methoxyphenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione, 3- {3-[(4-chlorophenyl)
-(1- (naphthalen-1-yl) ethylamino) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
Ten-1,2-dione, 3-hydroxy-4- {3-
[(1- (1-Naphthyl) ethylamino) -phenylmeth
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione, 3- {3-[(4-fluorophenyl)-(1
-(Naphthalen-1-yl) ethylamino) methyl] f
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione, 3-hydroxy-4- {3-[(1-
(1-Naphthyl) ethylamino)-(p-tolyl) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
On, 3- (3-{[1- (3-fluorophenyl) e
Tylamino]-(p-tolyl) methyldiphenylamido
No) 4-Hydroxy-3-cyclobutene-1,2-di
On, 3- (3-{[1- (3,4-difluorophenyl)
L-amino) ethylamino]-(p-tolyl) methyl
Enylamino) -4-hydroxy-3-cyclobutene-
1,2-dione and 4- {3- [1- (3,5-diph
Fluorophenyl) ethylamino]-(4-methylphenyl
Ru) methyl] phenylamino} -3-hydroxy-3-
Cyclobutene-1,2-dione. In the above formula, R¹, R^Two,
"Cycloalkyl group" in the definition of G and substituent group b
And "1 to 3 substituted with a group selected from the substituent group a
Cycloalkyl group "and" substituent groups a and b "
1 to 5 cycloalkyl groups substituted with the selected group "
Is, for example, cyclopropyl, cyclopropyl
Clobutyl, cyclopentyl, cyclohexyl, cyclo
Heptyl, norbornyl, adamantyl, indanyl
Examples of such a saturated carbocyclic group having 3 to 10 carbon atoms
Is fused to another cyclic group such as a benzene ring.
Is also good. As such a cycloalkyl group, preferably
Is C_Five-C₆A cycloalkyl group, most preferably a cycloalkyl group.
It is a rohexyl group. In the above formula, R¹, R^Two, G and substitution
“Aryl group” or “Substituent group a” in the definition of group b
Aryl groups substituted by 1 to 3 groups selected from
And 1 to 5 substituents selected from substituent groups a and b
The aryl part of the "substituted aryl group" is, for example,
Like nil, indenyl, 1-naphthyl, 2-naphthyl
Of aromatic hydrocarbon groups having 6 to 10 carbon atoms
Can be. R¹In the above, preferably phenyl or naphthyl
And most preferably a phenyl or 1-naphthyl group
And R^Two, G and the substituent group b,
Phenyl or naphthyl, most preferably phenyl
It is. In the above formula, R¹, R^TwoAnd G in the definition
1 to 3 groups selected from substituent groups a)
Selected from "substituted heterocyclic groups" and "substituent groups a and b".
Heterocyclic group substituted with 1 to 5 heterocyclic groups "
The amount of sulfur atom, oxygen atom and / or nitrogen atom is 1 to
A 5- to 7-membered heterocyclic group containing 3
Enyl, pyrrolyl, azepinyl, pyrazolyl, imidazo
Ryl, oxazolyl, isoxazolyl, thiazolyl, i
Sothiazolyl, 1,2,3-oxadiazolyl, tria
Zolyl, tetrazolyl, thiadiazolyl, pyranyl, pi
Lysyl, pyridazinyl, pyrimidinyl, pyrazinyl
Aromatic heterocyclic groups and morpholinyl, thiomorpholini
, Pyrrolidinyl, pyrrolinyl, imidazolidinyl, a
Midazolinyl, pyrazolidinyl, pyrazolinyl, piperi
Parts corresponding to these groups such as jyl and piperazinyl
Minor or completely reduced groups can be mentioned. Further
In addition, the heterocyclic group is combined with another cyclic group such as a benzene ring.
May be fused, for example, benzothienyl, benzo
Thiazolyl, benzoxazolyl, isobenzofurani
, Chromenil, xanthenyl, phenoxathiinyl,
Indolizinyl, isoindolyl, indolyl, indah
Zolyl, purinyl, quinolizinyl, isoquinolyl, quino
Lil, phthalazinyl, naphthyridinyl, quinoxalini
, Quinazolinyl, carbazolyl, carbolinyl,
Groups such as lysinyl and isoindolinyl may be mentioned.
it can. In such a heterocyclic group, preferably 5
5- to 6-membered aromatic heterocyclic group or 5 to 6 fused with a benzene ring
6-membered aromatic heterocyclic group, more preferably thienyl,
Furyl, pyrrolyl, thiazolyl, oxazolyl, imida
Thiol fused with zolyl, pyridyl, or benzene ring
Nil, furyl, pyrrolyl, thiazolyl, oxazolyl,
Imidazolyl or pyridyl group, more preferably
Is a thienyl or pyridyl group, most preferably 2
-Thienyl or 4-pyridyl group. In the above formula, R^Five
And "lower alkyl group" in the definition of substituent group a,
For example, methyl, ethyl, propyl, isopropyl, butyl
Chill, isobutyl, s-butyl, t-butyl, pliers
, Isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 4-methyl
Chillpentyl, 3-methylpentyl, 2-methylpentyl
, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl,
Such as 2,3-dimethylbutyl and 2-ethylbutyl groups
A linear or branched alkyl group having 1 to 6 carbon atoms,
Preferably C₁-C_FourAlkyl group, more preferably C₁
-C_TwoAn alkyl group, most preferably a methyl group.
You. In the above formula, R⁶And “low” in the definition of substituent group a.
"A lower alkoxy group" is an oxygen atom
Denote a group attached to a child, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy
Si, s-butoxy, t-butoxy, pentoxy, isope
Butoxy, 2-methylbutoxy, neopentoxy, hex
Siloxy, 4-methylpentoxy, 3-methylpent
Xy, 2-methylpentoxy, 3,3-dimethylbutoxy
Si, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy
Xy, 1,2-dimethylbutoxy, 1,3-dimethylbut
1 carbon atoms such as a toxy or 2,3-dimethylbutoxy group
From 6 to 6 linear or branched alkoxy groups, preferably
Is C₁-C_FourAn alkoxy group, more preferably C₁-C_Two
An alkoxy group, most preferably a methoxy group.
In the above formula, R⁶And the definition of “lower a
"Alkylthio group" is a group in which the "lower alkyl group" is a sulfur atom
Represents a group bonded to, for example, methylthio, ethylthio
E, propylthio, isopropylthio, butylthio, i
Sobutylthio, s-butylthio, t-butylthio, pen
Tylthio, isopentylthio, 2-methylbutylthio,
Neopentylthio, hexylthio, 4-methylpentyl
Thio, 3-methylpentylthio, 2-methylpentylthio
E, 3,3-dimethylbutylthio, 2,2-dimethylbut
Tylthio, 1,1-dimethylbutylthio, 1,2-dimethyl
Butylbutylthio, 1,3-dimethylbutylthio, 2,3
A straight chain having 1 to 6 carbon atoms such as dimethylbutylthio group;
A chain or branched alkylthio group, preferably₁-C_Four
Alkylthio group, more preferably C₁-C_TwoAlkyl
A thio group, most preferably a methylthio group. the above
Where R⁶“Amine residue” in the definition of
Or substituted hetero groups or nitrogen containing nitrogen atoms
Shows a ring, such amino residues, for example,
Amino group; hydroxyamino group; methylamino, ethyl
Amino, propylamino, isopropylamino, butyl
Amino, isobutylamino, s-butylamino, t-butyl
Tylamino, pentylamino, isopentylamino, 2
-Methylbutylamino, neopentylamino, 1-ethyl
Rupropylamino, hexylamino, isohexylamino
No, 4-methylpentylamino, 3-methylpentylua
Mino, 2-methylpentylamino, 1-methylpentyl
Amino, 3,3-dimethylbutylamino, 2,2-dimethyl
Butylbutylamino, 1,1-dimethylbutylamino,
1,2-dimethylbutylamino, 1,3-dimethylbuty
Ruamino, 2,3-dimethylbutylamino, 2-ethyl
One "lower alkyl group" such as butylamino group
A "mono-lower alkylamino group" attached to an amino group;
Methoxyamino, ethoxyamino, propoxyamino,
Isopropoxyamino, butoxyamino, isobutoxy
Amino, S-butoxyamino, t-butoxyamino,
Benzyloxyamino, isopentyloxyamino, 2-
Methylbutoxyamino, neopentyloxyamino, f
Xyloxyamino, dimethoxyamino, diethoxya
One or two such “lower alkoxy groups” such as mino;
Mono or di-lower alkoxyamino linked to a amino group
Group "; dimethylamino, diethylamino, N-ethyl-
N-methylamino, dipropylamino, dibutylamino
No, such as dipentylamino, dihexylamino group
"Di-alkyl" wherein two "lower alkyl groups" are bonded to an amino group.
Lower alkylamino group "; cyclopentylamino, cyclo
Rohexylamino, dicyclopentylamino, dicyclo
"The cycloalkyl group" such as hexylamino is 1
Or two substituted amino groups; sulfomethylamino, 2-
Sulfoethylamino, 3-sulfopropylamino, 4-
Sulfobutylamino, 5-sulfopentylamino, 6-
"Sulfo lower alkyl, such as sulfohexylamino
Group in which one or two groups have been substituted; carboxymethyl
Amino, 2-carboxyethylamino, 3-carboxy
Propylamino, 4-carboxybutylamino, 5-ca
Ruboxypentylamino, 6-carboxyhexylamino
No, methoxycarboxymethylamino, ethoxycarbo
Xymethylamino, 2-methoxycarboxyethylamido
No, 2-ethoxycarboxyethylamino, 3-methoxy
Cycarboxypropylamino, 3-ethoxycarboxy
Propylamino, 4-methoxycarboxybutylamido
No, 5-methoxycarboxypentylamino, 6-meth
"Carboxy or carboxyhexylamino"
Is lower alkyl substituted with lower alkoxycarbonyl
Group in which one or two groups have been substituted; pyrrolidino, pipet
Lysino, piperazino, N-methylpiperazino, morpholine
And nitrogen atoms such as thiomorpholino in the ring.
Japanese cyclic amine residue; anilino, benzylamino, N-methyl
Nitrogen such as tilanilino and N-methylbenzylamino
In which an aryl atom may be substituted with a "lower alkyl group".
Reel or aralkylamino group; pyridylamino,
N-methylpyridylamino, N-ethylpyridylamino
Is substituted with a "lower alkyl group".
Bond with a nitrogen atom such as a heteroarylamino group
Amine residues, preferably amino
Group, hydroxyamino group, mono-lower alkylamino group
Or a di-lower alkylamino group, "sulfo lower alkyl
Group or a substituted or unsubstituted amino group or carboxy or
Is lower alkyl substituted with lower alkoxycarbonyl
Group "is an amino group substituted by 1 or 2 groups, more preferably
Represents an amino group, a hydroxyamino group, a mono-lower alkyl
A diamino group or a di-lower alkylamino group,
Preferably, it is an amino group or a hydroxyamino group. the above
Wherein “C” in the definition of Z and G₁-C₆Alkylene
Group "and" substituted C₁-C₆Alkylene group "₁−
C₆The alkylene moiety is, for example, methylene, methylmethyl
Len, ethyl methylene, ethylene, propylene, trime
Tylene, 1-methylethylene, dimethylmethylene, tet
Ramethylene, 1-methyltrimethylene, 2-methyltri
Methylene, 3-methyltrimethylene, 1-methylpropyl
Len, 1,1-dimethylethylene, pentamethylene, 1
-Methyltetramethylene, 2-methyltetramethylene,
3-methyltetramethylene, 4-methyltetramethyle
1,1-dimethyltrimethylene, 2,2-dimethyl
Trimethylene, 3,3-dimethyltrimethylene, hexa
Methylene, 1-methylpentamethylene, 2-methylpen
Tamethylene, 3-methylpentamethylene, 4-methylpe
Tamethylene, 5-methylpentamethylene, 1,1-di
Methyltetramethylene, 2,2-dimethyltetramethyle
3,3-dimethyltetramethylene, 4,4-dimethyl
A linear or straight chain having 1 to 6 carbon atoms such as
Is a branched chain alkylene group;
₁-C_FourAlkylene group, more preferably C₁-C_TwoAl
A methylene group, most preferably a methylene group;
And preferably C₁-C_FourAn alkylene group,
Suitably a methylene, methylmethylene or ethylmethylene group
And most preferably a methylmethylene group. The above formula
Wherein “halogen atom” in the definition of substituent group “a” is
Atom, chlorine, bromine or iodine atom, preferably fluorine atom
Or a chlorine atom, most preferably a fluorine atom. Up
In the formula, “halogeno lower alkyl” in the definition of substituent group “a”
A "alkyl group" is a group in which a halogen atom
Represents a substituted group, for example, trifluoromethyl,
Chloromethyl, difluoromethyl, dichloromethyl, di
Bromomethyl, fluoromethyl, 2,2,2-trifur
Oroethyl, 2,2,2-trichloroethyl, 2-bro
Moethyl, 2-chloroethyl, 2-fluoroethyl, 2
-Iodoethyl, 3-chloropropyl, 4-fluorobu
Chill, 6-iodohexyl, 2,2-dibromoethyl
Yes, preferably C₁-C_FourA halogenoalkyl group,
Preferably C₁-C_TwoHalogenoalkyl group, the most preferred
Suitably, it is a trifluoromethyl group. In the above formula, a substituent
"Mono-lower alkylamino" in the definition of group a
Represents the same meaning as described above, and is preferably mono-C₁
-C_FourAlkylamino group, more preferably mono-C₁
-C_TwoAn alkylamino group, most preferably methyl
It is a mino group. In the above formula, in the definition of the substituent group a,
"Di-lower alkylamino group" is as defined above.
Denote, preferably di-C₁-C_FourAn alkylamino group
And more preferably di-C₁-C_TwoAn alkylamino group
And most preferably a dimethylamino group. In the above formula,
“Lower alkoxycarbonyl” in the definition of substituent group b
The `` group '' is the above-mentioned `` lower alkoxy group '' linked to a carbonyl group.
Represents a combined group, for example, methoxycarbonyl, ethoxy
Cicarbonyl, propoxycarbonyl, isopropoxy
Carbonyl, butoxycarbonyl, isobutoxycarbo
Nil, s-butoxycarbonyl, t-butoxycarbonyl
, Pentoxycarbonyl, isopentoxycarboni
, 2-methylbutoxycarbonyl, neopentoxyca
Rubonyl, hexyloxycarbonyl, 4-methylpen
Toxycarbonyl, 3-methylpentoxycarbonyl,
2-methylpentoxycarbonyl, 3,3-dimethylbut
Toxycarbonyl, 2,2-dimethylbutoxycarboni
1,1-dimethylbutoxycarbonyl, 1,2-di
Methylbutoxycarbonyl, 1,3-dimethylbutoxy
Carbonyl, 2,3-dimethylbutoxycarbonyl group
Straight or branched chain alkoxyca having 1 to 6 carbon atoms
A carbonyl group, preferably C₁-C_FourAlkoxycarbo
And more preferably C₁-C_TwoAlkoxycarbo
And most preferably a methoxycarbonyl group.
You. In the above formula, “mono-lower” in the definition of substituent group b
The “alkylcarbamoyl group” is the “lower alkyl group”
Represents a group bonded to one carbamoyl group.
Tylcarbamoyl, ethylcarbamoyl, propylcar
Bamoyl, isopropylcarbamoyl, butylcarbamo
Yl, isobutylcarbamoyl, s-butylcarbamoy
, T-butylcarbamoyl, pentylcarbamoyl,
Isopentylcarbamoyl, 2-methylbutylcarbamo
Yl, neopentylcarbamoyl, 1-ethylpropyl
Carbamoyl, hexylcarbamoyl group, preferably
Is Mono-C₁-C_FourAn alkylcarbamoyl group;
Preferably mono-C₁-C_TwoAn alkylcarbamoyl group
And most preferably a methylcarbamoyl group. The above formula
Wherein “di-lower alkyl carb” in the definition of substituent group b.
The “bamoyl group” is the above “C₁-C₆Two alkyl groups
A group attached to a rubamoyl group
Rubamoyl, diethylcarbamoyl, N-ethyl-N-
Methylcarbamoyl, dipropylcarbamoyl, Djibouti
Rucarbamoyl, dipentylcarbamoyl, dihexyl
A carbamoyl group, preferably di-C₁-C_FourAlkyl
A carbamoyl group, more preferably di-C₁-C_TwoAl
A carboxy group, most preferably dimethylcarbyl.
It is a bamoyl group. In the above formula, in the definition of the substituent group b,
Selected from “aryloxy groups” and “substituent group a”
Aryloxy group substituted by 1 to 3 substituents "
In the oxyl moiety, the aforementioned “aryl group” is bonded to an oxygen atom.
Indicates a combined group, for example, phenoxy, 1-indenyl
Oxy, 2-indenyloxy, 1-naphthyloxy,
A 2-naphthyloxy group, preferably a phenoxy group
is there. In the above formula, “aralkyl” in the definition of substituent group b
A group selected from the group consisting of
Of up to three substituted aralkyloxy groups "
The xy moiety is benzyl, α-naphthylmethyl, β-naphthyl.
Tylmethyl, indenylmethyl, diphenylmethyl,
Riphenylmethyl, 1-phenethyl, 2-phenethyl,
1-naphthylethyl, 2-naphthylethyl, 1-phenyl
Propyl, 2-phenylpropyl, 3-phenylpro
Pill, 1-naphthylpropyl, 2-naphthylpropyl,
3-naphthylpropyl, 1-phenylbutyl, 2-fe
N-butyl, 3-phenylbutyl, 4-phenylbuty
1-naphthylbutyl, 2-naphthylbutyl, 3-na
Futyl butyl, 4-naphthyl butyl, 1-phenyl pen
Tyl, 2-phenylpentyl, 3-phenylpentyl,
4-phenylpentyl, 5-phenylpentyl, 1-na
Futyl pentyl, 2-naphthyl pentyl, 3-naphthyl
Pentyl, 4-naphthyl pentyl, 5-naphthyl pliers
1-phenylhexyl, 2-phenylhexyl, 3
-Phenylhexyl, 4-phenylhexyl, 5-fe
Nylhexyl, 6-phenylhexyl, 1-naphthyl
Xyl, 2-naphthylhexyl, 3-naphthylhexyl
4-naphthylhexyl, 5-naphthylhexyl or
C such as 6-naphthylhexyl group₇-C₁₆Aralkyl
And preferably a benzyloxy group. The above formula
Wherein “arylthio group” in the definition of the substituent group b and
"1 to 3 substituted with a group selected from substituent group a
The arylthio portion of the "arylthio group"
A `` group '' indicates a group bonded to a sulfur atom, for example, phenyl
Luthio, 1-indenylthio, 2-indenylthio, 3
-Indenylthio, 1-naphthylthio, 2-naphthylthio
And preferably a phenylthio group. Above
And R<sup>Two</sup>Selected from the substituent group a in the definition of
Examples of "cycloalkyl group substituted by 1 to 3 groups"
As, for example, 2-fluorocyclopropyl, 2-
Chlorocyclopropyl, 2- or 3-fluorocyclyl
Lopentyl, 2- or 3-chlorocyclopentyl,
2-, 3- or 4-fluorocyclohexyl, 2
-, 3- or 4-chlorocyclohexyl, 2-, 3
-Or 4-bromocyclohexyl, 2-, 3-if
4-Iodocyclohexyl, 2-hydroxycyclo
Propyl, 2- or 3-hydroxycyclopentene
, 2-, 3- or 4-hydroxycyclohexyl
2-methylcyclopropyl, 2-ethylcyclopro
Pill, 2- or 3-methylcyclopentyl, 2-young
Or 3-ethylcyclopentyl, 2-, 3- or
4-methylcyclohexyl, 2-, 3- or 4-e
Tylcyclohexyl, 2-trifluoromethylcyclopropyl
Ropyl, 2- or 3-trifluoromethylcyclope
Methyl, 2-, 3- or 4-trifluoromethyl
Clohexyl, 2-methoxycyclopropyl, 2-but-
Or 3-methoxycyclopentyl, 2-, 3- or
4-methoxycyclohexyl, 2-, 3- or 4-
Ethoxycyclohexyl, 2-methylthiocyclopropyl
2-, 3- or 3-methylthiocyclopentyl, 2
-, 3- or 4-methylthiocyclohexyl, 2
-, 3- or 4-ethylthiocyclohexyl, 2
-, 3- or 4-formyloxycyclohexyl,
2-, 3- or 4-acetyloxycyclohexyl
, 2-, 3- or 4-propionyloxycyclo
Hexyl, 2-, 3- or 4-benzoyloxy
Clohexyl, 2-aminocyclopropyl, 2-young
Is 3-aminocyclopentyl, 2-, 3- or 4-
Aminocyclohexyl, 2-methylaminocyclopropyl
2-, 3- or 3-methylaminocyclopentyl, 2
-, 3- or 4-methylaminocyclohexyl, 2
-Dimethylaminocyclopropyl, 2- or 3-di
Methylaminocyclopentyl, 2-, 3- or 4-
Dimethylaminocyclohexyl, 3,4-difluorosi
Clohexyl, 3,4-dichlorocyclohexyl, 2,
3-dimethoxycyclohexyl, 3,4-dimethoxy
Clohexyl, 3,5-dimethoxycyclohexyl,
3,4,5-trimethoxycyclohexyl group;
Suitably, one to three substituted C<sub>Five</sub>-C<sub>6</sub>Cycloalkyl
Group (the substituent is a halogen atom, hydroxy, lower
From kill, halogeno lower alkyl and lower alkoxy groups
A group selected from the group consisting of: ) And most preferably
Is a single-substituted cyclohexyl group (the substituent is a halo
Gen atom, hydroxy, lower alkyl, halogeno lower
Selected from the group consisting of alkyl and lower alkoxy groups
Group. ). In the above, R<sup>Two</sup>In the definition of
1 to 3 substituted with a group selected from substituent group a
Examples of the "aryl group" include, for example, 2-, 3-
Or 4-fluorophenyl, 2-, 3- or 4
-Chlorophenyl, 2-, 3- or 4-bromophene
Nil, 2-, 3- or 4-iodophenyl, 2-,
3- or 4-hydroxyphenyl, 2-, 3-young
4-methylphenyl, 2-, 3- or 4-ethyl
Ruphenyl, 2-, 3- or 4-trifluoromethyl
Ruphenyl, 2-, 3- or 4-methoxyphenyi
2-, 3- or 4-ethoxyphenyl, 2-,
3- or 4-propoxyphenyl, 2-, 3-only
Or 4-isopropoxyphenyl, 2-, 3- or
4-methylthiophenyl, 2-, 3- or 4-ethyl
Luthiophenyl, 2-, 3- or 4-formyloxy
Cyphenyl, 2-, 3- or 4-acetyloxyf
Phenyl, 2-, 3- or 4-propionyloxyf
Phenyl, 2-, 3- or 4-benzoyloxyphene
Nil, 2-, 3- or 4-aminophenyl, 2-,
3- or 4-methylaminophenyl, 2-, 3-young
Or 4-dimethylaminophenyl, 3,4-difluoro
Rophenyl, 3,4-dichlorophenyl, 3,4-dib
Lomophenyl, 3,5-difluorophenyl, 3,5-
Dichlorophenyl, 3,5-dibromophenyl, 2,
3,4-trifluorophenyl, 2,3,4-trichloro
Rophenyl, 3,4,5-trifluorophenyl, 3,
4,5-trichlorophenyl, 2,3-dimethylphenyi
3,3-dimethylphenyl, 3,5-dimethylphenyl
Nil, 2,3-dimethoxyphenyl, 3,4-dimethoxy
Cyphenyl, 3,5-dimethoxyphenyl, 3,4,5
-Trimethoxyphenyl, 3-fluoro-4-methoxy
Phenyl, 4-methyl-2-methoxyphenyl, 6-phenyl
Fluoro-4-methyl-2-methoxyphenyl, 5-fur
Oroinden-3-yl, 5-fluoroinden-3-
Yl, 5-methylinden-3-yl, 5-methoxyi
Nden-3-yl, 5-fluoroinden-2-yl,
5-chloroinden-2-yl, 5-methylindene-
2-yl, 5-methoxyinden-2-yl, 5-fur
Olonaphthalen-2-yl, 5-fluoronaphthalene-
2-yl, 5-methylnaphthalen-2-yl, 5-metho
Xinaphthalen-2-yl, 5-fluoronaphthalene-
1-yl, 5-chloronaphthalen-1-yl, 5-methyl
Lunaphthalen-1-yl, 5-methoxynaphthalene-1
-Yl group, preferably 1 to 3 substituted ants
A substituent such as a halogen atom, hydroxy, lower
Alkyl, halogeno lower alkyl and lower alkoxy groups
Is a group selected from the group consisting of ) And better
Suitably, a monosubstituted aryl group wherein the substituent is a halo
Gen atom, hydroxy, lower alkyl, halogeno lower
Alkyl or lower alkoxy group. ) And most favorable
Suitably, 4-fluorophenyl, 4-chlorophenyl,
4-methylphenyl or 4-methoxyphenyl group
You. In the above, R<sup>Two</sup>"Substituent group a
Heterocyclic group substituted by 1 to 3 groups selected from
Examples of the body include, for example, 3-, 4- or 5-fluoro.
Lofran-2-yl, 2-, 4- or 5-fluoro
Furan-3-yl, 3-, 4- or 5-hydroxy
Furan-2-yl, 2-, 4- or 5-hydroxy
Furan-3-yl, 3-, 4- or 5-methylfura
2--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, 4- or 5-acetyloxyfuran-2-i
2-, 4- or 5-acetyloxyfuran-3
-Yl, 4- or 5-formyloxyfuran-2-
Yl, 2-, 4- or 5-formyloxyfuran
3-yl, 4- or 5-benzoyloxyfuran-
2-yl, 2-, 4- or 5-benzoyloxyf
Lan-3-yl, 3-, 4- or 5-fluorothio
Phen-2-yl, 3-, 4- or 5-bromothio
Phen-2-yl, 3-, 4- or 5-hydroxy
Thiophen-2-yl, 3-, 4- or 5-methyl
Thiophen-2-yl, 2-, 4- or 5-methyl
Thiophen-3-yl, 3-, 4- or 5-ethyl
Thiophen-2-yl, 2-, 4- or 5-ethyl
Thiophen-3-yl, 3-, 4- or 5-methoxy
Cythiophen-2-yl, 2-, 4- or 5-metho
Xythiophen-3-yl, 3-, 4- or 5-me
Tylthiothiophen-2-yl, 2-, 4- or 5
-Methylthiothiophen-3-yl, 3-, 4-
Is 5-acetyloxythiophen-2-yl, 2-, 4
-Or 5-acetyloxythiophen-3-yl,
3-, 4- or 5-formyloxythiophene-2
-Yl, 2-, 4- or 5-formyloxythiophene
Hen-3-yl, 3-, 4- or 5-benzoylo
Xythiophen-2-yl, 2-, 4- or 5-
Nzoyloxythiophen-3-yl, 3- or 4
-Fluorothiazol-5-yl, 3- or 4-h
Droxythiazol-5-yl, 3- or 4-methyl
Luthiazol-5-yl, 3-, 4- or 5-fur
Orobenzothiophen-2-yl, 2-, 4- or
5-fluorobenzothiophen-3-yl, 3-, 4-
Or 5-bromobenzothiophen-2-yl, 2
-, 4- or 5-bromobenzothiophen-3-i
, 3-, 4- or 5-hydroxybenzothiophene
2--2-yl, 2-, 4- or 5-hydroxybenz
Zothiophen-3-yl, 3-, 4- or 5-methyl
Rubenzothiophen-2-yl, 2-, 4- or 5
-Methylbenzothiophen-3-yl, 3-, 4-but-not
Or 5-methoxybenzothiophen-2-yl, 2-,
4- or 5-methoxybenzothiophen-3-i
4-, 5-, 6- or 7-methylbenzothiazo
-2-yl, 2- or 4-fluoropyridine-
3-yl, 2- or 3-fluoropyridin-4-i
, 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-metho
Xypyridin-4-yl, 2- or 3-methoxypi
Lysin-4-yl, 2- or 4-methylthiopyridi
N-3-yl, 2- or 3-methylthiopyridine-
4-yl, 2- or 4-acetyloxypyridine-
3-yl, 2- or 3-acetyloxypyridine-
4-yl, 2- or 4-formyloxypyridine-
3-yl, 2- or 3-formyloxypyridine-
4-yl, 2- or 4-benzoyloxypyridine
-3-yl, 2- or 3-benzoyloxypyridi
And is preferably substituted with 1 to 3 substituents.
A heterocyclic group (the substituent is a halogen atom, hydroxy,
Lower alkyl, halogeno lower alkyl and lower alkoxy
And a group selected from the group consisting of: )
More preferably, a single-substituted heterocyclic group (the substituent is
Logen atom, hydroxy, lower alkyl or lower alcohol
It is a xy group. ), And still more preferably one-substitution
A 5- or 6-membered aromatic heterocyclic group (the substituent is
Atom, hydroxy, lower alkyl, halogeno lower alkyl
A killed or lower alkoxy group. ) And most suitable
Is a single-substituted thienyl or pyridyl group (the
The substituent is a halogen atom, hydroxy, lower alkyl or
It is a lower alkoxy group. ). In the above, R
<sup>1</sup>In the definition of "a group selected from the substituent groups a and b
Specific examples of "a cycloalkyl group substituted with 1 to 5 carbon atoms"
For example, for example, R<sup>Two</sup>In the definition of “substituent group a
Cycloalkyl substituted by 1 to 3 groups selected from
Group ", 2-carboxycyclopropyl, 2- or
3-carboxycyclopentyl, 2-, 3- or 4
-Carboxycyclohexyl, 2-methoxycarbonyl
Cyclopropyl, 2- or 3-methoxycarbonyl
Cyclopentyl, 2-, 3- or 4-methoxycal
Bonylcyclohexyl, 2-, 3- or 4-carba
Moylcyclohexyl, 2-, 3- or 4-methyl
Carbamoylcyclohexyl, 2-, 3- or 4-
Dimethylcarbamoylcyclohexyl, 2-nitrocyclyl
Lopropyl, 2- or 3-nitrocyclopentyl,
2-, 3- or 4-nitrocyclohexyl, 2-butane
Or 3-cyclohexylcyclopentyl, 2-, 3-
Or 4-cyclohexylcyclohexyl, 2-fe
Nylcyclopropyl, 2- or 3-phenylcyclo
Pentyl, 2-, 3- or 4-phenylcyclohexene
Syl, 2-phenoxycyclopropyl, 2- or 3
-Phenoxycyclopentyl, 2-, 3- or 4-
Phenoxycyclohexyl, 2-benzyloxycyclo
Propyl, 2- or 3-benzyloxycyclopen
Butyl, 2-, 3- or 4-benzyloxycyclo
Xyl, 2-phenylthiocyclopropyl, 2-young
Is 3-phenylthiocyclopentyl, 2-, 3-
Is a 4-phenylthiocyclohexyl group, preferably
Is a cycloalkyl group having 1 to 3 substituents,
More preferably, it is a single-substituted cyclohexyl group. Up
In the description, R<sup>1</sup>"Substituent groups a and b
Aryl group substituted by 1 to 5 groups with a group selected from
As a specific example, for example, R<sup>Two</sup>In the definition of
Ants substituted with one to three groups by a group selected from group a
Group ", 2-, 3- or 4-carboxyphenyl
, 2-, 3- or 4-methoxycarbonylphenyi
2-, 3- or 4-ethoxycarbonylphenyl
2-, 3- or 4-carbamoylphenyl, 2
-, 3- or 4-methylcarbamoylphenyl, 2
-, 3- or 4-dimethylcarbamoylphenyl,
2-, 3- or 4-nitrophenyl, 2-, 3-butane
Or 4-cyclopentylphenyl, 2-, 3-
Is 4-cyclohexylphenyl, 2-, 3- or 4
-Phenoxyphenyl, 2-, 3- or 4-dife
Nil, 2-, 3- or 4-benzyloxyphenyl
3,4-dibenzyloxyphenyl, 3,5-dibe
Benzyloxyphenyl, 2-, 3- or 4-phenyl
Luthiophenyl, 5-nitroinden-3-yl, 5-
Cyclohexylinden-3-yl, 5-phenylin
Den-3-yl, 5-phenoxyinden-3-yl,
5-benzyloxyinden-3-yl, 5-phenyl
Thioinden-3-yl, 5-nitroinden-2-i
5-cyclohexylinden-2-yl, 5-fe
Nilinden-2-yl, 5-phenoxyindene-2
-Yl, 5-benzyloxyinden-2-yl, 5-
Phenylthioinden-2-yl, 5-nitronaphthale
2-yl, 5-cyclohexylnaphthalen-2-i
5-phenylnaphthalen-2-yl, 5-phenoxy
Sinaphthalen-2-yl, 5-benzyloxynaphthale
2-yl, 5-phenylthionaphthalen-2-i
5-nitronaphthalen-1-yl, 5-cyclohexyl
Silnaphthalen-1-yl, 5-phenylnaphthalene-
1-yl, 5-phenoxynaphthalen-1-yl, 5-
Benzyloxynaphthalen-1-yl, 5-phenylthio
An onaphthalen-1-yl group, preferably a substituent group
Ali substituted with 1 to 3 groups selected from a and b
And more preferably 1 to 3 substituted alcohols.
A reel group (the substituent is a substituent group a, a cycloalkyl
Group, aryl group, aryloxy group, aralkyloxy
Group, arylthio group, and substituent group a.
Cycloalkyl, aryl substituted with 1 to 3 groups
, Aryloxy, aralkyloxy and arylthio
A group selected from the group consisting of: )
More preferably, 1 to 3 substituted aryl groups (the substituted
The group is a halogen atom, a hydroxy group, a lower alkyl group,
Halogeno lower alkyl group, lower alkoxy group and nitro
A group selected from the group consisting of groups. ), And
More preferably, 3-fluorophenyl, 4-fluorophenyl
Phenyl, 3-chlorophenyl, 4-chlorophenyl,
3,4-difluorophenyl, 3,5-difluorophen
Nil, 3,4-dichlorophenyl, 3,5-dichlorophenyl
Phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl
Nyl, 3-methylphenyl, 4-methylphenyl, 3,
4-dimethylphenyl, 3-methoxyphenyl, 4-methyl
Toxiphenyl, 3,4-dimethoxyphenyl, 3,
4,5-trimethoxyphenyl or 3,4,5-trif
A fluorophenyl group, most preferably 3-fluoro
Phenyl, 3-chlorophenyl, 3,4-difluorophenyl
Phenyl, 3,5-difluorophenyl, 3,4-dichloro
Lophenyl or 3,5-difluorophenyl group.
In the above, R<sup>1</sup>"Substituent groups a and b in the definition of
A heterocyclic group substituted by 1 to 5 groups selected from
As a specific example, for example, R<sup>Two</sup>In the definition of
1 to 3 substituted heterocyclic groups selected from the group
Ring group ", 3-, 4- or 5-nitrothiophene-2
-Yl, 3-, 4- or 5-phenylthiophene-
2-yl, 2-, 4- or 5-nitrothiophene-
3-yl, 2-, 4- or 5-phenylthiophene
-3-yl, 1-, 2- or 3-hydroxypyridi
N-4-yl, 1-, 2- or 3-nitropyridine
-4-yl, 1-, 2- or 3-phenylpyridine
-4-yl group, preferably 1 to 3 substituted
A heterocyclic group (the substituent is a halogen atom, a hydroxy group,
Lower alkyl, halogeno lower alkyl, lower alkoxy
And a nitro group. )so
And more preferably a single-substituted heterocyclic group (the substituted
The group is a halogen atom, a hydroxy group, a lower alkyl,
From logeno lower alkyl, lower alkoxy and nitro groups
A group selected from the group consisting of: ), Particularly preferably
Is a single-substituted thienyl or pyridyl group (the substituent
Represents a halogen atom, a hydroxy group, a lower alkyl, a halo
Geno-lower alkyl, lower alkoxy and nitro groups
Group selected from the group ). Smell above
The definition of "substituted C<sub>1</sub>-C<sub>6</sub>Alkylene
Specific examples of `` group '' include, for example, hydroxymethylene,
Oxomethylene, cyclopentylmethylene, cyclohex
Silmethylene, phenylmethylene, 1-naphthylmethyle
, 2-naphthylmethylene, 4-fluorophenylmethyl
Len, 4-chlorophenylmethylene, 4-hydroxy
Phenylmethylene, 4-methylphenylmethylene, 1-na
Futylmethylene, 2-naphthylmethylene, 2-thienyl
Methylene, 4-pyridylmethylene, 1-hydroxyethyl
Len, 1-oxoethylene, 1-cyclopentylethyl
1-cyclohexylethylene, 1-phenylethyl
, 1- (1-naphthyl) ethylene, 1- (2-naphthyl)
Ru) ethylene, 1- (4-fluorophenyl) ethyl
1- (4-chlorophenyl) ethylene, 1- (4-
Hydroxyphenyl) ethylene, 1- (4-methylphen)
Nyl) ethylene, 1- (1-naphthyl) ethylene, 1-
(2-naphthyl) ethylene, 1- (2-thienyl) ethyl
Len, 1- (4-pyridyl) ethylene, 2-hydroxy
Ethylene, 2-oxoethylene, 2-cyclopentyl
Tylene, 2-cyclohexylethylene, 2-phenylethyl
Tylene, 2- (1-naphthyl) ethylene, 2- (2-na
Fthyl) ethylene, 2- (4-fluorophenyl) ethyl
Len, 2- (4-chlorophenyl) ethylene, 2- (4
-Hydroxyphenyl) ethylene, 2- (4-methylfuran)
Enyl) ethylene, 2- (1-naphthyl) ethylene, 2
-(2-naphthyl) ethylene, 2- (2-thienyl) e
Tylene, 2- (4-pyridyl) ethylene, 1-hydroxy
C-2-methylethylene, 2-methyl-1-oxoethyl
Len, 1-cyclopentyl-2-methylethylene, 1-
Cyclohexyl-2-methylethylene, 2-methyl-1
-Phenylethylene, 2-methyl-1- (1-naphthy
R) ethylene, 2-methyl-1- (2-naphthyl) ethyl
Len, 1- (4-fluorophenyl) -2-methylethyl
Len, 1- (4-chlorophenyl) -2-methylethyl
1- (4-hydroxyphenyl) -2-methylethyl
Len, 1- (4-methylphenyl) -2-methylethyl
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-cyclopentyltrimethyl
Len, 1-cyclohexyl trimethylene, 1-phenyl
Trimethylene, 1- (1-naphthyl) trimethylene, 1
-(2-naphthyl) trimethylene, 1- (4-fluoro
Phenyl) trimethylene, 1- (4-chlorophenyl)
Trimethylene, 1- (4-hydroxyphenyl) trime
Tylene, 1- (4-methylphenyl) trimethylene, 1
-(1-naphthyl) trimethylene, 1- (2-naphthyl)
L) trimethylene, 1- (2-thienyl) trimethyle
, 1- (4-pyridyl) trimethylene, 3-hydroxy
Citrimethylene, 3-oxotrimethylene, 3-cyclo
Pentyl trimethylene, 3-cyclohexyl trimethyle
, 3-phenyltrimethylene, 3- (1-naphthyl)
Trimethylene, 3- (2-naphthyl) trimethylene, 3
-(4-fluorophenyl) trimethylene, 3- (4-
Chlorophenyl) trimethylene, 3- (4-hydroxy
Phenyl) trimethylene, 3- (4-methylphenyl)
Trimethylene, 3- (1-naphthyl) trimethylene, 3
-(2-naphthyl) trimethylene, 3- (2-thienyl
L) trimethylene, 3- (4-pyridyl) trimethylene
Group, preferably hydroxy, oxo or aryl
C substituted with₁-C₆Alkylene group, more preferably
Is a C, substituted with hydroxy, oxo or aryl₁
-C_FourAlkylene group, most preferably hydroxy
Methylene substituted with cy, oxo or aryl; or
It is an ethylene group. "Pharmacologically acceptable salt"
Compound (I) of the present invention may be a basic group such as an amino group.
If it has, by reacting with an acid,
When it has an acidic group such as a boxy group, it reacts with a base.
The salt can be converted to a salt.
Show. As the salt based on a basic group, preferably,
Such as citrate, hydrochloride, hydrobromide, hydroiodide
Hydrohalides, nitrates, perchlorates, sulfates, phosphorus
Inorganic salts such as acid salts; methanesulfonate, trifluoro
Lower grades such as methanesulfonate and ethanesulfonate
Alkane sulfonate, benzene sulfonate, p-to
Aryl sulfonates such as ruene sulfonate, vinegar
Acid, malate, fumarate, succinate, citrate
Acid salt, ascorbate, tartrate, oxalate, maleic
Organic acid salts such as acid salts; and glycine salts, lysine salts,
Guinine salt, ornithine salt, glutamate, asparagine
Amino acid salts such as phosphates,
Suitably, a hydrohalide salt may be mentioned. one
On the other hand, a salt based on an acidic group is preferably sodium
Alkali metal salts such as salts, potassium salts, lithium salts,
Alkaline earth gold like calcium salt, magnesium salt
Metal salts such as genus salts, aluminum salts and iron salts; ammonium
Inorganic salts such as salts, t-octylamine salts, dibenzyl
Amine salt, morpholine salt, glucosamine salt, phenylg
Lysine alkyl ester salt, ethylenediamine salt, N-
Methylglucamine salt, guanidine salt, diethylamine
Salt, triethylamine salt, dicyclohexylamine salt,
N, N'-dibenzylethylenediamine salt, chloropro
Caine salt, procaine salt, diethanolamine salt, N-
Benzylphenethylamine salt, piperazine salt, tetrame
Tyl ammonium salt, tris (hydroxymethyl) amido
Amine salts such as organic salts such as methane salts;
Salt, lysine salt, arginine salt, ornithine salt, gluta
Amino acid salts such as minate and aspartate
Can be Compounds of the invention having the general formula (I)
Has various asymmetric carbon atoms in the molecule,
Has isomers. In the compounds of the present invention, these
Isomers and mixtures of these isomers are all single
It is represented by a formula, that is, a general formula (I). Therefore, the present invention
Of these isomers and any proportion of these isomers
It also includes all mixtures. General formula of the present invention
In the compound having (I), -GR¹Group is
formula

Embedded image Wherein R ⁰ and R ¹ may be substituted on an asymmetric carbon atom, in particular, R ⁰ is a methyl group and R ¹ is a phenyl group or a phenyl group having a substituent. In such a case, a compound having an R configuration is preferable. The compound having the general formula (I) of the present invention can be left in the air or
By performing recrystallization, water may be absorbed, adsorbed water may be formed, or a hydrate may be formed. Such a hydrate is also included in the present invention. The “ester” in the above refers to the ester, since the compound (I) of the present invention can be converted into an ester, and such esters include “esters of hydroxy group” and “esters of 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" refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. As the "general protecting group" for the "ester of a hydroxy group", preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-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 "Aromatics such as natural nitrated arylcarbonyl groups, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, and arylated arylcarbonyl groups 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,
"Silyl groups" such as tri-lower alkylsilyl groups substituted with one or two aryl groups such as diphenylbutylsilyl, diphenylisopropylsilyl, 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, 2,2,2 "Alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl;
“Substituted ethyl groups” such as lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl, and halogenated ethyl groups 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 ". As the “general protecting group” for the “ester of the carboxy group”, preferably, the above “lower alkyl group”; ethenyl, 1-propenyl, 2-propenyl,
-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-
Lower alkynyl groups such as pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl;
A hydroxy "lower alkyl group" such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl; "Lower aliphatic acyl"-"lower alkyl group";"aralkylgroup";"silylgroup"."Protecting group that can be cleaved in vivo by a biological method such as hydrolysis" means a protecting group that is cleaved in a human body by a biological method such as hydrolysis and generates a free acid or a salt thereof. In other words, whether or not such a derivative is administered by intravenous injection to an experimental animal such as a rat or mouse, and then examining the body fluid of the animal to detect the original compound or its pharmacologically acceptable salt The “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxy group” is preferably formyloxymethyl, acetoxymethyl, dimethylamino. Acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxy Chill, 1-formyloxyethyl ethyl, 1-acetoxyethyl, 1-propionyloxy-ethyl, 1-butyryloxy-ethyl, 1
-Pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1
-Butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl,
-Acetoxybutyl, 1-propionyloxybutyl,
Such as 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl 1-("lower aliphatic acyl" oxy) "lower alkyl group", cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, -Cyclohexylcarbonyloxypropyl, 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 that 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
A lower alkoxy lower alkyl group such as propoxymethyl, isopropoxymethyl, n-butoxymethyl and t-butoxymethyl, a lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxyethoxymethyl, and an aryl such as phenoxymethyl "Oxy" lower alkyl groups "," alkoxyalkyl groups "such as halogenated lower alkoxy lower alkyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; methoxycarbonylmethyl; "Lower alkoxy" carbonyl "lower alkyl group";"cyano" lower alkyl group "such as cyanomethyl and 2-cyanoethyl;""loweralkyl" thiomethyl group "such as methylthiomethyl and ethylthiomethyl; phenylthiomethyl , Naphthylthiome An "aryl" thiomethyl group "such as 2-methylsulfonylethyl and 2-trifluoromethanesulfonylethyl; a" lower alkyl "optionally substituted with halogen; a sulfonyl" lower alkyl group "; 2- “Aryl” sulfonyl “lower alkyl group” such as benzenesulfonylethyl and 2-toluenesulfonylethyl; the above “1- (acyloxy)“ lower alkyl group ””; the above “phthalidyl group”; the above “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 derivative” may be a derivative other than the “pharmacologically acceptable salt” and the “ester thereof” when the compound (I) of the present invention has an amino group and / or a carboxy group. Derivatives are shown below. Such derivatives include, for example, amide derivatives. Specific examples of the compound having the general formula (I) of the present invention include, for example, compounds described in Tables 1 to 6 below.
The present invention is not limited to these compounds.
In addition, the compounds of Table 1 to Table 6 are each represented by the formula (I-1)-
It has the structural formula of (I-6). In Tables 1 to 6, R ¹ and R ²
And the substituents of A represent the following groups.

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Embedded image Further, the abbreviations of the above 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. [Table 1]

Embedded image 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)- . [Table 2]

Embedded image  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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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--(CH_Two)_Two-2-1612 (b-20) (b-34) HH (a-14) -CH- -NH- -CH (Me)-2-1613 (b-20) (b-34) HH (a-14 ) -CH- -NH- -CH_TwoCH (Me)-2-1614 (b-20) (b-34) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1615 (b-20) (b-34) HH (a-14) -CH- -NH- -COCH (Me)-2-1616 (b-20) (b-34) HH (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-Cl H (a-14) -CH- -NH- -CH (Me)-2-1619 (b-20) (b-34) 4-OH H (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) HH (a-14) -CH- -NH- -CH_Two-2-1624 (b-20) (b-35) H H (a-14) -CH- -NH--(CH_Two)_Two-2-1625 (b-20) (b-35) HH (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) HH (a-14) -CH- -NH--(CH_Two)_Three-2-1628 (b-20) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (Me)-2-1629 (b-20) (b-35) H H (a-14) -CH- -NH- -CH_TwoCH (OH)-2-1630 (b-20) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (= O)-2-1631 (b-20) (b-35) H H (a-14) -CH- -NH- -CH_TwoC (Ph)-2-1632 (b-20) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (Me)-2-1633 (b-20) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoCH (OH)-2-1634 (b-20) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (= O)-2-1635 (b-20) (b-35) H H (a-14) -CH- -NH--(CH_Two)_TwoC (Ph)-2-1636 (b-20) (b-35) HH (a-14) -CH- -NH- -CO- 2-1637 (b-20) (b-35) HH (a- 14) -CH- -NH- -COCH_Two-2-1638 (b-20) (b-35) H H (a-14) -CH- -NH- -CO (CH_Two)_Two-2-1639 (b-20) (b-35) HH (a-14) -CH- -NH- -COCH (Me)-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_TwoC (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)_TwoC (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_TwoC (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)_TwoC (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_TwoC (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_TwoC (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_TwoC (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_TwoC (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-Me OH (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_TwoC (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 (CH₂)₂-2-3339 (b-14) (b-73) H H
(A-1) -CH- -NH- -CH (Me) -2-3340 (b-14) (b-73) H H
(A-1) -CH- -NH- -CH (Et) -2-3341 (b-14) (b-73) H H
(A-1) -CH- -NH--(CH₂)₃-2-3342 (b-14) (b-73) H H
(A-1) -CH- -NH- -CH₂CH (Me) -2-3343 (b-14) (b-73) H H
(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) H H
(A-1) -CH- -S- -CH (Me) -2-3346 (b-14) (b-73) 4-F H
(A-1) -CH- -NH- -CH (Me) -2-3347 (b-14) (b-73) 6-F H
(A-1) -CH- -NH- -CH (Me) -2-3348 (b-14) (b-73) 4-ClH
(A-1) -CH- -NH- -CH (Me) -2-3349 (b-14) (b-73) 6-ClH
(A-1) -CH- -NH- -CH (Me) -2-3350 (b-14) (b-73) 4-MeOH
(A-1) -CH- -NH- -CH (Me) -2-3351 (b-14) (b-73) 6-MeOH
(A-1) -CH- -NH- -CH (Me) -2-3352 (b-14) (b-73) H H
(A-1) N-CO--CH (Me) -2-3353 (b-14) (b-74) H H
(A-1) -CH- -NH- -CH (Me) -2-3354 (b-14) (b-76) H H
(A-1) -CH- -NH- -CH (Me) -2-3355 (b-14) (b-77) H H
(A-1) -CH- -NH- -CH (Me) -2-3356 (b-14) (b-77) 6-ClH
(A-1) -CH- -NH- -CH (Me) -2-3357 (b-14) (b-77) 6-F H
(A-1) -CH- -NH- -CH (Me) -2-3358 (b-14) (b-77) 6-MeOH
(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- -CH₂-2-3361 (b-18) (b-7) H H
(A-1) -CH- -NH (CH₂)₂-2-3362 (b-18) (b-7) H H
(A-1) -CH- -NH- -CH (Et) -2-3363 (b-18) (b-7) HH
(A-1) -CH- -NH--(CH₂)₃-2-3364 (b-18) (b-7) H H
(A-1) -CH- -NH- -CH₂CH (Me) -2-3365 (b-18) (b-7) H H
(A-1) -CH- -NH- -COCH (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)-  . [Table 3]

Embedded image  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)-  . [Table 4]

Embedded image Compd. R ¹ R ² R ³ R ⁴ AG No. Substituent No. Substituent No. Substituent No. 4-1 (b-7) (b-35) HH (a-1) -CH (Me)-4-2 (b-11) (b-35) HH (a-1) -CH (Me)- 4-3 (b-18) (b-35) HH (a-1) -CH (Me)-4-4 (b-20) (b-35) HH (a-1) -CH (Me)- 4-5 (b-73) (b-35) HH (a-1) -CH (Me)-4-6 (b-77) (b-35) HH (a-1) -CH (Me)- 4-7 (b-7) (b-35) HH (a-3) -CH (Me)-4-8 (b-11) (b-35) HH (a-3) -CH (Me)- 4-9 (b-18) (b-35) HH (a-3) -CH (Me)-4-10 (b-7) (b-35) HH (a-5) -CH (Me)- 4-11 (b-11) (b-35) HH (a-5) -CH (Me)-4-12 (b-18) (b-35) HH (a-5) -CH (Me)- 4-13 (b-20) (b-35) HH (a-5) -CH (Me)-4-14 (b-73) (b-35) HH (a-5) -CH (Me)- 4-15 (b-77) (b-35) HH (a-5) -CH (Me)-4-16 (b-7) (b-35) HH (a-7) -CH (Me)- 4-17 (b-11) (b-35) HH (a-7) -CH (Me)-4-18 (b-18) (b-35) HH (a-7) -CH (Me)- 4-19 (b-7) (b-7) HH (a-14) -CH (Me)-4-20 (b-7) (b-35) HH (a-14) -CH (Me)- 4-21 (b-11) (b-7) HH (a-14) -CH (Me)-4-22 (b-11) (b-35) HH (a-14) -CH (Me)- 4-23 (b-12) (b-35) HH (a-14) -CH (Me)-4-24 (b-15) (b-35) HH (a-14) -CH (Me)- 4-25 (b-18) (b-7) HH (a-14) -CH (Me)-4-26 (b-18) (b-35) HH (a-14) -CH (Me)- 4-27 (b-19) (b-35) HH (a-14) -CH (Me)-4-28 (b-20 ) (b-7) HH (a-14) -CH (Me)-4-29 (b-20) (b-35) HH (a-14) -CH (Me)-4-30 (b-21 ) (b-35) HH (a-14) -CH (Me)-4-31 (b-24) (b-35) HH (a-14) -CH (Me)-4-32 (b-25 ) (b-35) HH (a-14) -CH (Me)-4-33 (b-72) (b-35) HH (a-14) -CH (Me)-4-34 (b-73 ) (b-7) HH (a-14) -CH (Me)-4-35 (b-73) (b-35) HH (a-14) -CH (Me)-4-36 (b-74 ) (b-35) HH (a-14) -CH (Me)-4-37 (b-76) (b-35) HH (a-14) -CH (Me)-4-38 (b-77 ) (b-7) HH (a-14) -CH (Me)-4-39 (b-77) (b-35) HH (a-14) -CH (Me) -4-40 (b-7 ) (b-35) HH (a-15) -CH (Me)-4-41 (b-11) (b-35) HH (a-15) -CH (Me)-4-42 (b-18 ) (b-35) HH (a-15) -CH (Me)-4-43 (b-20) (b-35) HH (a-15) -CH (Me)-4-44 (b-73 ) (b-35) HH (a-15) -CH (Me)-4-45 (b-77) (b-35) HH (a-15) -CH (Me)-4-46 (b-7 ) (b-35) HH (a-18) -CH (Me)-4-47 (b-11) (b-35) HH (a-18) -CH (Me)-4-48 (b-18 ) (b-35) HH (a-18) -CH (Me)-4-49 (b-20) (b-35) HH (a-18) -CH (Me) -4-50 (b-73 ) (b-35) HH (a-18) -CH (Me)-4-51 (b-77) (b-35) HH (a-18) -CH (Me)-4-52 (b-7 ) (b-35) HH (a-19) -CH (Me)-4-53 (b-11) (b-35) HH (a-19) -CH (Me)-4-54 (b-18 ) (b-35) HH (a-19) -CH (Me)-4-55 (b-7) (b-35) HH (a-20) -CH (Me)-4-56 (b-11) (b-35) HH (a-20) -CH (Me)-4-57 (b-18) (b-35) HH (a-20) -CH (Me)-4-58 (b-20) (b-35) HH (a-20) -CH (Me)-4-59 (b-73) (b-35) HH (a-20) -CH (Me)-4-60 (b-77) (b-35) HH (a-20) -CH (Me)-4-61 (b-7) (b-35) HH (a-24) -CH (Me)-4-62 (b-11) (b-35) HH (a-24) -CH (Me)-4-63 (b-18) (b-35) HH (a-24) -CH (Me)-4-64 (b-7) (b-35) HH (a-26) -CH (Me)-4-65 (b-11) (b-35) HH (a-26) -CH (Me)-4-66 (b-18) (b-35) HH (a-26) -CH (Me)-4-67 (b-20) (b-35) HH (a-26) -CH (Me)-4-68 (b-73) (b-35) HH (a-26) -CH (Me)-4-69 (b-77) (b-35) HH (a-26) -CH (Me)-4-70 (b-7) (b-35) HH (a-28) -CH (Me)-4-71 (b-11) (b-35) HH (a-28) -CH (Me)-4-72 (b-18) (b-35) HH (a-28) -CH (Me)-4-73 (b-7) (b-35) HH (a-31) -CH (Me)-4-74 (b-11) (b-35) HH (a-31) -CH (Me)-4-75 (b-18) (b-35) HH (a-31) -CH (Me)-4-76 (b-20) (b-35) HH (a-31) -CH (Me)-4-77 (b-73) (b-35) HH (a-31) -CH (Me)-4-78 (b-77) (b-35) HH (a-31) -CH (Me)-4-79 (b-7) (b-35) HH (a-33) -CH (Me)-4-80 (b-11) (b-35) HH (a-33) -CH (Me)-4-81 (b- 18) (b-35) HH (a-33) -CH (Me)-4-82 (b-7) (b-35) HH (a-43) -CH (Me) -4-83 (b- 11) (b-35) HH (a-43) -CH (Me)-4-84 (b-18) (b-35) HH (a-43) -CH (Me) -4-85 (b- 20) (b-35) HH (a-43) -CH (Me)-4-86 (b-73) (b-35) HH (a-43) -CH (Me) -4-87 (b- 77) (b-35) HH (a-43) -CH (Me)-4-88 (b-7) (b-35) HH (a-45) -CH (Me)-4-89 (b- 11) (b-35) HH (a-45) -CH (Me)-4-90 (b-18) (b-35) HH (a-45) -CH (Me)- . [Table 5]

Embedded image Compd. R ¹ R ² R ³ R ⁴ AG No. Substituent No. Substituent No. Substituent No. 5-1 (b-2) (b-35) HH (a-1) -CH (Me)-5-2 (b-7) (b-7) HH (a-1) -CH (Me)- 5-3 (b-7) (b-7) HH (a-1) -COCH (Me)-5-4 (b-7) (b-35) HH (a-1) -CH2- 5-5 (b-7) (b-35) HH (a-1) -CH (Me)-5-6 (b-8) (b-35) HH (a-1) -CH (Me) -5- 7 (b-11) (b-7) HH (a-1) -CH (Me)-5-8 (b-11) (b-7) HH (a-1) -COCH (Me)-5- 9 (b-11) (b-35) HH (a-1) -CH (Me)-5-10 (b-11) (b-35) HH (a-1) -COCH (Me) -5- 11 (b-12) (b-7) HH (a-1) -CH (Me)-5-12 (b-12) (b-35) HH (a-1) -CH (Me)-5- 13 (b-15) (b-7) HH (a-1) -CH (Me)-5-14 (b-15) (b-35) HH (a-1) -CH (Me)-5- 15 (b-18) (b-7) HH (a-1) -CH (Me)-5-16 (b-18) (b-7) HH (a-1) -COCH (Me)-5- 17 (b-18) (b-35) HH (a-1) -CH (Me)-5-18 (b-18) (b-35) HH (a-1) -COCH (Me) -5- 19 (b-19) (b-7) HH (a-1) -CH (Me)-5-20 (b-19) (b-35) HH (a-1) -CH (Me)-5- 21 (b-20) (b-7) HH (a-1) -CH (Me)-5-22 (b-20) (b-7) HH (a-1) -COCH (Me) -5- 23 (b-20) (b-35) HH (a-1) -CH (Me)-5-24 (b-20) (b-35) HH (a-1) -COCH (Me) -5- 25 (b-21) (b-7) HH (a-1) -CH (Me) -5-26 (b-21) (b-35) HH (a-1) -CH (Me) -5- 27 (b-24) (b-7) HH (a-1) -CH (Me)-5-28 (b-24) (b-35 ) HH (a-1) -CH (Me)-5-29 (b-25) (b-7) HH (a-1) -CH (Me) -5-30 (b-25) (b-35 ) HH (a-1) -CH (Me) -5-31 (b-72) (b-7) HH (a-1) -CH (Me) -5-32 (b-72) (b-35 ) HH (a-1) -CH (Me) -5-33 (b-73) (b-7) HH (a-1) -CH (Me) -5-34 (b-73) (b-7 ) HH (a-1) -COCH (Me) -5-35 (b-73) (b-35) HH (a-1) -CH (Me) -5-36 (b-73) (b-35 ) HH (a-1) -COCH (Me) -5-37 (b-74) (b-7) HH (a-1) -CH (Me) -5-38 (b-74) (b-35 ) HH (a-1) -CH (Me)-5-39 (b-76) (b-7) HH (a-1) -CH (Me) -5-40 (b-76) (b-35 ) HH (a-1) -CH (Me) -5-41 (b-77) (b-7) HH (a-1) -CH (Me) -5-42 (b-77) (b-7 ) HH (a-1) -COCH (Me) -5-43 (b-77) (b-35) HH (a-1) -CH (Me) -5-44 (b-77) (b-35 ) HH (a-1) -COCH (Me) -5-45 (b-7) (b-35) HH (a-2) -CH (Me) -5-46 (b-11) (b-35 ) HH (a-2) -CH (Me) -5-47 (b-18) (b-35) HH (a-2) -CH (Me) -5-48 (b-20) (b-35 ) HH (a-2) -CH (Me) -5-49 (b-73) (b-35) HH (a-2) -CH (Me) -5-50 (b-77) (b-35 ) HH (a-2) -CH (Me) -5-51 (b-7) (b-7) HH (a-3) -CH (Me) -5-52 (b-7) (b-35 ) HH (a-3) -CH (Me) -5-53 (b-11) (b-7) HH (a-3) -CH (Me) -5-54 (b-11) (b-35 ) HH (a-3) -CH (Me)-5-55 (b-12) (b-35) HH ( a-3) -CH (Me)-5-56 (b-15) (b-35) HH (a-3) -CH (Me) -5-57 (b-18) (b-7) HH ( a-3) -CH (Me)-5-58 (b-18) (b-35) HH (a-3) -CH (Me) -5-59 (b-19) (b-35) HH ( a-3) -CH (Me)-5-60 (b-20) (b-7) HH (a-3) -CH (Me)-5-61 (b-20) (b-35) HH ( a-3) -CH (Me)-5-62 (b-21) (b-35) HH (a-3) -CH (Me) -5-63 (b-24) (b-35) HH ( a-3) -CH (Me)-5-64 (b-25) (b-35) HH (a-3) -CH (Me) -5-65 (b-72) (b-35) HH ( a-3) -CH (Me)-5-66 (b-73) (b-7) HH (a-3) -CH (Me) -5-67 (b-73) (b-35) HH ( a-3) -CH (Me)-5-68 (b-74) (b-35) HH (a-3) -CH (Me) -5-69 (b-76) (b-35) HH ( a-3) -CH (Me)-5-70 (b-77) (b-7) HH (a-3) -CH (Me) -5-71 (b-77) (b-35) HH ( a-3) -CH (Me)-5-72 (b-7) (b-35) HH (a-4) -CH (Me) -5-73 (b-11) (b-35) HH ( a-4) -CH (Me)-5-74 (b-18) (b-35) HH (a-4) -CH (Me) -5-75 (b-20) (b-35) HH ( a-4) -CH (Me)-5-76 (b-73) (b-35) HH (a-4) -CH (Me) -5-77 (b-77) (b-35) HH ( a-4) -CH (Me)-5-78 (b-2) (b-35) HH (a-5) -CH (Me)-5-79 (b-7) (b-7) HH ( a-5) -CH (Me)-5-80 (b-7) (b-7) HH (a-5) -COCH (Me)-5-81 (b-7) (b-35) HH ( a-5) -CH (Me)-5-82 (b-7) (b-35) HH (a-5) -COCH ( Me)-5-83 (b-8) (b-35) HH (a-5) -CH (Me)-5-84 (b-11) (b-7) HH (a-5) -CH ( (Me)-5-85 (b-11) (b-7) HH (a-5) -COCH (Me)-5-86 (b-11) (b-35) HH (a-5) -CH ( Me)-5-87 (b-11) (b-35) HH (a-5) -COCH (Me)-5-88 (b-12) (b-7) HH (a-5) -CH ( (Me)-5-89 (b-12) (b-35) HH (a-5) -CH (Me)-5-90 (b-15) (b-7) HH (a-5) -CH ( (Me)-5-91 (b-15) (b-35) HH (a-5) -CH (Me)-5-92 (b-18) (b-7) HH (a-5) -CH ( (Me)-5-93 (b-18) (b-7) HH (a-5) -COCH (Me)-5-94 (b-18) (b-35) HH (a-5) -CH ( (Me)-5-95 (b-18) (b-35) HH (a-5) -COCH (Me)-5-96 (b-19) (b-7) HH (a-5) -CH ( (Me)-5-97 (b-19) (b-35) HH (a-5) -CH (Me)-5-98 (b-20) (b-7) HH (a-5) -CH ( (Me)-5-99 (b-20) (b-7) HH (a-5) -COCH (Me) -5-100 (b-20) (b-35) HH (a-5) -CH ( (Me)-5-101 (b-20) (b-35) HH (a-5) -COCH (Me)-5-102 (b-21) (b-7) HH (a-5) -CH ( Me)-5-103 (b-21) (b-35) HH (a-5) -CH (Me)-5-104 (b-24) (b-7) HH (a-5) -CH ( Me)-5-105 (b-24) (b-35) HH (a-5) -CH (Me)-5-106 (b-25) (b-7) HH (a-5) -CH ( (Me)-5-107 (b-25) (b-35) HH (a-5) -CH (Me)-5-108 (b-72) (b-7) HH (a-5) -CH ( Me)-5-109 (b-72) (b-35) HH (a- 5) -CH (Me)-5-110 (b-73) (b-7) HH (a-5) -CH (Me)-5-111 (b-73) (b-7) HH (a- 5) -COCH (Me)-5-112 (b-73) (b-35) HH (a-5) -CH (Me)-5-113 (b-73) (b-35) HH (a- 5) -COCH (Me)-5-114 (b-74) (b-7) HH (a-5) -CH (Me)-5-115 (b-74) (b-35) HH (a- 5) -CH (Me)-5-116 (b-76) (b-7) HH (a-5) -CH (Me)-5-117 (b-76) (b-35) HH (a- 5) -CH (Me)-5-118 (b-77) (b-7) HH (a-5) -CH (Me)-5-119 (b-77) (b-7) HH (a- 5) -COCH (Me)-5-120 (b-77) (b-35) HH (a-5) -CH (Me)-5-121 (b-77) (b-35) HH (a- 5) -COCH (Me)-5-122 (b-7) (b-35) HH (a-6) -CH (Me)-5-123 (b-11) (b-35) HH (a- 6) -CH (Me)-5-124 (b-18) (b-35) HH (a-6) -CH (Me)-5-125 (b-20) (b-35) HH (a- 6) -CH (Me)-5-126 (b-73) (b-35) HH (a-6) -CH (Me)-5-127 (b-77) (b-35) HH (a- 6) -CH (Me)-5-128 (b-7) (b-7) HH (a-7) -CH (Me)-5-129 (b-7) (b-35) HH (a- 7) -CH (Me)-5-130 (b-11) (b-7) HH (a-7) -CH (Me)-5-131 (b-11) (b-35) HH (a- 7) -CH (Me)-5-132 (b-12) (b-35) HH (a-7) -CH (Me)-5-133 (b-15) (b-35) HH (a- 7) -CH (Me)-5-134 (b-18) (b-7) HH (a-7) -CH (Me)-5-135 (b-18) (b-35) HH (a- 7) -CH (Me)-5-13 6 (b-19) (b-35) HH (a-7) -CH (Me) -5-137 (b-20) (b-7) HH (a-7) -CH (Me) -5- 138 (b-20) (b-35) HH (a-7) -CH (Me) -5-139 (b-21) (b-35) HH (a-7) -CH (Me) -5- 140 (b-24) (b-35) HH (a-7) -CH (Me) -5-141 (b-25) (b-35) HH (a-7) -CH (Me) -5- 142 (b-72) (b-35) HH (a-7) -CH (Me) -5-143 (b-73) (b-7) HH (a-7) -CH (Me) -5- 144 (b-73) (b-35) HH (a-7) -CH (Me) -5-145 (b-74) (b-35) HH (a-7) -CH (Me) -5- 146 (b-76) (b-35) HH (a-7) -CH (Me) -5-147 (b-77) (b-7) HH (a-7) -CH (Me) -5- 148 (b-77) (b-35) HH (a-7) -CH (Me) -5-149 (b-7) (b-35) HH (a-8) -CH (Me) -5- 150 (b-11) (b-35) HH (a-8) -CH (Me) -5-151 (b-18) (b-35) HH (a-8) -CH (Me) -5- 152 (b-20) (b-35) HH (a-8) -CH (Me) -5-153 (b-73) (b-35) HH (a-8) -CH (Me) -5- 154 (b-77) (b-35) HH (a-8) -CH (Me) -5-155 (b-7) (b-35) HH (a-10) -CH (Me) -5- 156 (b-11) (b-35) HH (a-10) -CH (Me) -5-157 (b-18) (b-35) HH (a-10) -CH (Me) -5- 158 (b-7) (b-35) HH (a-11) -CH (Me) -5-159 (b-11) (b-35) HH (a-11) -CH (Me) -5- 160 (b-18) (b-35) HH (a-11) -CH (Me) -5-161 (b-20) (b-35) HH (a-11) -CH (Me) -5- 162 (b-73) (b -35) HH (a-11) -CH (Me)-5-163 (b-77) (b-35) HH (a-11) -CH (Me) -5-164 (b-7) (b -35) HH (a-12) -CH (Me) -5-165 (b-11) (b-35) HH (a-12) -CH (Me) -5-166 (b-18) (b -35) HH (a-12) -CH (Me)-5-167 (b-2) (b-7) HH (a-14) -CH (Me) -5-168 (b-2) (b -35) HH (a-14) -CH (Me)-5-169 (b-7) (b-7) HH (a-14) -CH (Me) -5-170 (b-7) (b -7) HH (a-14) -COCH (Me)-5-171 (b-7) (b-12) HH (a-14) -CH (Me) -5-172 (b-7) (b -15) HH (a-14) -CH (Me)-5-173 (b-7) (b-34) HH (a-14) -CH (Me) -5-174 (b-7) (b -35) HH (a-14) -CH (Me)-5-175 (b-7) (b-35) HH (a-14) -COCH (Me)-5-176 (b-7) (b -37) HH (a-14) -CH (Me)-5-177 (b-7) (b-73) HH (a-14) -CH (Me) -5-178 (b-7) (b -77) HH (a-14) -CH (Me) -5-179 (b-8) (b-35) HH (a-14) -CH (Me) -5-180 (b-9) (b -35) HH (a-14) -CH (Me)-5-181 (b-10) (b-35) HH (a-14) -CH (Me)-5-182 (b-11) (b -7) HH (a-14) -CH (Me) -5-183 (b-11) (b-7) HH (a-14) -COCH (Me) -5-184 (b-11) (b -12) HH (a-14) -CH (Me) -5-185 (b-11) (b-15) HH (a-14) -CH (Me) -5-186 (b-11) (b -34) HH (a-14) -CH (Me) -5-187 (b-11) (b-35) HH (a-14) -CH (Me) -5-188 (b-11) (b -35) HH (a-14) -COCH (Me)-5-189 (b-11) (b-37) HH (a-14) -CH (Me)-5-190 (b-11) (b -73) HH (a-14) -CH (Me) -5-191 (b-11) (b-77) HH (a-14) -CH (Me) -5-192 (b-12) (b -7) HH (a-14) -CH (Me) -5-193 (b-12) (b-7) HH (a-14) -COCH (Me) -5-194 (b-12) (b -35) HH (a-14) -CH (Me)-5-195 (b-12) (b-35) HH (a-14) -COCH (Me)-5-196 (b-13) (b -35) HH (a-14) -CH (Me) -5-197 (b-14) (b-35) HH (a-14) -CH (Me) -5-198 (b-15) (b -7) HH (a-14) -CH (Me)-5-199 (b-15) (b-7) HH (a-14) -COCH (Me) -5-200 (b-15) (b -35) HH (a-14) -CH (Me) -5-201 (b-15) (b-35) HH (a-14) -COCH (Me) -5-202 (b-17) (b -35) HH (a-14) -CH (Me) -5-203 (b-18) (b-7) HH (a-14) -CH (Me) -5-204 (b-18) (b -7) HH (a-14) -COCH (Me) -5-205 (b-18) (b-12) HH (a-14) -CH (Me) -5-206 (b-18) (b -15) HH (a-14) -CH (Me)-5-207 (b-18) (b-34) HH (a-14) -CH (Me) -5-208 (b-18) (b -35) HH (a-14) -CH (Me) -5-209 (b-18) (b-35) HH (a-14) -COCH (Me) -5-210 (b-18) (b -37) HH (a-14) -CH (Me)-5-211 (b-18) (b-73) HH (a-14) -CH (Me)-5-212 (b-18) (b -77) HH (a-14) -CH (Me)-5-213 (b-19) (b-7) HH (a-14) -CH (Me)-5-214 (b-19) (b-7) HH (a-14) -COCH (Me)-5-215 (b-19) (b-35) HH (a-14) -CH (Me)-5-216 (b-19) (b-35) HH (a-14) -COCH (Me)-5-217 (b-20) (b-7) HH (a-14) -CH (Me)-5-218 (b-20) (b-7) HH (a-14) -COCH (Me)-5-219 (b-20) (b-12) HH (a-14) -CH (Me)-5-220 (b-20) (b-15) HH (a-14) -CH (Me)-5-221 (b-20) (b-34) HH (a-14) -CH (Me)-5-222 (b-20) (b-35) HH (a-14) -CH (Me)-5-223 (b-20) (b-35) HH (a-14) -COCH (Me)-5-224 (b-20) (b-37) HH (a-14) -CH (Me)-5-225 (b-20) (b-73) HH (a-14) -CH (Me)-5-226 (b-20) (b-77) HH (a-14) -CH (Me)-5-227 (b-21) (b-7) HH (a-14) -CH (Me)-5-228 (b-21) (b-7) HH (a-14) -COCH (Me)-5-229 (b-21) (b-35) HH (a-14) -CH (Me)-5-230 (b-21) (b-35) HH (a-14) -COCH (Me)-5-231 (b-23) (b-35) HH (a-14) -CH (Me)-5-232 (b-24) (b-7) HH (a-14) -CH (Me)-5-233 (b-24) (b-7) HH (a-14) -COCH (Me)-5-234 (b-24) (b-35) HH (a-14) -CH (Me)-5-235 (b-24) (b-35) HH (a-14) -COCH (Me)-5-236 (b-25) (b-7) HH (a-14) -CH (Me)-5-237 (b-25) (b-7) HH (a-14) -COCH (Me)-5-238 (b-25) (b-35) HH (a-14) -CH (Me)-5-239 (b-2 5) (b-35) HH (a-14) -COCH (Me)-5-240 (b-35) (b-35) HH (a-14) -CH (Me)-5-241 (b- 72) (b-7) HH (a-14) -CH (Me) -5-242 (b-72) (b-7) HH (a-14) -COCH (Me) -5-243 (b- 72) (b-35) HH (a-14) -CH (Me)-5-244 (b-72) (b-35) HH (a-14) -COCH (Me) -5-245 (b- 73) (b-7) HH (a-14) -CH (Me) -5-246 (b-73) (b-7) HH (a-14) -COCH (Me) -5-247 (b- 73) (b-12) HH (a-14) -CH (Me) -5-248 (b-73) (b-15) HH (a-14) -CH (Me) -5-249 (b- 73) (b-34) HH (a-14) -CH (Me) -5-250 (b-73) (b-35) HH (a-14) -CH (Me) -5-251 (b- 73) (b-35) HH (a-14) -COCH (Me)-5-252 (b-73) (b-37) HH (a-14) -CH (Me) -5-253 (b- 73) (b-73) HH (a-14) -CH (Me) -5-254 (b-73) (b-77) HH (a-14) -CH (Me) -5-255 (b- 74) (b-7) HH (a-14) -CH (Me) -5-256 (b-74) (b-7) HH (a-14) -COCH (Me) -5-257 (b- 74) (b-35) HH (a-14) -CH (Me) -5-258 (b-74) (b-35) HH (a-14) -COCH (Me) -5-259 (b- 75) (b-35) HH (a-14) -CH (Me) -5-260 (b-76) (b-7) HH (a-14) -CH (Me) -5-261 (b- 76) (b-7) HH (a-14) -COCH (Me)-5-262 (b-76) (b-35) HH (a-14) -CH (Me) -5-263 (b- 76) (b-35) HH (a-14) -COCH (Me)-5-264 (b-77) (b-7) HH (a- 14) -CH (Me)-5-265 (b-77) (b-7) HH (a-14) -COCH (Me) -5-266 (b-77) (b-12) HH (a- 14) -CH (Me)-5-267 (b-77) (b-15) HH (a-14) -CH (Me)-5-268 (b-77) (b-34) HH (a- 14) -CH (Me)-5-269 (b-77) (b-35) HH (a-14) -CH (Me)-5-270 (b-77) (b-35) HH (a- 14) -COCH (Me)-5-271 (b-77) (b-37) HH (a-14) -CH (Me)-5-272 (b-77) (b-73) HH (a- 14) -CH (Me)-5-273 (b-77) (b-77) HH (a-14) -CH (Me)-5-274 (b-78) (b-35) HH (a- 14) -CH (Me)-5-275 (b-79) (b-35) HH (a-14) -CH (Me) -5-276 (b-2) (b-35) HH (a- 15) -CH (Me)-5-277 (b-7) (b-7) HH (a-15) -CH (Me)-5-278 (b-7) (b-7) HH (a- 15) -COCH (Me)-5-279 (b-7) (b-35) HH (a-15) -CH (Me) -5-280 (b-7) (b-35) HH (a- 15) -COCH (Me)-5-281 (b-8) (b-35) HH (a-15) -CH (Me)-5-282 (b-11) (b-7) HH (a- 15) -CH (Me)-5-283 (b-11) (b-7) HH (a-15) -COCH (Me) -5-284 (b-11) (b-35) HH (a- 15) -CH (Me)-5-285 (b-11) (b-35) HH (a-15) -COCH (Me)-5-286 (b-12) (b-7) HH (a- 15) -CH (Me)-5-287 (b-12) (b-35) HH (a-15) -CH (Me) -5-288 (b-15) (b-7) HH (a- 15) -CH (Me)-5-289 (b-15) (b-35) HH (a-15) -CH (Me) -5-290 (b-18) (b-7) HH (a-15) -CH (Me) -5-291 (b-18) (b-7) HH (a-15) -COCH (Me) -5-292 (b-18) (b-35) HH (a-15) -CH (Me) -5-293 (b-18) (b-35) HH (a-15) -COCH (Me) -5-294 (b-19) (b-7) HH (a-15) -CH (Me) -5-295 (b-19) (b-35) HH (a-15) -CH (Me) -5-296 (b-20) (b-7) HH (a-15) -CH (Me) -5-297 (b-20) (b-7) HH (a-15) -COCH (Me) -5-298 (b-20) (b-35) HH (a-15) -CH (Me) -5-299 (b-20) (b-35) HH (a-15) -COCH (Me) -5-300 (b-21) (b-7) HH (a-15) -CH (Me) -5-301 (b-21) (b-35) HH (a-15) -CH (Me) -5-302 (b-24) (b-7) HH (a-15) -CH (Me) -5-303 (b-24) (b-35) HH (a-15) -CH (Me) -5-304 (b-25) (b-7) HH (a-15) -CH (Me) -5-305 (b-25) (b-35) HH (a-15) -CH (Me) -5-306 (b-72) (b-7) HH (a-15) -CH (Me) -5-307 (b-72) (b-35) HH (a-15) -CH (Me) -5-308 (b-73) (b-7) HH (a-15) -CH (Me) -5-309 (b-73) (b-7) HH (a-15) -COCH (Me) -5-310 (b-73) (b-35) HH (a-15) -CH (Me)-5-311 (b-73) (b-35) HH (a-15) -COCH (Me)-5-312 (b-74) (b-7) HH (a-15) -CH (Me) -5-313 (b-74) (b-35) HH (a-15) -CH (Me) -5-314 (b-76) (b-7) HH (a-15) -CH (Me)-5-315 (b-76) (b-35) HH (a-15) -CH (Me)- 5-316 (b-77) (b-7) HH (a-15) -CH (Me)-5-317 (b-77) (b-7) HH (a-15) -COCH (Me)- 5-318 (b-77) (b-35) HH (a-15) -CH (Me)-5-319 (b-77) (b-35) HH (a-15) -COCH (Me)- 5-320 (b-2) (b-35) HH (a-18) -CH (Me)-5-321 (b-7) (b-7) HH (a-18) -CH (Me)- 5-322 (b-7) (b-7) HH (a-18) -COCH (Me)-5-323 (b-7) (b-35) HH (a-18) -CH (Me)- 5-324 (b-7) (b-35) HH (a-18) -COCH (Me)-5-325 (b-8) (b-35) HH (a-18) -CH (Me)- 5-326 (b-11) (b-7) HH (a-18) -CH (Me)-5-327 (b-11) (b-7) HH (a-18) -COCH (Me)- 5-328 (b-11) (b-35) HH (a-18) -CH (Me)-5-329 (b-11) (b-35) HH (a-18) -COCH (Me)- 5-330 (b-12) (b-7) HH (a-18) -CH (Me)-5-331 (b-12) (b-35) HH (a-18) -CH (Me)- 5-332 (b-15) (b-7) HH (a-18) -CH (Me)-5-333 (b-15) (b-35) HH (a-18) -CH (Me)- 5-334 (b-18) (b-7) HH (a-18) -CH (Me)-5-335 (b-18) (b-7) HH (a-18) -COCH (Me)- 5-336 (b-18) (b-35) HH (a-18) -CH (Me)-5-337 (b-18) (b-35) HH (a-18) -COCH (Me)- 5-338 (b-19) (b-7) HH (a-18) -CH (Me)-5-339 (b-19) (b-35) HH (a-18) -CH (Me)- 5-340 (b-20) (b-7) HH (a-18) -CH (Me)-5-341 (b-20) (b-7) HH (a-18 ) -COCH (Me)-5-342 (b-20) (b-35) HH (a-18) -CH (Me) -5-343 (b-20) (b-35) HH (a-18 ) -COCH (Me)-5-344 (b-21) (b-7) HH (a-18) -CH (Me) -5-345 (b-21) (b-35) HH (a-18 ) -CH (Me)-5-346 (b-24) (b-7) HH (a-18) -CH (Me)-5-347 (b-24) (b-35) HH (a-18 ) -CH (Me)-5-348 (b-25) (b-7) HH (a-18) -CH (Me)-5-349 (b-25) (b-35) HH (a-18 ) -CH (Me)-5-350 (b-72) (b-7) HH (a-18) -CH (Me) -5-351 (b-72) (b-35) HH (a-18 ) -CH (Me)-5-352 (b-73) (b-7) HH (a-18) -CH (Me) -5-353 (b-73) (b-7) HH (a-18 ) -COCH (Me)-5-354 (b-73) (b-35) HH (a-18) -CH (Me) -5-355 (b-73) (b-35) HH (a-18 ) -COCH (Me)-5-356 (b-74) (b-7) HH (a-18) -CH (Me)-5-357 (b-74) (b-35) HH (a-18 ) -CH (Me)-5-358 (b-76) (b-7) HH (a-18) -CH (Me) -5-359 (b-76) (b-35) HH (a-18 ) -CH (Me)-5-360 (b-77) (b-7) HH (a-18) -CH (Me) -5-361 (b-77) (b-7) HH (a-18 ) -COCH (Me)-5-362 (b-77) (b-35) HH (a-18) -CH (Me)-5-363 (b-77) (b-35) HH (a-18 ) -COCH (Me)-5-364 (b-7) (b-7) HH (a-19) -CH (Me)-5-365 (b-7) (b-35) HH (a-19 ) -CH (Me)-5-366 (b-11) (b-7) HH (a-19) -CH (Me)-5-367 (b-11) (b- 35) HH (a-19) -CH (Me) -5-368 (b-12) (b-35) HH (a-19) -CH (Me) -5-369 (b-15) (b- 35) HH (a-19) -CH (Me) -5-370 (b-18) (b-7) HH (a-19) -CH (Me) -5-371 (b-18) (b- 35) HH (a-19) -CH (Me)-5-372 (b-19) (b-35) HH (a-19) -CH (Me) -5-373 (b-20) (b- 7) HH (a-19) -CH (Me) -5-374 (b-20) (b-35) HH (a-19) -CH (Me) -5-375 (b-21) (b- 35) HH (a-19) -CH (Me)-5-376 (b-24) (b-35) HH (a-19) -CH (Me) -5-377 (b-25) (b- 35) HH (a-19) -CH (Me)-5-378 (b-72) (b-35) HH (a-19) -CH (Me)-5-379 (b-73) (b- 7) HH (a-19) -CH (Me) -5-380 (b-73) (b-35) HH (a-19) -CH (Me) -5-381 (b-74) (b- 35) HH (a-19) -CH (Me) -5-382 (b-76) (b-35) HH (a-19) -CH (Me) -5-383 (b-77) (b- 7) HH (a-19) -CH (Me)-5-384 (b-77) (b-35) HH (a-19) -CH (Me) -5-385 (b-2) (b- 35) HH (a-20) -CH (Me) -5-386 (b-7) (b-7) HH (a-20) -CH (Me) -5-387 (b-7) (b- 7) HH (a-20) -COCH (Me) -5-388 (b-7) (b-35) HH (a-20) -CH (Me) -5-389 (b-7) (b- 35) HH (a-20) -COCH (Me)-5-390 (b-8) (b-35) HH (a-20) -CH (Me)-5-391 (b-11) (b- 7) HH (a-20) -CH (Me) -5-392 (b-11) (b-7) HH (a-20) -COCH (Me) -5-393 (b-1 1) (b-35) HH (a-20) -CH (Me)-5-394 (b-11) (b-35) HH (a-20) -COCH (Me)-5-395 (b- 12) (b-7) HH (a-20) -CH (Me)-5-396 (b-12) (b-35) HH (a-20) -CH (Me)-5-397 (b- 15) (b-7) HH (a-20) -CH (Me) -5-398 (b-15) (b-35) HH (a-20) -CH (Me) -5-399 (b- 18) (b-7) HH (a-20) -CH (Me) -5-400 (b-18) (b-7) HH (a-20) -COCH (Me) -5-401 (b- 18) (b-35) HH (a-20) -CH (Me) -5-402 (b-18) (b-35) HH (a-20) -COCH (Me) -5-403 (b- 19) (b-7) HH (a-20) -CH (Me) -5-404 (b-19) (b-35) HH (a-20) -CH (Me) -5-405 (b- 20) (b-7) HH (a-20) -CH (Me) -5-406 (b-20) (b-7) HH (a-20) -COCH (Me) -5-407 (b- 20) (b-35) HH (a-20) -CH (Me) -5-408 (b-20) (b-35) HH (a-20) -COCH (Me) -5-409 (b- 21) (b-7) HH (a-20) -CH (Me) -5-410 (b-21) (b-35) HH (a-20) -CH (Me) -5-411 (b- 24) (b-7) HH (a-20) -CH (Me) -5-412 (b-24) (b-35) HH (a-20) -CH (Me) -5-413 (b- 25) (b-7) HH (a-20) -CH (Me) -5-414 (b-25) (b-35) HH (a-20) -CH (Me) -5-415 (b- 72) (b-7) HH (a-20) -CH (Me) -5-416 (b-72) (b-35) HH (a-20) -CH (Me) -5-417 (b- 73) (b-7) HH (a-20) -CH (Me) -5-418 (b-73) (b-7) HH (a-20) -COCH (Me )-5-419 (b-73) (b-35) HH (a-20) -CH (Me)-5-420 (b-73) (b-35) HH (a-20) -COCH (Me )-5-421 (b-74) (b-7) HH (a-20) -CH (Me)-5-422 (b-74) (b-35) HH (a-20) -CH (Me )-5-423 (b-76) (b-7) HH (a-20) -CH (Me)-5-424 (b-76) (b-35) HH (a-20) -CH (Me )-5-425 (b-77) (b-7) HH (a-20) -CH (Me)-5-426 (b-77) (b-7) HH (a-20) -COCH (Me )-5-427 (b-77) (b-35) HH (a-20) -CH (Me)-5-428 (b-77) (b-35) HH (a-20) -COCH (Me )-5-429 (b-7) (b-35) HH (a-21) -CH (Me)-5-430 (b-11) (b-35) HH (a-21) -CH (Me )-5-431 (b-18) (b-35) HH (a-21) -CH (Me)-5-432 (b-20) (b-35) HH (a-21) -CH (Me )-5-433 (b-73) (b-35) HH (a-21) -CH (Me)-5-434 (b-77) (b-35) HH (a-21) -CH (Me )-5-435 (b-7) (b-7) HH (a-24) -CH (Me)-5-436 (b-7) (b-35) HH (a-24) -CH (Me )-5-437 (b-11) (b-7) HH (a-24) -CH (Me) -5-438 (b-11) (b-35) HH (a-24) -CH (Me )-5-439 (b-12) (b-35) HH (a-24) -CH (Me)-5-440 (b-15) (b-35) HH (a-24) -CH (Me )-5-441 (b-18) (b-7) HH (a-24) -CH (Me) -5-442 (b-18) (b-35) HH (a-24) -CH (Me )-5-443 (b-19) (b-35) HH (a-24) -CH (Me)-5-444 (b-20) (b-7) HH (a-2 4) -CH (Me)-5-445 (b-20) (b-35) HH (a-24) -CH (Me) -5-446 (b-21) (b-35) HH (a- 24) -CH (Me)-5-447 (b-24) (b-35) HH (a-24) -CH (Me) -5-448 (b-25) (b-35) HH (a- 24) -CH (Me)-5-449 (b-72) (b-35) HH (a-24) -CH (Me) -5-450 (b-73) (b-7) HH (a- 24) -CH (Me)-5-451 (b-73) (b-35) HH (a-24) -CH (Me)-5-452 (b-74) (b-35) HH (a- 24) -CH (Me)-5-453 (b-76) (b-35) HH (a-24) -CH (Me) -5-454 (b-77) (b-7) HH (a- 24) -CH (Me)-5-455 (b-77) (b-35) HH (a-24) -CH (Me) -5-456 (b-2) (b-35) HH (a- 26) -CH (Me)-5-457 (b-7) (b-7) HH (a-26) -CH (Me)-5-458 (b-7) (b-7) HH (a- 26) -COCH (Me)-5-459 (b-7) (b-35) HH (a-26) -CH (Me)-5-460 (b-7) (b-35) HH (a- 26) -COCH (Me)-5-461 (b-8) (b-35) HH (a-26) -CH (Me)-5-462 (b-11) (b-7) HH (a- 26) -CH (Me)-5-463 (b-11) (b-7) HH (a-26) -COCH (Me) -5-464 (b-11) (b-35) HH (a- 26) -CH (Me)-5-465 (b-11) (b-35) HH (a-26) -COCH (Me)-5-466 (b-12) (b-7) HH (a- 26) -CH (Me)-5-467 (b-12) (b-35) HH (a-26) -CH (Me)-5-468 (b-15) (b-7) HH (a- 26) -CH (Me)-5-469 (b-15) (b-35) HH (a-26) -CH (Me) -5-470 (b-18) (b-7) HH (a-26) -CH (Me)-5-471 (b-18) (b-7) HH (a-26) -COCH (Me) -5-472 (b-18) (b-35) HH (a-26) -CH (Me) -5-473 (b-18) (b-35) HH (a-26) -COCH (Me) -5-474 (b-19) (b-7) HH (a-26) -CH (Me)-5-475 (b-19) (b-35) HH (a-26) -CH (Me) -5-476 (b-20) (b-7) HH (a-26) -CH (Me)-5-477 (b-20) (b-7) HH (a-26) -COCH (Me) -5-478 (b-20) (b-35) HH (a-26) -CH (Me) -5-479 (b-20) (b-35) HH (a-26) -COCH (Me) -5-480 (b-21) (b-7) HH (a-26) -CH (Me) -5-481 (b-21) (b-35) HH (a-26) -CH (Me) -5-482 (b-24) (b-7) HH (a-26) -CH (Me) -5-483 (b-24) (b-35) HH (a-26) -CH (Me) -5-484 (b-25) (b-7) HH (a-26) -CH (Me) -5-485 (b-25) (b-35) HH (a-26) -CH (Me) -5-486 (b-72) (b-7) HH (a-26) -CH (Me) -5-487 (b-72) (b-35) HH (a-26) -CH (Me) -5-488 (b-73) (b-7) HH (a-26) -CH (Me) -5-489 (b-73) (b-7) HH (a-26) -COCH (Me) -5-490 (b-73) (b-35) HH (a-26) -CH (Me)-5-491 (b-73) (b-35) HH (a-26) -COCH (Me) -5-492 (b-74) (b-7) HH (a-26) -CH (Me) -5-493 (b-74) (b-35) HH (a-26) -CH (Me) -5-494 (b-76) (b-7) HH (a-26) -CH (Me) -5-495 (b-76) (b-35) HH (a-26) -CH (Me) -5-496 (b-77) (b-7) HH (a-26) -CH (Me) -5-497 (b-77) (b-7) HH (a-26) -COCH (Me) -5-498 (b-77) (b-35) HH (a-26) -CH (Me) -5-499 (b-77) (b-35) HH (a-26) -COCH (Me) -5-500 (b-7) (b-35) HH (a-27) -CH (Me) -5-501 (b-11) (b-35) HH (a-27) -CH (Me) -5-502 (b-18) (b-35) HH (a-27) -CH (Me) -5-503 (b-20) (b-35) HH (a-27) -CH (Me) -5-504 (b-73) (b-35) HH (a-27) -CH (Me) -5-505 (b-77) (b-35) HH (a-27) -CH (Me) -5-506 (b-7) (b-7) HH (a-28) -CH (Me) -5-507 (b-7) (b-35) HH (a-28) -CH (Me) -5-508 (b-11) (b-7) HH (a-28) -CH (Me) -5-509 (b-11) (b-35) HH (a-28) -CH (Me) -5-510 (b-12) (b-35) HH (a-28) -CH (Me) -5-511 (b-15) (b-35) HH (a-28) -CH (Me) -5-512 (b-18) (b-7) HH (a-28) -CH (Me) -5-513 (b-18) (b-35) HH (a-28) -CH (Me) -5-514 (b-19) (b-35) HH (a-28) -CH (Me) -5-515 (b-20) (b-7) HH (a-28) -CH (Me) -5-516 (b-20) (b-35) HH (a-28) -CH (Me) -5-517 (b-21) (b-35) HH (a-28) -CH (Me) -5-518 (b-24) (b-35) HH (a-28) -CH (Me) -5-519 (b-25) (b-35) HH (a-28) -CH (Me) -5-520 (b-72) (b-35) HH (a-28) -CH (Me) -5-521 (b-73) (b-7) HH (a-28) -CH (Me) -5-522 (b-73) (b-35) HH (a-28) -CH (Me)-5-523 (b-74) (b-35) HH (a-28) -CH (Me) -5-524 (b-76) (b-35) HH (a-28) -CH (Me)-5-525 (b-77) (b-7) HH (a-28) -CH (Me) -5-526 (b-77) (b-35) HH (a-28) -CH (Me)-5-527 (b-7) (b-35) HH (a-29) -CH (Me) -5-528 (b-11) (b-35) HH (a-29) -CH (Me)-5-529 (b-18) (b-35) HH (a-29) -CH (Me) -5-530 (b-20) (b-35) HH (a-29) -CH (Me)-5-531 (b-73) (b-35) HH (a-29) -CH (Me) -5-532 (b-77) (b-35) HH (a-29) -CH (Me)-5-533 (b-2) (b-35) HH (a-31) -CH (Me) -5-534 (b-7) (b-7) HH (a-31) -CH (Me)-5-535 (b-7) (b-7) HH (a-31) -COCH (Me) -5-536 (b-7) (b-35) HH (a-31) -CH (Me)-5-537 (b-7) (b-35) HH (a-31) -COCH (Me) -5-538 (b-8) (b-35) HH (a-31) -CH (Me)-5-539 (b-11) (b-7) HH (a-31) -CH (Me) -5-540 (b-11) (b-7) HH (a-31) -COCH (Me)-5-541 (b-11) (b-35) HH (a-31) -CH (Me) -5-542 (b-11) (b-35) HH (a-31) -COCH (Me)-5-543 (b-12) (b-7) HH (a-31) -CH (Me) -5-544 (b-12) (b-35) HH (a-31) -CH (Me)-5-545 (b-15) (b-7) HH (a-31) -CH (Me) -5-546 (b-15) (b-35) HH (a-31) -CH (Me)-5-547 (b-18) (b-7) HH (a-31) -CH (Me)-5-548 (b-18) (b-7) HH (a-31) -COCH (Me)-5-549 (b-18) (b-35) HH (a-31) -CH (Me)-5-550 (b-18) (b-35) HH (a-31) -COCH (Me)-5-551 (b-19) (b-7) HH (a-31) -CH (Me)-5-552 (b-19) (b-35) HH (a-31) -CH (Me)-5-553 (b-20) (b-7) HH (a-31) -CH (Me)-5-554 (b-20) (b-7) HH (a-31) -COCH (Me)-5-555 (b-20) (b-35) HH (a-31) -CH (Me)-5-556 (b-20) (b-35) HH (a-31) -COCH (Me)-5-557 (b-21) (b-7) HH (a-31) -CH (Me)-5-558 (b-21) (b-35) HH (a-31) -CH (Me)-5-559 (b-24) (b-7) HH (a-31) -CH (Me)-5-560 (b-24) (b-35) HH (a-31) -CH (Me)-5-561 (b-25) (b-7) HH (a-31) -CH (Me)-5-562 (b-25) (b-35) HH (a-31) -CH (Me)-5-563 (b-72) (b-7) HH (a-31) -CH (Me)-5-564 (b-72) (b-35) HH (a-31) -CH (Me)-5-565 (b-73) (b-7) HH (a-31) -CH (Me)-5-566 (b-73) (b-7) HH (a-31) -COCH (Me)-5-567 (b-73) (b-35) HH (a-31) -CH (Me)-5-568 (b-73) (b-35) HH (a-31) -COCH (Me)-5-569 (b-74) (b-7) HH (a-31) -CH (Me)-5-570 (b-74) (b-35) HH (a-31) -CH (Me)-5-571 (b-76) (b-7) HH (a-31) -CH (Me)-5-572 (b-76) (b-35) HH (a-31) -CH (Me)-5-573 (b-77) (b- 7) HH (a-31) -CH (Me) -5-574 (b-77) (b-7) HH (a-31) -COCH (Me) -5-575 (b-77) (b- 35) HH (a-31) -CH (Me)-5-576 (b-77) (b-35) HH (a-31) -COCH (Me)-5-577 (b-7) (b- 35) HH (a-32) -CH (Me) -5-578 (b-11) (b-35) HH (a-32) -CH (Me) -5-579 (b-18) (b- 35) HH (a-32) -CH (Me) -5-580 (b-20) (b-35) HH (a-32) -CH (Me) -5-581 (b-73) (b- 35) HH (a-32) -CH (Me)-5-582 (b-77) (b-35) HH (a-32) -CH (Me)-5-583 (b-7) (b- 7) HH (a-33) -CH (Me) -5-584 (b-7) (b-35) HH (a-33) -CH (Me) -5-585 (b-11) (b- 7) HH (a-33) -CH (Me) -5-586 (b-11) (b-35) HH (a-33) -CH (Me) -5-587 (b-12) (b- 35) HH (a-33) -CH (Me) -5-588 (b-15) (b-35) HH (a-33) -CH (Me) -5-589 (b-18) (b- 7) HH (a-33) -CH (Me) -5-590 (b-18) (b-35) HH (a-33) -CH (Me) -5-591 (b-19) (b- 35) HH (a-33) -CH (Me) -5-592 (b-20) (b-7) HH (a-33) -CH (Me) -5-593 (b-20) (b- 35) HH (a-33) -CH (Me) -5-594 (b-21) (b-35) HH (a-33) -CH (Me) -5-595 (b-24) (b- 35) HH (a-33) -CH (Me) -5-596 (b-25) (b-35) HH (a-33) -CH (Me) -5-597 (b-72) (b- 35) HH (a-33) -CH (Me) -5-598 (b-73) (b-7) HH (a-33) -CH (Me) -5-599 (b -73) (b-35) HH (a-33) -CH (Me)-5-600 (b-74) (b-35) HH (a-33) -CH (Me) -5-601 (b -76) (b-35) HH (a-33) -CH (Me) -5-602 (b-77) (b-7) HH (a-33) -CH (Me) -5-603 (b -77) (b-35) HH (a-33) -CH (Me)-5-604 (b-7) (b-35) HH (a-34) -CH (Me) -5-605 (b -11) (b-35) HH (a-34) -CH (Me) -5-606 (b-18) (b-35) HH (a-34) -CH (Me) -5-607 (b -20) (b-35) HH (a-34) -CH (Me)-5-608 (b-73) (b-35) HH (a-34) -CH (Me) -5-609 (b -77) (b-35) HH (a-34) -CH (Me)-5-610 (b-7) (b-35) HH (a-36) -CH (Me) -5-611 (b -11) (b-35) HH (a-36) -CH (Me)-5-612 (b-18) (b-35) HH (a-36) -CH (Me) -5-613 (b -20) (b-35) HH (a-36) -CH (Me)-5-614 (b-73) (b-35) HH (a-36) -CH (Me) -5-615 (b -77) (b-35) HH (a-36) -CH (Me)-5-616 (b-7) (b-35) HH (a-38) -CH (Me) -5-617 (b -11) (b-35) HH (a-38) -CH (Me)-5-618 (b-18) (b-35) HH (a-38) -CH (Me)-5-619 (b -7) (b-35) HH (a-39) -CH (Me) -5-620 (b-11) (b-35) HH (a-39) -CH (Me) -5-621 (b -18) (b-35) HH (a-39) -CH (Me)-5-622 (b-20) (b-35) HH (a-39) -CH (Me) -5-623 (b -73) (b-35) HH (a-39) -CH (Me)-5-624 (b-77) (b-35) HH (a-39) -CH (Me)- 5-625 (b-7) (b-35) HH (a-41) -CH (Me)-5-626 (b-11) (b-35) HH (a-41) -CH (Me)- 5-627 (b-18) (b-35) HH (a-41) -CH (Me)-5-628 (b-2) (b-35) HH (a-43) -CH (Me)- 5-629 (b-7) (b-7) HH (a-43) -CH (Me)-5-630 (b-7) (b-7) HH (a-43) -COCH (Me)- 5-631 (b-7) (b-35) HH (a-43) -CH (Me)-5-632 (b-7) (b-35) HH (a-43) -COCH (Me)- 5-633 (b-8) (b-35) HH (a-43) -CH (Me)-5-634 (b-11) (b-7) HH (a-43) -CH (Me)- 5-635 (b-11) (b-7) HH (a-43) -COCH (Me)-5-636 (b-11) (b-35) HH (a-43) -CH (Me)- 5-637 (b-11) (b-35) HH (a-43) -COCH (Me)-5-638 (b-12) (b-7) HH (a-43) -CH (Me)- 5-639 (b-12) (b-35) HH (a-43) -CH (Me)-5-640 (b-15) (b-7) HH (a-43) -CH (Me)- 5-641 (b-15) (b-35) HH (a-43) -CH (Me)-5-642 (b-18) (b-7) HH (a-43) -CH (Me)- 5-643 (b-18) (b-7) HH (a-43) -COCH (Me)-5-644 (b-18) (b-35) HH (a-43) -CH (Me)- 5-645 (b-18) (b-35) HH (a-43) -COCH (Me)-5-646 (b-19) (b-7) HH (a-43) -CH (Me)- 5-647 (b-19) (b-35) HH (a-43) -CH (Me)-5-648 (b-20) (b-7) HH (a-43) -CH (Me)- 5-649 (b-20) (b-7) HH (a-43) -COCH (Me)-5-650 (b-20) (b-35) HH (a-43 ) -CH (Me)-5-651 (b-20) (b-35) HH (a-43) -COCH (Me)-5-652 (b-21) (b-7) HH (a-43 ) -CH (Me)-5-653 (b-21) (b-35) HH (a-43) -CH (Me) -5-654 (b-24) (b-7) HH (a-43 ) -CH (Me)-5-655 (b-24) (b-35) HH (a-43) -CH (Me) -5-656 (b-25) (b-7) HH (a-43 ) -CH (Me)-5-657 (b-25) (b-35) HH (a-43) -CH (Me) -5-658 (b-72) (b-7) HH (a-43 ) -CH (Me)-5-659 (b-72) (b-35) HH (a-43) -CH (Me)-5-660 (b-73) (b-7) HH (a-43 ) -CH (Me)-5-661 (b-73) (b-7) HH (a-43) -COCH (Me)-5-662 (b-73) (b-35) HH (a-43 ) -CH (Me)-5-663 (b-73) (b-35) HH (a-43) -COCH (Me)-5-664 (b-74) (b-7) HH (a-43 ) -CH (Me)-5-665 (b-74) (b-35) HH (a-43) -CH (Me)-5-666 (b-76) (b-7) HH (a-43 ) -CH (Me)-5-667 (b-76) (b-35) HH (a-43) -CH (Me) -5-668 (b-77) (b-7) HH (a-43 ) -CH (Me)-5-669 (b-77) (b-7) HH (a-43) -COCH (Me)-5-670 (b-77) (b-35) HH (a-43 ) -CH (Me)-5-671 (b-77) (b-35) HH (a-43) -COCH (Me)-5-672 (b-7) (b-35) HH (a-44 ) -CH (Me)-5-673 (b-11) (b-35) HH (a-44) -CH (Me)-5-674 (b-18) (b-35) HH (a-44 ) -CH (Me)-5-675 (b-20) (b-35) HH (a-44) -CH (Me) -5-676 (b-73) (b -35) HH (a-44) -CH (Me) -5-677 (b-77) (b-35) HH (a-44) -CH (Me) -5-678 (b-7) (b -7) HH (a-45) -CH (Me) -5-679 (b-7) (b-35) HH (a-45) -CH (Me) -5-680 (b-11) (b -7) HH (a-45) -CH (Me)-5-681 (b-11) (b-35) HH (a-45) -CH (Me)-5-682 (b-12) (b -35) HH (a-45) -CH (Me) -5-683 (b-15) (b-35) HH (a-45) -CH (Me) -5-684 (b-18) (b -7) HH (a-45) -CH (Me)-5-685 (b-18) (b-35) HH (a-45) -CH (Me) -5-686 (b-19) (b -35) HH (a-45) -CH (Me) -5-687 (b-20) (b-7) HH (a-45) -CH (Me) -5-688 (b-20) (b -35) HH (a-45) -CH (Me) -5-689 (b-21) (b-35) HH (a-45) -CH (Me) -5-690 (b-24) (b -35) HH (a-45) -CH (Me)-5-691 (b-25) (b-35) HH (a-45) -CH (Me)-5-692 (b-72) (b -35) HH (a-45) -CH (Me)-5-693 (b-73) (b-7) HH (a-45) -CH (Me) -5-694 (b-73) (b -35) HH (a-45) -CH (Me)-5-695 (b-74) (b-35) HH (a-45) -CH (Me) -5-696 (b-76) (b -35) HH (a-45) -CH (Me)-5-697 (b-77) (b-7) HH (a-45) -CH (Me)-5-698 (b-77) (b -35) HH (a-45) -CH (Me)-5-699 (b-7) (b-35) HH (a-46) -CH (Me)-5-700 (b-11) (b -35) HH (a-46) -CH (Me) -5-701 (b-18) (b-35) HH (a-46) -CH (Me) -5-702 (b-2 0) (b-35) HH (a-46) -CH (Me)-5-703 (b-73) (b-35) HH (a-46) -CH (Me) -5-704 (b- 77) (b-35) HH (a-46) -CH (Me)-5-705 (b-7) (b-35) HH (a-47) -CH (Me) -5-706 (b- 11) (b-35) HH (a-47) -CH (Me)-5-707 (b-18) (b-35) HH (a-47) -CH (Me)- . [Table 6]

Embedded image Compd. R ¹ R ² R ³ R ⁴ AG No. Substituent No. Substituent No. Substituent No. 6-1 (b-7) (b-7) HH (a-1) -CH (Me)-6-2 (b-7) (b-35) HH (a-1) -CH (Me)- 6-3 (b-11) (b-7) HH (a-1) -CH (Me)-6-4 (b-11) (b-35) HH (a-1) -CH (Me)- 6-5 (b-12) (b-35) HH (a-1) -CH (Me)-6-6 (b-15) (b-35) HH (a-1) -CH (Me)- 6-7 (b-18) (b-7) HH (a-1) -CH (Me)-6-8 (b-18) (b-35) HH (a-1) -CH (Me)- 6-9 (b-19) (b-35) HH (a-1) -CH (Me)-6-10 (b-20) (b-7) HH (a-1) -CH (Me)- 6-11 (b-20) (b-35) HH (a-1) -CH (Me)-6-12 (b-21) (b-35) HH (a-1) -CH (Me)- 6-13 (b-24) (b-35) HH (a-1) -CH (Me)-6-14 (b-25) (b-35) HH (a-1) -CH (Me)- 6-15 (b-72) (b-35) HH (a-1) -CH (Me)-6-16 (b-73) (b-7) HH (a-1) -CH (Me)- 6-17 (b-73) (b-35) HH (a-1) -CH (Me)-6-18 (b-74) (b-35) HH (a-1) -CH (Me)- 6-19 (b-76) (b-35) HH (a-1) -CH (Me)-6-20 (b-77) (b-7) HH (a-1) -CH (Me)- 6-21 (b-77) (b-35) HH (a-1) -CH (Me)-6-22 (b-11) (b-35) HH (a-2) -CH (Me)- 6-23 (b-18) (b-35) HH (a-2) -CH (Me)-6-24 (b-20) (b-35) HH (a-2) -CH (Me)- 6-25 (b-7) (b-35) HH (a-3) -CH (Me)-6-26 (b-11) (b-35) HH (a-3) -CH (Me)- 6-27 (b-18) (b-35) HH (a-3) -CH (Me)-6-28 (b-20) (b-35) HH (a-3) -CH (Me)-6-29 (b-73) (b-35) HH (a-3) -CH (Me) -6-30 (b-77) (b-35) HH (a-3) -CH (Me)-6-31 (b-11) (b-35) HH (a-4) -CH (Me) -6-32 (b-18) (b-35) HH (a-4) -CH (Me)-6-33 (b-20) (b-35) HH (a-4) -CH (Me) -6-34 (b-7) (b-7) HH (a-5) -CH (Me)-6-35 (b-7) (b-35) HH (a-5) -CH (Me) -6-36 (b-11) (b-7) HH (a-5) -CH (Me)-6-37 (b-11) (b-35) HH (a-5) -CH (Me) -6-38 (b-12) (b-35) HH (a-5) -CH (Me)-6-39 (b-15) (b-35) HH (a-5) -CH (Me) -6-40 (b-18) (b-7) HH (a-5) -CH (Me)-6-41 (b-18) (b-35) HH (a-5) -CH (Me)-6-42 (b-19) (b-35) HH (a-5) -CH (Me)-6-43 (b-20) (b-7) HH (a-5) -CH (Me)-6-44 (b-20) (b-35) HH (a-5) -CH (Me)-6-45 (b-21) (b-35) HH (a-5) -CH (Me) -6-46 (b-24) (b-35) HH (a-5) -CH (Me)-6-47 (b-25) (b-35) HH (a-5) -CH (Me) -6-48 (b-72) (b-35) HH (a-5) -CH (Me)-6-49 (b-73) (b-7) HH (a-5) -CH (Me) -6-50 (b-73) (b-35) HH (a-5) -CH (Me)-6-51 (b-74) (b-35) HH (a-5) -CH (Me)-6-52 (b-76) (b-35) HH (a-5) -CH (Me)-6-53 (b-77) (b-7) HH (a-5) -CH (Me)-6-54 (b-77) (b-35) HH (a-5) -CH (Me)-6-55 (b-11) (b-35) HH (a-6) -CH (Me)-6-56 (b-18) (b-35) HH (a-6) -CH (Me)-6-57 (b-20) (b-35) HH (a-6) -CH (Me)-6-58 (b-7) (b-35) HH (a-7) -CH (Me)-6-59 (b-11) (b-35) HH (a-7) -CH (Me)-6-60 (b-18) (b-35) HH (a-7) -CH (Me)-6-61 (b-20) (b-35) HH (a-7) -CH (Me)-6-62 (b-73) (b-35) HH (a-7) -CH (Me)-6-63 (b-77) (b-35) HH (a-7) -CH (Me)-6-64 (b-11) (b-35) HH (a-8) -CH (Me)-6-65 (b-18) (b-35) HH (a-8) -CH (Me)-6-66 (b-20) (b-35) HH (a-8) -CH (Me)-6-67 (b-11) (b-35) HH (a-11) -CH (Me)-6-68 (b-18) (b-35) HH (a-11) -CH (Me)-6-69 (b-20) (b-35) HH (a-11) -CH (Me)-6-70 (b-2) (b-35) HH (a-14) -CH (Me)-6-71 (b-7) (b-7) HH (a-14) -CH (Me)-6-72 (b-7) (b-7) HH (a-14) -COCH (Me)-6-73 (b-7) (b-35) HH (a-14) -CH (Me)-6-74 (b-7) (b-35) HH (a-14) -COCH (Me)-6-75 (b-8) (b-35) HH (a-14) -CH (Me)-6-76 (b-11) (b-7) HH (a-14) -CH (Me)-6-77 (b-11) (b-7) HH (a-14) -COCH (Me)-6-78 (b-11) (b-35) HH (a-14) -CH (Me)-6-79 (b-11) (b-35) HH (a-14) -COCH (Me)-6-80 (b-12) (b-7) HH (a-14) -CH (Me)-6-81 (b-12) (b-35) HH (a-14) -CH (Me)-6-82 (b-15) (b-7) HH (a-14) -CH (Me)-6-83 (b-15) (b-35) HH (a-14) -CH (Me) -6-84 (b-18) (b-7) HH (a-14) -CH (Me)-6-85 (b-18) (b-7) HH (a-14) -COCH (Me)-6-86 (b-18) (b-35) HH (a-14) -CH (Me)-6-87 (b-18) (b-35) HH (a-14) -COCH (Me)-6-88 (b-19) (b-7) HH (a-14) -CH (Me)-6-89 (b-19) (b-35) HH (a-14) -CH (Me) -6-90 (b-20) (b-7) HH (a-14) -CH (Me)-6-91 (b-20) (b-7) HH (a-14) -COCH (Me)-6-92 (b-20) (b-35) HH (a-14) -CH (Me)-6-93 (b-20) (b-35) HH (a-14) -COCH (Me)-6-94 (b-21) (b-7) HH (a-14) -CH (Me)-6-95 (b-21) (b-35) HH (a-14) -CH (Me) -6-96 (b-24) (b-7) HH (a-14) -CH (Me)-6-97 (b-24) (b-35) HH (a-14) -CH (Me) -6-98 (b-25) (b-7) HH (a-14) -CH (Me)-6-99 (b-25) (b-35) HH (a-14) -CH (Me) -6-100 (b-72) (b-7) HH (a-14) -CH (Me)-6-101 (b-72) (b-35) HH (a-14) -CH (Me) -6-102 (b-73) (b-7) HH (a-14) -CH (Me)-6-103 (b-73) (b-7) HH (a-14) -COCH (Me)-6-104 (b-73) (b-35) HH (a-14) -CH (Me)-6-105 (b-73) (b-35) HH (a-14) -COCH (Me)-6-106 (b-74) (b-7) HH (a-14) -CH (Me)-6-107 (b-74) (b-35) HH (a-14) -CH (Me) -6-108 (b-76) (b-7) HH ( a-14) -CH (Me)-6-109 (b-76) (b-35) HH (a-14) -CH (Me)-6-110 (b-77) (b-7) HH ( a-14) -CH (Me)-6-111 (b-77) (b-7) HH (a-14) -COCH (Me)-6-112 (b-77) (b-35) HH ( a-14) -CH (Me)-6-113 (b-77) (b-35) HH (a-14) -COCH (Me)-6-114 (b-7) (b-7) HH ( a-15) -CH (Me)-6-115 (b-7) (b-35) HH (a-15) -CH (Me)-6-116 (b-11) (b-7) HH ( a-15) -CH (Me)-6-117 (b-11) (b-35) HH (a-15) -CH (Me)-6-118 (b-12) (b-35) HH ( a-15) -CH (Me)-6-119 (b-15) (b-35) HH (a-15) -CH (Me)-6-120 (b-18) (b-7) HH ( a-15) -CH (Me)-6-121 (b-18) (b-35) HH (a-15) -CH (Me)-6-122 (b-19) (b-35) HH ( a-15) -CH (Me)-6-123 (b-20) (b-7) HH (a-15) -CH (Me)-6-124 (b-20) (b-35) HH ( a-15) -CH (Me)-6-125 (b-21) (b-35) HH (a-15) -CH (Me)-6-126 (b-24) (b-35) HH ( a-15) -CH (Me)-6-127 (b-25) (b-35) HH (a-15) -CH (Me)-6-128 (b-72) (b-35) HH ( a-15) -CH (Me)-6-129 (b-73) (b-7) HH (a-15) -CH (Me)-6-130 (b-73) (b-35) HH ( a-15) -CH (Me)-6-131 (b-74) (b-35) HH (a-15) -CH (Me)-6-132 (b-76) (b-35) HH ( a-15) -CH (Me)-6-133 (b-77) (b-7) HH (a-15) -CH (Me)-6-134 (b-77) (b- 35) HH (a-15) -CH (Me)-6-135 (b-7) (b-7) HH (a-18) -CH (Me)-6-136 (b-7) (b- 35) HH (a-18) -CH (Me)-6-137 (b-11) (b-7) HH (a-18) -CH (Me) -6-138 (b-11) (b- 35) HH (a-18) -CH (Me)-6-139 (b-12) (b-35) HH (a-18) -CH (Me)-6-140 (b-15) (b- 35) HH (a-18) -CH (Me)-6-141 (b-18) (b-7) HH (a-18) -CH (Me) -6-142 (b-18) (b- 35) HH (a-18) -CH (Me)-6-143 (b-19) (b-35) HH (a-18) -CH (Me)-6-144 (b-20) (b- 7) HH (a-18) -CH (Me)-6-145 (b-20) (b-35) HH (a-18) -CH (Me)-6-146 (b-21) (b- 35) HH (a-18) -CH (Me)-6-147 (b-24) (b-35) HH (a-18) -CH (Me) -6-148 (b-25) (b- 35) HH (a-18) -CH (Me)-6-149 (b-72) (b-35) HH (a-18) -CH (Me)-6-150 (b-73) (b- 7) HH (a-18) -CH (Me)-6-151 (b-73) (b-35) HH (a-18) -CH (Me)-6-152 (b-74) (b- 35) HH (a-18) -CH (Me)-6-153 (b-76) (b-35) HH (a-18) -CH (Me)-6-154 (b-77) (b- 7) HH (a-18) -CH (Me)-6-155 (b-77) (b-35) HH (a-18) -CH (Me)-6-156 (b-7) (b- 35) HH (a-19) -CH (Me)-6-157 (b-11) (b-35) HH (a-19) -CH (Me)-6-158 (b-18) (b- 35) HH (a-19) -CH (Me)-6-159 (b-20) (b-35) HH (a-19) -CH (Me)-6-160 (b-73 ) (b-35) HH (a-19) -CH (Me)-6-161 (b-77) (b-35) HH (a-19) -CH (Me)-6-162 (b-7 ) (b-7) HH (a-20) -CH (Me)-6-163 (b-7) (b-35) HH (a-20) -CH (Me)-6-164 (b-11 ) (b-7) HH (a-20) -CH (Me)-6-165 (b-11) (b-35) HH (a-20) -CH (Me)-6-166 (b-12 ) (b-35) HH (a-20) -CH (Me)-6-167 (b-15) (b-35) HH (a-20) -CH (Me)-6-168 (b-18 ) (b-7) HH (a-20) -CH (Me)-6-169 (b-18) (b-35) HH (a-20) -CH (Me)-6-170 (b-19 ) (b-35) HH (a-20) -CH (Me)-6-171 (b-20) (b-7) HH (a-20) -CH (Me)-6-172 (b-20 ) (b-35) HH (a-20) -CH (Me)-6-173 (b-21) (b-35) HH (a-20) -CH (Me)-6-174 (b-24 ) (b-35) HH (a-20) -CH (Me)-6-175 (b-25) (b-35) HH (a-20) -CH (Me)-6-176 (b-72 ) (b-35) HH (a-20) -CH (Me)-6-177 (b-73) (b-7) HH (a-20) -CH (Me)-6-178 (b-73 ) (b-35) HH (a-20) -CH (Me)-6-179 (b-74) (b-35) HH (a-20) -CH (Me)-6-180 (b-76 ) (b-35) HH (a-20) -CH (Me)-6-181 (b-77) (b-7) HH (a-20) -CH (Me)-6-182 (b-77 ) (b-35) HH (a-20) -CH (Me)-6-183 (b-11) (b-35) HH (a-21) -CH (Me)-6-184 (b-18 ) (b-35) HH (a-21) -CH (Me)-6-185 (b-20) (b-35) HH (a-21) -CH (Me)-6-186 (b-7) (b-35) HH (a-24) -CH (Me)-6-187 (b-11) (b-35) HH (a-24) -CH (Me)-6-188 (b-18) (b-35) HH (a-24) -CH (Me)-6-189 (b-20) (b-35) HH (a-24) -CH (Me)-6-190 (b-73) (b-35) HH (a-24) -CH (Me)-6-191 (b-77) (b-35) HH (a-24) -CH (Me)-6-192 (b-7) (b-7) HH (a-26) -CH (Me)-6-193 (b-7) (b-35) HH (a-26) -CH (Me)-6-194 (b-11) (b-7) HH (a-26) -CH (Me)-6-195 (b-11) (b-35) HH (a-26) -CH (Me)-6-196 (b-12) (b-35) HH (a-26) -CH (Me)-6-197 (b-15) (b-35) HH (a-26) -CH (Me)-6-198 (b-18) (b-7) HH (a-26) -CH (Me)-6-199 (b-18) (b-35) HH (a-26) -CH (Me) -6-200 (b-19) (b-35) HH (a-26) -CH (Me)-6-201 (b-20) (b-7) HH (a-26) -CH (Me)-6-202 (b-20) (b-35) HH (a-26) -CH (Me)-6-203 (b-21) (b-35) HH (a-26) -CH (Me)-6-204 (b-24) (b-35) HH (a-26) -CH (Me) -6-205 (b-25) (b-35) HH (a-26) -CH (Me) -6-206 (b-72) (b-35) HH (a-26) -CH (Me) -6-207 (b-73) (b-7) HH (a-26) -CH (Me) -6-208 (b-73) (b-35) HH (a-26) -CH (Me)-6-209 (b-74) (b-35) HH (a-26) -CH (Me) -6-210 (b-76) (b-35) HH (a-26) -CH (Me)-6-211 (b-77) (b-7) HH (a-26) -CH (Me)- 6-212 (b-77) (b-35) HH (a-26) -CH (Me)-6-213 (b-11) (b-35) HH (a-27) -CH (Me)- 6-214 (b-18) (b-35) HH (a-27) -CH (Me)-6-215 (b-20) (b-35) HH (a-27) -CH (Me)- 6-216 (b-7) (b-35) HH (a-28) -CH (Me)-6-217 (b-11) (b-35) HH (a-28) -CH (Me)- 6-218 (b-18) (b-35) HH (a-28) -CH (Me)-6-219 (b-20) (b-35) HH (a-28) -CH (Me)- 6-220 (b-73) (b-35) HH (a-28) -CH (Me)-6-221 (b-77) (b-35) HH (a-28) -CH (Me)- 6-222 (b-11) (b-35) HH (a-29) -CH (Me)-6-223 (b-18) (b-35) HH (a-29) -CH (Me)- 6-224 (b-20) (b-35) HH (a-29) -CH (Me)-6-225 (b-7) (b-7) HH (a-31) -CH (Me)- 6-226 (b-7) (b-35) HH (a-31) -CH (Me)-6-227 (b-11) (b-7) HH (a-31) -CH (Me)- 6-228 (b-11) (b-35) HH (a-31) -CH (Me)-6-229 (b-12) (b-35) HH (a-31) -CH (Me)- 6-230 (b-15) (b-35) HH (a-31) -CH (Me)-6-231 (b-18) (b-7) HH (a-31) -CH (Me)- 6-232 (b-18) (b-35) HH (a-31) -CH (Me)-6-233 (b-19) (b-35) HH (a-31) -CH (Me)- 6-234 (b-20) (b-7) HH (a-31) -CH (Me)-6-235 (b-20) (b-35) HH (a-31) -CH (Me)- 6-236 (b-21) (b-35) HH (a-31) -CH (Me)-6-237 (b-24) (b-35) HH (a-31) -C H (Me)-6-238 (b-25) (b-35) HH (a-31) -CH (Me)-6-239 (b-72) (b-35) HH (a-31)- CH (Me)-6-240 (b-73) (b-7) HH (a-31) -CH (Me)-6-241 (b-73) (b-35) HH (a-31)- CH (Me)-6-242 (b-74) (b-35) HH (a-31) -CH (Me)-6-243 (b-76) (b-35) HH (a-31)- CH (Me)-6-244 (b-77) (b-7) HH (a-31) -CH (Me)-6-245 (b-77) (b-35) HH (a-31)- CH (Me)-6-246 (b-11) (b-35) HH (a-32) -CH (Me)-6-247 (b-18) (b-35) HH (a-32)- CH (Me)-6-248 (b-20) (b-35) HH (a-32) -CH (Me)-6-249 (b-7) (b-35) HH (a-33)- CH (Me)-6-250 (b-11) (b-35) HH (a-33) -CH (Me)-6-251 (b-18) (b-35) HH (a-33)- CH (Me)-6-252 (b-20) (b-35) HH (a-33) -CH (Me)-6-253 (b-73) (b-35) HH (a-33)- CH (Me)-6-254 (b-77) (b-35) HH (a-33) -CH (Me)-6-255 (b-11) (b-35) HH (a-34)- CH (Me)-6-256 (b-18) (b-35) HH (a-34) -CH (Me)-6-257 (b-20) (b-35) HH (a-34)- CH (Me)-6-258 (b-11) (b-35) HH (a-36) -CH (Me)-6-259 (b-18) (b-35) HH (a-36)- CH (Me)-6-260 (b-20) (b-35) HH (a-36) -CH (Me)-6-261 (b-11) (b-35) HH (a-39)- CH (Me)-6-262 (b-18) (b-35) HH (a-39) -CH (Me)-6-263 (b-20) (b-35) H H (a-39) -CH (Me)-6-264 (b-7) (b-7) HH (a-43) -CH (Me)-6-265 (b-7) (b-35) HH (a-43) -CH (Me)-6-266 (b-11) (b-7) HH (a-43) -CH (Me)-6-267 (b-11) (b-35) HH (a-43) -CH (Me)-6-268 (b-12) (b-35) HH (a-43) -CH (Me)-6-269 (b-15) (b-35) HH (a-43) -CH (Me)-6-270 (b-18) (b-7) HH (a-43) -CH (Me) -6-271 (b-18) (b-35) HH (a-43) -CH (Me)-6-272 (b-19) (b-35) HH (a-43) -CH (Me)-6-273 (b-20) (b-7) HH (a-43) -CH (Me)-6-274 (b-20) (b-35) HH (a-43) -CH (Me)-6-275 (b-21) (b-35) HH (a-43) -CH (Me)-6-276 (b-24) (b-35) HH (a-43) -CH (Me)-6-277 (b-25) (b-35) HH (a-43) -CH (Me)-6-278 (b-72) (b-35) HH (a-43) -CH (Me)-6-279 (b-73) (b-7) HH (a-43) -CH (Me)-6-280 (b-73) (b-35) HH (a-43) -CH (Me)-6-281 (b-74) (b-35) HH (a-43) -CH (Me)-6-282 (b-76) (b-35) HH (a-43) -CH (Me)-6-283 (b-77) (b-7) HH (a-43) -CH (Me)-6-284 (b-77) (b-35) HH (a-43) -CH (Me) -6-285 (b-11) (b-35) HH (a-44) -CH (Me)-6-286 (b-18) (b-35) HH (a-44) -CH (Me)-6-287 (b-20) (b-35) HH (a-44) -CH (Me)-6-288 (b-7) (b-35) HH (a-45) -CH (Me)-6-289 (b-11) (b- 35) HH (a-45) -CH (Me)-6-290 (b-18) (b-35) HH (a-45) -CH (Me)-6-291 (b-20) (b- 35) HH (a-45) -CH (Me)-6-292 (b-73) (b-35) HH (a-45) -CH (Me)-6-293 (b-77) (b- 35) HH (a-45) -CH (Me)-6-294 (b-11) (b-35) HH (a-46) -CH (Me)-6-295 (b-18) (b- 35) HH (a-46) -CH (Me)-6-296 (b-20) (b-35) HH (a-46) -CH (Me)- . In Table 1-6 above, suitable compounds include, for example, compound numbers: 1-41, 1-78, 1-86, 1-92, 2-1-2-6
4, 2-74-2-86, 2-89 -2-106, 2-116, 2-117, 2-237,
2-377, 2-403, 2-407, 2-450, 2-479, 2-480, 2-481, 2
-492, 2-499, 2-500, 2-554, 2-574, 2-577, 2-583, 2-
584, 2-585, 2-592, 2-691, 2-698, 2-699, 2-713, 2-7
55, 2-762, 2-763, 2-835, 2-838, 2-844,2-845, 2-84
6, 2-815, 2-952, 2-1085, 2-1256, 2-1286, 2-1287, 2
-1288, 2-1299, 2-1306, 2-1307, 2-1359, 2-1360, 2-1
379, 2-1382, 2-1388, 2-1389, 2-1390, 2-1496, 2-152
3, 2-1565, 2-1625, 2-1627, 2-1628, 2-1654, 2-1655,
2-1666, 2-1772, 2-1831, 2-1941, 2-1946, 2-1962, 2
-2256, 2-2274, 2-2295, 2-2309, 2-3090-2-3514, 3-
79, 3-94, 3-100, 3-169, 3-187, 3-208, 3-401, 5-94,
5-208 and 5-401 can be mentioned, and more preferable compounds are exemplified compound numbers: 2-2-2-58, 2-74, 2-81, 2-237, 2-4
50, 2-479, 2-480, 2-481, 2-492, 2-499, 2-500, 2-55
4, 2-583, 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, 2-12
99, 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
-1625,2-1627, 2-1628, 2-1654, 2-1655, 2-1666, 2-17
72, 2-1831, 2-1941, 2-1962, 2-2274, 2-2295, 2-2309,
2-3108-2-3118, 2-3136, 2-3157-2-3165, 2-3178-
2-3180, 2-3185, 2-3186, 2-3191-2-3201, 2-3217-
2-3222, 2-3376-2-3390, 2-3400-2-3406, 2-3414,
2-3438-2-3461, 2-3471-2-3477, 2-3479- 2-3514,
3-79, 3-94, 3-100, 3-169, 3-187 and 3-208 can be mentioned, and more preferable compounds are exemplified compound numbers: 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, 2-5
4, 2-56, 2-237, 2-450, 2-479, 2-480, 2-481, 2-492,
2-554, 2-583, 2-584, 2-585, 2-691, 2-713, 2-755, 2
-815, 2-844, 2-845, 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, 2-2
295, 2-2309, 2-3136, 2-3161, 2-3162, 2-3164, 2-319
7, 2-3377, 2-3386, 2-3400, 2-3457, 2-3485, 2-3497,
2-3502, 2-3504, 3-94 and 3-208 can be mentioned, and the most preferable compound is exemplified compound No. 2-5: 3- (3-{(4-fluorophenyl)-[1 -Phenylethylamino] methyl {phenylamino) -4-hydroxy-3-cyclobutene-1,
2-dione, Exemplified Compound No. 2-6: 3- (3-{(4-chlorophenyl)-[1-phenylethylamino] -methyl} phenylamino) -4-hydroxy-3-cyclobutene-1,
2-dione, Exemplified Compound No. 2-8: 3-hydroxy-4- (3-
{(4-methoxyphenyl)-[1-phenylethylamino] methyl} phenylamino) -3-cyclobutene-
1,2-dione, 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) ethylamino) -phenylmethyl] phenylamino} -3-hydroxy-3-cyclobutene- 1,
2-dione, Exemplified Compound No. 2-18: 3- (3-{(4-fluorophenyl)-[1- (3-fluorophenyl) -ethylamino] methyl} phenylamino) -4-hydroxy-3-
Cyclobutene-1,2-dione, Exemplified Compound No. 2-19: 4- {3-[(4-chlorophenyl)-(1- (3-fluorophenyl) ethylamino)
Methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, Exemplified Compound No. 2-21: 3- {3-[[1- (3-fluorophenyl) ethylamino]-(4-methoxy) Phenyl) methyl] phenylamino} -4-hydroxy-3-
Cyclobutene-1,2-dione, Exemplified Compound No. 2-37: 4- {3-[(1- (3,4-difluorophenyl) ethylamino) -phenylmethyl]
Phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, Exemplified Compound No. 2-39: 3- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluoro Phenyl) methyl] phenylamino} -4-hydroxy-
3-cyclobutene-1,2-dione, Exemplified Compound No. 2-40: 4- {3-[(4-chlorophenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl] phenylamino} -3 -Hydroxy-3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-42: 4- {3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3 -Hydroxy-
3-cyclobutene-1,2-dione, Exemplified Compound No. 2-53: 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamino}- 3-hydroxy-
3-cyclobutene-1,2-dione, Exemplified Compound No. 2-54: 4- {3-[(4-chlorophenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl] phenylamino} -3 -Hydroxy-3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-56: 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3 -Hydroxy-
3-cyclobutene-1,2-dione, Exemplified Compound No. 2-128: 4- {3-[(1- (3,5-
Difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, exemplified compound No. 2-237: 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-492: 3-amino-4- [3-((4
-Fluorophenyl)-(1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, Exemplified Compound No. 2-554: 3-amino-4- [3-((4
-Methoxyphenyl)-(1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, Exemplified compound number 2-691: 3-amino-4- [3- (4-
Pyridyl- (1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, exemplified compound number 2-815: 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, Exemplified Compound No. 2-1299: 3-amino-4- [3- ( (4
-Fluorophenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-1359: 3-amino-4- [3- (4-
Methoxyphenyl- (1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, exemplified compound number 2-1496: 3-amino-4- [3- ( 4
-Pyridyl- (1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, Exemplified Compound No. 2-1523: 3-amino-4- [3- ( Phenyl- (1- (3,5-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-
1,2-dione, Exemplified Compound No. 2-1565: 3-amino-4- [3-((4
-Fluorophenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-1625: 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-1962: 3-amino-4- [3-((4
-Methoxyphenyl)-(1- (4-pyridyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, Exemplified Compound No. 2-2295: 3-amino-4- [3-(( 4
-Methoxyphenyl)-(1- (3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3
-Cyclobutene-1,2-dione, Exemplified Compound No. 2-3136: 3- {3-[(4-chlorophenyl)-(1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -4-hydroxy -3-
Cyclobutene-1,2-dione, Exemplified Compound No. 2-3161: 3-hydroxy-4- {3-
[(1- (1-Naphthyl) ethylamino) -phenylmethyl] phenylamino} -3-cyclobutene-1,2-
Dione, Exemplified Compound No. 2-3162: 3- {3-[(4-fluorophenyl)-(1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -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-cyclobutene-
1,2-dione, Exemplified Compound No. 2-3197: 3- (3-{[1- (3-fluorophenyl) ethylamino]-(p-tolyl) methyl} phenylamino) -4-hydroxy-3-cyclobutene -1,2-dione, exemplified compound number 2-3386: 3- (3-{[1- (3,4-
Difluorophenylamino) ethylamino]-(p-tolyl) methyl @ phenylamino) -4-hydroxy-3
-Cyclobutene-1,2-dione, and Exemplified Compound No. 2-3457: 4- {3- [1- (3,5-difluorophenyl) ethylamino]-(4-methylphenyl) methyl] phenylamino} -3 -Hydroxy-3
-Cyclobutene-1,2-dione.

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be produced according to the method described below. Method A is a method for producing compound (I).

Embedded imageIn the above formula, R¹, R^Two, R^Three, R^Four, R^Five, R⁶, D,
E, G, X, Y, Z and dashed lines are as defined above.
And R^1aIs R¹Included as a substituent in the group
Amino, hydroxy and / or carboxy groups are protected
Amino, hydroxy and / or carboxy groups which may be
Is another R¹Represents a group similar to the group in the definition of the group of,
R^2a, R^3a, R^4aAnd R^6aIs R^Two, R^Three, R^FourAnd R
⁶Amino and / or arsenic included as a substituent in the group
Amino group and / or hydrido group which may be protected
Other than Roxy^Two, R^Three, R^FourAnd R⁶Definition of the group
And the same groups as in^5aIs R^FiveIn the base
The hydroxy group contained as a substituent may be protected
Other R which is a hydroxy group^FiveAs in the definition of the group
And Q is a group which is usually eliminated as a nucleophilic residue.
There is no particular limitation as long as it is present, preferably chlorine, bromine, iodine
Halogen atoms, such as methoxy; ethoxy, low
Higher alkoxy groups; trichloromethyloxy
Halogenomethyloxy group; methanesulfonyloxy, d
Lower alkanesulfonyl such as tansulfonyloxy
Oxy group; trifluoromethanesulfonyloxy, pen
Halogeno low such as tafluoroethanesulfonyloxy
Alkanesulfonyloxy group; benzenesulfonylo
Xy, p-toluenesulfonyloxy, p-nitroben
Arylsulfonyloxy such as zensulfonyloxy
And most preferably a halogen atom.
And a lower alkoxy group. In the above, R^1a, R
^2a, R^3a, R^4aAnd R^6aIn the definition of "even if protected
"Protecting group" of "good amino group" is used in the field of organic synthetic chemistry.
In particular, any amino or imino protecting group used
Without limitation, for example, formyl, acetyl, pro
Pionyl, butyryl, isobutyryl, valeryl, isoba
Relyl, pivaloyl, hexanoyl, acryloyl,
Lower aliphatic acyls such as tacryloyl and crotonoyl
Group, chloroacetyl, dichloroacetyl, trichloroa
Halogeno lower radicals such as cetyl and trifluoroacetyl
Lower carbonyl groups, lower alcohols such as methoxyacetyl
Such as a lower alkylcarbonyl group substituted with
"Aliphatic acyls";
Combined C₇-C₁₁Aromatic acyl group, 2-bromobenzoi
Halogeno C such as 4-chlorobenzoyl₇-C_{1 1}
Aromatic acyl group, 2,4,6-trimethylbenzoyl,
C substituted by lower alkyl such as 4-toluoyl₇
-C₁₁Aromatic acyl group, lower alkyl such as 4-anisoyl
C substituted with lucoxy₇-C₁₁Aromatic acyl group, 4-
Nito like nitrobenzoyl, 2-nitrobenzoyl
C substituted with b₇-C₁₁Aromatic acyl group, 2- (meth
Lower alkoxyca such as (xoxycarbonyl) benzoyl
C substituted with rubonyl₇-C₁₁Aromatic acyl group, 4-
C substituted with an aryl such as phenylbenzoyl₇
-C₁₁"Aromatic acyls" such as aromatic acyl groups;
Lower alkoxycarbonyl group, 2,2,2-trichloroe
Toxicarbonyl, 2-trimethylsilylethoxy
With halogens such as bonyl or tri-lower alkylsilyl
"Alkoxy" such as substituted lower alkoxycarbonyl group
Cycarbonyls "; vinyloxycarbonyl, allylo
"Alkenyloxycarbonyl, such as xycarbonyl
"; Benzyloxycarbonyl, 4-methoxybenzyl
Ruoxycarbonyl, 3,4-dimethoxybenzyloxy
Cicarbonyl, 2-nitrobenzyloxycarbonyl,
Such as 4-nitrobenzyloxycarbonyl,
Aryl ring substituted with at most 2 lower alkoxy or nitro
Aralkyloxycarbonyls which may be substituted ";
Limethylsilyl, triethylsilyl, isopropyldim
Tylsilyl, t-butyldimethylsilyl, methyldiiso
Propylsilyl, methyldi-t-butylsilyl, trii
Tri-lower alkylsilyl groups such as isopropylsilyl,
Diphenylmethylsilyl, diphenylbutylsilyl, di
Phenylisopropylsilyl, phenyldiisopropyl
Selected from aryls such as silyl and lower alkyls
"Silyls" such as a silyl group substituted three times with a group
Jill, phenethyl, 3-phenylpropyl, α-naphthy
Methyl, β-naphthylmethyl, diphenylmethyl,
Riphenylmethyl, α-naphthyldiphenylmethyl, 9
One to three aryl groups such as anthrylmethyl
Substituted lower alkyl group, 4-methylbenzyl, 2,
4,6-trimethylbenzyl, 3,4,5-trimethyl
Benzyl, 4-methoxybenzyl, 4-methoxyphenyl
Rudiphenylmethyl, 2-nitrobenzyl, 4-nitro
Benzyl, 4-chlorobenzyl, 4-bromobenzyl,
4-cyanobenzyl, 4-cyanobenzyldiphenylmeth
Chill, bis (2-nitrophenyl) methyl, piperonyl
Lower alkyl, lower alkoxy, nitro, halo such as
1-3 aryl groups whose aryl rings have been substituted with
"Aralkyl" such as a lower alkyl group substituted with a reel group;
Or N, N-dimethylaminomethylene, benzylidene
Den, 4-methoxybenzylidene, 4-nitrobenzyl
Den, salicylidene, 5-chlorosalicylidene, diphe
Nilmethylene, (5-chloro-2-hydroxyphenyl)
L) forms "Schiff bases" such as phenylmethylene
A substituted methylene group ";
Group acyl group, C₇-C_{1 1}Aromatic acyl group or alkoxy
A carbonyl group, more preferably a lower aliphatic acyl group
Or a lower alkoxycarbonyl group, most preferably
It is an acetyl group or a t-butoxycarbonyl group. the above
In, R^1a, R^2a, R^3a, R^4a, R^5aAnd R^6aConstant
"Protection of an optionally protected hydroxy group"
Group '' is a hydroxy group used in the field of synthetic organic chemistry.
The protective group is not particularly limited as long as it is, for example,
Shows the same meaning as the above, preferably a lower aliphatic acyl
Group, C₇-C₁₁Aromatic acyl group, lower alkoxycarbo
A lower group or a (lower alkoxy) methyl group.
Suitably, C₇-C₁₁Aromatic acyl group or (lower alkoxy
B) a methyl group, most preferably a benzoyl group or
It is a toxicoxy group. In the above, R^1aIn the definition of
"Protecting group" of "optionally protected carboxy group"
Is the protection of carboxy groups used in the field of synthetic organic chemistry.
Although it is not particularly limited as long as it is a protecting group, for example, as described above
And a lower alkyl group or a benzyl group.
And an benzyl group. Step A1 has the general formula (I)
A step of producing a compound having the general formula (II)
A compound having the general formula (III) in an inert solvent
After reacting with the compound^1a, R^2a, R^3a, R
^4a, R^5a, And R^6aAmino, hydroxy and / or
Or by removing the protecting group of the carboxy group
You. The inert solvent used in the above reaction is inactive in this reaction
Is not particularly limited as long as it is sexually active.
Fats such as sun, heptane, ligroin, petroleum ether
Aliphatic hydrocarbons, such as benzene, toluene and xylene
Aromatic hydrocarbons; chloroform, dichloromethane,
Halogen such as 1,2-dichloroethane, carbon tetrachloride
Hydrocarbons: methyl acetate, ethyl acetate, propyl acetate
Esters such as toluene, butyl acetate and diethyl carbonate;
Ethyl ether, diisopropyl ether, tetrahydride
Lofran, dioxane, dimethoxyethane, diethylene
Ethers such as glycol dimethyl ether; meta
Knol, ethanol, n-propanol, isopropano
-N-butanol, isobutanol, t-butanol
, Isoamyl alcohol, diethylene glycol,
Lyserine, octanol, cyclohexanol, methyl
Alcohols such as cellosolve; acetonitrile, a
Nitriles such as sobutyronitrile; formamide,
Dimethylformamide, dimethylacetamide, hexa
Amides such as methylphosphoric triamide; water; or above
A mixed solvent of the above solvents; preferably alcohols
(Most preferably methanol). The reaction temperature is
Varies depending on the starting compound, catalyst used, solvent, etc.
Usually, -20 ° C to 150 ° C (preferably 0 ° C to 50 ° C)
° C). The reaction time depends on the starting compound and the catalyst used.
It depends on the solvent, solvent, reaction temperature, etc.
24 hours (preferably 15 minutes to 12 hours)
You. In the compound (I), R⁶Is a lower grade
The compound which is a thio group is dissolved in an inert solvent (preferably an alcohol).
-20 ° C to 150 ° C (preferably
Is at 0 ° C. to 50 ° C.) for 5 minutes to 24 hours (preferably
For 15 minutes to 12 hours), ammonia or HR '
Wherein R ′ represents an amine residue.
By R⁶Can produce a compound where is an amine residue
it can. Further, in the compound (I), R⁶But lower al
The compound which is a oxy group is placed in an inert solvent (preferably
Coals or mixed solvent of alcohol and water), base
Below (preferably organic amines), -20 ° C to 150 ° C
(Preferably 0 ° C. to 50 ° C.) for 5 minutes to 24 hours
(Preferably, 15 minutes to 12 hours), the following general formula (I)
V) H_TwoN-R "(IV) wherein R" is a sulfo lower alkyl group or
Xy lower alkyl group. With the compound having
By letting R⁶Is a "sulfo lower alkyl group" or
An amino group substituted with a "carboxy lower alkyl group"
Certain compounds can be prepared. Furthermore, compounds
In (I), R⁶Is a lower alkoxy group
In an inert solvent (preferably alcohols or halogens).
Hydrocarbons), -20 ° C to 150 ° C (preferably 0
5 to 24 hours (preferably 15 ° C. to 50 ° C.).
Minutes to 12 hours), and⁶
Is a hydroxy group.
Removal of protecting groups for amino, hydroxy and carboxy groups
Although it depends on the type, it is generally the technology of synthetic organic chemistry.
For example, T.W. Green, (Protective
 Groups in Organic Synthesis), John Wiley & Sons:
J.F.W.McOmis, (Protective Groups in OrganicChemis
try), by the method described in Plenum Press as follows
It can be carried out. When the protecting group of the amino group is a silyl,
In general, tetrabutylammonium fluoride, fluorine
Like hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride
Treatment with a compound that produces a stable fluorine anion
Removed. Solvents used in the above reactions inhibit the reaction
There is no particular limitation as long as it is not performed.
Ether, diisopropyl ether, tetrahydrof
Orchid, dioxane, dimethoxyethane, diethylenegly
Ethers such as coal dimethyl ether are preferred.
You. The reaction temperature and reaction time are not particularly limited.
Usually performed at 0 ° C to 50 ° C for 10 minutes to 18 hours
You. When the amino-protecting group is an aliphatic acyl or aromatic acyl
, Alkoxycarbonyls or Schiff bases
A substituted methylene group, the presence of an aqueous solvent
Removal by treatment with an acid or base in the presence
Can be. As the acid used in the above reaction, usually an acid
If they are used as such and do not inhibit the reaction,
Although not limited to, for example, hydrobromic acid, hydrochloric acid, sulfuric acid,
Inorganic acids such as chloric, phosphoric and nitric acids, preferably salts
Is an acid. As the base used in the above reaction, a compound
There is no particular limitation as long as it does not affect the other parts of
However, preferably, lithium carbonate, sodium carbonate, carbonic acid
Alkali metal carbonates such as potassium; lithium hydroxide
Alkalis such as sodium hydroxide, potassium hydroxide
Limetal hydroxides; lithium methoxide, sodium
Toxide, sodium ethoxide, potassium tert-but
Metal alkoxides such as oxides; aqueous ammonia, concentrated
Ammonia, such as ammonia-methanol, is used.
Can be The solvent used in the above reaction may be a conventional solvent.
There is no particular limitation as long as it is used for the water splitting reaction
Is, for example, methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
, T-butanol, isoamyl alcohol, diethyl
Glycol, glycerin, octanol, cyclohexyl
Alcohols such as sanol and methyl cellosolve;
Ethyl ether, diisopropyl ether, tetrahydride
Lofran, dioxane, dimethoxyethane, diethylene
Ethers such as glycol dimethyl ether; water;
A mixed solvent of water and the above organic solvent;
Ters (most preferably dioxane). Reaction temperature
The reaction time depends on the starting compound, solvent and acid used.
The reaction depends on the base, etc., and is not particularly limited.
To control, usually at 0 ° C to 150 ° C for 1 hour
Incubate for up to 10 hours. When the amino-protecting group is
Or aralkyloxycarbonyls
Is usually brought into contact with a reducing agent in an inert solvent.
(Preferably catalytic reduction at room temperature under a catalyst)
It is preferable to use a method or a method of removing using an oxidizing agent. contact
Solvents used for removal by reduction are not suitable for this reaction.
There is no particular limitation so long as it is active.
Fats such as butane, heptane, ligroin, petroleum ether
Aromatic hydrocarbons, such as toluene, benzene and xylene
Aromatic hydrocarbons: methyl acetate, ethyl acetate, pro-acetic acid
Esters such as pills, butyl acetate, diethyl carbonate;
Diethyl ether, diisopropyl ether, tetrahi
Drofuran, dioxane, dimethoxyethane, diethyle
Ethers such as ethylene glycol dimethyl ether;
Tanol, ethanol, n-propanol, isopropanol
Knol, n-butanol, isobutanol, t-butano
-Isoamyl alcohol, diethylene glycol,
Glycerin, octanol, cyclohexanol, methyl
Alcohols such as Lucerosolve; Organics such as acetic acid
Acids; water; a mixed solvent of the above solvent and water;
Are alcohols, ethers, organic acids or water (most
Preferably, alcohols or organic acids). Return
The catalyst used for the original removal is
Usually limited, as long as it is used for catalytic reduction reaction
But preferably, palladium-carbon, Raney-nicke
Metal, platinum oxide, platinum black, rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used. Pressure is not particularly limited
Is usually performed at 1 to 10 atm. Reaction temperature and reaction
The reaction time varies depending on the starting compound, catalyst, solvent, etc.,
Usually performed at 0 ° C to 100 ° C for 5 minutes to 24 hours
It is. As a solvent used in removal by oxidation
Is not particularly limited as long as it does not participate in the reaction.
However, it is preferably a water-containing organic solvent. Such organic solvent
As the medium, for example, chloroform, dichloromethane,
Halogen such as 1,2-dichloroethane, carbon tetrachloride
Hydrocarbons; nitriles such as acetonitrile,
Ethyl ether, diisopropyl ether, tetrahydride
Lofran, dioxane, dimethoxyethane, diethylene
Ethers such as glycol dimethyl ether;
Ketones such as tons; formamide, dimethylform
Amide, dimethylacetamide, hexamethylphosphate
Amides such as lamide; and dimethyl sulfoxide
Sulfoxides; sulfolane; and preferably
Are halogenated hydrocarbons, ethers or sulfoxy
(Most preferably halogenated hydrocarbons or sulfo)
Oxides). The oxidizing agent used is
There is no particular limitation as long as the compound is used.
Is potassium persulfate, sodium persulfate, ammonium
Cerium nitrate (CAN), 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ) is used
Can be The reaction temperature and reaction time are as follows:
Although it varies depending on the solvent and the like, it is usually 1 ° C. to 150 ° C.
Run for 0 minutes to 24 hours. Also, protection of amino group
When the group is an aralkyl group, use a protecting group with an acid.
Can also be removed. The acid used in the above reaction is
Be used as an acid catalyst in normal reactions
Although there is no particular limitation, for example, hydrochloric acid, hydrobromic acid, sulfuric acid
Inorganic acids such as acid, perchloric acid, phosphoric acid; acetic acid, formic acid, oxalic acid
Acid, methanesulfonic acid, p-toluenesulfonic acid, can
Fursulfonic acid, trifluoroacetic acid, trifluoromethyl
Bronsted acids, such as organic acids such as tansulfonic acid;
Zinc chloride, tin tetrachloride, boron trichloride, borant
Lewis acids such as fluoride, boron tribromide;
Acidic ion exchange resin; preferably an inorganic acid or
Mechanical acid (most preferably hydrochloric acid, acetic acid or trifluorovinegar)
Acid). Inert solvent used in the above first-stage reaction
Is not particularly limited as long as it is inert to the reaction.
However, for example, hexane, heptane, ligroin, petroleum
Aliphatic hydrocarbons such as ether; benzene, tolue
Aromatic hydrocarbons such as xylene and xylene; chloroform
, Dichloromethane, 1,2-dichloroethane, tetrachloride
Halogenated hydrocarbons such as carbon; methyl acetate, acetic acid
Ethyl, propyl acetate, butyl acetate, diethyl carbonate
Unesters; diethyl ether, diisopropyl ether
-Tel, tetrahydrofuran, dioxane, dimethoxy
Like ethane, diethylene glycol dimethyl ether
Ethers: methanol, ethanol, n-propano
-Isopropanol, n-butanol, isobutanol
-T-butanol, isoamyl alcohol, diethyl
Lenglycol, glycerin, octanol, cyclohexane
Alcohols such as xanol and methyl cellosolve;
Formamide, dimethylformamide, dimethylacetate
Amides, such as amides, hexamethylphosphoric triamide
Water; or a mixed solvent of water or the above solvents;
Include ethers, alcohols or water (most preferably
Is dioxane, tetrahydrofuran, ethanol or
Water). The reaction temperature depends on the starting compound, the acid used,
Usually varies from -20 ° C to boiling point
(Preferably 0 ° C. to 100 ° C.). The reaction time is
Depends on starting compound, acid used, solvent, reaction temperature, etc.
However, usually 15 minutes to 48 hours (preferably 30 minutes
Minutes to 20 hours). When the protecting group of the amino group is
When it is a nyloxycarbonyl, it is usually an amino group.
When the protecting group is the above-mentioned aliphatic acyls, aromatic acyls,
Substituted to form oxycarbonyls or Schiff bases
In the same manner as in the removal reaction
And by treating with a base. Allylo
In the case of a xycarbonyl group, in particular, palladium and
Liphenylphosphine or nickel tetracarboni
The method of removal using a simple
Can be applied. As protecting groups for hydroxy groups,
When rils are used, tetrabutyl fluoride is usually used.
Ammonium, hydrofluoric acid, hydrofluoric acid-pyridine, fluorinated
Treated with compounds that generate fluoride anions, such as potassium
Or hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphorus
Inorganic acids such as acids or acetic acid, formic acid, oxalic acid, methanesulfo
Acid, p-toluenesulfonic acid, camphorsulfone
Acid, trifluoroacetic acid, trifluoromethanesulfonic acid
It can be removed by treating with an organic acid such as still,
Formic acid, acetic acid, professional
By adding an organic acid such as pionic acid, the reaction
May promote. Inert solvent used in the above reaction
Is not particularly limited as long as it is inert to the reaction.
However, preferably, diethyl ether, diisopropyl
Luether, tetrahydrofuran, dioxane, dimethoate
Xyethane, diethylene glycol dimethyl ether
Such ethers; acetonitrile, isobutyronitrile
Nitriles such as toluene; organic acids such as acetic acid; water;
A mixed solvent of solvents. The reaction temperature and reaction time
Although it depends on the feed compound, catalyst, solvent, etc., it is usually 0 ° C
1 hour at 100 ° C (preferably 10 ° C to 50 ° C)
For 24 hours. When the protecting group of the hydroxy group is
Aralkyls or aralkyloxycarbonyls
Contact with the reducing agent, usually in an inert solvent.
(Preferably catalytic reduction at room temperature under a catalyst).
Or a method of removing with an oxidizing agent.
The solvent used for removal by catalytic reduction
There is no particular limitation as long as it is not involved in
Fats such as butane, heptane, ligroin, petroleum ether
Aromatic hydrocarbons, such as toluene, benzene and xylene
Aromatic hydrocarbons; such as ethyl acetate and propyl acetate
Esters: diethyl ether, diisopropyl ether
, Tetrahydrofuran, dioxane, dimethoxyeta
, Such as diethylene glycol dimethyl ether
-Tels; methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
, T-butanol, isoamyl alcohol, diethyl
Glycol, glycerin, octanol, cyclohexyl
Alcohols such as sanol and methyl cellosolve;
Lumamide, dimethylformamide, dimethylacetoa
Mido, N-methyl-2-pyrrolidone, hexamethylphosphine
Amides such as acid triamide; fats such as formic acid and acetic acid
Fatty acids; water; mixed solvents of the above solvents;
Alcohols (most preferably methanol). Return
The catalyst used for the removal by
There is no particular limitation as long as it is used for the original reaction,
For example, palladium-carbon, palladium-black, Raney-ni
Nickel, platinum oxide, platinum black, rhodium-aluminium oxide
, Triphenylphosphine-rhodium chloride, palladium
Barium sulfate, preferably palladium-carbon.
is there. The pressure is not particularly limited, but is usually 1 to 10 atm.
It is done in. The reaction temperature and reaction time are as follows:
Usually varies from 0 ° C to 100 ° C, depending on the catalyst, solvent, etc.
(Preferably 20 ° C. to 70 ° C.) for 5 minutes to 48 hours
(Preferably 1 hour to 24 hours). By oxidation
The solvent used in the removal is involved in this reaction.
There is no particular limitation as long as it is not present, but preferably
Solvent. As such an organic solvent, preferably,
Ketones such as setone; methylene chloride, chloropho
Halogenated hydrocarbons such as lume and carbon tetrachloride;
Nitriles such as tonitrile; diethyl ether,
Ethers such as trahydrofuran and dioxane;
Methylformamide, dimethylacetamide, hexame
Amides such as tyl phosphoric acid triamide; and dimethyl
Sulfoxides such as sulfoxide;
it can. As the oxidizing agent used, it is used for oxidation
There is no particular limitation as long as it is a compound.
Lium, sodium persulfate, ammonium cerium
Trait (CAN), 2,3-dichloro-5,6-disi
Ano-p-benzoquinone (DDQ) is used. reaction
The temperature and reaction time depend on the starting compound, catalyst, solvent, etc.
Different, but usually at 0 ° C. to 150 ° C. for 10 minutes to 2
Run for 4 hours. In liquid ammonia or in
Tanol, ethanol, n-propanol, isopropanol
Knol, n-butanol, isobutanol, t-butano
-Isoamyl alcohol, diethylene glycol,
Glycerin, octanol, cyclohexanol, methyl
In alcohols such as Lucerosolve, -78
Between 0 ° C and 0 ° C, such as metallic lithium and metallic sodium
Can be removed by the action of alkali metals
You. Further, in a solvent, aluminum chloride-sodium iodide
Or an alkyl group such as trimethylsilyl iodide
It can be removed using rill halides. Used
The solvent used is not particularly limited as long as it does not participate in the reaction.
Although not limited to, preferably, methylene chloride, chloro
Halogenated hydrocarbons such as form and carbon tetrachloride;
Nitriles such as cetonitrile; mixed solvents of the above solvents
Medium. The reaction temperature and reaction time
Although it varies depending on the substance, the solvent, etc., it is usually 0 ° C to 50 ° C,
Performed for 5 minutes to 72 hours. The reaction substrate is sulfur source
In the case of having an atom, preferably, aluminum chloride-iodide
Sodium is used. When the protecting group of the hydroxy group is
Aliphatic acyls, aromatic acyls or alkoxycarbonyl
If it is a group, it is treated with a base in a solvent.
More removed. The base used in the above reaction
If it does not affect the rest of the compound
Although not particularly limited, for example, lithium carbonate, sodium carbonate
Alkali metal carbonates such as potassium and potassium carbonate; charcoal
Lithium hydrogen oxyate, sodium bicarbonate, potassium bicarbonate
Alkali metal bicarbonates such as lithium; lithium hydroxide,
Alkali gold such as sodium hydroxide and potassium hydroxide
Group hydroxides: lithium methoxide, sodium methoxide
Sid, sodium ethoxide, potassium-t-butoxy
Metal alkoxides such as ammonia;
Ammonia such as methanol-methanol;
Suitably, alkali metal hydroxides, metal alkoxides
Or ammonia (most preferably an alkali metal hydroxide
Or metal alkoxides). Solvent used
Are those used in normal hydrolysis reactions
Although there is no particular limitation, for example, diethyl ether,
Sopropyl ether, tetrahydrofuran, dioxa
, Dimethoxyethane, diethylene glycol dimethyl
Ethers such as ethers; methanol, ethanol
N-propanol, isopropanol, n-butano
-Isobutanol, t-butanol, isoamyl urea
Alcohol, diethylene glycol, glycerin, octa
Like knol, cyclohexanol, methyl cellosolve
Preferred are alcohols; water; and mixed solvents of the above solvents.
You. The reaction temperature and reaction time vary depending on the starting compound used.
There are no particular restrictions depending on the base, solvent, etc.
Usually, at -20 ° C to 150 ° C for 1 hour
For between 10 and 10 hours. A protecting group for a hydroxy group,
Alkoxymethyls, tetrahydropyranyls, tetra
Hydrothiopyranyls, tetrahydrofuranyls, tet
Lahydrothiofuranyl or substituted ethyls
In case, it is usually removed by treating with acid in a solvent.
Is done. The acids used are usually Bronsted
Limited as long as it is used as an acid or Lewis acid
Not preferred, preferably hydrogen chloride; like hydrochloric acid, sulfuric acid, nitric acid
Inorganic acids; or acetic acid, trifluoroacetic acid, methanesulfo
Acid and organic acids such as p-toluenesulfonic acid
Stended acid: a Lewis acid such as boron trifluoride
But strongly acidic cation exchange like Dowex 50W
Resins can also be used. The solution used in the above reaction
The medium is not particularly limited as long as it is inert to the reaction.
But not, for example, hexane, heptane, ligroin, stone
Aliphatic hydrocarbons such as oil ethers; benzene, tol
Aromatic hydrocarbons such as ene and xylene; methylene glycol
Chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenation such as chlorobenzene and dichlorobenzene
Hydrocarbons; ethyl formate, ethyl acetate, propyl acetate,
Esters such as butyl acetate and diethyl carbonate;
Luether, diisopropyl ether, tetrahydrofur
Orchid, dioxane, dimethoxyethane, diethylenegly
Ethers such as coal dimethyl ether; methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
, Isoamyl alcohol, diethylene glycol,
Lyserine, octanol, cyclohexanol, methyl
Alcohols such as cellosolve; acetone, methyl ether
Tyl ketone, methyl isobutyl ketone, isophorone,
Ketones such as clohexanone; water; a mixture of the above solvents
Solvent; preferably, ethers (most preferably,
Tetrahydrofuran) or alcohols (most preferably
Is methanol). The reaction temperature and reaction time
It depends on the starting compound, the acid used, the solvent, etc.
Usually, -10 ° C to 200 ° C (preferably 0 ° C to 150 ° C)
° C) for 5 minutes to 48 hours (preferably 30 minutes to
10 hours). When the protecting group of the hydroxy group is
When it is a ruoxycarbonyl, it is usually hydroxy
When the protecting group for the group is the above-mentioned aliphatic acyls, aromatic acyls or
For the removal reaction when is an alkoxycarbonyl
In the same manner as in the above, it is achieved by treating with a base.
In addition, in the case of an allyloxycarbonyl group,
And triphenylphosphine or bis (methyldi
Phenylphosphine) (1,5-cyclooctadiene)
Uses iridium (I) hexafluorophosphate
Removal method is simple and can be carried out with few side reactions.
Can be. The protecting group of the carboxy group is a lower alkyl group
Or lower alkyl, lower alkoxy, nitro, halogen
Or 1 to 3 aryls which may be substituted with cyano
When it is a lower alkyl group substituted with
When the protecting group for the droxy group is the aforementioned aliphatic acyl or aromatic
Removal of sils or alkoxycarbonyls
Achieved by treating with a base under the same conditions
Is done. Also, amino, hydroxy and / or carboxy
The removal of the protecting group of the thio group is performed in any order,
The following can be performed. After the completion of the reaction,
Compound (I) is collected from the reaction mixture according to a conventional method.
You. For example, the reaction mixture is appropriately neutralized, and
If present, remove by filtration, then add water and ethyl acetate
Add an immiscible organic solvent such as
The organic layer is separated, washed with water, etc., and dried over anhydrous magnesium sulfate.
Water, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.
It is obtained by removing the solvent after drying. Obtained
If necessary, the desired compound may be used in a conventional manner, e.g., recrystallization, reprecipitation.
Ordinarily used for separation and purification of organic compounds
Combining methods as appropriate, applying chromatography,
Separation and purification can be achieved by eluting with an eluent.
Wear. Method B is for compound (I) wherein D is -CH-
Wherein E is a group having -NH-
(Ic) wherein D is a group having -CH- and E is an oxygen atom
Or a compound (Id) in which D is -CH-
Wherein E is -NH- and G is -CO-G_a-
Having a group (in the above formula, G_aIs a single bond or C₁-C_FiveArchi
It is a len group. And D is a carbon atom
And E is a group having ＮN—O—
Product (If) and D are -CH- groups and E is -C
A method for producing a compound (Ig) which is a group having O-
is there.

Embedded image

Embedded image In the above formula, R ¹ , R ^1a , R ^Two , R ^2a , R ^Three , R ^3a ,
R ^Four , R ^4a , A, G, Ga and Q are the same as those described above.
Show significance, R ⁷ Is formyl, carboxy or lower
A alkoxycarbonyl group; ⁸ Is lithium, mug
Such as nesium, zinc, cadmium, tin, cerium
A ′ represents a metal atom, and A ′ is a substituent in the definition of A
Contained amino and / or hydroxy groups are protected
Other A groups which are amino and / or hydroxy groups which may be
And X represents an oxygen atom or
S represents a sulfur atom, and W represents a halogen atom. Step B1
Is a step of producing a compound having the general formula (VII)
A compound having the general formula (V) in an inert solvent
A compound having the general formula (VI) or an acid addition salt thereof (eg,
Reacts with mineral salts such as hydrochloride, nitrate and sulfate)
For example, p-toluene sulfone
Heat condensation using organic sulfonic acid such as acid as catalyst
Process or Lewis acid or acid ion exchange such as titanium tetrachloride
It is carried out by a method of condensation using an exchange resin. The above reaction
The inert solvent used for the reaction is one that is inert to the reaction.
If it is not particularly limited, for example, hexane, hepta
Aliphatic hydrocarbons such as oils, ligroins, and petroleum ethers
And aromatic carbons such as benzene, toluene and xylene
Hydrogens; chloroform, dichloromethane, 1,2-dic
Halogenated hydrocarbons such as loroethane and carbon tetrachloride
Classes: methyl acetate, ethyl acetate, propyl acetate, butyric acetate
And esters such as diethyl carbonate; diethyl ether
, Diisopropyl ether, tetrahydrofuran, di
Oxane, dimethoxyethane, diethylene glycol di
Ethers such as methyl ether; methanol, eta
Knol, n-propanol, isopropanol, n-butyl
Tanol, isobutanol, t-butanol, isoamido
Ru alcohol, diethylene glycol, glycerin, e
Of ketanol, cyclohexanol and methyl cellosolve
Such alcohols; formamide, dimethylforma
Amide, dimethylacetamide, trihexamethylphosphate
Amides such as amides; water; or water or a mixture of the above solvents
A solvent; preferably a halogenated hydrocarbon (most
Preferably dichloromethane). In addition,
When compound (VI) is an acid addition salt, a base is used.
And react. As such a base
For example, lithium carbonate, sodium carbonate, potassium carbonate
Alkali metal carbonates such as uranium; Lithium bicarbonate
Such as water, sodium bicarbonate and potassium bicarbonate.
Lucari metal bicarbonates; lithium hydride, sodium hydride
Alkali metal hydrides such as potassium and potassium hydride
, Lithium hydroxide, sodium hydroxide, potassium hydroxide
Alkali metal hydroxides such as lithium methoxy
, Sodium methoxide, sodium ethoxide, mosquito
Alkali metal alkoxy such as lium t-butoxide
Compounds: triethylamine, tributylamine, diisoprop
Propyl ethylamine, N-methylmorpholine, pyridi
, 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 (DA
BCO), 1,8-diazabicyclo [5.4.0] -7
Organic amines such as undecene (DBU);
Organic amines (most preferably triethyl alcohol).
Min). The inert solvent used in the above reaction is
There is no particular limitation as long as it is inert to the reaction.
For example, hexane, heptane, ligroin, petroleum ether
Aliphatic hydrocarbons such as benzene, toluene, xy
Aromatic hydrocarbons such as len; chloroform, dichloromethane
Like dichloromethane, 1,2-dichloroethane, carbon tetrachloride
Halogenated hydrocarbons; acetic acid, methyl acetate, ethyl acetate
Such as toluene, propyl acetate, butyl acetate, diethyl carbonate
Esters: diethyl ether, diisopropyl ether
, Tetrahydrofuran, dioxane, dimethoxyeta
, Such as diethylene glycol dimethyl ether
-Tels; methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
, T-butanol, isoamyl alcohol, diethyl
Glycol, glycerin, octanol, cyclohexyl
Alcohols such as sanol and methyl cellosolve;
Lumamide, dimethylformamide, dimethylacetoa
Amides, amides such as hexamethylphosphoric triamide
Water; or a mixed solvent of water or the above solvents;
Include halogenated hydrocarbons (most preferably dichlorometa
). The reaction temperature depends on the starting compound, base, solvent, etc.
More generally, but usually between -20 ° C and 200 ° C,
When condensing using isocyanic acid, it is preferably 10 ° C to 40 ° C.
℃, and heat condensation using organic sulfonic acid as catalyst
In this case, the temperature is preferably from 50 ° C to 150 ° C. The reaction time is
Depending on the starting compound, base, solvent, reaction temperature, etc.,
Usually, 15 minutes to 48 hours (preferably 1 hour to 3 hours)
0 hours). After completion of the reaction, the target compound (V
II) is collected from the reaction mixture in a conventional manner. An example
For example, the reaction mixture is appropriately neutralized, and insolubles are present.
If necessary, after filtration, remove water and ethyl acetate.
Add an immiscible organic solvent to the organic layer containing the target compound.
Was separated and washed with water, etc., then anhydrous magnesium sulfate, anhydrous
After drying over sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
It is obtained by distilling off the solvent. Obtained objectives
If necessary, the compound may be subjected to conventional methods, for example, recrystallization, reprecipitation, etc.
Usually, a method commonly used for separation and purification of organic compounds is appropriately used.
Combination, chromatography, with appropriate eluent
It can be separated and purified by elution. No.
Step B2 is a step for producing compound (Ic).
After reduction of compound (VII) in an active solvent,
R ^1a , R ^2a , R ^3a , R ^4a Amino and ar in A ′
Removal of the protecting groups for the droxy and / or carboxy groups
Is performed by Inert solvent used in the above reaction
Is not particularly limited as long as it is inert to the reaction.
However, for example, hexane, heptane, ligroin, petroleum
Aliphatic hydrocarbons such as ether; benzene, tolue
Aromatic hydrocarbons such as xylene and xylene; chloroform
, Dichloromethane, 1,2-dichloroethane, tetrachloride
Halogenated hydrocarbons such as carbon; acetic acid, methyl acetate
, Ethyl acetate, propyl acetate, butyl acetate, carbonate carbonate
Esters such as tyl; diethyl ether, diisoprop
Propyl ether, tetrahydrofuran, dioxane, di
Methoxyethane, diethylene glycol dimethyl ether
Ethers such as methanol; methanol, ethanol, n-
Propanol, isopropanol, n-butanol, a
Sobutanol, t-butanol, isoamyl alcohol
, Diethylene glycol, glycerin, octano
Such as cyclohexanol and methyl cellosolve.
Alcohols: formamide, dimethylformamide, diamine
Methylacetamide, hexamethylphosphoric triamide
Such amides; water; or water or a mixed solvent of the above solvents;
And preferably esters, alcohols or ethers.
Ters (most preferably acetic acid, ethanol or tetra
Hydrofuran). Reducing agent used in the above reaction
Is, for example, sodium borohydride,
Hydrogenation such as Titanium, Sodium Cyanoborohydride
Boron alkali metals; diisobutylaluminum hydride
System, lithium aluminum hydride, triethoxy hydride
Aluminum hydride compounds such as lithium aluminum
Material; Raney nickel; bromine, preferably borohydride
Alkali metals (most preferably cyanoborohydride
Lium). The reaction temperature depends on the starting compound used.
Although it depends on the type of the reducing agent and the solvent, it is usually -20.
C. to 150 ° C., preferably 10 ° C. to 80 ° C.
You. The reaction time depends on the starting compound, the reducing agent used,
It usually varies from 15 minutes to 24 minutes, depending on the medium, reaction temperature, etc.
Time, preferably 30 minutes to 16 hours. Desired
R performed by ^1a , R ^2a , R ^3a , R ^4a And in A '
Protecting groups for amino, hydroxy and / or carboxy groups
Is a method for removing amino and hydride in the above-mentioned Method A, Step A1 step.
Method for removing protecting groups for roxy and / or carboxy groups
Is performed in the same manner as described above. After completion of the reaction, the target compound of the reaction
(Ic) is collected from the reaction mixture according to a conventional method.
For example, the reaction mixture is appropriately neutralized and insolubles are present.
If necessary, remove by filtration and then remove water and ethyl acetate.
Add an immiscible organic solvent
Separate the layers and wash with water, etc.
Dry with sodium hydrogen sulfate, anhydrous sodium hydrogen carbonate, etc.
Thereafter, it is obtained by distilling off the solvent. Eyes obtained
If necessary, conventional compounds may be used, for example, recrystallization, reprecipitation, etc.
The method commonly used for the separation and purification of organic compounds
Appropriate elution using appropriate combination and chromatography
Can be separated and purified by eluting with
You. Step B3 is a step of producing compound (Id).
In the presence or absence of an inert solvent (preferably
Below), reacting a compound having the general formula (VIII) with a base
And reacting with a compound having the general formula (IX)
Further, if desired, R ^1a , R ^2a , R ^3a , R ^4a And in A '
Protecting groups for amino, hydroxy and / or carboxy groups
Is carried out. Used in the above reaction
The base is, for example, one used in the above-mentioned Method B, Step B1.
And the same as those described above.
Hydrides (most preferably sodium hydride)
You. The inert solvent used in the above reaction is inactive in this reaction
Is not particularly limited as long as it is sexually active.
Fats such as sun, heptane, ligroin, petroleum ether
Aliphatic hydrocarbons, such as benzene, toluene and xylene
Aromatic hydrocarbons: diethyl ether, diisopropyl
Luether, tetrahydrofuran, dioxane, dimethoate
Xyethane, diethylene glycol dimethyl ether
Such ethers; dimethylformamide, dimethyla
Acetamide, hexamethylphosphoric triamide
Amides; or a mixed solvent of the above solvents;
Amides (most preferably dimethylformamide)
You. Reaction temperature when reacting compound (VIII) with a base
The degree depends on the starting compound, base used, solvent, etc.
However, it is usually -50 ° C to 200 ° C (preferably 0 ° C
To 120 ° C). Reaction of compound (VIII) with a base
The reaction time for the reaction is based on the starting compound, the base used,
Although it depends on the solvent, the reaction temperature, etc., it is usually from 15 minutes
24 hours (preferably 1 hour to 10 hours).
Next, the reaction temperature when reacting with the compound (IX) is as follows.
Usually, -20 ° C to 200 ° C (preferably 0 ° C to 150 ° C)
° C). Then, the reaction when reacting with compound (IX)
The reaction time is generally 15 minutes to 48 hours (preferably 3 minutes).
0 minute to 24 hours). Done as desired
R ^1a , R ^2a , R ^3a , R ^4a And A 'for A' and A '
Method for removing protecting groups for roxy and / or carboxy groups
Is the amino, hydroxy and / or
Is carried out in the same way as removing the protecting group of the carboxy group.
You. After completion of the reaction, the target compound (Id) of the reaction is subjected to a conventional method.
Thus, it is taken from the reaction mixture. For example, reaction mixing
Neutralize the substance as appropriate, and filter out any insoluble matter.
After removal, do not mix with water and ethyl acetate
Organic solvent containing the target compound, and
After washing with anhydrous magnesium sulfate and anhydrous sodium sulfate
After drying with anhydrous sodium bicarbonate
It is obtained by doing. The obtained target compound is necessary
In general, organic compounds such as recrystallization, reprecipitation, etc.
The methods commonly used for the separation and purification of
Apply chromatography and elute with a suitable eluent
Can be separated and purified. Step B4 is:
A step of separately producing a compound (Id), wherein an inert solvent
Wherein the group having -XH of the compound having the general formula (X)
Is converted to a leaving group Q in the presence or absence of a Lewis acid.
After that, the compound is reacted with compound (IX), ^1a , R
^2a , R ^3a , R ^4a And amino, hydroxy and A ′ in A ′
And / or removal of the protecting group of the carboxy group.
Will be Examples of the reagent forming the leaving group Q include, for example,
Tansulfonyl chloride, P-toluenesulfonyl chloride
Sulfonyl halides such as lido; thionyl chloride,
Thion such as thionyl bromide, thionyl iodide
Nyl halides: sulfuryl chloride, sulfuryl bromide
Sulfurylhala, like midi, sulfuryl iodide
Iides; trihalo such as phosphorus trichloride, phosphorus tribromide, and phosphorus triiodide
Phosphorus genides; such as phosphorus pentachloride, phosphorus pentabromide and phosphorus pentaiodide
Phosphorus halides: phosphorus oxychloride, phosphorus oxybromide, oxy
Phosphorus halides such as phosphorus oxyhalides such as phosphorus iodide;
Agent such as methyltrioxorhenium (VII)
And a rhenium reagent;
It is a reagent. As the Lewis acid used in the above reaction,
For example, zinc halides such as zinc iodide, zinc chloride;
Tin halides such as tin tetrachloride; boron trichloride
Like boron, boron trifluoride, boron tribromide
A halogenated boron;
Zinc logenide (particularly preferably zinc iodide). Above
The inert solvent used in the reaction is inert to the reaction.
Is not particularly limited as long as it is
Carbonization such as oil, ligroin or petroleum ether
Hydrogens; aromatics such as benzene, toluene and xylene
Hydrocarbons; dichloromethane, 1,2-dichloroeta
Halogenated hydrocarbons such as carbon tetrachloride;
Ether, diisopropyl ether, tetrahydrof
Orchid, dioxane, dimethoxyethane, diethylenegly
Ethers such as coal dimethyl ether; acetone
Such as ketones; formamide, dimethylformamid
Dimethylacetamide, hexamethylphosphate tria
Amides such as amides; such as dimethyl sulfoxide
Sulfoxides; sulfolane; preferably aromatic
Hydrocarbons (particularly preferably benzene). Reaction temperature
Depends on the starting compound, the reagent used, the solvent, etc.
However, usually -20 ° C to 100 ° C (preferably 0 ° C to
50 ° C.). The reaction time depends on the starting compound used.
Normally 15 minutes, depending on the reagent, solvent, reaction temperature, etc.
Time to 150 hours (preferably 30 minutes to 100 hours
Between). Optional R ^1a , R ^2a , R ^3a , R
^4a And amino, hydroxy and / or cal in A ′
The method of removing the protecting group of the boxy group is the same as the method A
Protection of amino, hydroxy and / or carboxy groups
It is performed in the same manner as the method for removing a group. After the reaction,
The target compound (Id) can be prepared from the reaction mixture according to a conventional method.
Collected from. For example, the reaction mixture is appropriately neutralized,
If insolubles are present, they are removed by filtration and then
Add an immiscible organic solvent such as ethyl acetate to
The organic layer containing the compound is separated, washed with water, etc.
Gnesium, anhydrous sodium sulfate, anhydrous sodium bicarbonate
The solvent is obtained by evaporating the solvent after drying with
You. The obtained target compound can be used in a conventional manner, for example,
Usually used for separation and purification of organic compounds such as crystallization and reprecipitation.
Applied chromatography by appropriately combining the methods
Separation and purification by elution with a suitable eluent.
Can be Step B5 has the general formula (XII)
Is a process for producing a compound,
General formula using a reducing agent such as phenylphosphine
By reducing the compound having (XI)
You. The inert solvent used in the above reaction is involved in the reaction.
There is no particular limitation as long as it is not present.
It is the same as that used in the step B1, preferably
A mixed solvent of ters and water (most preferably tetrahydro
A mixed solvent of furan and water). The reaction temperature depends on the starting compound.
Although it depends on the substance, reducing agent, solvent, etc., it is usually 20 ° C.
The temperature is 150 ° C., preferably 50 ° C. to 100 ° C.
The reaction time depends on the starting compound, reducing agent, solvent, reaction temperature, etc.
More usually, but usually 15 minutes to 24 hours (preferably
Is 1 hour to 12 hours). After the reaction,
The target compound (XII) is a reaction mixture according to a conventional method.
Collected from. For example, the reaction mixture is appropriately neutralized,
If insolubles are present, they are removed by filtration and then
Add an immiscible organic solvent such as ethyl acetate to
The organic layer containing the compound is separated, washed with water, etc.
Gnesium, anhydrous sodium sulfate, anhydrous sodium bicarbonate
The solvent is obtained by evaporating the solvent after drying with
You. The obtained target compound can be used in a conventional manner, for example,
Usually used for separation and purification of organic compounds such as crystallization and reprecipitation.
Applied chromatography by appropriately combining the methods
Separation and purification by elution with a suitable eluent.
Can be Step B6 has the general formula (Ie)
Is a process for producing a compound, comprising the steps of:
In the presence or absence (preferably in the presence) of the compound (X
II) or an acid addition salt thereof having the general formula (XIII)
After reaction with the compound ^1a , R ^2a ,
R ^3a , R ^4a And amino, hydroxy and / or A ′
Or by removing the protecting group of the carboxy group
You. The inert solvent used in the above reaction is inactive in this reaction
Is not particularly limited as long as it is sexually active.
Fats such as sun, heptane, ligroin, petroleum ether
Aliphatic hydrocarbons, such as benzene, toluene and xylene
Aromatic hydrocarbons; chloroform, dichloromethane,
Halogen such as 1,2-dichloroethane, carbon tetrachloride
Hydrocarbons: methyl acetate, ethyl acetate, propyl acetate
Esters such as toluene, butyl acetate and diethyl carbonate;
Ethyl ether, diisopropyl ether, tetrahydride
Lofran, dioxane, dimethoxyethane, diethylene
Ethers such as glycol dimethyl ether; meta
Knol, ethanol, n-propanol, isopropano
-N-butanol, isobutanol, t-butanol
, Isoamyl alcohol, diethylene glycol,
Lyserine, octanol, cyclohexanol, methyl
Alcohols such as cellosolve; formamide, dimethyl
Tylformamide, dimethylacetamide, hexamethyi
Amides such as triphosphoric triamide; acetonitrile
Water; or a mixed solution of water or the above solvents
And a nitrile. In the above reaction
As the base used, for example, the above-mentioned Method B, Step B1
The same ones as used in
Suitably organic amines (most preferably triethylamine)
It is. The reaction temperature depends on the starting compound, base, solvent, etc.
Although different, it is usually −20 ° C. to 150 ° C., preferably
Is 0 ° C to 100 ° C. The reaction time depends on the starting compound,
Normally 15 minutes, depending on base, solvent, reaction temperature, etc.
In between 24 hours (preferably 30 minutes to 16 hours)
is there. Compound (XII) or an acid addition salt thereof is
By reacting with a compound having the general formula (XIV)
Alternatively, compound (Ie) can be produced separately. Compound
In product (XIV) ⁷ Is a formyl group,
Compound (XII) or an acid addition salt thereof in an active solvent
The reaction is carried out by reacting the compound (XIV). the above
The inert solvent used in the reaction is inert to the reaction.
Is not particularly limited as long as it is
Fats such as butane, heptane, ligroin, petroleum ether
Aromatic hydrocarbons such as benzene, toluene and xylene
Aromatic hydrocarbons: diethyl ether, diisopropyl
Ether, tetrahydrofuran, dioxane, dimethoxy
Cietan, diethylene glycol dimethyl ether
Ethers; methanol, ethanol, n-propane
Knol, isopropanol, n-butanol, isobutanol
Knol, t-butanol, isoamyl alcohol, die
Tylene glycol, glycerin, octanol, cyclo
Alcohols such as hexanol and methyl cellosolve
, Formamide, dimethylformamide, dimethyla
Acetamide, hexamethylphosphoric triamide
Amides; acids such as acetic acid and propionic acid; dimethyls
Sulfoxides such as sulfoxide; sulfolane; or
A mixed solvent of the above solvents;
(Most preferably tetrahydrofuran). Reaction temperature
Depends on the starting compound, base used, solvent, etc.
However, usually, 0 ° C to 200 ° C (preferably, 10 ° C to 1 ° C)
20 ° C). The reaction time depends on the starting compound used.
Normally 1 hour, depending on base, solvent, reaction temperature, etc.
50 to 50 hours (preferably 5 to 24 hours)
You. In the compound (XIV), R ⁷ Is a carboxy group
In the case where the compound (XIV) or its reverse compound is
Responsive derivatives (acid halides, active esters or mixed
Acid anhydrides) with compound (XII) or an acid addition salt thereof.
It is performed by reacting. Acid halide method is inactive
Compound (XIV) is converted to a halogenating agent (eg,
Oxalyl chloride, thionyl chloride, thionyl bromide, oxa
Acid chloride, oxalic acid dichloride, phosphorus oxychloride,
(Phosphorous chloride, phosphorus pentachloride, etc.)
The compound (XII) or its acid halides
Acid addition salt in an inert solvent in the presence or absence of a base
Under (preferably in the presence of)
You. The base used in the above reaction is, for example, the method B
The same ones as used in the step B1 may be mentioned.
And preferably, organic amines (most preferably,
). The inert solvent used in the above reaction is
There is no particular limitation as long as it is inactive, but for example,
Of hexane, heptane, ligroin or petroleum ether
Such as aliphatic hydrocarbons; benzene, toluene, xylene
Aromatic hydrocarbons such as dichloromethane; dichloromethane, chloro
Like form, 1,2-dichloroethane, carbon tetrachloride
Halogenated hydrocarbons: diethyl ether, diisopro
Pill ether, tetrahydrofuran, dioxane, dime
Toxiethane, diethylene glycol dimethyl ether
Ethers, such as acetone; ketones, such as acetone;
Muamide, dimethylformamide, dimethylacetamide
And amides such as hexamethylphosphoric triamide;
Sulfoxides such as dimethyl sulfoxide; sulfora
Preferably halogenated hydrocarbons, ethers
Or amides (most preferably, dichloromethane,
Loroform, tetrahydrofuran or dimethylforma
Mid). The reaction temperature depends on the starting compounds, reagents, etc.
Although different, the reaction of the halogenating agent with the compound (XIV)
Acid halides and compounds (XII) or acid addition salts thereof
The reaction is usually at -20 ° C to 150 ° C.
Suitably, the reaction of the halogenating agent with compound (X) is -10
C. to 100 ° C., and acid halides and a compound (XI
The reaction with I) or an acid addition salt thereof is carried out at -20 ° C to 100 ° C.
° C. The reaction time depends on the starting compound, reagent, reaction temperature, etc.
The reaction between the halogenating agent and compound (XIV)
Acid halides and compound (XII) or an acid thereof
The reaction with the addition salt is usually carried out for 30 minutes to 80 hours (good).
Suitably 1 hour to 48 hours). Active ester method
Is an active esterification with compound (XIV) in an inert solvent
After reacting the reagents to produce active esters,
In a medium, in the presence or absence (preferably in the presence) of a base,
Reacting with compound (XII) or an acid addition salt thereof
Done by Active ester used in the above reaction
The agent is, for example, N-hydroxysuccinimide, 1-
Hydroxybenzotriazole, N-hydroxy-5-
N such as norbornene-2,3-dicarboximide
-Hydroxy compounds; such as dipyridyl disulfide
Disulfide compound; dicyclohexylcarbodiimide
Carbodiimides such as; carbonyldiimidazole;
Good in the presence of a condensing agent such as triphenylphosphine;
Performed appropriately. The inert solvent used in the above reaction is
There is no particular limitation as long as it is inert to the reaction.
For example, hexane, heptane, ligroin or petroleum oil
Aliphatic hydrocarbons such as ter; benzene, toluene,
Aromatic hydrocarbons such as xylene; dichloromethane,
Halogen such as 1,2-dichloroethane, carbon tetrachloride
Hydrocarbons: diethyl ether, diisopropyl ether
Ter, tetrahydrofuran, dioxane, dimethoxye
Like tan, diethylene glycol dimethyl ether
Ethers; ketones such as acetone; formami
Dimethylformamide, dimethylacetamide,
Amides such as xamethylphosphoric triamide; dimethyl
Sulfoxides such as rusulfoxide; sulfolane;
And preferably ethers or amides (most preferred
Include dioxane, tetrahydrofuran or dimethylpho
Lumamide). The base used in the above reaction is, for example,
For example, the same as those used in the acid halide method
Bases. The reaction temperature depends on the starting compound.
The active esterification reaction varies depending on the product, reagent, etc.
Then, -70 ° C to 150 ° C (preferably -10 ° C to
100 ° C.), the active ester and the compound (XII)
Or -20 ° C to 100
° C (preferably 0 ° C to 50 ° C). The reaction time is
It depends on the starting compound, reagent, reaction temperature, etc.
Sterilization reaction and active esters and compound (XII)
Or the reaction with the acid addition salt thereof, usually for 30 minutes to
80 hours (preferably 1 hour to 48 hours). Mixed
The acid anhydride method is used in the presence or absence of a base in an inert solvent.
Compound (XIV) in the presence (preferably in the presence) of a mixed acid
After reacting an anhydride agent to produce mixed acid anhydrides,
In an inert solvent, the mixed acid anhydride and the compound (XII) or
Is carried out by reacting the acid addition salt. the above
The base used in the reaction is, for example, the acid halide method described above.
Bases similar to those used in
Preferably organic amines (most preferably pyridine)
It is. The mixed acid anhydride agent used in the above reaction is, for example,
For example, ethyl chlorocarbonate, isobutyl chlorocarbonate
Carbonyl lower alkyl halides, like pivaloyl chloride
Lower alkanoyl halide; cyanophosphonic acid die
Di-lower alkyls such as tyl and diphenyl cyanophosphonate
Killed or diaryl cyanophosphoric acid, preferably
Is di-lower alkyl or diaryl cyanophosphoric acid
(Most preferably diethyl cyanophosphonate).
Inert solvent used when producing mixed acid anhydrides
Is a substance that does not inhibit the reaction and dissolves the starting material to some extent
There is no particular limitation as long as it is present, for example, hexane, hepta
Carbonization such as oil, ligroin or petroleum ether
Hydrogens; aromatics such as benzene, toluene and xylene
Hydrocarbons; dichloromethane, 1,2-dichloroeta
Halogenated hydrocarbons such as carbon tetrachloride;
Ether, diisopropyl ether, tetrahydrof
Orchid, dioxane, dimethoxyethane, diethylenegly
Ethers such as coal dimethyl ether; acetone
Such as ketones; formamide, dimethylformamid
Dimethylacetamide, hexamethylphosphate tria
Amides such as amides; such as dimethyl sulfoxide
Sulfoxides; sulfolane;
Ters or amides (most preferably, tetrahydrofura
Or dimethylformamide). Mixed acid anhydrides
The reaction temperature in the reaction for producing
Etc., but usually -50 ° C to 100 ° C (preferably
Is 0 ° C. to 60 ° C.). Manufacturing mixed acid anhydrides
The reaction time in the reaction is the starting compound, reagent, reaction temperature
It usually varies from 30 minutes to 72 hours (preferably
1 hour to 24 hours). Mixed acid anhydrides
The reaction with compound (XII) or an acid addition salt thereof is inactive.
In a solvent, in the presence or absence of a base (preferably,
The base and the inert solvent used in
Used in the reaction to produce the mixed anhydrides described above
It is the same as what is done. Mixed acid anhydrides and compounds (X
The reaction temperature in the reaction of II) or an acid addition salt thereof is as follows:
Although it varies depending on the starting compounds, reagents, etc., it is usually -30 ° C
It is 100 ° C (preferably 0 ° C to 80 ° C). mixture
Reaction between acid anhydrides and compound (XII) or an acid addition salt thereof
The reaction time in the reaction depends on the starting compound, reagent, reaction temperature, etc.
It usually varies from 5 minutes to 24 hours (preferably
Is 30 minutes to 16 hours). In addition, this reaction
Di-lower alkyl cyanophosphoric acid or diaryl
When using an anophosphoric acid, the compound may be used in the presence of a base.
(XII) and the compound (XIV) may be directly reacted.
it can. In the compound (XIV), R ⁷ Is a lower grade
When it is a cyclocarbonyl group, it may be in the presence of an inert solvent or
In the presence (preferably in the absence), in the presence or absence of a base
Below (preferably in the absence), compound (XII) or a compound thereof
The reaction is carried out by reacting the acid addition salt with compound (XIV).
Will be Compound (XII) or an acid addition salt thereof and compound
Base used in the reaction for reacting (XIV)
Are, for example, the same as those used in the aforementioned Method B, Step B1.
And organic amines are preferred.
(Most preferably pyridine). Compound (XII)
Or a reaction for reacting an acid addition salt thereof with compound (XIV)
The inert solvent used for the reaction is one that is inert to the reaction.
If it is not particularly limited, for example, hexane, hepta
Aliphatic hydrocarbons such as oils, ligroins, and petroleum ethers
And aromatic carbons such as benzene, toluene and xylene
Hydrogens: diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether
Alcohols: methanol, ethanol, n-propanol, a
Sopropanol, n-butanol, isobutanol, t
-Butanol, isoamyl alcohol, diethylene glycol
Coal, glycerin, octanol, cyclohexano
Alcohols such as methyl and methyl cellosolve; formaldehyde
Amide, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; or
A mixed solvent of the above solvents;
Are amides (most preferably, tetrahydrofuran,
Xane or dimethylformamide). Reaction temperature
Depends on the starting compound, base used, solvent, etc.
However, it is usually 0 ° C to 200 ° C (preferably 50 ° C to 1 ° C).
50 ° C.). The reaction time depends on the starting compound used.
Normally 1 hour, depending on base, solvent, reaction temperature, etc.
50 to 50 hours (preferably 5 to 24 hours)
You. Optional R ^1a , R ^2a , R ^3a , R ^4a as well as
Amino, hydroxy and / or carboxy in A '
The method for removing the protecting group of the group is described in Step A1 of Method A.
Removes protecting groups for mino, hydroxy and / or carboxy groups
It is performed in the same way as the method of leaving. After completion of the reaction,
Compound (Ie) is collected from the reaction mixture according to a conventional method.
Is done. For example, appropriately neutralize the reaction mixture,
If present, remove by filtration, then add water and
Add an immiscible organic solvent such as tyl to
Separate the organic layer containing water, wash with water, etc.
Sodium, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.
And then the solvent is distilled off. Get
If necessary, the desired compound can be used in a conventional manner, for example, recrystallization, recrystallization,
Usually used for separation and purification of organic compounds such as precipitation
Combine methods appropriately, apply chromatography, and
Can be separated and purified by eluting with
it can. Step B7 is a compound having the general formula (If)
Is a step of preparing a compound (V) in an inert solvent.
A compound having the general formula (XV) or an acid addition salt thereof (eg,
Reacts with mineral salts such as hydrochloride, nitrate and sulfate)
And optionally R ^1a , R ^2a , R ^3a , R ^4a And A '
Amino, hydroxy and / or carboxy groups
This is carried out by removing a protecting group, and the compound (V) is compounded.
The method of reacting the compound (XV) with, for example, p-toluene
Heat shrinkage using organic sulfonic acid such as sulfonic acid as catalyst
Using a Lewis acid such as titanium tetrachloride
It is performed by a method of condensation. Compound (V) as a compound
The method of reacting with (XV) is the same as the above-mentioned Method B, Step B1.
And optionally R ^1a , R ^2a , R ^3a , R
^4a And amino, hydroxy and / or cal in A ′
The method of removing the protecting group of the boxy group is the same as the method A
Protection of amino, hydroxy and / or carboxy groups
It is performed in the same manner as the method for removing a group. After the reaction,
The target compound (If) is prepared by reacting the reaction mixture according to a conventional method.
Collected from. For example, the reaction mixture is appropriately neutralized,
If insolubles are present, they are removed by filtration and then
Add an immiscible organic solvent such as ethyl acetate to
The organic layer containing the compound is separated, washed with water, etc.
Gnesium, anhydrous sodium sulfate, anhydrous sodium bicarbonate
The solvent is obtained by evaporating the solvent after drying with
You. The obtained target compound can be used in a conventional manner, for example,
Usually used for separation and purification of organic compounds such as crystallization and reprecipitation.
Applied chromatography by appropriately combining the methods
Separation and purification by elution with a suitable eluent.
Can be Step B8 has the general formula (XVI)
Is a process to produce a compound
Reacting the product (VIII) with an alkali metal cyanide
This is done by: Alkali gold used in the above reaction
As the cyanide of the genus, for example, lithium cyanide, silicon
Sodium and potassium cyanide
Wear. The inert solvent used in the above reaction is
Although it is not particularly limited as long as it is inert in response, for example,
Such as heptane, ligroin or petroleum ether
Aliphatic hydrocarbons such as benzene, toluene and xylene
Aromatic hydrocarbons; dichloromethane, 1,2-dic
Halogenated hydrocarbons such as loroethane and carbon tetrachloride
, Diethyl ether, diisopropyl ether, tet
Lahydrofuran, dioxane, dimethoxyethane, diee
Ethers such as tylene glycol dimethyl ether
: Ketones such as acetone; formamide, dimethyl
Ruformamide, dimethylacetamide, hexamethyl
Amides such as phosphoric acid triamide; dimethyl sulfoxide
Sulfoxides such as sides; sulfolane;
Suitably ethers (particularly preferably tetrahydrofuran)
It is. The reaction temperature depends on the starting compound, solvent, etc.
However, usually 0 ° C to 200 ° C (preferably 10 ° C to 5 ° C)
0 ° C). The reaction time depends on the starting compound, solvent, and reaction temperature.
Although it varies depending on the degree, etc., it is usually 15 minutes to 24 hours (preferably
Suitably 30 minutes to 16 hours). After the reaction,
The target compound (XVI) of this reaction is mixed with the reaction mixture according to a conventional method.
Collected from the compound. For example, appropriately neutralize the reaction mixture
And if insolubles were present, they were removed by filtration.
Then, add an immiscible organic solvent such as water and ethyl acetate.
The organic layer containing the target compound is separated and washed with water, etc.
Anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous carbonic acid
After drying with sodium hydrogen, the solvent is distilled off.
Obtained. If necessary, the obtained target compound can be obtained by a conventional method,
Usually, separation and purification of organic compounds such as recrystallization and reprecipitation
Chromatography by appropriately combining commonly used methods
And elute with a suitable eluent.
Can be separated and purified. Step B9 is a process represented by the general formula (X)
VII) to produce a compound having
Compound (XVI) is hydrolyzed with an acid or alkali in a solvent.
This is done by disassembly. Hydrolysis by acids is
1 hour with hydrous mineral acid such as hydrochloric acid, hydrous sulfuric acid, hydrous nitric acid
Room temperature for 10 to 10 hours (preferably 3 to 7 hours)
Treated at a temperature of 100 to 100 ° C (preferably 50 to 100 ° C)
It is done by doing. Hydrolysis by alkali is
1 to 10 equivalents (preferably 1 to 5 equivalents) of hydroxide
Such as titanium, sodium hydroxide and potassium hydroxide
Lucari metal hydroxide, calcium hydroxide, barium hydroxide
1 to 10 equivalents of alkaline earth metal hydroxide such as
(Preferably 1 to 6 equivalents) using an inert solvent (preferably
Contains alcohol such as water, methanol and ethanol
, Ethers such as tetrahydrofuran and dioxane
Or a mixed solvent of these solvents)
(Preferably 20 ° C. to 100 ° C.) for 30 minutes to 48
Time (preferably 1 to 24 hours)
Is performed. After completion of the reaction, the target compound (XVI
I) is collected from the reaction mixture according to a conventional method. example
If necessary, neutralize the reaction mixture and remove any insolubles.
If necessary, after filtration, remove water and ethyl acetate
Add an immiscible organic solvent, and remove the organic layer containing the target compound.
Separate and wash with water etc., then anhydrous magnesium sulfate, anhydrous sulfur
After drying with sodium acid, anhydrous sodium bicarbonate, etc.
Obtained by distilling off the agent. Obtained purpose compound
If necessary, the product may be passed through conventional methods such as recrystallization, reprecipitation, etc.
Usually, a method commonly used for separation and purification of organic compounds is appropriately used.
Combination, chromatography, with appropriate eluent
It can be separated and purified by elution. No.
Step B10 includes reacting a compound having the general formula (XVIII)
A compound (XVI) in an inert solvent.
Converting the carboxy group of I) to a group having -COQ
This step is a compound of Step B4 of Method B described above.
A method of converting a group having -XH in (X) to a leaving group Q,
The same is done. Step B11 has the general formula (Ig).
Is a process for producing a compound,
Compound (XVII) in the presence or absence of a didium catalyst
I) was reacted with a compound having the general formula (XIX)
Later, if desired, R ^1a , R ^2a , R ^3a , R ^4a And in A '
Protecting groups for amino, hydroxy and / or carboxy groups
Is carried out. Used in the above reaction
The inert solvent used is not particularly limited as long as it is inert to the reaction.
Although not limited to, for example, heptane, ligroin or
Or hydrocarbons such as petroleum ethers;
Aromatic hydrocarbons such as toluene, toluene and xylene;
Of chloromethane, 1,2-dichloroethane, carbon tetrachloride
Such halogenated hydrocarbons; diethyl ether, dii
Sopropyl ether, tetrahydrofuran, dioxa
, Dimethoxyethane, diethylene glycol dimethyl
Ethers such as ether; ketones such as acetone
, Formamide, dimethylformamide, dimethyla
Acetamide, hexamethylphosphoric triamide
Amides; sulfoxides such as dimethyl sulfoxide
And sulfolane; and preferably ethers (especially preferred).
Suitably tetrahydrofuran). The reaction temperature depends on the raw materials
Although it varies depending on the compound, solvent, etc., it is usually from -80 ° C to 5 ° C.
0 ° C, preferably -50 ° C to 0 ° C. When reacting
The time varies depending on the starting compound, solvent, reaction temperature, etc.,
Usually 15 minutes to 24 hours (preferably 30 minutes to
12 hours). After completion of the reaction, the target compound of the reaction
(Ig) is collected from the reaction mixture according to a conventional method.
For example, the reaction mixture is appropriately neutralized and insolubles are present.
If necessary, remove by filtration and then remove water and ethyl acetate.
Add an immiscible organic solvent
Separate the layers and wash with water, etc.
Dry with sodium hydrogen sulfate, anhydrous sodium hydrogen carbonate, etc.
Thereafter, it is obtained by distilling off the solvent. Eyes obtained
If necessary, conventional compounds may be used, for example, recrystallization, reprecipitation, etc.
The method commonly used for the separation and purification of organic compounds
Appropriate elution using appropriate combination and chromatography
Can be separated and purified by eluting with
You. In the method C, in the compound (I), D is a nitrogen atom.
R is a group having -NH and G is -CO-G _a With
(Ih), wherein D is a nitrogen atom and E is
A compound (Ii) which is an oxygen atom or a sulfur atom, wherein D is nitrogen
A compound (I) in which E is a group having -NH-
j), D is a nitrogen atom and E is a group having -NH-
G is C ₁ -C ₆ A compound (Ija) which is an alkylene group,
And D is a nitrogen atom and E is a group having -CO-
This is a method for producing compound (Ik).

Embedded imageIn the above formula, R¹, R^1a, R^Two, R^2a, R^Three, R^3a, R^Four, R
^4a, R⁷, A, A ', G, G_a, Q, X and W are as described above.
Shows the same meaning as_bIs C₁-C₆Alkylene
Represents a group. Step C1 is a step for preparing a compound (Ih).
In an inert solvent, the compound represented by the general formula (XX) or its acid
An addition salt (preferably a hydrochloride) is compound (XIII) or
After reacting with (XIV), optionally^1a, R^2a, R
^3a, R^4aAnd A ', amino, hydroxy and / or
Is carried out by removing the protecting group of the carboxy group,
This step is performed in the same manner as in the B method, step B6. No. C
Step 2 is a step of producing compound (Ii),
In a solvent, in the presence or absence of a base (preferably
Below) and a compound having the general formula (XXI)
After reacting with a compound having II), if desired
R^1a, R^2a, R^3a, R^4aAnd A 'in A and A'
Removing the protecting groups for the roxy and / or carboxy groups
This step is performed in the same manner as in the above-mentioned Method B, Step B4.
Is In step C3, compound (Ii) is separately produced
A process in an inert solvent in an organic base (preferably
Having the general formula (XXIII) in the presence of (ethylamine)
Is reacted with a compound having the general formula (XXIV).
And optionally R^1a, R^2a, R^3a, R^4aAnd A '
Amino, hydroxy and / or carboxy groups
This step is performed by removing the protecting group.
This is performed in the same manner as in step B3. The step C4 is a compound (I)
j) in the presence of a base in an inert solvent
Compound (XX) under or in the absence (preferably in the presence)
After reacting with compound (XXII), R^1a,
R^2a, R^3a, R^4aAmino and hydroxy in A ′
And / or by removing the protecting group of the carboxy group
This step is performed in the same manner as the A method step A1.
You. Step C5 comprises reacting a compound having the general formula (XXV)
A step of preparing a compound represented by the general formula (XIV) in an inert solvent:
Compound having (a) and compound (XX) or an acid addition salt thereof
(Eg, mineral salts such as hydrochloride, nitrate, sulfate)
The reaction is performed by, for example, p-toluenes
Heat condensation using organic sulfonic acid such as sulfonic acid as catalyst
Using a Lewis acid such as titanium tetrachloride
This step is performed according to the B method B1 step.
Is performed in the same manner as In Step C6, the compound (Ija) is
In the production step, the compound (XXV) is reacted with a reducing agent.
And optionally R^1a, R^2a, R^3a, R^4aAnd A '
Of the amino, hydroxy and / or carboxy groups in
This step is performed by removing the protecting group.
This is performed in the same manner as in the method step B2. The compound (XX)
After catalytic reduction of V), R^1a, R^2a, R^3a,
R ^4aAnd A 'amino, hydroxy and / or
The compound can also be obtained by removing the protective group of the ruboxyl group.
(Ija) can be produced. Used for catalytic reduction
If the solvent used is an inert solvent for this reaction,
Although not particularly limited, for example, hexane, heptane, rig
Aliphatic hydrocarbons such as loin and petroleum ether;
Aromatic hydrocarbons such as ene, benzene, xylene;
Methyl acetate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether;
Diisopropyl ether, tetrahydrofuran, diox
Sun, dimethoxyethane, diethylene glycol dimethy
Ethers such as toluene; methanol, ethanol
, N-propanol, isopropanol, n-butanol
-Isobutanol, t-butanol, isoamyl urea
Alcohol, diethylene glycol, glycerin, octa
Like knol, cyclohexanol, methyl cellosolve
Alcohols; organic acids such as acetic acid; water;
A mixed solvent of water and water; preferably alcohols;
Ethers, organic acids or water (most preferably alcohol
Or organic acids). Used for catalytic reduction reaction
The catalyst used is usually the one used in the catalytic reduction reaction.
There is no particular limitation as long as the
Um-carbon, Raney-nickel, platinum oxide, platinum black, log
-Aluminum oxide, triphenylphosphine-salt
Rhodium chloride, palladium-barium sulfate, preferably
Is palladium-carbon. Pressure is not particularly limited
Is usually performed at 1 to 10 atm. The reaction temperature is
Although it depends on the starting compound, base, solvent, etc., it is usually -20.
C. to 150 ° C., preferably 0 ° C. to 100 ° C.
You. The reaction time is the starting compound, base, solvent, reaction temperature, etc.
It usually varies from 15 minutes to 24 hours (preferably
Is 30 minutes to 16 hours). Done as desired
R^1a, R^2a, R^3a, R^4aAmino and ar in A '
For removing the protecting group of droxy and / or carboxy group
The method comprises the step of A1 step A1, wherein the amino, hydroxy and / or
Or in the same manner as removing the carboxy group protecting group
It is. After completion of the reaction, the target compound (Ija) of the reaction is usually
Collected from the reaction mixture according to the method. For example, the reaction
Neutralize the mixture appropriately, and filter out any insolubles.
After removal by filtration, mix with water and
Add an organic solvent, separate the organic layer containing the target compound,
After washing with water, etc., anhydrous magnesium sulfate, anhydrous sodium sulfate
Solvent, after drying with anhydrous sodium hydrogencarbonate, etc.
It is obtained by doing. Required target compound obtained
If this is the case, ordinary methods such as recrystallization, reprecipitation, etc.
Combination of methods commonly used for separation and purification of compounds
Apply chromatography and elute with a suitable eluent.
Can be separated and purified. Step C7
Is a step of producing a compound (Ik), wherein an inert solvent
Wherein the compound having the general formula (XXVI) and the compound (XX)
III) or an acid addition salt thereof (eg, hydrochloride, nitrate,
(A mineral acid salt such as sulfate), and
^1a, R^2a, R^3a, R^4aAnd the amino, hydro
Removing the protecting groups of the xy and / or carboxy groups
Compound (XXVI) and Compound (XXII)
In the method of reacting I) or an acid addition salt thereof,
R of compound (XIV) in step B6 of method B⁷Is formyl
The reaction is carried out in the same manner as in the case of
R^1a, R^2a, R^3a, R^4aAnd amino in A ',
Removes protecting groups for hydroxy and / or carboxy groups
The method comprises the amino, hydroxy and
And / or the same as in the method for removing the protecting group of the carboxy group.
Is Starting compounds (II), (III), (IV),
(V), (VI), (VIII), (IX), (X),
(XI), (XIII), (XIV), (XV), (X
IX), (XX), (XXI), (XXII), (XX
III), (XXIV), (XXIVa) and (XXV)
I) is a known or known method or a method analogous thereto.
Therefore, it is easily manufactured. [For example, J. Org. Chem., 5
6, 1445-1453 (1991), Organic Reaction, vol. 5, 301-
330 (1949) etc.]. Starting compounds (II), (V), (VI
II), (X), (XI), (XX), (XXI) and
(XXIII) can also be produced, for example, by the following method.
it can. Method D comprises compound (II) and compound (I)
In I), R^5aIs a hydrogen atom (II)
a) and Z is C₁-C₆An alkylene group and R^5aBut water
This is a method for producing compound (IIb) which is an elementary atom.

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;
_a represents a single bond or a C ₁ -C ₅ alkylene group, and Z _b represents
It represents a C ₁ -C ₆ alkylene group. Step D1 is a step for producing a compound (IIa), which is carried out in an inert solvent (preferably alcohols or ethers) by the general formula (XXV).
II) with a reducing agent (preferably tin (II) chloride, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride);
5 at 20 ° C to 150 ° C (preferably 10 ° C to 80 ° C)
The reaction is carried out for 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 a zinc-acetic acid method, a tin-alcohol method, or a tin-hydrochloric acid method. Step D2 is a step for producing a compound (IIb), which is carried out in an inert solvent (preferably alcohols or ethers) by the general formula (XXV).
This step is carried out by reacting the compound having III) with a reducing agent (preferably an aluminum hydride compound), and this step is carried out in the same manner as the above-mentioned Method D, Step D1. Step D3 is a step of producing a compound having the general formula (XXX), and the presence of a base (preferably an alkali metal bicarbonate or an organic amine) in an inert solvent (preferably an amide). The reaction is carried out by reacting the compound (IIa) with a compound having the general formula (XXIX).
This is performed in the same manner as in the method A1 step. Step D4 is a step of producing compound (II), which is performed by reducing compound (XXX) in an inert solvent. This step is performed in the same manner as in 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. 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 can be eluted with a suitable 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, applying chromatography. Can be separated and purified. Method E can be carried out using compounds (XXVII), (XXVII)
The following general formula (XXXI) containing I) and (IIa)

Embedded image [Wherein R ^1a , R ^2a , R ^3a , R ^4a , D, E, G and Z have the same meanings as described above, and R ⁹ represents an optionally protected amino group, cyano group Or a nitro group. Is a process for producing a compound having the following formula: That is, in compound (XXXI), compound (XXXI) wherein D is a group having -CH- and E is a group having -NH-
a) a compound (XXXIb) in which D is a group having -CH- and E is an oxygen atom or a sulfur atom, D is a group having -CH-, E is a group having the formula -NH-, and G is −
CO-G _a - compound is a group having a (XXXIc),
A compound (XXXId) in which D is a carbon atom and E is a group having ＮNO— and a compound (XXXIe) in which D is a group having —CH— and E is a group having —CO— are produced. Is the way.

Embedded image

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 meanings 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 (eg, hydrochloride, nitrate) in an inert solvent. , A sulfate, etc.), and this step is carried out in the same manner as the above-mentioned Method B, Step B1. Step E2 is a step of producing compound (XXXIa), which is carried out by reducing compound (XXXIII) in an inert solvent. This step is carried out in the same manner as in Method B, step B2. The step E3 is a step of producing the compound (XXXIb). In the step of reacting the compound having the general formula (XXXIV) with a base in the presence or absence (preferably in the presence) of an inert solvent, This step 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.
The step E4 is a step of separately producing the compound (XXXIb). In the step E4, the group having —XH of the compound having the general formula (XXXV) is removed in an inert solvent in the presence or absence of a Lewis acid. After conversion into group Q, 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 B4. Step E5 is a reaction of the general formula (XXXV)
A step of producing a compound having I), wherein the group having -XH of the compound having the general formula (XXXV) is converted to a leaving group Q in an inert solvent in the presence or absence of a base. This step is carried out in the same manner as in the reaction of converting the group having -XH of compound (X) into leaving group Q in compound (X) of Method B, Step B4. Step E6 is a reaction of the general formula (XXXV)
This is a step of producing a compound having II), which is carried out by azide-forming the compound (XXXVI) in an inert solvent. The inert solvent used in the above reaction,
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting material to some extent, for example, benzene, toluene,
Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride and chloroform;
Ethers such as ter, tetrahydrofuran, dioxane and dimethoxyethane; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and nitriles such as acetonitrile; Are amides (most preferably dimethylformamide). The reagent used in the above reaction is not particularly limited as long as it is usually used for azidation. For example, a diarylphosphoric azide derivative such as diphenylphosphoric acid azide; trimethylsilyl azide and triethylsilyl azide Trialkylsilyl azides; alkali metal azides such as sodium azide and potassium azide;
Preferred are alkali metal azide salts (most preferably sodium azide). A catalyst may be used in the above reaction. For example, trialkylsilyl triflates such as trimethylsilyl triflate and triethylsilyl triflate, trifluoroborane etherate, aluminum chloride, zinc chloride and the like can be used. Such Lewis acids can be mentioned. The reaction temperature varies depending on the starting compound, the reagent used, the solvent, and the like.
The temperature is 20 ° C to 100 ° C (preferably 0 ° C to 50 ° C). The reaction time depends on the starting compound, the reagent used, the solvent,
Although it depends on the reaction temperature and the like, it is usually 15 minutes to 50 hours (preferably 30 minutes to 12 hours). E7
The step is a step for producing a compound having the general formula (XXXVIII), and using a reducing agent such as triphenylphosphine in an inert solvent to obtain a compound (XXXVII)
This step is carried out by reducing the B method B5
It is performed in the same manner as the process. In step E8, compound (XXX)
Ic) to produce a compound (XXXVII)
This step is carried out by reacting I) with compound (XIII) or (XIV), and this step is carried out in the same manner as in the above-mentioned Method B, Step B6. Step E9 is a step of producing compound (XXXId), and in an inert solvent, compound (XXXI)
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). Will be Step E10 is a step of producing a compound having the general formula (XXXIX), and is carried out by reacting the compound (XXXIV) with an alkali metal cyanide in an inert solvent. It is performed in the same manner as the process. The step E11 is a step for producing a compound having the general formula (XXXX), and is carried out by hydrolyzing the compound (XXXIX) with an acid or an alkali in an inert solvent. It is performed in the same manner as the process. The 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. Method B B1
This is performed in the same manner as in step 0. Step E13 is a compound (X)
XXIe) is carried out by reacting the compound (XXXXI) with the compound (XIX) in an inert solvent in the presence or absence of a palladium catalyst. This is performed in the same manner as in the 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, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After washing with water, etc., anhydrous magnesium sulfate, anhydrous sodium sulfate,
It is obtained by drying over anhydrous sodium hydrogen carbonate or the like and then distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable 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, applying chromatography. Can be separated and purified. Method F is for compound (XXXI) in which D is a nitrogen atom and E is -NH
- a group having a G is -CO-G _a - compound is a group having a (XXXIf), D is a nitrogen atom E is an oxygen atom or a sulfur atom compound (XXXIg), D is is nitrogen atom A compound (X wherein E is a group having -NH-
XXIh), compound D is a group having the -NH- is a nitrogen atom E G is C ₁ -C ₆ alkylene group (XX
XIha) and a compound (XXXIi) in which D is a nitrogen atom and E is a group having —CO—.

Embedded image In the above formula, 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 meanings as described above. Step F1 is a step of producing compound (XXXIf) in an inert solvent in the presence or absence (preferably in the presence) of a base, a compound represented by the general formula (XXXXXXII) or an acid addition salt thereof (preferably, Is a hydrochloride) with the compound (XII)
This step is performed by reacting with (I) or (XIV), and this step is performed in the same manner as in the above-mentioned Method B, Step B6. The step F2 is a step for producing a compound (XXXIg). This step is performed in the same manner as in the above-mentioned Method B, Step B4. Step F3 is a step of separately producing compound (XXXIg),
By reacting a compound having the general formula (XXXXXXIV) with a compound (XXIV) in an inert solvent in the presence of an organic base (preferably triethylamine);
This step is performed in the same manner as in the B method, step B3. F4
The step is a step of producing compound (XXXIh),
Compound (XXXII) is converted to compound (XXII) in the presence or absence (preferably in the presence) of a base in an inert solvent.
This step is carried out by reacting
This is performed in the same manner as in one step. Step F5 is a process represented by the general formula (XX)
XXV), wherein compound (XIVa) is converted to compound (XXXXXXII) in an inert solvent.
Or a method of reacting with an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate or sulfate), for example, by heat-condensing with an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst. Alternatively, the condensation is performed using a Lewis acid such as titanium tetrachloride, and this step is performed in the same manner as the B method, the B1 step. Step F6 is:
A step of producing compound (XXXIha), which is performed by reducing compound (XXXV). This step is performed in the same manner as in the above-mentioned Method C, Step C6. The step F7 is a step for producing a compound having the compound (XXXIi). (A mineral acid salt such as a sulfate).
It is performed in the same manner as the process. 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. 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 can be eluted with a suitable 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, applying chromatography. Can be separated and purified. The starting compounds (V), (VIII), (X) and (X)
I) is represented by the following general formula (XXXXVII)

Embedded image [In the above formula, R ^2a , R ^3a , R ^4a and Z have the same meanings as described above, and R ^9a is an amino group which may be a protected amino group included in the definition of the R ⁹ group. Some other R
^And R ¹⁰ represents a halogen atom, azide or -X when the broken line represents a single bond.
When a group having H (wherein X has the same meaning as described above) is shown, and the broken line indicates a double bond, it indicates an oxygen atom. Is used in place of compound (II), and compound (I) is used in the same manner as in the method described in the above-mentioned Method A.
The compound can be produced by reacting with II).
Further, the starting compounds (XX), (XXI) and (XXII)
I) is a compound represented by the following general formula (XXXXVIII)

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 (in the above formula, X Represents the same meaning as described above.) With the compound (I)
It can be produced by reacting with compound (III) in the same manner as described in the above-mentioned Method A, using instead of I). Method G is a method for producing compound (XXXII).

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 ′ (a substituent group a ′ is The amino and / or hydroxy group included in the definition of the group of the substituent group a 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 by 1 to 3 groups with a group selected from
¹² represents a lower alkyl group. Step G1 is a step for producing a compound (XXXII), which is performed by reacting a compound of the general formula (IL)
In an inert solvent (preferably, hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene) with a compound having the general formula (L)
The reaction is performed at 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 producing the compound (XXXII). In the step G2, the compound having the general formula (LI) is dissolved in an inert solvent (preferably,
Hexane, cyclohexane, benzene, toluene, hydrocarbons such as xylene or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
Having the general formula (LII) in the presence of ethers such as dimethoxyethane and diethylene glycol dimethyl ether) and a base (preferably organolithiums such as n-butyllithium, t-butyllithium and phenyllithium) Compound and -150 ° C to 50 ° C (preferably-
The reaction is carried out at 100 ° C. to 0 ° C. for 15 minutes to 24 hours (preferably 30 minutes to 16 hours). 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 of producing a compound having the general formula (XXXIIa), wherein the compound (IL) is
In an inert solvent (preferably hexane, cyclohexane,
Hydrocarbons such as benzene, toluene and xylene),
A compound having the general formula (LIII);
The reaction is carried out at 00 ° C. (preferably 0 ° C. to 150 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 20 hours). In addition, compound (IL) is mixed with compound (LIII) in an inert solvent (preferably, halogen hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, and sulfoxides such as dimethyl sulfoxide). The reaction is also carried out by condensation using Lewis acids (preferably aluminum chloride, zinc chloride) at a temperature of 20 ° C to 200 ° C (preferably 50 ° C to 15 ° C).
(0 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 16 hours). 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,
If insolubles are present, they are removed by filtration, and an immiscible organic solvent such as water and ethyl acetate is added.The organic layer containing the target compound is separated, washed with water and the like, and then dried over anhydrous magnesium sulfate and sulfuric anhydride. It is obtained by drying with sodium or anhydrous sodium hydrogen carbonate and then distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable 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, applying chromatography. Can be separated and purified. Starting compounds (XXIX), (XXXI
V), (XXXV), (XXXXII), (XXXXI)
II), (XXXXXXIV), (XXXXVI), (I
L), (L), (LI), (LII) and (LIII)
Is readily known or is easily produced according to known or analogous methods [eg, Acta. Chim. Acad. Hum
g., 34, 75-76 (1962), Chem. Ber., 28, 1625 (189
5), Chem. Abstr., 71, 123951j (1969), etc.]. The compound of the present invention having the above general formula (I), a pharmaceutically acceptable salt thereof or an ester thereof has an excellent ileal bile acid transporter inhibitory activity. The general formula (I) of the present invention
When a compound having the formula (I), a pharmacologically acceptable salt thereof or an ester thereof is used as the above-mentioned therapeutic or prophylactic agent, excipients, diluents, etc. per se or appropriate pharmacologically acceptable And administered, for example, orally with tablets, capsules, granules, powders or syrups, or parenterally with injections or suppositories. These formulations may contain excipients (eg, lactose, sucrose, glucose, mannitol, saccharide derivatives such as sorbitol;
Corn starch, potato starch, alpha 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,
Inorganic excipients such as synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. Can be mentioned. ), 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; Sulfate; glycol;
Fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; it can. ), Binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Examples include polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients. ), Disintegrants (eg, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; chemically modified such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone) Starch and celluloses), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol Phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, Normally used sweeteners, acidulants, can be mentioned perfumes.), It is prepared in a known manner by using additives such as diluents. The amount used depends on the symptoms, age, etc., but in the case of oral administration, the lower limit is 1 day per day.
mg (preferably 10 mg), upper limit 2000 mg (preferably 400 mg), and in the case of intravenous administration, the lower limit is 0.1 mg (preferably 1 mg) per day, and the upper limit is 50 mg.
It is desirable to administer 0 mg (preferably 300 mg) to an adult 1 to 6 times a day depending on the symptoms.

The following examples and test examples show the present invention.
Although described in more detail, the scope of the present invention is not limited to these.
Not something. Ac and Et shown below are before
The consent was shown. Example 13-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
] -N-[(R) -1-phenylethyl] amine 3 g of 3-nitrobenzophenone and (R) -1-phenyl
3.4 ml of ethylamine in 60 ml of anhydrous dichloromethane
And 7.3 ml of triethylamine was added. reaction
The solution was cooled on ice and 1.74 ml of titanium tetrachloride in anhydrous dichloroform.
After slowly adding a diluted solution of methane (17 ml), at room temperature
Stir for 2 hours. Sodium bicarbonate solution
Ethyl acetate was added, and the precipitated insoluble material was filtered through Celite.
Removed. After separating the organic layer of the filtrate, the aqueous layer was ethyl acetate.
Extracted. Wash the combined organic layers with saturated saline
After drying over sodium sulfate, the solvent is concentrated under reduced pressure.
5.41 g of the min compound was obtained as a dark brown oil. Profit
The oil obtained was dissolved in 100 ml of ethanol and hydrogenated.
3.3 g of sodium cyanoborohydride and 1.1 ml of acetic acid
In addition, the mixture was heated under reflux for 1.5 hours. The solvent of the reaction mixture was removed under reduced pressure.
Concentrate and neutralize the residue with aqueous sodium bicarbonate solution.
Extracted three times with ethyl acid. Ethyl acetate layer with saturated saline
After washing and drying over anhydrous magnesium sulfate, the solvent is removed under reduced pressure.
Distilled off. Silica gel column chromatography of the residue
(Eluent: cyclohexane / ethyl acetate = 19/1)
Pressure Chromatography Using Rover and Rover Columns
(Eluent: cyclohexane / ethyl acetate = 19/1)
Separation and purification by isomer, the isomer (A) of the title compound is yellow oil
1.43 g as isomer, isomer (B) as yellow oil
1.12 g were obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-phenylethyl)
Ruamino) methyl] phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
[(R) -1-phenylethyl] amine isomer (A)
1.43 g was dissolved in 30 ml of methanol and nickel chloride was added.
2.04 g of toluene hexahydrate was added. Boron hydride under ice cooling
After adding 650 mg of sodium in small portions
Stir for 30 minutes. Add acetone to the reaction solution and stir for 20 minutes
Thereafter, the solvent was distilled off under reduced pressure. Sodium bicarbonate water in the residue
The solution was added and the aqueous layer was extracted three times with ethyl acetate. Acetic acid
The chill layer is washed with saturated saline and then dried over anhydrous magnesium sulfate.
After drying, the solvent was distilled off under reduced pressure. Silica gel residue
Chromatography (elution solvent: cyclohexane / vinegar)
Separation and purification with ethyl acetate = 3/1) to give the isomer of the title compound
1.24 g of (A) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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
-((R) -1-phenylethyl) amine isomer
(B) 1.71 g was dissolved in 30 ml of methanol,
2.42 g of nickel hexahydrate and sodium borohydride
Isomer (A) of Example (1b) using 772 mg of
In the same manner as in the production of
1.41 g of compound (B) was obtained as a yellow oil. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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- (phenyl-
((R) -1-phenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 3- [phenyl-((R) -1-phenylethylamido)
No.) Methyl] phenylamine isomer (A) 1.24 g
Is dissolved in 30 ml of methanol and 3,4-dimethoxy-
1.17 g of 3-cyclobutene-1,2-dione at room temperature
added. After the reaction solution was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure.
Distilled off under. Silica gel column chromatography of the residue
-(Elution solvent: cyclohexane / ethyl acetate = 1/1)
Separate and purify the isomer (A) of the title compound as a white foam
1.21 g was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 3- [phenyl-((R) -1-phenylethylamido)
No) Isomer of methyl] phenylamine (B) 1.41 g
Is dissolved in 30 ml of methanol and 3,4-dimethoxy-
796 mg of 3-cyclobutene-1,2-dione was added,
In the same manner as in the method for producing the isomer (A) of Example (1c)
The reaction was carried out to give the isomer (B) of the title compound as a white foam.
1.21 g was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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) phenylamido
No] -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
Dissolve 1 g in ethanol 25 ml and add 2N ammonia
-Add 12 ml of ethanol solution and stir at room temperature for 2 hours
did. After distilling off the solvent of the reaction solution under reduced pressure, the precipitated solid
Is suspended in ethyl acetate and collected by filtration to give the isomer of the title compound.
574 mg of (A) was obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 1.31 (3H, d, J = 6.6
Hz), 3.57 (1H, q, J = 6.5Hz), 4.49 (1H, s), 6.98 (1H,
d, J = 7.5Hz), 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
Dissolve 3 g in 30 ml of ethanol and add 2N ammonia
-Add 15 ml of an ethanol solution, and proceed as in Example (1d).
The reaction was carried out in the same manner as in the method for producing
546 mg of isomer (B) of the compound was obtained as a yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 1.29 (3H, d, J = 6.7
Hz), 3.51 (1H, q, J = 6.5Hz), 4.46 (1H, s), 6.91 (1H,
d, J = 7.8Hz), 7.18-7.35 (13H, m). Melting point: 196-198 ° C Optical rotation: [α]_D= + 10.3 (c = 1.0, Et
OH). Example 23-amino-4- [3- (phenyl-((S) -1-F
Enylethylamino) methyl) phenylamino] -3-
Cyclobutene-1,2-dione (Exemplary Compound No. 2-4)
50) 3-nitrobenzophenone and (S) -1-phenylethyl
The reaction was carried out in the same manner as in Example 1 using
461 mg of isomer (A) of the title compound and
431 mg of body (B) was 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). Example 33-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-nitto
Lophenyl) methyl] -N- (3-phenylpropyl)
Amine 2 g of 3-nitro-4'-methoxybenzophenone and 3-
2.22 ml of phenylpropylamine was added to anhydrous dichloromethan.
Dissolve in 20 ml of tan and 4.33 ml of triethylamine
Was added. The reaction solution was ice-cooled, and titanium tetrachloride (1.03 ml) was added.
Slowly add a 10 ml diluted solution of anhydrous dichloromethane
After that, the mixture was stirred at room temperature for 1 hour. NaHCO 3 in the reaction solution
An aqueous solution of lithium and ethyl acetate are added, and the precipitated insolubles are
Filtered off with light. After separating the organic layer of the filtrate,
The layers were extracted with ethyl acetate. Combine organic layers with saturated saline
After washing with water and drying over anhydrous sodium sulfate, the solvent is removed under reduced pressure.
2. Concentrate under reduced pressure to remove the imine compound as a dark brown oil.
26 g were obtained. Dissolve the obtained oil in 60 ml of ethanol.
1.96 g of sodium cyanoborohydride and vinegar
The reaction was carried out in the same manner as in Example (1a) by adding 0.67 ml of acid.
This gave 2.79 g of the title compound as a pale yellow oil.
Was. NMR spectrum (CDCl_Three) δppm: 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-phenyl
Rupropylamino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- (3-phenylpropyl) amine
2.79 g was dissolved in 60 ml of methanol and nickel chloride was added.
3.56 g of sodium hexahydrate and sodium borohydride
Using 12 g, the reaction was carried out in the same manner as in Example (1b).
2.02 g of the title compound was obtained as a pale yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(3-phenylpropylamino) methyl) f
Enylamino] -3-cyclobutene-1,2- Zeon 3-[(4-methoxyphenyl)-(3-phenylpropyl
Lamino) methyl] phenylamine in 2.02 g
Dissolved in 40 ml of 3,4-dimethoxy-3-cyclyl
867 mg of lobutene-1,2-dione was added,
The reaction was carried out in the same manner as in (1c), to give the title compound a pale yellow foam.
1.82 g were obtained as a product. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Nyl)-(3-phenylpropylamino) methyl) fe
Nylamino] -3-cyclobutene-1,2-di on 3-methoxy-4- [3-((4-methoxyphenyl)
-(3-phenylpropylamino) methyl) phenyla
Mino] -3-cyclobutene-1,2-dione 1.82 g
8 ml of 2N ammonia-ethanol solution was added to
The reaction was carried out in the same manner as in Example (1d), and the title compound was converted to yellow.
1.58 g was obtained as a solid. NMR spectrum (DMSO-d₆) δppm: 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,
 d, J = 7.6 Hz), 7.12-7.40 (10H, m). Melting point: 178-180 ° C. Example 43-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
Min 2 g of 3-nitro-4'-methoxybenzophenone and 2-
1.97 ml of phenylethylamine was added to anhydrous dichlorometa
Dissolved in 20 ml of triethylamine and 4.33 ml of triethylamine.
added. The reaction solution was cooled on ice and 1.03 ml of titanium tetrachloride was added.
Slowly add 10 ml of anhydrous dichloromethane
Then, the mixture was stirred at room temperature for 1 hour. NaHCO 3 in the reaction solution
Aqueous solution and ethyl acetate, and the precipitated insoluble
It was removed by filtration through a syringe. After separating the organic layer of the filtrate, the aqueous layer
Was extracted with ethyl acetate. Combine organic layers with saturated saline
After drying with anhydrous sodium sulfate, the solvent is removed under reduced pressure.
Concentrate to convert the imine compound as an orange oil.
91 g were obtained. Dissolve the obtained oil in 60 ml of ethanol.
1.96 g of sodium cyanoborohydride and vinegar
The reaction was carried out in the same manner as in Example (1a) by adding 0.67 ml of acid.
This gave 2.70 g of the title compound as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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-fe
Nylethylamino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
1) 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 Example (1b) using 2 g, and
1.74 g of the compound was obtained as a colorless transparent oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(2-phenylethylamino) methyl) fe
Nylamino] -3-cyclobutene-1,2-di on 3-[(4-methoxyphenyl)-(2-phenylethyl
Lamino) methyl] phenylamine (1.74 g)
Dissolved in 40 ml of 3,4-dimethoxy-3-cyclyl
Example 1 was added with 776 mg of lobutene-1,2-dione.
The reaction was carried out in the same manner as in (1c), and the title compound was converted into a yellow foam.
1.88 g was obtained as a product. NMR spectrum (CDCl_Three) 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-methoxy
Nyl)-(2-phenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-di In 3-methoxy-4- [3-((4-methoxyphenyl)
-(2-phenylethylamino) methyl) phenylamido
No] -3-cyclobutene-1,2-dione in 1.88 g
8.4 ml of 2N ammonia-ethanol solution was added,
The reaction was carried out in the same manner as in Example (1d), to give the title compound.
1.66 g were obtained as a yellow solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 53-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)
Amine 2.0 g of 3-nitro-4'-methoxybenzophenone
2.27 ml of 2-phenylpropylamine was added to anhydrous dichloromethane.
Dissolved in 20 ml of dichloromethane and 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.
slowly add 10 ml diluted solution of anhydrous dichloromethane
After the dropwise addition, the mixture was stirred at room temperature for 1 hour. Bicarbonate in the reaction solution
An aqueous solution of sodium and ethyl acetate were added, and the insolubles precipitated
Was removed by filtration through Celite. Separate the organic layer of the filtrate
Thereafter, the aqueous layer was extracted with ethyl acetate. Saturate the combined organic layers
Wash with brine and dry over anhydrous sodium sulfate.
Was concentrated under reduced pressure to obtain an imine compound. The oil obtained
The product is dissolved in 60 ml of ethanol and hydrogenated cyanated borane is dissolved.
1.96 g of sodium hydrogen chloride and 0.67 ml of acetic acid were added,
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted into a yellow oil.
3.17 g was obtained as a product. NMR spectrum (CDCl_Three) δppm: 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-phenyl
Rupropylamino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- (2-phenylpropyl) amine
3.17 g was dissolved in 60 ml of methanol and nickel chloride was added.
3.7 g of sodium hexahydrate and sodium borohydride
Using 18 g, the reaction was carried out in the same manner as in Example (1b).
2.52 g of the title compound was obtained as a purple transparent oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(2-phenylpropylamino) methyl)
Enylamino] -3-cyclobutene-1,2- Zeon 3-[(4-methoxyphenyl)-(2-phenylpropyl
Lamino) methyl] phenylamine in 2.52 g
Dissolved in 25 ml of 3,4-dimethoxy-3-cyclyl
1.09 g of lobutene-1,2-dione was added,
The reaction was carried out in the same manner as in (1c), and the title compound was colored pink.
2.35 g were obtained as a foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Nyl)-(2-phenylpropylamino) methyl) fe
Nylamino] -3-cyclobutene-1,2-di on 3-methoxy-4- [3-((4-methoxyphenyl)
-(2-phenylpropylamino) methyl) phenyla
Mino] -3-cyclobutene-1,2-dione 2.35 g
Add 10.2 ml of 2N ammonia-ethanol solution to
The reaction was carried out in the same manner as in Example (1d) to give the title compound
Was obtained as a yellow solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 63-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 2 g of 3-nitro-4'-methoxybenzophenone and 3,
2.09 ml of 3-diphenylpropylamine was added to anhydrous dichloromethane.
Dissolved in 20 ml of dichloromethane, and triethylamine 4.3
3 ml was added. The reaction solution was ice-cooled, and titanium tetrachloride 1.0
Slowly add 3 ml of anhydrous dichloromethane 10 ml diluted solution
Then, the mixture was stirred at room temperature for 1 hour. Carbonated water in the reaction solution
An aqueous solution of sodium hydrogen chloride and ethyl acetate were added, and the
The material was removed by filtration through Celite. Separate the organic layer of the filtrate
Thereafter, the aqueous layer was extracted with ethyl acetate. Saturate the combined organic layers
Wash with brine and dry over anhydrous sodium sulfate.
Was concentrated under reduced pressure to give the imine compound as a brown oil.
3.62 g were obtained. 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 repeated in the same manner as in Example (1a).
To give the title compound as an orange oil, 3.5.
3 g were obtained. NMR spectrum (CDCl_Three) 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-di
Phenylpropylamino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- (3,3-diphenylpropyl) a
Dissolve 3.53 g of min in 70 ml of ethanol, and add
3.71 g of nickel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 1.18 g.
2.67 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(3,3-diphenylpropylamino) methyl
Ru) phenylamino] -3-cyclobutene-1 , 2-di
on 3-[(4-methoxyphenyl)-(3,3-diphenyl
Propylamino) methyl] phenylamine 1.99 g
Dissolve in methanol (40 ml) and add 3,4-dimethoxy-3
-701 mg of cyclobutene-1,2-dione were added,
The reaction was carried out in the same manner as in Example (1c), and the title compound was pale yellow.
1.86 g of a colored foam were obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Nyl)-(3,3-diphenylpropylamino) methyl
Ru) phenylamino] -3-cyclobutene-1, 2-di
on 3-methoxy-4- [3-((4-methoxyphenyl)
-(3,3-diphenylpropylamino) methyl) fe
Nylamino] -3-cyclobutene-1,2-dione
To 86 g, add 7 ml of 2N ammonia-ethanol solution.
The reaction was carried out in the same manner as in Example (1d) to give the title compound.
Was obtained as a pale yellow solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 73-amino-4- [3-((4-methoxyphenyl)-
(2,2-diphenylethylamino) methyl] phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound number 2-560) (7a) N-[(4-methoxyphenyl)-(3-nitro
Rophenyl) methyl] -N- (2,2-diphenylethyl
Le) amine 1.5 g of 3-nitro-4'-methoxybenzophenone
2.29 g of 2,2-diphenylethylamine was added to anhydrous dichloromethane.
Dissolved in 15 ml of dichloromethane and triethylamine 3.2.
2 ml was added. The reaction solution was cooled on ice and titanium tetrachloride 0.7
Slowly add 7 ml of anhydrous dichloromethane 10 ml diluted solution
Then, the mixture was stirred at room temperature for 1 hour. Carbonated water in the reaction solution
An aqueous solution of sodium hydrogen chloride and ethyl acetate were added, and the
The material was removed by filtration through Celite. Separate the organic layer of the filtrate
Thereafter, the aqueous layer was extracted with ethyl acetate. Saturate the combined organic layers
Wash with brine and dry over anhydrous sodium sulfate.
Was concentrated under reduced pressure to convert the imine compound into an orange oil.
3.82 g was obtained. The obtained oily substance was washed with ethanol 60
dissolved in sodium cyanoborohydride 1.4
6 g and 0.5 ml of acetic acid were added and the same as in Example (1a)
The reaction was carried out to give 2.54 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-di
Phenylethylamino) methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- (2,2-diphenylethyl) ami
Dissolve 2.54 g of methanol in 50 ml of methanol, and add
2.76 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 878 mg.
2.02 g of the title compound as a colorless transparent oil
Was. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(2,2-diphenylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1, 2-di
on 3-[(4-methoxyphenyl)-(2,2-diphenyl
Ethylamino) methyl] phenylamine (2.02 g)
Dissolved in 40 ml of ethanol, 3,4-dimethoxy-3-
Add 731 mg of cyclobutene-1,2-dione, and perform
The reaction was carried out in the same manner as in Example (1c) to give the title compound as a white foam.
1.35 g was obtained as a solid. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Nyl)-(2,2-diphenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2 -Zeon 3-methoxy-4- [3-((4-methoxyphenyl)
-(2,2-diphenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 1.3
5 ml of 2N ammonia-ethanol solution 5.2 ml
In addition, the reaction was carried out in the same manner as in Example (1d) to give the title compound.
Was obtained as a pale yellow solid. NMR spectrum (DMSO-d₆) δppm: 3.07 (2H, d, J = 6.9
Hz), 3.69 (3H, s), 4.22 (1H, t, J = 6.9Hz), 4.79 (1H, b
r.s), 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. Example 83-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
2- (3-fluorophenyl) ethylamine 2.04m
was dissolved in 20 ml of anhydrous dichloromethane, and triethyl
4.33 ml of amine were added. The reaction solution is cooled on ice and tetrachloride
Dilute 1.03 ml of titanium with 10 ml of anhydrous dichloromethane
After the solution was slowly added dropwise, the mixture was stirred at room temperature for 1 hour. Anti
An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to the reaction solution,
The precipitated insoluble matter was removed by filtration through Celite. Filtrate
After separating the organic layer, the aqueous layer was extracted with ethyl acetate. Matching
The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
After drying, the solvent is concentrated under reduced pressure to remove the imine compound
2.76 g were obtained as a dicolor oil. Remove the resulting oil
Dissolved in 60 ml of ethanol, and hydrated sodium cyanoborohydride
Example with addition of 1.96 g of lithium and 0.67 ml of acetic acid
Reaction was carried out in the same manner as in (1a), and the title compound was converted into a yellow oily substance.
2.51 g was obtained. NMR spectrum (CDCl_Three) δppm: 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).(8b) 3-[(4-methoxyphenyl)-(2- (3
-Fluorophenyl) ethylamino) methyl] phenyl
Amine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- [2- (3-fluorophenyl) e
Dissolve 2.51 g of [tyl] amine in 50 ml of methanol
3.14 g of nickel chloride hexahydrate and borohydride
As in Example (1b) using 1.0 g of sodium hydrogen
The reaction was carried out to give 1.94 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(2- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobut Ten
1,2-dione 3-[(4-methoxyphenyl)-(2- (3-fluoro
Lphenyl) ethylamino) methyl] phenylamine
1.94 g was dissolved in 40 ml of methanol, and
Methoxy-3-cyclobutene-1,2-dione 824m
g, and the reaction was carried out in the same manner as in Example (1c) to give the title.
2.07 g of the compound was obtained as a white foam. NMR spec
Torr (CDCl_Three) δppm: 2.77-2.88 (4H, m), 3.76 (3H, s),
4.44 (3H, s), 4.78 (1H, br.s), 6.79-6.97 (5H, m), 7.0
3-7.28 (7H, m).(8d) 3-amino-4- [3-((4-methoxy
Nyl)-(2- (3-fluorophenyl) ethylami
No) methyl) phenylamino] -3-cyclobute N-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(2- (3-fluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
2N ammonia-ethanol solution 9 per 2.07g
The reaction was performed in the same manner as in Example (1d), and
The compound was obtained as a yellow solid (1.73 g). NMR spectrum (DMSO-d₆) δppm: 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. Example 93-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-nitro
Rophenyl) methyl] -N- [1- (3,5-difluoro
Phenyl) ethyl] amine 1.5 g of 3-nitro-4'-methoxybenzophenone
1- (3,5-difluorophenyl) ethylamine hydrochloride
Dissolve 2.26 g of the salt in 30 ml of anhydrous dichloromethane,
4.8 ml of triethylamine were added. Cool the reaction solution with ice
And 0.77 ml of titanium tetrachloride in anhydrous dichloromethane 1
After slowly adding 0 ml of the diluted solution, the mixture is stirred at room temperature for 1 hour.
Stirred. Aqueous sodium bicarbonate solution and ethyl acetate
The precipitated insoluble material was removed by filtration through Celite.
Was. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate.
Was. The combined organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
After drying with thorium, the solvent is concentrated under reduced pressure to give the imine compound.
The product was obtained as orange oil in an amount of 3.12 g. Got
The oil was dissolved in 60 ml of ethanol and hydrogenated for cyanation.
Add 1.46 g of sodium borohydride and 0.5 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted to yellow.
2.65 g were obtained as an oil. NMR spectrum (CDCl_Three) δppm: 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) ethylamino) methyl
Ru] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- [1- (3,5-difluorophenyl)
2.65 g of [r) ethyl] amine in 50 ml of methanol
3.16 g of nickel chloride hexahydrate dissolved and hydrogenated
Same as Example (1b) using 1.0 g of sodium borohydride
To give the title compound as a pale orange oil.
2.24 g was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,5-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
N-1,2-dione 3-[(4-methoxyphenyl)-(1- (3,5-di
Fluorophenyl) ethylamino) methyl] phenyla
Dissolve 2.24 g of min in 20 ml of methanol, and add
-Dimethoxy-3-cyclobutene-1,2-dione 95
0 mg was added, and the reaction was carried out in the same manner as in Example (1c).
2.2 g of the title compound were obtained as a white foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Nyl)-(1- (3,5-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cycl Lobuten
-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,5-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
2.2 N ammonia-ethanol in 2.2 g of 1,2-dione
9.2 ml of the solution was added, and the reaction
To give 1.86 g of the title compound as a yellow solid.
Was. NMR spectrum (DMSO-d₆) δppm: 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. Example 103-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-d
Trophenyl) methyl] -N- [1- (4-pyridyl) e
Tyl] amine 2 g of 3-nitro-4'-methoxybenzophenone and 1-
1.91 g of (4-pyridyl) ethylamine was added to anhydrous dichloromethane.
Dissolved in 40 ml of methanol and 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.
slowly add 10 ml diluted solution of anhydrous dichloromethane
After the dropwise addition, the mixture was stirred at room temperature for 1 hour. Bicarbonate in the reaction solution
An aqueous solution of sodium and ethyl acetate were added, and the insolubles precipitated
Was removed by filtration through Celite. Separate the organic layer of the filtrate
Thereafter, the aqueous layer was extracted with ethyl acetate. Saturate the combined organic layers
Wash with brine and dry over anhydrous sodium sulfate.
Was concentrated under reduced pressure to convert the imine compound into an orange oil.
3.13 g were obtained. 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 same as in Example (1a)
The reaction was carried out to give the title compound as a yellow oil (2.41 g).
Obtained. NMR spectrum (CDCl_Three) δppm: 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] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
L) Methyl] -N- [1- (4-pyridyl) ethyl] ami
Was dissolved in 40 ml of ethanol, and
3.14 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 1.0 g, and
1.09 g of the title compound was obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (4-pyridyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 3-[(4-methoxyphenyl)-(1- (4-pyridyl)
1.09 g of ethylamino) methyl] phenylamine
Dissolved in 20 ml of ethanol, 3,4-dimethoxy-3-
Add 511 mg of cyclobutene-1,2-dione and run
The reaction was carried out in the same manner as in Example (1c) to give the title compound as a yellow foam.
1.21 g of a product was obtained. NMR spectrum (CDCl_Three) δppm: 1.25-1.40 (3H, m),
3.60-3.75 (1H, m), 3.75and 3.80 (total 3H, each s),
4.50-4.60 (1H, m), 6.65-8.65 (12H, m).(10d) 3-amino-4- [3-((4-methoxy
Enyl)-(1- (4-pyridyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (4-pyridyl) ethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 1.2
Dissolve 1 g in 10 ml of ethanol and add 2N ammonia
-Add 6 ml of ethanol solution, as in Example (1d)
To give 1.0 g of the title compound as a yellow solid.
Obtained. NMR spectrum (DMSO-d₆) δppm: 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). Example 113-amino-4- [3-((4-methoxyphenyl)-
(1- (2-thienyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound number 2-1899) (11a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -N- [1- (2-thienyl) e
Tyl] amine 1.41 g of 3-nitro-4'-methoxybenzophenone
And 1.78 g of 1- (2-thienyl) ethylamine hydrochloride
Dissolve in 20 ml of anhydrous dichloromethane and add
4.6 ml was added. The reaction solution is cooled on ice and titanium tetrachloride
0.73 ml of anhydrous dichloromethane 10 ml diluted solution
After the dropwise addition, the mixture was stirred at room temperature for 1 hour. To the reaction solution
An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to precipitate
The insoluble matter was removed by filtration through Celite. Organic layer of filtrate
After separation, the aqueous layer was extracted with ethyl acetate. Organic combined
Wash the layer with saturated saline and dry over anhydrous sodium sulfate
After that, the solvent is concentrated under reduced pressure to remove the imine compound to a red oily substance.
2.35 g was obtained. 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 same as in Example (1a).
The reaction was carried out in the same manner as in 2.1 to give the title compound as a yellow oil.
1 g was obtained. NMR spectrum (CDCl_Three) δppm: 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] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
L) methyl] -N- [1- (2-thienyl) ethyl] ami
Was dissolved in 40 ml of ethanol.
2.71 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 863 mg.
1.66 g of the title compound as a dark brown oil
Was. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (2-thienyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 3-[(4-methoxyphenyl)-(1- (2-thienyl)
1.66 g of ethylamino) methyl] phenylamine
Dissolved in 30 ml of ethanol, 3,4-dimethoxy-3-
Add 767 mg of cyclobutene-1,2-dione and run
The reaction was carried out in the same manner as in Example (1c) to give the title compound as a white foam.
1.97 g of a product was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (2-thienyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (2-thienyl) ethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 1.9
7 g was dissolved in 40 ml of ethanol, and 2N ammonia was added.
-Add 10 ml of ethanol solution and proceed as in Example (1d).
The title compound was converted to a yellow solid in 1.5
9 g were obtained. NMR spectrum (DMSO-d₆) δppm: 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. Example 123-amino-4- [3- (phenyl- (1- (3,5-
Difluorophenyl) ethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound number 2-1523) (12a) N-[(3-nitrophenyl) -phenyl-
Methyl] -N- [1- (3,5-difluorophenyl) e
Tyl] amine 2.0 g of 3-nitrobenzophenone and 1- (3,5-di
3.41 g of (fluorophenyl) ethylamine hydrochloride
Dissolve in 40 ml of water dichloromethane and add triethylamine
7.3 ml were added. The reaction solution is cooled on ice and titanium tetrachloride
1.16 ml of dilute solution of 11 ml of anhydrous dichloromethane
After the dropwise addition, the mixture was stirred at room temperature for 1 hour. To the reaction solution
An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to precipitate
The insoluble matter was removed by filtration through Celite. Organic layer of filtrate
After separation, the aqueous layer was extracted with ethyl acetate. Organic combined
Wash the layer with saturated saline and dry over anhydrous sodium sulfate
Thereafter, the solvent was concentrated under reduced pressure to obtain an imine compound. Get
Dissolve the imine compound in 60 ml of ethanol
2.21 g of sodium cyanoborohydride and 0.76 of acetic acid
The reaction was carried out in the same manner as in Example (1a) by adding
To give the isomer (A) of the title compound as a colorless oil
904 mg, 897 mg of isomer (B) as a white solid
Obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-difluoro)
Lphenyl) ethylamino) methyl] phenylamine N-[(3-nitrophenyl) -phenylmethyl] -N-
Of [1- (3,5-difluorophenyl) ethyl] amine
Dissolve 900 mg of isomer (A) in 20 ml of methanol
And 1.14 g of nickel chloride hexahydrate and borohydride
As in Example (1b) using 363 mg of sodium hydrogen
To give the isomer (A) of the title compound as a pale yellow oil.
As a result, 739 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). N-[(3-nitrophenyl) -phenylmethyl] -N
-[1- (3,5-difluorophenyl) ethyl] amine
Isomer (B) 890mg dissolved in methanol 20ml
And 1.14 g of nickel chloride hexahydrate and borohydride
As in Example (1b) using 363 mg of sodium hydrogen
To give the isomer (B) of the title compound as a colorless oil
791 mg was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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- (phenyl- (1
-(3,5-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 3- [phenyl- (1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamine isomer (A)
733 mg was dissolved in 10 ml of methanol, and
Methoxy-3-cyclobutene-1,2-dione 341 m
g, and the reaction was carried out in the same manner as in Example (1c).
814 mg of the compound isomer (A) was obtained as a white solid.
Was. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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)
Dissolve 785 mg in 10 ml of methanol, and add
Methoxy-3-cyclobutene-1,2-dione 355 m
g, and the reaction was carried out in the same manner as in Example (1c).
888 mg of the compound isomer (B) was obtained as a white foam.
Was. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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- (phenyl- (1-
(3,5-difluorophenyl) ethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione 3-methoxy-4- [3- (phenyl- (1- (3,5
-Difluorophenyl) ethylamino) methyl) phenyl
Isomer of [lamino] -3-cyclobutene-1,2-dione
Dissolve 810 mg of body (A) in 5 ml of tetrahydrofuran
And add 3.6 ml of 2N ammonia-ethanol solution.
The reaction was carried out in the same manner as in Example (1d) to give the title compound
733 mg of isomer (A) was obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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) fe
Nylamino] -3-cyclobutene-1,2-dione
880 mg of the isomer (B) was dissolved in 5 ml of ethanol,
4.0 ml of normal ammonia-ethanol solution was added,
The reaction was carried out in the same manner as in Example (1d) to give the isomer of the title compound.
708 mg of the compound (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 133-amino-4- [3-((3,4-dimethylphenyi)
)-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-di on
(Exemplified Compound No. 2-533) (13a) N-[(3-nitrophenyl)-(3,4-di
Methylphenyl) methyl] -N-((S) -1-phenyl
Ethyl) amine 3-nitro-3 ', 4'-dimethylbenzophenone
0 g and (S) -1-phenylethylamine 1.99 ml
Was dissolved in 20 ml of anhydrous dichloromethane.
4.33 ml of min was added. The reaction solution is cooled on ice and
Dissolution of 1.03 ml of tan in 10 ml of anhydrous dichloromethane
After the solution was slowly added dropwise, the mixture was stirred at room temperature for 1 hour. reaction
An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the solution,
The insolubles thus obtained were removed by filtration through Celite. With filtrate
After separating the organic layer, the aqueous layer was extracted with ethyl acetate. Combined
The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After drying, the solvent is concentrated under reduced pressure to give the imine compound as a yellow oil.
2.92 g was obtained as a product. The oil obtained is ethanol
Dissolve in 60ml and add sodium cyanoborohydride
Example (1a) by adding 2.21 g and 0.76 ml of acetic acid
Reaction and separation and purification were performed in the same manner as in
1.10 g of (A) as a colorless oil, isomer (B)
1.19 g was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-dimethylphenyl)-
((S) -1-phenylethylamino) methyl] phenyl
Luamine N-[(3-nitrophenyl)-(3,4-dimethylphen)
Nyl) methyl] -N-((S) -1-phenylethyl) a
1.10 g of isomer of amine (A) in 20 ml of methanol
1.45 g of nickel chloride hexahydrate dissolved and hydrogenated
Example (1b) using 469 mg of sodium boron
The reaction was carried out in the same manner to convert the isomer (A) of the title compound into a yellow oil.
954 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). N-[(3-nitrophenyl)-(3,4-dimethylphenyl)
Enyl) methyl] -N-((S) -1-phenylethyl
L) 1.19 g of the amine isomer (B)
1.57 g of nickel chloride hexahydrate and
Example (1) using 500 mg of sodium borohydride
The reaction was carried out in the same manner as in b), and the isomer (B)
849 mg was obtained as a colorless oil. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-dimethyl
Tylphenyl)-((S) -1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Zeon 3-[(3,4-dimethylphenyl)-((S) -1-F
Isomer of phenylethylamino) methyl] phenylamine
(A) 950 mg was dissolved in 15 ml of methanol,
4-dimethoxy-3-cyclobutene-1,2-dione 4
30 mg was added, and the reaction was carried out in the same manner as in Example (1c).
To give the isomer (A) of the title compound as a white foam.
6 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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-F
Isomer of phenylethylamino) methyl] phenylamine
(B) 845 mg was dissolved in 15 ml of methanol,
4-dimethoxy-3-cyclobutene-1,2-dione 3
82 mg was added, and the reaction was carried out in the same manner as in Example (1c).
To give the isomer (B) of the title compound as a white foam.
04 g was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-dimethyl
Ruphenyl)-((S) -1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene- 1,2
-Zeon 3-methoxy-4- [3-((3,4-dimethylphenyi)
)-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2-dione
Of isomer (A) of 970 mg in 10 ml of ethanol
And add 4.4 ml of 2N ammonia-ethanol solution.
The reaction was carried out in the same manner as in Example (1d) to give the title compound
604 mg of isomer (A) was obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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
Of isomer (B) (1.04 g) in ethanol (10 ml)
And add 4.8 ml of 2N ammonia-ethanol solution.
The reaction was carried out in the same manner as in Example (1d) to give the title compound
899 mg of isomer (B) was obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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. Example 143-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
Le) amine 2.0 g of 4-chloro-3-nitrobenzophenone
1.94 ml of (S) -1-phenylethylamine, tri
For 4.2 ml of ethylamine and 1.16 ml of titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a), and the imine compound
I got Obtained imine compound and borohydride cyanide
Performed using 1.91 g of sodium and 0.65 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted into a yellow oil.
2.89 g was obtained as a product. NMR spectrum (CDCl_Three) δppm: 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] phenylamine N-[(4-chloro-3-nitrophenyl) -phenyl
Methyl] -N-((S) -1-phenylethyl) amine
2.89 g, 3.76 g of nickel chloride hexahydrate and water
Example (1b) using 1.2 g of sodium borohydride
And react the title compound as a pale yellow oil.
2.36 g were obtained. NMR spectrum (CDCl_Three) δppm: 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-5- (f
Enyl-((S) -1-phenylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 2-chloro-3- [phenyl-((S) -1-phenyl
2.36 g of ethylamino) methyl] phenylamine,
3,4-dimethoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 1.05 g of
Thus, 2.42 g of the title compound was obtained as a white foam. NMR spectrum (CDCl_Three) δppm: 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- (f
Nyl-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2 -Zeon
Hydrochloride 3-methoxy-4- [2-chloro-5- (phenyl-
((S) -1-phenylethylamino) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-dione 2.4
Dissolve 2 g in 25 ml of ethanol and add 2N ammonia
Example 1d, adding 10.8 ml of an ethanol solution
The reaction was carried out in the same manner as Crude crude obtained by concentrating the reaction solution
The product is dissolved in 20 ml of ethyl acetate, and 4N-HCl / vinegar is added.
5.4 ml of ethyl acid was added to form the hydrochloride. solid
Is suspended in ether and collected by filtration to give the title compound as a pale yellow solid.
2.32 g was obtained as a body. NMR spectrum (DMSO-d₆) δppm: 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. Example 153-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
Le) amine 2.0 g of 2-chloro-5-nitrobenzophenone
1.94 ml of (S) -1-phenylethylamine, tri
4.2 ml of ethylamine and 1.0 ml of titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a) using
Compound was obtained. The obtained imine compound and hydrogenated cyanide
Using 1.91 g of sodium iodide and 0.65 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was
2.58 g were obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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] phenylamine N-[(2-chloro-5-nitrophenyl) -phenyl
Methyl] -N-((S) -1-phenylethyl) amine
2.58 g, 3.33 g of nickel chloride hexahydrate and water
Example (1) using 1.06 g of sodium borohydride
The reaction was carried out in the same manner as in b), followed by separation and purification.
Isomer (A) as a colorless oil 771 mg, isomer
659 mg of (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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 =
8.2Hz), 7.15-7.37 (10H, m). Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-5- (f
Enyl-((S) -1-phenylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
on 2-chloro-3- [phenyl-((S) -1-phenyl
Ethylamino) methyl] phenylamine isomer (A)
765 mg and 3,4-dimethoxy-3-cyclobute
Example (1c) using 339 mg of N-1,2-dione
The reaction was carried out in the same manner as described above, and the isomer (A)
800 mg were obtained as a colored foam. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 2-chloro-3- [phenyl-((S) -1-phenyl
Ethylamino) methyl] phenylamine isomer (B)
654 mg and 3,4-dimethoxy-3-cyclobute
Example (1c) using 290 mg of N-1,2-dione
The reaction was carried out in the same manner as in
246 mg were obtained as a colored foam. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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- (f
Nyl-((S) -1-phenylethylamino) methyl)
Phenylamino] -3-cyclobutene-1,2 -Zeon 3-methoxy-4- [4-chloro-5- (phenyl-
((S) -1-phenylethylamino) methyl) phenyl
Isomer of [lamino] -3-cyclobutene-1,2-dione
800 mg of body (A) and 2 N ammonia-ethanol
Using 3.6 ml of the toluene solution as in Example (1d)
To give the isomer (A) of the title compound as a pale yellow solid
620 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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) phenyl
Isomer of [lamino] -3-cyclobutene-1,2-dione
246 mg of body (B) and 2 N ammonia-ethanol
Reaction in the same manner as in Example (1d) using 1.2 ml of
To give the isomer (B) of the title compound as a pale yellow solid.
133 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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. Example 163-amino-4- [2-methoxy-5-((4-fluoro
Rophenyl)-((S) -1-phenylethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplary Compound No. 2-501) (16a) N-[(4-methoxy-3-nitrophenyl)
)-(4-fluorophenyl) methyl] -N-((S)
-1-phenylethyl) amine 4-methoxy-3-nitro-4'-fluorobenzophene
2.0 g of nonone and (S) -1-phenylethylamine
98 ml, triethylamine 4.3 ml and titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a) using 1.03 ml.
Thus, 2.96 g of an imine compound was obtained as a yellow oil.
Obtained imine compound and sodium borohydride cyanide
Example using 1.96 g of acetic acid and 0.67 ml of acetic acid
The reaction was carried out in the same manner as in (1a), followed by separation and purification to give the title compound
Isomer (A) as a yellow oil (678 mg, isomer)
1.31 g of (B) was obtained as a white solid. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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, 8.9Hz), 8.54 (1H, d, J = 2.9Hz). Isomer (B) NMR spectrum (CDCl_Three) δppm: 1.38 (3H, d, J = 6.6H
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-fluorophenyl
)-((S) -1-phenylethylamino) methyl]
Phenylamine N-[(4-methoxy-3-nitrophenyl)-(4-f
Fluorophenyl) methyl] -N-((S) -1-phenyl
670 mg of isomer (A) of ethyl) amine and nickel chloride
Hexahydrate and sodium borohydride 2
A reaction was carried out in the same manner as in 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_Three) δppm: 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-phenyl
(Ethyl) amine isomer (B) (1.4 g) and nickel chloride
1.76 g of sodium hexahydrate and sodium borohydride 5
The reaction was carried out in the same manner as in Example (1b) using 60 mg,
The isomer (B) of the title compound was converted into a colorless oily substance (844 m).
g was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy-5
((4-fluorophenyl)-((S) -1-phenyle
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 2-methoxy-5-[(4-fluorophenyl)-
((S) -1-phenylethylamino) methyl] phenyl
Isomer (A) of 635 mg and 3,4-dimethyl
254 mg of toxic-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using
635 mg of the compound isomer (A) was obtained as a white foam.
Was. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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] phenyl
Isomer (B) of 840 mg and 3,4-dimethyl
358 mg of toxic-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using
811 mg of the compound isomer (B) was obtained as a pale yellow foam.
Was. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-5
((4-fluorophenyl)-((S) -1-phenyle
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-methoxy-4- [2-methoxy-5-((4-fur
Orophenyl)-((S) -1-phenylethylamido
No) methyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione isomer (A) and 2N
Performed using 2.8 ml of ammonia-ethanol solution
The reaction was carried out in the same manner as in Example (1d) to give the isomer of the title compound.
491 mg of (A) was obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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-fur
Orophenyl)-((S) -1-phenylethylamido
No) methyl) phenylamino] -3-cyclobutene-
805 mg of 1,2-dione isomer (B) and 2N
Performed using 3.4 ml of ammonia-ethanol solution
The reaction was carried out in the same manner as in Example (1d) to give the isomer of the title compound.
700 mg of (B) was obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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. Example 173-amino-4- [2,3-dimethoxy-5-((4-
Fluorophenyl)-((S) -1-phenylethyla
Mino) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-502) (17a) N-[(3,4-dimethoxy-5-nitroph
Enyl)-(5-fluorophenyl) methyl] -N-
((S) -1-phenylethyl) amine 3,4-dimethoxy-5-nitro-4'-fluoroben
2.0 g of zophenone and (S) -1-phenylethylamido
1.68 ml of triethylamine, 3.66 ml of triethylamine and
Same as Example (1a) using 0.87 ml of titanium tetrachloride
The reaction was carried out in the same manner to obtain an imine compound. The obtained imine
Compound and sodium cyanoborohydride 1.67
g, using 0.57 ml of acetic acid in the same manner as in Example (1a).
The reaction was carried out and the title compound was converted into an orange oil.
73 g were obtained. NMR spectrum (CDCl_Three) δppm: 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-fluoro
Phenyl)-((S) -1-phenylethylamino) methyl
Ru] phenylamine N-[(3,4-dimethoxy-5-nitrophenyl)-
N- (4-fluorophenyl) methyl]-((S) -1-F
2.73 g of phenylethyl) amine, nickel chloride hexahydrate
3.19 g and sodium borohydride 1.01 g
The reaction was carried out in the same manner as in Example (15b) using
To give the isomer (A) of the title compound as a yellow oil in 8%.
95 mg, isomer (B) 319 m as a pale yellow oil
g was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) 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-phenyl)
Ruethylamino) methyl) phenylamino] -3-cycl
Lobutene-1,2-dione 2,3-dimethoxy-5-[(4-fluorophenyl)-
((S) -1-phenylethylamino) methyl] phenyl
890 mg of isoamine (A)
343 mg of toxic-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using
762 mg of the compound isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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)-
((S) -1-phenylethylamino) methyl] phenyl
1.15 g of isoamine (B) and 3,4-dimer
455 mg of tox-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using
789 mg of the compound isomer (B) was obtained as a white foam.
Was. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-dimethoxy-5
-((4-fluorophenyl)-((S) -1-phenyl
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione 3-methoxy-4- [2,3-dimethoxy-5-((4
-Fluorophenyl)-((S) -1-phenylethyl
Amino) methyl) phenylamino] -3-cyclobutene
755 mg of isomer (A) of 1,2-dione and
Using 3.0 ml of a constant ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d) to give the isomer of the title compound.
638 mg of the compound (A) was obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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-phenylethyl
Amino) methyl) phenylamino] -3-cyclobutene
785 mg of isomer (B) of 1,2-dione and
Using 3.2 ml of a constant ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d) to give the isomer of the title compound.
680 mg of the compound (B) was obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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. Example 183-amino-4- [3- (4-methoxyphenyl-
((R) -1- (3,4-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cyclobut Ten
-1,2-dione (Exemplary Compound No. 2-1359) (18a) N-[(3-nitrophenyl)-(4-metho
[Xyphenyl) methyl] -N-((R) -1- (3,4
-Difluorophenyl) ethyl) amine 3 g of 4-methoxy-3'-nitro-benzophenone
(R) -1- (3,4-difluorophenyl) ethyla
3.96 g of minmandelic acid salt, triethylamine
75 ml, titanium tetrachloride 1.54 ml, hydrogenated cyanation
Using 3.26 g of sodium boron and 1.0 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) to give the title compound an orange color.
1.27 g were obtained as an oil. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-((R)
-1- (3,4-difluorophenyl) ethylamino)
Methyl] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N-((R) -1- (3,4-difluoro)
1.27 g of (phenyl) ethyl) amine in methanol 5
0 ml, and 1.52 g of nickel chloride hexahydrate and
Example using 510 mg of sodium and sodium borohydride
The reaction was carried out in the same manner as in (1b). Diastereomer
Ricagel column chromatography (elution solvent: acetic acid
(Toluene / toluene = 1/8).
235 mg of isomer (A) as a yellow oil, isomer
240 mg of (B) was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-methoxy
Phenyl)-((R) -1- (3,4-difluorophene)
Nyl) ethylamino) methyl) phenylamino ] -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1-
(3,4-difluorophenyl) ethylamino) methyl
Phenylamine isomer (A) 225 mg
Dissolved in 5 ml of 3,4-dimethoxy-3-cyclohexane.
Example (1) using 174 mg of butene-1,2-dione
The reaction was carried out in the same manner as in c) to convert the isomer (A) of the title compound.
293 mg were obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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-
(3,4-difluorophenyl) ethylamino) methyl
Phenylamine isomer (B) 230 mg
Dissolved in 5 ml of 3,4-dimethoxy-3-cyclohexane.
Example using 177 mg of butene-1,2-dione
The reaction was carried out in the same manner as in (1c) to give an isomer of the title compound.
320 mg of (B) were obtained as a yellow oil. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-((R) -1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-
Clobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-((R) -1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
280 mg of the isomer 1,2-dione isomer (A)
In 5 ml of 2N ammonia-ethanol
1 ml of the solution was added, and the reaction was carried out in the same manner as in Example (1d).
The isomer (A) of the title compound was converted into a yellow solid in 190
mg. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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: 171-173 ° C. Optical rotation: [α]_D: -33.8 (c = 1.0, EtO
H) 3-Methoxy-4- [3-((4-methoxyphenyl)
-((R) -1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
280 mg of isomer (B) of 1,2-dione
In 5 ml of 2N ammonia-ethanol
1 ml of the solution was added, and the reaction was carried out in the same manner as in Example (1d).
The isomer (B) of the title compound was converted to a yellow solid by 180
mg. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 193-amino-4- [3- (4-methoxyphenyl-
((S) -1- (3,4-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cyclobutene
-1,2-dione (Exemplary Compound No. 2-1359) (19a) N-[(3-nitrophenyl)-(4-metho
[Xyphenyl) methyl] -N-[(S) -1- (3,4
-Difluorophenyl) ethyl] amine 3 g of 4-methoxy-3'-nitro-benzophenone
(S) -1- (3,4-difluorophenyl) -ethyl
Amine Mandelate, 5.41 g, triethylamine
9.75 ml, titanium tetrachloride 1.54 ml, hydrogen hydride
3.26 g of sodium borohydride and 1.0 ml of acetic acid
And reacted in the same manner as in Example (1a) to give the title compound.
1.60 g were obtained as an orange oil. NMR spectrum (CDCl_Three) δppm: 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) ethylamino)
Methyl] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N-[(S) -1- (3,4-difluoro)
Lphenyl) ethyl] amine in methanol
0 ml, dissolving 1.79 g of nickel chloride hexahydrate and
Example using sodium borohydride and 600mg
The reaction was carried out in the same manner as in (1b). Diastereomer
Ricagel column chromatography (elution solvent: acetic acid
(Toluene / toluene = 1/8).
199 mg of isomer (A) as a yellow oil, isomer
290 mg of (B) was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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 = 8.7Hz), 6.92-6.97 (1H, m), 7.05-7.19 (5H, m). Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-((S) -1- (3,4-difluorophene)
Nyl) ethylamino) methyl) phenylamino ] -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((S) -1-
(3,4-difluorophenyl) ethylamino) methyl
Phenylamine isomer (A) 180 mg
Dissolved in 10 ml of 3,4-dimethoxy-3-cyclyl
Example using 139 mg of lobutene-1,2-dione
The reaction is carried out in the same manner as in (1c) to give the isomer of the title compound
220 mg of (A) was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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-
(3,4-difluorophenyl) ethylamino) methyl
Phenylamine isomer (B) 270 mg
Dissolved in 10 ml of 3,4-dimethoxy-3-cyclyl
Example using lobutene-1,2-dione 208mg
The reaction is carried out in the same manner as in (1c) to give the isomer of the title compound
160 mg of (B) was obtained as a pale yellow oil. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-((S) -1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-
Clobutene-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
220 mg of isomer (A) of 1,2-dione
In 5 ml of 2N ammonia-ethanol
1 ml of the solution was added, and the reaction was carried out in the same manner as in Example (1d).
The isomer (A) of the title compound was converted to a yellow solid by
mg. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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: 171-173 ° C. Optical rotation: [α]_D: +32.5 (c = 1.0, EtO
H) 3-Methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-cyclobute
Of 1,2-dione isomer (B) in 150 mg
In 5 ml of 2N ammonia-ethanol
1 ml of the solution was added, and the reaction was carried out in the same manner as in Example (1d).
The isomer (B) of the title compound was converted to a yellow solid by 130
mg. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 203-amino-4- [3-((4-methoxyphenyl)-
((S) -1- (3-fluorophenyl) ethylami
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-815) (20a) N-[(3-nitrophenyl)-(4-metho
[Xyphenyl) methyl] -N-[(S) -1- (3-f
Fluorophenyl) ethyl] amine 2.0 g of 4-methoxy-3'-nitrobenzophenone
Of (S) -1- (3-fluorophenyl) ethylamine
2.73 g of hydrochloride, 6.50 ml of triethylamine,
1.03 ml of titanium chloride, sodium borohydride cyanide
Example 1 (2.15 g) and 0.67 ml of acetic acid.
The reaction was carried out in the same manner as in a) to give the title compound as a yellow oil.
2.77 g was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-((S)
-1- (3-Fluorophenyl) ethylamino) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N-[(S) -1- (3-fluorophene)
Nyl) ethyl] amine (2.70 g) in methanol (100 m)
3.37 g of nickel chloride hexahydrate and water
Example (1) using 1.13 g of sodium borohydride
The reaction was carried out in the same manner as in b) to give the title compound as a yellow oil.
2.32 g was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-((S) -1- (3-fluorophenyl)
Ethylamino) methyl) phenylamino] -3 -Cyclo
Butene-1,2-dione 3-[(4-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenyl
Dissolve 2.27 g of amine in 50 ml of methanol,
4-dimethoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using 1.84 g.
Was. The crude product was subjected to reverse phase HPLC [elution solvent: acetonitrile
/ Acetic acid buffer (water: acetic acid: triethylamine = 1000:
2: 2) = 40/60].
Isomer (A) as pale yellow foam, 145 mg, isomer
350 mg of (B) was obtained as a yellow foam. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-methoxy
Enyl)-((S) -1- (3-fluorophenyl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylami
No) methyl) phenylamino] -3-cyclobutene-
130 mg of 1,2-dione isomer (A)
Dissolve in 5 ml, 2N ammonia-ethanol solution 1
The reaction was carried out in the same manner as in Example (1d).
110 mg of isomer (A) of the title compound was obtained as a yellow solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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) ethylami
No) methyl) phenylamino] -3-cyclobutene-
330 mg of 1,2-dione isomer (B)
Dissolve in 5 ml, 2N ammonia-ethanol solution 2
The reaction was carried out in the same manner as in Example (1d).
282 mg of isomer (B) of the title compound was obtained as a yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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, 8.0Hz). Melting point: 178-181 ° C Optical rotation: [α]_D: -106.8 (c = 0.5, EtO
H). Example 213-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
In 2.0 g of (3-nitrophenyl) -2-thienyl ketone
1.94 ml of (S) -1-phenylethylamine, tri
Using 4.2 ml of ethylamine and 1.0 ml of titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a), and the imine compound
I got Obtained imine compound and borohydride cyanide
Performed using 1.91 g of sodium and 0.65 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was orange
2.58 g were obtained as a colored oil. NMR spectrum (CDCl_Three) δppm: 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-phenylethylamino)-
2-thienylmethyl] phenylamine N-[(3-nitrophenyl) -2-thienylmethyl]
-N-((S) -1-phenylethyl) amine 4.56
g, nickel chloride hexahydrate 6.42 g and hydrogenated boron
Same as Example (15b) using 2.04 g of sodium hydrogen
The reaction is carried out in the same manner and purification is carried out to give the isomer (A) of the title compound.
936 mg as a pale yellow oil, isomer (B) as pale yellow
380 mg were obtained as an oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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) methyl) -Fe
Nylamino] -3-cyclobutene-1,2-di on 3-[((S) -1-phenylethylamino) -2-thienyl
[Methyl] -phenylamine isomer (A) 930 m
g, 3,4-dimethoxy-3-cyclobutene-1,2-
Reaction was carried out in the same manner as in Example (1c) using 466 mg of dione.
To give the isomer (A) of the title compound as a white foam.
932 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 3-[((S) -1-phenylethylamino) -2-thienyl
[Methyl] phenylamine isomer (B) (375 mg),
3,4-dimethoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 185 mg of
Thus, the isomer (B) of the title compound was converted into a white foam by
71 mg were obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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] phenyl
Ruamino] -3-cyclobutene-1,2-dione 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, the reaction was carried out in the same manner as in Example (1d).
654 mg of isomer (A) of the title compound as a yellow solid
Obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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 = 7.9Hz). 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 Example (1d).
391 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 223-amino-4- [3- (2-thienyl-((R) -1
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (Exemplary Compound No. 2
-646) 2.0 g of (3-nitrophenyl) -2-thienyl ketone
Using (R) -1-phenylethylamine 1.94 ml
Then, the reaction was carried out in the same manner as in Example 21 to obtain a title compound.
1.25 g of the isomer (A) and 762 mg of the isomer (B) were obtained.
Was. 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). Example 233-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
In 2.0 g of (3-nitrophenyl) -4-pyridyl ketone
(S) -1-phenylethylamine 2.24 ml, tri
4.89 ml of ethylamine and 1.16 of titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a) using
Compound was obtained. The obtained imine compound and hydrogenated cyano
2.21 g of sodium borohydride and 0.76 ml of acetic acid
And the reaction was carried out in the same manner as in Example (1a).
1.09 g of isomer (A) as pale yellow oil, isomer
1.02 g of (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 1.40 (3
H, d, J = 6.6Hz), 3.60 (1H, q, J = 6.6Hz), 4.69 (1H, s),
 7.19-7.38 (7H, m), 7.53 (1H, t, J = 7.8Hz), 7.63 (1H, m
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-phenylethylamine)-
4-pyridylmethyl] phenylamine N-[(3-nitrophenyl) -4-pyridylmethyl]
-N-((S) -1-phenylethyl) amine isomer
(A) 1.09 g, nickel chloride hexahydrate 1.57 g and
Example using and 500 mg of sodium borohydride
The reaction was carried out in the same manner as in (1b), and the isomer of the title compound was obtained.
752 mg of (A) was obtained as a pale yellow oil. Isomer
(A) NMR spectrum (CDCl_Three) δppm: 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]
-N-((S) -1-phenylethyl) amine isomer
(B) 1.02 g, nickel chloride hexahydrate 1.47 g
Example using 470 mg of sodium borohydride
The reaction was carried out in the same manner as in (1b), and the isomer of the title compound was obtained.
694 mg of (B) was obtained as a pale yellow oil. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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) methyl) phenyl
Ruamino] -3-cyclobutene-1,2-di In 3-[((S) -1-phenylethylamine) -4-pyridi
[Methyl] phenylamine isomer (A) (745 mg)
And 3,4-dimethoxy-3-cyclobutene-1,2-
Reaction was carried out in the same manner as in Example (1c) using 373 mg of dione.
To give the isomer (A) of the title compound as a pale yellow solid
805 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 3-[((S) -1-phenylethylamine) -4-pyridi
[Methyl] phenylamine isomer (B) (690 mg)
And 3,4-dimethoxy-3-cyclobutene-1,2-
Reaction was carried out in the same manner as in Example (1c) using 355 mg of dione.
To give the isomer (B) of the title compound as a pale yellow solid.
604 mg were obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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) phenyl
Ruamino] -3-cyclobutene-1,2-dione 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 Example (1d).
Isomer (A) of the title compound as an orange solid
5 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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 Example (1d).
The isomer (B) of the title compound was converted into a pale yellow solid in an amount of 412 m
g. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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 = 5.7Hz). Melting point: 168-171 ° C Optical rotation: [α]_D= + 23.5 (c = 1.0, Et
OH). Example 243-amino-4- [3- (4-pyridyl-((R) -1
-Phenylethylamino) methyl) phenylamino]-
3-cyclobutene-1,2-dione (exemplified compound Object number 2
−691) (3-nitrophenyl) -4-pyridyl ketone and (R)-
As in Example 23 using 1-phenylethylamine
Perform the reaction to obtain the isomer (A) and the isomer of the title compound.
(B) was obtained. 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). Example 253-amino-4- [3-((3,4-dimethoxyphenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclo Butene
1,2-dione and its hydrochloride (Exemplary Compound No. 2-
1397) (25a) 3-[(3,4-dimethoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl] -phenylamine 3,4-dimethoxy-3'-nitro-benzophenone
2.0 g and 1- (3,4-difluorophenyl) ethyl
Amine hydrochloride (2.48 g) was added to anhydrous dichloromethane (60 m).
and triethylamine (5.82 ml) was added.
The reaction solution was cooled on ice, and 0.92 ml of titanium tetrachloride in anhydrous dichloromethane was added.
After slowly adding a 10 ml diluted solution of chloromethane,
Stirred at warm for 2 hours. Sodium bicarbonate aqueous solution
Liquid and ethyl acetate are added, and the precipitated insoluble matter is removed by filtration.
did. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate.
did. The combined organic layer was washed with a saturated saline solution,
After drying over sodium, the solvent is concentrated under reduced pressure to iminate
The compound was obtained as an oil. The resulting oil is washed with methanol
Dissolved in 100 ml, 3.31 g of nickel chloride hexahydrate
Was added. 1.11 g of sodium borohydride under ice-cooling
Is added in small portions and then stirred at room temperature for 3 hours
did. Water and ethyl acetate were added to the reaction solution, and the precipitated insolubles
Was removed by filtration. After separating the organic layer of the filtrate, the aqueous layer is
Extracted with ethyl acid. Wash the combined organic layers with saturated saline
After drying with anhydrous sodium sulfate, the solvent is concentrated under reduced pressure.
Was. The obtained residue is subjected to silica gel column chromatography.
-(Eluent: cyclohexane / ethyl acetate = 5/1)
The title compound was isolated as a yellow oil in 1.4.
5 g were obtained. NMR spectrum (CDCl_Three) δppm: 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-dimethyl
Toxiphenyl)-(1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino] -3-
Clobutene-1,2-dione 3-[(3,4-dimethoxyphenyl)-(1- (3,
4-difluorophenyl) ethylamino) methyl] fe
Dissolve 500 mg of nilamine in 10 ml of methanol,
3,4-dimethoxy-3-cyclobutene-1,2-di
The reaction was carried out as in Example (1c) with the addition of
Thus, 450 mg of the title compound was obtained as a brown foam. NMR spectrum (CDCl_Three) δppm: 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-dimethoate)
Xyphenyl)-(1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenylamino]- 3-sh
Clobutene-1,2-dione 3-methoxy-4- [3-((3,4-dimethoxyfe
Nyl)-(1- (3,4-difluorophenyl) ethyl
Amino) methyl) phenylamino] -3-cyclobutene
Dissolve 450 mg of -1,2-dione in 5 ml of ethanol
And add 1 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d), and the title compound was converted to yellow.
298 mg were obtained as a colored solid. NMR spectrum (DMSO-d₆) δppm: 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-dimethoxy)
Cyphenyl)-(1- (3,4-difluorophenyl)
Ethylamino) methyl) phenylamino] -3 -Cyclo
Butene-1,2-dione hydrochloride 3-amino-4- [3-((3,4-dimethoxyphenyl)
)-(1- (3,4-difluorophenyl) ethyla
Mino) methyl) phenylamino] -3-cyclobutene-
Dissolve 145 mg of 1,2-dione in 5 ml of ethyl acetate
Then, add 1 ml of 4N hydrogen chloride-ethyl acetate solution and add 15 ml.
For a minute. The precipitated solid product is collected by filtration and
155m and the title compound as a pale yellow solid (155m).
g was obtained. NMR spectrum (DMSO-d₆) δppm: 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. Example 263-amino-4- [3-((4-fluorophenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene -1,2
-Dione (Exemplary Compound No. 2-1299) (26a) N-[(3-nitrophenyl)-(4-fur
Orophenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 2.0 g of 4-fluoro-3'-nitro-benzophenone
And 1- (3,4-difluorophenyl) ethylamine
3.16 g of hydrochloride, 6.82 ml of triethylamine,
1.08 ml of titanium chloride, sodium cyanoborohydride
Example (1) using 2.28 g of aluminum and 0.7 ml of acetic acid.
The reaction was carried out in the same manner as in a) to give the title compound as a yellow oil.
3.03 g was obtained. NMR spectrum (CDCl_Three) δppm: 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) ethylamino) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(4-fluorophenyl
M)]-N- [1- (3,4-difluorophenyl)
(3) Dissolve 3.0 g of ethyl] amine in 50 ml of methanol.
Then, 3.69 g of nickel chloride hexahydrate and hydrogenated hydrogen
Example 1 (15b) using 1.24 g of sodium iodide
Perform the same reaction to separate and purify the isomers of the title compound.
630 mg of (A) as pale yellow oil, isomer (B)
Was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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, 5.5Hz). Isomer (B) NMR spectrum (CDCl_Three) δppm: 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
m).(26c) 3-methoxy-4- [3-((4-fluoro
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-[(4-fluorophenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
520 mg of the isomer of amine (A) in 20 ml of methanol
Dissolve, 3,4-dimethoxy-3-cyclobutene-1,
As in Example (1c) using 174 mg of 2-dione
The reaction is carried out to give the isomer (A) of the title compound as a colorless foam
650 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 3-[(4-fluorophenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
550 mg of the isomer (B) of min in 20 ml of methanol
Dissolve, 3,4-dimethoxy-3-cyclobutene-1,
As in Example (1c) using 439 mg of 2-dione
To give the isomer (B) of the title compound as a colorless foam
670 mg were obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-fluorofuran
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-ci Clobute
N-1,2-dione 3-methoxy-4- [3-((4-fluorophenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) Ethyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione isomer (A)
Dissolve in 20 ml, 2N ammonia-ethanol solution
5 ml was added, and the reaction was carried out in the same manner as in Example (1d).
366 m of the title compound isomer (A) as a pale yellow solid.
g was obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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 [deg.] C 3-methoxy-4- [3-((4-fluorophenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione isomer (B)
Dissolve in 20 ml, 2N ammonia-ethanol solution
5 ml was added, and the reaction was carried out in the same manner as in 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-d₆) δppm: 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. Example 273-amino-4- [3- (3-methoxyphenyl-
((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1 , 2-dione (Exemplary Compound No. 2-802) (27a) N-[(3-nitrophenyl)-(3-meth
[Xyphenyl) methyl] -N-[(S) -1- (3-full
Orophenyl) ethyl] amine 2.0 g of 3-methoxy-3'-nitro-benzophenone
And (S) -1- (3-fluorophenyl) ethylamine
2.73 g of the hydrochloride, 6.50 ml of triethylamine,
1.03 ml of titanium tetrachloride, borohydride cyanate
Example using 2.15 g of lithium and 0.67 ml of acetic acid
The reaction was carried out in the same manner as in (1a) to give the title compound as a yellow oil.
2.93 g was obtained as a product. NMR spectrum (CDCl_Three) δppm: 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) ethylamino) methyl]
Phenylamine N-[(3-nitrophenyl)-(3-methoxyphenyl
M)]-N-[(S) -1- (3-fluorophenyl)
2.79 g of ethyl) amine in 50 ml of methanol
3.49 g of nickel chloride hexahydrate dissolved and hydrogenated
Example (1b) using 1.17 g of sodium boron
After conducting the reaction in the same manner, the residue was subjected to silica gel column chromatography.
Chromatography (elution solvent: toluene / ethyl acetate = 8 /
1-5 / 1) and reverse layer medium pressure
Chromatography [elution solvent: acetonitrile / acetic acid buffer
Water solution (water: acetic acid: triethylamine = 1000: 2: 2)
= 35/65] and isomers of the title compound
700 mg of (A) as a yellow oil, isomer (B)
220 mg were obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-methoxy
Phenyl)-((S) -1- (3-fluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione 3-[(3-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenyl
640 mg of amine isomer (A) in 20 ml of methanol
Dissolved in 3,4-dimethoxy-3-cyclobutene-
Same as Example (1c) using 519 mg of 1,2-dione
The title compound was converted to pale yellow foam by 8
00 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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] phenyl
Amine isomer (B) (210 mg) in methanol (10 ml)
And dissolved in 3,4-dimethoxy-3-cyclobutene-1,2
-Using 170 mg of dione as in Example (1c)
The title compound was converted to a pale yellow foam by 267 m
g was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-((S) -1- (3-fluorophenyl) e
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-methoxy-4- [3-((3-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamido
No) 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
l, and the reaction was carried out in the same manner as in Example (1d).
147 mg of the compound isomer (A) was obtained as a yellow solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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: 155-156 ° C Optical rotation: [α]_D: +13.2 (c = 0.5, EtO
H) 3-Methoxy-4- [3-((3-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
200 mg of 1,2-dione isomer (B)
Dissolve in 10 ml, 2N ammonia-ethanol solution
1 ml was added, and the reaction was carried out in the same manner as in Example (1d).
158 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 282- [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)
Enyl) ethylamino) methyl) phenylamino] -3
-Isomer of cyclobutene-1,2-dione (A) 200
mg, 2-aminoethanesulfonic acid 109 mg and
0.12 ml of liethylamine is added to 5 ml of ethanol-water 2
The resulting mixture was dissolved in a 1 ml mixed solution and stirred at room temperature for 1 hour. Reaction solution
Diluted with ethyl acetate and saturated aqueous sodium bicarbonate,
After washing with saturated saline, dry over anhydrous magnesium sulfate
The solvent was distilled off under reduced pressure. The residue is triturated with diethyl ether.
And dried to give 40% sodium salt of the title compound.
130 mg were obtained as a yellow solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 293-amino-4- [3- (2-methoxyphenyl-
((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1 , 2-dione (Exemplary Compound No. 2-797) (29a) N-[(3-nitrophenyl)-(2-meth
[Xyphenyl) methyl] -N-[(S) -1- (3-full
Orophenyl) ethyl] amine 2.0 g of 2-methoxy-3'-nitro-benzophenone
And (S) -1- (3-fluorophenyl) ethylamine
2.73 g of the hydrochloride, 6.50 ml of triethylamine,
1.03 ml of titanium tetrachloride, borohydride cyanate
Performed using 2.15 g of lithium and 0.67 ml of acetic acid
Reaction was carried out in the same manner as in Example (1a) to give the title compound as a yellow oil.
3.10 g was obtained as a product. NMR spectrum (CDCl_Three) δppm: 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) -ethylamino) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(2-methoxyphenyl
M)]-N-[(S) -1- (3-fluorophenyl)
2.) Ethyl] amine 2.96 g in methanol 50 ml
3.70 g of nickel chloride hexahydrate dissolved and hydrogenated
Example (1b) using 1.24 g of sodium boron
The reaction was performed similarly. The crude product was subjected to reverse phase HPLC [elution
Agent: acetonitrile / acetate buffer aqueous solution (water: acetic acid: tri
Ethylamine = 1000: 2: 2) = 40/60]
To give the isomer (A) of the title compound as a yellow oil in the form of 5
40 mg, 800 mg of isomer (B) as a yellow oil
Obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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-methoxy
Phenyl)-((S) -1- (3-fluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
Butene-1,2-dione 3-[(2-methoxyphenyl)-((S) -1- (3
-Fluorophenyl) ethylamino) methyl] phenyl
400 mg of amine isomer (A) in 10 ml of methanol
Dissolved in 3,4-dimethoxy-3-cyclobutene-
Same as Example (1c) using 324 mg of 1,2-dione
The isomer (A) of the title compound was converted to pale yellow
470 mg was obtained as an oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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] phenyl
730 mg of amine isomer (B) in 10 ml of methanol
Dissolved in 3,4-dimethoxy-3-cyclobutene-
Same as Example (1c) using 592 mg of 1,2-dione
The isomer (B) of the title compound was converted to pale yellow
850 mg were obtained as a foam. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-((S) -1- (3-fluorophenyl) e
Tylamino) methyl) phenylamino] -3-cyclobut
Ten-1,2-dione 3-methoxy-4- [3-((2-methoxyphenyl)
-((S) -1- (3-fluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
390 mg of 1,2-dione isomer (A)
Dissolve in 10 ml, 2N ammonia-ethanol solution
2 ml was added, and the reaction was carried out in the same manner as in Example (1d).
323 mg of isomer (A) of the title compound as a yellow solid
Obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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 =
7.2Hz). 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) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
300 mg of 1,2-dione isomer (B)
Dissolve in 10 ml, 2N ammonia-ethanol solution
2 ml was added, and the reaction was carried out in the same manner as in Example (1d).
235 mg of isomer (B) of the title compound as a yellow solid
Obtained. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 303-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-metho
[Xyphenyl) methyl] -N-((R) -1-cyclo
Xylethyl) amine 2.0 g of 4-methoxy-3'-nitro-benzophenone
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, as in Example (1a)
The reaction was carried out to give 2.68 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-((R)
-1-cyclohexylethylamino) methyl] phenyl
Amine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N-((R) -1-cyclohexylethyl
B) Dissolve 2.60 g of amine in 50 ml of methanol,
3.35 g of nickel chloride hexahydrate and sodium borohydride
The same procedure as in Example (1b) was carried out using 1.12 g of thorium.
1.83 g of the title compound as a colorless oil.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-((R) -1-cyclohexylethylamido
No) methyl) phenylamino] -3-cyclobut Ten
1,2-dione 3- [4-methoxyphenyl)-((R) -1-cyclo
[Hexylethylamino) methyl] phenylamine 1.6
5 g was dissolved in 50 ml of methanol to give 3,4-dimethoxy.
1.39 g of c-3-cyclobutene-1,2-dione
And reacting in the same manner as in Example (1c) to give the title compound
Was obtained as a colorless foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-((R) -1-cyclohexylethylamido
No) methyl) phenylamino] -3-cyclobute N-
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-((R) -1-cyclohexylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
Dissolve 500mg in 20ml of ethanol and add 2N
Example 5 (1) was added with 5 ml of an ammonia-ethanol solution.
The reaction was carried out in the same manner as in d) to give the title compound as a yellow solid.
412 mg were obtained. NMR spectrum (DMSO-d₆) δppm: 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). Example 313-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-metho
[Xyphenyl) methyl] -N-((S) -1-cyclo
Xylethyl) amine 2.0 g of 4-methoxy-3'-nitro-benzophenone
And 2.4 of (S) -1-cyclohexyl-ethylamine
4 g, triethylamine 4.33 ml, titanium tetrachloride
1.03 ml, sodium borohydride 2.1
As in Example (1a) using 5 g and 0.67 ml of acetic acid
To give 2.73 of the title compound as a yellow oil.
g was obtained. NMR spectrum (CDCl_Three) δppm: 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] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N-((S) -1-cyclohexylethyl
(2) Dissolve 2.63 g of amine in 50 ml of methanol,
3.39 g of nickel chloride hexahydrate and sodium borohydride
The same procedure as in Example (1b) was carried out using 1.14 g of thorium.
And 2.42 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-((S) -1-cyclohexylethylamido
No) methyl) phenylamino] -3-cyclobut Ten
1,2-dione 3-[(4-methoxyphenyl)-((S) -1-cycl
Rohexylethylamino) methyl] phenylamine
35 g was dissolved in 50 ml of methanol, and
1.13 g of xy-3-cyclobutene-1,2-dione
And the reaction was carried out in the same manner as in Example (1c).
1.01 g of the compound was obtained as a yellow foam. NMR spectrum (CDCl_Three) δppm: 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-methoxyphen)
Nyl-((S) -1-cyclohexylethylamino) meth
Tyl) phenylamino] -3-cyclobutene- 1,2-
Zeon 3-methoxy-4- [3-((4-methoxyphenyl)
-((S) -1-cyclohexylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
Dissolve 960mg in 20ml of ethanol and add 2N
Example 5 (1) was added with 5 ml of an ammonia-ethanol solution.
The reaction was carried out in the same manner as in d) to give the title compound as a yellow solid.
780 mg were obtained. NMR spectrum (DMSO-d₆) δppm: 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). Example 323-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 3.0 g of cyclohexyl-3-nitrophenyl ketone,
1- (3,4-difluorophenyl) ethylamine salt
Acid salt 4.98 g, triethylamine 10.8 ml, tetrasalt
1.70 ml of titanium chloride, 6.11 of nickel chloride hexahydrate
g and 2.05 g of sodium borohydride
The reaction was carried out in the same manner as in Example (25a), and the title compound was converted to yellow.
1.59 g were obtained as an oil. NMR spectrum (CDCl_Three) δppm: 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-((cyclohexy
Ru- (1- (3,4-difluorophenyl) ethylami
No) methyl) phenylamino] -3-cyclobut Ten
1,2-dione 3- [cyclohexyl- (1- (3,4-difluorophenyl)
Enyl) ethylamino) -methyl] phenylamine 50
0 mg was dissolved in 50 ml of methanol, and
413 mg of xy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using the title compound
Was obtained as a yellow foam. NMR spectrum (CDCl_Three) δppm: 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- (cyclohexyl-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene -1,2
-Zeon 3-methoxy-4- [3- (cyclohexyl- (1-
(3,4-difluorophenyl) ethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1,2-di
Dissolve 300mg in 10ml of ethanol and add 2N
2 ml of an ammonia-ethanol solution was added, and Example (1) was added.
The reaction was carried out in the same manner as in d) to give the title compound as a yellow solid.
230 mg were obtained. NMR spectrum (DMSO-d₆) δppm: 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. Example 333-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-metho
[Xyphenyl) methyl] -N- [1- (4-acetylo
Xyphenyl) ethyl] amine 4-methoxy-3'-nitrobenzophenone 500mg
And acetic acid 4- (1-aminoethyl) phenyl ester
Hydrochloride 1.0 g, triethylamine 1.63 ml, tetrasalt
0.26 ml titanium hydride, sodium borohydride cyanide
Example (1) using 543 mg
The reaction was carried out in the same manner as in a) to convert the title compound into a yellow oil.
215 mg were obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-(1-
(4-acetyloxyphenyl) ethylamino) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
L) methyl] -N- [1- (4-acetyloxyphenyl)
L) Ethyl] amine 200mg in ethanol 10ml
After dissolution, 451 mg of tin chloride 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 mixture.
In addition, the precipitated insolubles were separated by filtration. Separate the organic layer of the filtrate
After separation, the aqueous layer was extracted with ethyl acetate. Combined organic layers
Wash with saturated saline, dry over anhydrous magnesium sulfate and dissolve
The solvent was distilled off under reduced pressure to give the title compound as a yellow oil.
0 mg was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (4-acetyloxyphenyl) d
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-[(4-methoxyphenyl)-(1- (4-acetyl
Ruoxyphenyl) ethylamino) methyl] phenyla
Dissolve 160 mg of min in 5 ml of methanol and add 3,4
-Dimethoxy-3-cyclobutene-1,2-dione 11
The reaction was carried out in the same manner as in Example (1c) using 6 mg,
172 mg of the title compound was obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (4-hydroxyphenyl) ethyla
Mino) methyl) phenylamino] -3-cyclo Butene
1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (4-acetyloxyphenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
Dissolve 160 mg of 1,2-dione in 5 ml of ethanol
And add 2 ml of 2N ammonia-ethanol solution,
Stirred overnight at room temperature. The solvent is distilled off under reduced pressure.
Powdered with a mixed solvent of tyl ether and ethyl acetate and collected by filtration
The solid was washed with diethyl ether to remove the title compound
115 mg were obtained as a colored solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 343-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-metho
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] ether 1- (3,4-difluorophenyl) ethyl alcohol
920 mg and 4-methoxy-3'-nitro-diphenyl
Dissolve 151 mg of methanol in 50 ml of anhydrous benzene.
And add methyltrioxorhenium (VII) 29mg.
The reaction was carried out at room temperature for 3 days and further with heating under reflux for 4 hours. Dissolution
After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography.
Chromatography (elution solvent: cyclohexane / ethyl acetate
= 10/1 to 8/1) to give the title compound as a yellow oil
160 mg was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethyloxy) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
M)]-N- [1- (3,4-difluorophenyl)
L) Ethyl] ether 150mg in methanol 10ml
179 mg of nickel chloride hexahydrate and hydrogen
Example (1b) using 60 mg of sodium borohydride
The reaction was carried out in the same manner to give the title compound as a yellow oil.
25 mg were obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tyloxy) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-[(4-methoxyphenyl)-(1- (3,4-di
Fluorophenyl) ethyloxy) methyl] phenyla
Dissolve 115 mg of min in 10 ml of methanol, and add
-Dimethoxy-3-cyclobutene-1,2-dione 8
The reaction was carried out in the same manner as in Example (1c) using 8.5 mg.
This gave 135 mg of the title compound as a yellow foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruoxy) methyl) phenylamino] -3-ci Clobute
N-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethyloxy
C) methyl) phenylamino] -3-cyclobutene-
Dissolve 130 mg of 1,2-dione in 5 ml of ethanol
And add 1 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d), and the title compound was converted to yellow.
104 mg were obtained as a colored solid. NMR spectrum (DMSO-d₆) 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. Example 353-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-1359) (35a) N-[(3-nitrophenyl)-(4-metho
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 6.40 g of 3-nitro-4'-methoxybenzophenone
And 1- (3,4-difluorophenyl) ethylamine salt
8.71 g of acid salt were added to 120 ml of anhydrous dichloromethane,
Dissolved in 17.3 ml of ethylamine. Cool the reaction solution with ice
And 3.0 ml of titanium tetrachloride in anhydrous dichloromethane 30
After slowly adding the diluted solution, the mixture is stirred at room temperature for 1 hour.
did. Aqueous sodium bicarbonate solution and ethyl acetate
, And the precipitated insoluble matter is removed by filtration through Celite.
Was. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate.
Was. The combined organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
After drying with thorium, the solvent is concentrated under reduced pressure to give the imine compound.
The product was obtained as a dark brown oil (10.7 g). The resulting oil
Is dissolved in 80 ml of methanol, and boron cyanide hydride is dissolved.
6.28 g of sodium and 2.1 ml of acetic acid are added, and
The mixture was refluxed while heating. The solvent of the reaction solution is concentrated under reduced pressure, and the residue is removed.
Neutralize with aqueous sodium bicarbonate and then with ethyl acetate three times
Extracted. The ethyl acetate layer was washed with saturated saline,
After drying over magnesium acid, the solvent was distilled off under reduced pressure. Residue
To silica gel column chromatography (eluent solvent
Sun / ethyl acetate = 8/1) to give the title compound
7.17 g of a stereomeric mixture was obtained as a yellow oil.
Was. NMR spectrum (CDCl_Three) δppm: 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
h s), 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) ethylamino) methyl
Ru] phenylamine N-[(3-nitrophenyl)-(4-methoxyphenyl
Ru) methyl] -N- [1- (3,4-difluorophenyl)
6.84 g of ethyl) amine in 140 ml of methanol
Dissolved, 8.26 g of nickel chloride hexahydrate, borohydride
2.60 g of sodium hydrogen chloride was added, and the same as in Example (15b) was performed.
And purify it to give the less polar isomer of the title compound.
2.35 g of (A) as a pale yellow oil, highly polar isomer
3.16 g of (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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 = 8.6Hz). Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-[(4-methoxyphenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
Dissolve 252 mg of the isomer of amine (A) in 8 ml of methanol.
Understand that 3,4-dimethoxy-3-cyclobutene-1,2
-Dione (194 mg) was added and the reaction was carried out
To give the isomer (A) of the title compound as a white foam.
Thus, 301 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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-di
Fluorophenyl) ethylamino) methyl] phenyla
247 mg of isomer (B) of min in 10 ml of methanol
Dissolve, 3,4-dimethoxy-3-cyclobutene-1,
190 mg of 2-dione was added, and the same as in Example (1c).
The reaction was carried out to give the isomer (B) of the title compound as a white foam.
259 mg was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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). Example 363- (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-difluorophene)
Nyl) 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 ethanol solution was added, and the same as in Example (1d).
The reaction was carried out in the same manner, and
g was obtained. NMR spectrum (DMSO-d₆) δppm: 1.26 (3H,
d, J = 6.5Hz), 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 =
8.4Hz). Example 373- (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-difluorophene)
Nyl) ethylamino) methyl) phenylamino] -3-
Isomer of cyclobutene-1,2-dione (B) 181m
g in 8 ml of ethanol and 2N dimethylamine
-2.5 ml of a methanol solution are added, as in Example (1d)
The reaction was carried out in the same manner, and the title compound was converted into a white solid by 143.
mg. NMR spectrum (DMSO-d₆) δppm: 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. Example 383-amino-4- [N- (3-((4-methoxyphenyl
)-(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
Ru) phenyl] carbamic acid methyl ester 3-[(4-methoxyphenyl)-of Example (35b)
(1- (3,4-difluorophenyl) ethylamino)
Methyl] phenylamine with N, N-dimethylacetamide
Dissolve in 10 ml and add 1.1 ml of methyl chloroformate under ice-cooling
Was added dropwise, followed by stirring for 1 hour. Hydrogen carbonate
An aqueous thorium solution was added, and the aqueous layer was extracted three times with ethyl acetate.
Was. The ethyl acetate layer was washed with water and saturated saline, and then dried.
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. Residue
To silica gel column chromatography (eluent:
(Xan / ethyl acetate = 4/1) to give the title compound
563 mg were obtained as a colored oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Lamino) methyl) phenyl] amine [3-((4-methoxyphenyl)-(1- (3,4-
Difluorophenyl) ethylamino) methyl) phenyl
Carbamic acid methyl ester (560 mg)
Dissolved in 15 ml of lahydrofuran, aluminum hydride
250 mg of lithium was added and the mixture was heated under reflux for 4 hours. below freezing
After adding 4.0 g of sodium sulfate decahydrate, the insoluble matter was added.
Was filtered through Celite. Dry the filtrate over anhydrous sodium sulfate
The solvent was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
Matography (elution solvent: hexane / ethyl acetate = 4
/ 1) to give 215m of the title compound as a yellow oil.
g was obtained. NMR spectrum (CDCl_Three) δppm: 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-N- (3
-((4-methoxyphenyl)-(1- (3,4-diph
Fluorophenyl) ethylamino) methyl) -f Henil)
Amino] -3-cyclobutene-1,2-dione N- [3-((4-methoxyphenyl)-(1- (3,
4-difluorophenyl) ethylamino) methyl) fe
Nyl] -N-methylamine in 210 mg of methanol
dissolved in 3,4-dimethoxy-3-cyclobutene
117 mg of -1,2-dione were added, and the same as in Example (1c).
The reaction was carried out in the same manner to give the title compound as a white foam.
92 mg were obtained. NMR spectrum (CDCl_Three) δppm: 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-meth
Xyphenyl)-(1- (3,4-difluorophenyl)
Ru) ethylamino) methyl) phenyl) -N-meth Chilua
Mino] -3-cyclobutene-1,2-dione 3-methoxy-4- [N-methyl-N- (3-((4-
Methoxyphenyl)-(1- (3,4-difluorophene)
Nyl) ethylamino) methyl) phenyl) amino] -3
188 mg of cyclobutene-1,2-dione in ethanol
Dissolved in 6 ml of 2N ammonia-ethanol solution
2 ml was added, and the reaction was carried out in the same manner as in Example (1d).
140 mg of the title compound were obtained as a yellow solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 393-amino-4- [4-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) -phenylamino] -3-cyclobutene-1,
2-dione (Exemplary Compound No. 3-208) (39a) N-[(4-nitrophenyl)-(4-metho
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 4-nitro-4'-methoxybenzophenone 2.13
g, 1- (3,4-difluorophenyl) ethylamine
2.90 g of hydrochloride, 5.8 ml of triethylamine, tetrasalt
1.0 ml titanium hydride, sodium cyanoborohydride
Using 2.09 g and 0.7 ml of acetic acid, Example (1a)
Perform the same reaction to give the title compound as a pale yellow oil.
3.21 g were obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
Ru] phenylamine N-[(4-nitrophenyl)-(4-methoxyphenyl
M)]-N- [1- (3,4-difluorophenyl)
3.20 g of ethyl] amine are dissolved in 60 ml of methanol.
, 3.82 g of nickel chloride hexahydrate, borohydride
As in Example (1b), using 1.21 g of sodium
React and purify the product, low-polar isomer (A) of the title compound
As a pale yellow oil, 720 mg, highly polar isomer (B)
Was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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
= 8.6Hz). Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 4-[(4-methoxyphenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
710 mg of the isomer of amine (A) in 15 ml of methanol
Dissolve, 3,4-dimethoxy-3-cyclobutene-1,
Add 410 mg of 2-dione and proceed as in Example (1c).
The reaction was carried out to give the isomer (A) of the title compound as a colorless oil
597 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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). 4-[(4-methoxyphenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
790 mg of the isomer (B) of min in 15 ml of methanol
Dissolve, 3,4-dimethoxy-3-cyclobutene-1,
456 mg of 2-dione was added, and the same as in Example (1c).
The reaction was performed to convert the isomer (B) of the title compound into a white solid.
480 mg was obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-ci Clobute
N-1,2-dione 3-methoxy-4- [4-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
570 mg of 1,2-dione isomer (A)
Dissolve in 5 ml, 2N ammonia-ethanol solution
1.5 ml was added and the reaction was carried out in the same manner as in Example (1d).
To give the isomer (A) of the title compound as a pale yellow solid.
6 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
390 mg of 1,2-dione isomer (B) was added to ethanol
Dissolved in 5 ml of 2N ammonia-ethanol solution 5
ml, and the reaction was carried out in the same manner as in Example (1d).
298 mg of isomer (B) of the title compound was obtained as a white solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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). Example 403-amino-4- [2-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione (Exemplary Compound No. 1-86) (40a) 2-[(4-methoxyphenyl)-(1-
(3,4-difluorophenyl) ethylamino) methyl
Ru] phenylamine 2-amino-4'-methoxybenzophenone 2.12
g, 1- (3,4-difluorophenyl) ethylamine
3.60 g of hydrochloride, 7.8 ml of triethylamine, tetrasalt
1.1 ml titanium hydride, sodium cyanoborohydride
Using 2.34 g and 0.8 ml of acetic acid, Example (1a)
Perform a similar reaction to mix the diastereomers of the title compound.
The product was obtained as a colorless oil (2.05 g). NMR spectrum (CDCl_Three) δppm: 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
h s), 6.59-7.24 (9H, m), 6.84 and 6.92 (total 2H, d,
 J = 8.6Hz).(40b) 3-methoxy-4- [2-((4-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 2-[(4-methoxyphenyl)-(1- (3,4-di
Fluorophenyl) ethylamino) methyl] phenyla
Dissolve 1.30 g of min in 20 ml of methanol, and add
-Dimethoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c).
The diastereomer mixture of the title compound as a white solid 9
52 mg were obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-ci Clobute
N-1,2-dione 3-methoxy-4- [2-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) phenylamino] -3-cyclobutene-
Dissolve 305 mg of 1,2-dione in 6 ml of methylene chloride
And add 3 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d) to give the title compound
Obtain 204 mg of the stereomeric mixture as a pale yellow solid
Was. NMR spectrum (DMSO-d₆) δppm: 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). Example 413-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) benzylamino] -3-cyclobutene-1,2
-Dione (Exemplary Compound No. 2-2027) (41a) N-[(3-cyanophenyl)-(4-metho
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 1.40 g of 3-cyano-4'-methoxybenzophenone
And 1- (3,4-difluorophenyl) ethylamine salt
1.83 g of acid salt, 4.1 ml of triethylamine, tetrachloride
0.7 ml of titanium, sodium cyanoborohydride
Example 1. Using 1.49 g and 0.5 ml of acetic acid,
Perform a similar reaction to obtain a mixture of diastereomers of the title compound.
The compound was obtained as a pale yellow oil (2.16 g). NMR spectrum (CDCl_Three) δppm: 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-phenyl)-
(4-methoxyphenyl) methyl] -N- [1- (3,
4-difluorophenyl) ethyl] amine N-[(3-cyanophenyl)-(4-methoxyphenyl
M)]-N- [1- (3,4-difluorophenyl)
1.65 g of ethyl) amine
Dissolved in 20 ml of 1N aluminum hydride under ice-cooling.
15ml of lithium / tetrahydrofuran solution
Then, the mixture was stirred at room temperature for 4 hours. Add sodium sulfate to the reaction solution.
15 g of uranium decahydrate was added, and the insoluble matter was filtered through Celite.
The filtrate was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
Matography (elution solvent: methylene chloride / methanol
= 20/1), diastereomer of the title compound
1.59 g of the mixture was obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) benzylamino] -3- Cyclob
Ten-1,2-dione N-[(3-aminomethylphenyl)-(4-methoxy
Phenyl) methyl] -N- [1- (3,4-difluoro
Phenyl) ethyl] amine (290 mg)
1,4-dimethoxy-3-cyclobutene-
216 mg of 1,2-dione was added and the same as in Example (1c).
Reaction as described above, diastereomer mixture of the title compound
272 mg of the product was obtained as a colorless oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) -e
Tylamino) methyl) benzylamino] -3- Cyclob
Ten-1,2-dione 3-methoxy-4- [3-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) benzylamino] -3-cyclobutene-
Dissolve 268 mg of 1,2-dione in 4 ml of ethanol
And add 4 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d) to give the title compound
160 mg of the stereoisomeric mixture was obtained as a white solid.
Was. NMR spectrum (DMSO-d₆) δppm: 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. Example 423- (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-difluorophene)
Nyl) ethylamino) methyl) benzylamino] -3-
300 mg of cyclobutene-1,2-dione in methanol
Dissolve in 5 ml, 2N methylamine-methanol solution
5 ml was added, and the reaction was carried out in the same manner as in Example (1d).
Diastereomeric mixture of the title compound as a white solid
190 mg were obtained. NMR spectrum (DMSO-d₆) δppm: 1.26 (3H, d, J = 6.0
Hz), 3.11 (3H, s), 3.42-3.53 (1H, m), 3.68 and 3.72
(total 3H, 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. Example 433-amino-4- [4-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) benzylamino] -3-cyclobutene-1,2
-Dione (Exemplary Compound No. 3-292) (43a) N-[(4-cyanophenyl)-(4-metho
[Xyphenyl) methyl] -N- [1- (3,4-difur
Orophenyl) ethyl] amine 1.18 g of 4-cyano-4'-methoxybenzophenone
And 1- (3,4-difluorophenyl) ethylamine salt
Acid salt 1.54 g, triethylamine 3.6 ml, tetrachloride
0.4ml titanium, sodium cyanoborohydride
Using 1.25 g and 0.4 ml of acetic acid, Example (1a)
Perform a similar reaction to obtain a mixture of diastereomers of the title compound.
1.76 g of the compound was obtained as a colorless oil. NMR spectrum (CDCl_Three) δppm: 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
h s), 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-phenyl)-
(4-methoxyphenyl) methyl] -N- [1- (3,
4-difluorophenyl) ethyl] amine dihydrochloride N-[(4-cyanophenyl)-(4-methoxyphenyl
M)]-N- [1- (3,4-difluorophenyl)
1.74 g of ethyl) amine
Aluminum hydride under ice-cooling.
700 mg was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution
Add 10 g of sodium sulfate decahydrate and remove insolubles
The filtrate was concentrated under reduced pressure. A small amount of residue
Dissolve in Teru, add 3 ml of 4N hydrochloric acid / ethyl acetate,
The resulting precipitate was collected by filtration. Wash the solid with ether and dry
To give the diastereomer mixture of the title compound as a white solid.
2.01 g was obtained. NMR spectrum (DMSO-d₆) δppm: 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-methoxy
Phenyl)-(1- (3,4-difluorophenyl) e
Tylamino) methyl) benzylamino] -3- Cyclob
Ten-1,2-dione N-[(4-aminomethylphenyl)-(4-methoxy
Phenyl) methyl] -N- [1- (3,4-difluoro
Phenyl) ethyl] amine dihydrochloride
Add 5 ml of aqueous sodium hydroxide solution and add ethyl acetate.
Extracted. The ethyl acetate layer was washed with saturated saline,
After drying over sodium acid, the solvent was concentrated under reduced pressure. Got
Dissolve 670 mg of yellow oil in 15 ml of methanol
3,4-dimethoxy-3-cyclobutene-1,2-
332 mg of dione was added and reacted in the same manner as in Example (1c).
To give a diastereomer mixture of the title compound in white
615 mg were obtained as a foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Lamino) methyl) benzylamino] -3-si Clobute
N-1,2-dione 3-methoxy-4- [4-((4-methoxyphenyl)
-(1- (3,4-difluorophenyl) ethylamido
No) methyl) benzylamino] -3-cyclobutene-
Dissolve 608 mg of 1,2-dione in 6 ml of ethanol
And add 4 ml of 2N ammonia-ethanol solution,
The reaction was carried out in the same manner as in Example (1d) to give the title compound
Obtain 450 mg of the stereoisomeric mixture as a pale yellow solid
Was. NMR spectrum (DMSO-d₆) δppm: 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
h s), 7.19 and 7.23 (total 2H, each d, J = 8.1Hz), 6.
93-7.82 (9H, m). Melting point: 220-225 ° C. Example 44N- [3- (2-amino-3,4-dioxo-1-cycl)
Lobutenylamino) 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.
531 mg of -3-cyclobutene-1,2-dione at room temperature
Added in. After the reaction solution was stirred at 50 ° C. for 1 hour, the solvent was removed.
The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography.
Fee (elution solvent: methylene chloride / ethyl acetate = 1/1)
And purified the title compound as a yellow solid. 589
mg. NMR spectrum (DMSO-d₆) δppm: 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,
d, J = 8.7Hz).(44b) N- [3- (2-methoxy-3,4-dioxy)
So-1-cyclobutenylamino) phenyl] -N- (4
-Methoxyphenyl) -2-phenylpropio Namid 900 mg of 2-phenylpropionic acid was added to methylene chloride 1
0 ml, oxalic acid chloride 0.8 ml, N, N
Add 1 drop of dimethylformamide and stir at room temperature for 2 hours
did. The yellow oil obtained after concentration under reduced pressure was N, N-dimethyl
Dissolve in 4 ml of luacetamide and add 3-methoxy-4- [3
-(4-methoxyphenylamino) phenyl] amino-
576 mg of 3-cyclobutene-1,2-dione N, N
-Add 4 ml of dimethylacetamide solution under ice-cooling, and add
Stir for 3 hours. Add saturated aqueous sodium bicarbonate
After that, the mixture was extracted with ethyl acetate. The ethyl acetate layer with water and
After washing with saturated saline and drying over anhydrous sodium sulfate, reduce
It was concentrated under reduced pressure. Silica gel column chromatography of the residue
-(Elution solvent: methylene chloride / ethyl acetate = 2/1)
Separation and purification gave 603 mg of the title compound as a purple foam.
Was. NMR spectrum (CDCl_Three) δppm: 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-phenylpropiona Mid N- [3- (2-methoxy-3,4-dioxo-1-cy)
Clobutenylamino) phenyl] -N- (4-methoxy
Phenyl) -2-phenylpropionamide 600 mg
Dissolve in 4 ml of ethanol and add 2N ammonia-ethanol
6 ml of the reaction solution was added, and the reaction was carried out in the same manner as in Example (1d).
This gave 521 mg of the title compound as a yellow solid. NMR spectrum (CDCl_Three) δppm: 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. Example 453-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]
Amine 2.57 g of 3-nitro-4'-methoxybenzophenone
And 2.35 g of 3-fluorobenzylamine
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted into a yellow oil.
3.29 g was obtained as a product. NMR spectrum (CDCl_Three) δppm: 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-fluorobenzylamino)-
(4-methoxyphenyl) methyl] phenylamine (3-fluoro-benzyl)-[(4-methoxyphenyl
) -3- (nitrophenyl) methyl] amine 3.27
The reaction was carried out in the same manner as in Example (1b) using
The compound was obtained as a pale yellow oil (2.74 g). NMR spectrum (CDCl_Three) δppm: 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-fluorobenzylamido
No)-(4-methoxyphenyl) methyl) phenylamido
No] -4-methoxy-3-cyclobutene-1,2 -Geo
In 3-[(3-fluorobenzylamino)-(4-methoxy
[Ciphenyl) methyl] phenylamine (409 mg) and 3,
4-dimethoxy-3-cyclobutene-1,2-dione 1
The reaction was carried out in the same manner as in Example (1c) using 73 mg,
490 mg of the title compound was obtained as a pale yellow oil. NMR spectrum (CDCl_Three) δppm: 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-fluoro
Benzylamino)-(4-methoxyphenyl) methyl)
Enylamino] -3-cyclobutene-1,2- Zeon 3- [3-((3-fluorobenzylamino)-(4-
Methoxyphenyl) methyl) phenylamino] -4-me
423 mg of tox-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1d) using
This gave 327 mg of the product as a pale yellow solid. Melting point: 209-212 ° C NMR spectrum (DMSO-d₆) δppm: 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). Example 46N-[(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
Enyl) methane (25.8 g) in dimethylformamide 20
0 ml and dissolve 26.1 g of sodium azide under ice-cooling.
The mixture was further stirred for 1 hour. The mixture was further stirred at room temperature for 1 hour.
Thereafter, dimethylformamide was distilled off under reduced pressure. Obtained residue
Water was added to the residue and extracted twice with ethyl acetate. Combined vinegar
The ethyl acid layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
After drying with a solvent, the solvent was distilled off under reduced pressure. Silica gel residue
Ram chromatography (elution solvent: n-hexane / vinegar)
(Ethyl acetate = 6/1), and the title compound was yellow.
18.6 g were obtained as an oil. NMR spectrum (CDCl_Three) δppm: 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-nitrophen
Nyl) 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. Triphenylphos
It was confirmed that the fins had dissolved and the generation of nitrogen had ended
Thereafter, 20 ml of water was added, and the mixture was heated under reflux for 6 hours. Reaction solution
Trahydrofuran is distilled off and the residue is extracted with ethyl acetate.
Was. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
After drying with a solvent, the solvent was distilled off under reduced pressure. Silica gel residue
Ram chromatography (elution solvent: n-hexane / vinegar)
Separation and purification with ethyl acetate = 2/1) to obtain a colorless oil.
Was. The obtained free form was dissolved in 4N hydrogen chloride-ethyl acetate.
Solution, and the solvent is evaporated to dryness.
The title compound was suspended in pill ether and collected by filtration.
13.8 g was obtained. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)-(3-d
Trophenyl) methyl] benzamide Amino- (4-methoxyphenyl)-(3-nitrophen
Nyl) methane 3.12 g of acetonitrile 20
and add 2.95 ml of triethylamine.
And stirred at room temperature for 20 minutes. The reaction solution is cooled on ice and
Dissolve 1.49 g of zonzoyl in 10 ml of acetonitrile
Solution was added dropwise little by little and then at room temperature for 30 minutes
Stirred. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution.
And extracted with ethyl acetate. The obtained organic layer was washed with saturated salt
After washing with water and drying over anhydrous magnesium sulfate, the solvent was reduced.
The pressure was distilled off to obtain a light brown solid. This solid in methanol
Suspended and collected by filtration, washed with ether and dried,
3.29 g of the title compound were obtained as a white solid. NMR spectrum (CDCl_Three) δppm: 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-metho
Xyphenyl) methyl] benzamide hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl
3.24 g of methyl] benzamide in ethanol-concentrated
The mixture was added little by little to the hydrochloric acid (1: 1) mixture at room temperature. Reaction liquid
Is cooled on ice, and 6.78 g of tin (II) chloride is added little by little.
After stirring at room temperature for 20 minutes, the mixture was refluxed for 2 hours. Cooling
Thereafter, the reaction solution was neutralized by adding an aqueous solution of sodium hydroxide,
The precipitated insoluble matter was removed by filtration through Celite. Acetic acid in the filtrate
Extract with ethyl, wash the organic layer with saturated saline,
After drying over magnesium acid, the solvent was distilled off under reduced pressure. The residue
Silica gel column chromatography (elution solvent: n-
Hexane / ethyl acetate = 2/1) Separation and purification, colorless
An oil was obtained. 4N hydrogen chloride-vinegar
Solid obtained by dissolving in ethyl acetate solution and evaporating the solvent to dryness
Was suspended in ether and collected by filtration to give the title compound as a white solid.
2.68 g were obtained as a body. NMR spectrum (DMSO-d₆) δppm: 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-dio
Oxocyclobut-1-enylamino) phenyl)-(4
-Methoxyphenyl) methyl] benzamide N-[(3-aminophenyl)-(4-methoxyphenyl
555 mg of methyl] benzamide hydrochloride
Dissolved in 15 ml of 3,4-dimethoxy-3-cyclyl
428 mg of lobutene-1,2-dione were added at room temperature.
After stirring at room temperature for 10 minutes, 153 mg of triethylamine
Is dissolved in 10 ml of methanol dropwise.
Then, the mixture was stirred at room temperature for 1 hour. 0.5N hydrochloric acid in the reaction solution
In addition, the mixture was made weakly acidic and extracted with ethyl acetate. Bored organic layer
Wash with brine, dry over anhydrous magnesium sulfate, dissolve
The medium was distilled off under reduced pressure. The residue is purified by silica gel column chromatography.
Raffy (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_Three) δppm: 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
So-1-cyclobutenylamino) phenyl)-(4-meth
Toxiphenyl) methyl] benzamide N-[(3- (2-methoxy-3,4-dioxo-cyclic)
Lobut-1-enylamino) phenyl)-(4-methoxy)
Using 489 mg of [cyphenyl) methyl] benzamide
The reaction was carried out in the same manner as in Example (1d), and the title compound was converted to yellow.
301 mg were obtained as a solid. NMR spectrum (DMSO-d₆) δppm: 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). Example 47N-[(3- (2-amino-3,4-dioxo-cyclo
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] -3-fluoro-benzure Mid (example
Compound No. 2-826) (47a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -3-fluorobenzamide Amino- (4-methoxyphenyl)-(3-nitrophen
Nyl) methane hydrochloride (1.50 g) and 3-fluorobe chloride
In the same manner as in Example (46c), using 811 mg of nzoyl
The reaction was carried out, and 1.73 g of the title compound was converted into a white solid.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-metho
Xyphenyl) methyl] -3-fluorobenzamide
Hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl
L) Methyl] -3-fluorobenzamide 617 mg
Dissolve in ethanol (20 ml) and tin (II) chloride 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 solution of sodium hydrogen carbonate was added to the reaction solution to precipitate it.
The insoluble matter thus removed was removed by filtration through Celite. Ethyl acetate was added to the filtrate.
The organic layer was washed with saturated saline and dried over anhydrous sulfuric acid.
After drying with gnesium, the solvent was distilled off under reduced pressure. Obtained residue
A 4N hydrogen chloride-ethyl acetate solution was added to the residue to precipitate.
The solid was collected by filtration, and 468 mg of the title compound was obtained as a white solid.
Obtained. NMR spectrum (DMSO-d₆) δppm: 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-dio
Oxo-cyclobut-1-enylamino) phenyl)-
(4-methoxyphenyl) methyl] -3-fluoro Robben
Zuamide N-[(3-aminophenyl)-(4-methoxyphenyl
Ru) Methyl] -3-fluorobenzamide hydrochloride 24
4 mg and 3,4-dimethoxy-3-cyclobutene-1,
As in Example (46e) using 107 mg of 2-dione
To give 285 mg of the title compound as a white solid.
I got NMR spectrum (CDCl_Three) δppm: 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-dioxo
Socyclobut-1-enylamino) phenyl)-(4-
Methoxyphenyl) methyl] -3-fluorobe Zudami
Do N-[(3- (2-methoxy-3,4-dioxocyclo
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] -3-fluorobenzamide 269
The reaction was carried out in the same manner as in Example (1d) using
230 mg of the compound were obtained as a yellow solid. NMR spectrum (DMSO-d₆) δppm: 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). Example 48N-[(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-d
Trophenyl) methyl] -4-fluorobenzamide Amino- (4-methoxyphenyl)-(3-nitrophen
Nyl) methane hydrochloride (1.51 g) and 4-fluorobe chloride
In the same manner as in Example (46c) using 813 mg of nzoyl
The reaction was carried out, and 1.72 g of the title compound was obtained as a white solid.
Obtained. NMR spectrum (CDCl_Three) δppm: 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-metho
Xyphenyl) methyl] -4-fluorobenzamide
Hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl
L) methyl] -4-fluorobenzamide (1.72 g)
Example (47b) using 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_Three) 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-dio
Oxo-cyclobut-1-enylamino) phenyl)-
(4-methoxyphenyl) methyl] -4-fluoro Robben
Zuamide N-[(3-aminophenyl)-(4-methoxyphenyl
Ru) Methyl] -4-fluorobenzamide hydrochloride 67
4 mg and 3,4-dimethoxy-3-cyclobutene-1,
As in Example (46e) using 250 mg of 2-dione
To give 399 mg of the title compound as a yellow solid.
I got Melting point: 115-116 ° C NMR spectrum (DMSO-d₆) δppm: 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-dioxy
So-cyclobut-1-enylamino) phenyl)-(4
-Methoxyphenyl) methyl] -4-fluoro Benzua
Mid N-[(3- (2-methoxy-3,4-dioxo-cyclic)
Lobut-1-enylamino) phenyl)-(4-methoxy)
[Ciphenyl) methyl] -4-fluorobenzamide 34
The reaction was carried out in the same manner as in Example (1d) using
223 mg of the title compound was obtained as a yellow solid. Melting point: 212-213 ° C (decomposition) NMR spectrum (DMSO-d₆) δppm: 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). Example 493-amino-4- [3- (benzyloxyimino- (4
-Methoxyphenyl) -methyl) phenylamino] -3
-Cyclobutene-1,2-dione (Exemplary Compound No. 5-
4) (49a) (4-methoxyphenyl)-(3-nitroph
Enyl) methanone O-benzyloxime (4-methoxyphenyl)-(3-nitrophenyl) meth
Dissolve 2.44 g of tanone in 40 ml of anhydrous dichloromethane
And 3.02 g of O-benzylhydroxylamine and
Add 7.9 ml of ethylamine and stir for 15 minutes under ice-cooling
did. To the reaction mixture was added 1.51 ml of titanium tetrachloride in anhydrous dichloromethane.
30 ml of methanol solution is slowly added dropwise at room temperature for 1 hour.
While stirring. Saturated aqueous sodium bicarbonate solution
Ethyl acetate was added, and the precipitated insoluble material was filtered through Celite.
Removed. After separating the organic layer of the filtrate, the aqueous layer was ethyl acetate.
Extracted. Wash the combined organic layers with saturated saline
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Remaining
The residue is subjected to silica gel column chromatography (eluent:
n-hexane / ethyl acetate = 9/1).
1.81 g of a pale yellow oil was obtained. Add ethanol to this
And the precipitated solid is collected by filtration to give the title compound
1.54 g of the compound (A) was obtained as a white solid. Concentrate the filtrate
To give isomer (B) a 2: 1 mixture with isomer (A)
Thus, 764 mg was obtained as a pale yellow oil. Isomer (A) Melting point: 100-101 ° C NMR spectrum (CDCl_Three) δppm: 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_Three) δppm: 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)
Enyl) methanone O-benzyloxime (4-methoxyphenyl)-(3-nitrophenyl) meth
Tanone O-benzyl-oxime isomer (A) 974
mg and tin (II) chloride 2.55 g in ethanol 30 ml
Was added and heated under reflux for 1 hour. Ethanol was distilled off
Thereafter, the residue was diluted with ethyl acetate, and the ethyl acetate layer was diluted to 5 N.
Wash with aqueous sodium hydroxide, water and saturated saline
Was. After drying the organic layer over anhydrous magnesium sulfate, the solvent was reduced.
The title compound isomer (A) was converted to a yellow oily substance under reduced pressure.
893 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) δppm: 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) meth
Mixture of isomers (B) of tanone O-benzyl oxime
Using 752 mg and 1.97 g of tin (II) chloride
The reaction was carried out in the same manner as in Example (1b), and the isomer of the title compound was obtained.
(B) as a 2: 1 mixture with isomer (A) to give a yellow oil
623 mg of a product were obtained. Isomer (B) NMR spectrum (CDCl_Three) δppm: 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- (benzyloxyimino- (4-
Methoxyphenyl) -methyl) phenylamino] -4-
Methoxy-3-cyclobutene-1,2-dione (3-aminophenyl)-(4-methoxyphenyl) meth
Isomer of Tanone O-benzyl-oxime (A) 886
mg and 3,4-dimethoxy-3-cyclobutene-1,2
-Using 757 mg of dione as in Example (1c)
To give the isomer (A) of the title compound as a yellow foam.
1.09 g was obtained. Isomer (A) Melting point: 70-71 ° C NMR spectrum (CDCl_Three) δppm: 3.81 (3H, s), 4.35 (3H
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) meth
Mixture of isomers (B) of tanone O-benzyl oxime
593 mg and 3,4-dimethoxy-3-cyclobutene-
Same as Example (1c) using 507 mg of 1,2-dione
And reacting isomer (B) of the title compound with isomer
690 mg of yellow foam as a 2: 1 mixture with (A)
Obtained. Isomer (B) Melting point: 71-72 ° C NMR spectrum (CDCl_Three) δppm: 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- (benzyloxyi
Mino- (4-methoxyphenyl) methyl) phenylami
No] -3-cyclobutene-1,2-dione 3- [3- (benzyloxyimino- (4-methoxyphenyl)
Enyl) methyl) phenylamino] -4-methoxy-3
-Isomer of cyclobutene-1,2-dione (A) 780
The reaction was carried out in the same manner as in Example (1d) using
869 mg of compound isomer (A) was obtained as a yellow solid. Isomer (A) Melting point: 245-248 ° C (decomposition) NMR spectrum (DMSO-d₆) δppm: 3.76 (3H, s), 5.15
(2H, s), 6.90-6.95 (3H, m), 7.22-7.58 (10H, m). 3- [3- (benzyloxyimino- (4-methoxy
Enyl) methyl) phenylamino] -4-methoxy-3
-Blend of isomer (B) of cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1d) using 442 mg of the product.
The isomer (B) of the title compound and the isomer (A)
As one mixture, 190 mg of a yellow foam was obtained. Isomer (B) Melting point: 218-220 ° C NMR spectrum (DMSO-d₆) δppm: 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). Example 50N-[(3- (2-amino-3,4-dioxocyclobu
To-1-enylamino) phenyl)-(4-methoxyphenyl)
Enyl) methyl] -2-phenylpropionamide (eg
Compound number 2-464) (50a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -2-phenylpropionami
Do Amino- (4-methoxyphenyl)-(3-nitrophen
Nyl) methane hydrochloride (2.58 g) in anhydrous dichloromethane
Dissolve in 50 ml and add 1.77 g of triethylamine
And stirred under ice-cooling. Add 2-phenylpropionic acid to the reaction mixture
1.32 g and 20 ml of dichloromethane were added.
Add 10 ml of water dimethylformamide to completely dissolve
I let you. Add 1-ethyl-3- (3-dimethylamino) to the reaction mixture.
Propyl) carbodiimide hydrochloride (2.40 g)
The solution suspended in 30 ml of methane was added dropwise little by little,
Stirred at warm for 2 hours. A saturated saline solution was added to the reaction solution, and acetic acid was added.
Extracted with ethyl. The organic layer was washed with a saturated saline solution and dried.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Residue
To silica gel column chromatography (elution solvent: n
-Hexane / ethyl acetate = 2/1).
2.41 g of the title compound was obtained as a colorless oil. NMR spectrum (CDCl_Three) δppm: 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-metho
Xyphenyl) methyl] -2-phenylpropionami
De hydrochloride N-[(4-methoxyphenyl)-(3-nitrophenyl
L) methyl] -2-phenylpropionamide 2.37
Example (47) using g and 5.76 g of tin (II) chloride.
Reaction was carried out in the same manner as in b), and the title compound was converted into a white solid.
1.96 g were obtained. NMR spectrum (DMSO-d₆) δppm: 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-dio
Oxocyclobut-1-enylamino) phenyl)-(4
-Methoxyphenyl) methyl] -2-phenyl Propio
Namide N-[(3-aminophenyl)-(4-methoxyphenyl
Ru) methyl] -2-phenylpropionamide hydrochloride
555 mg and 3,4-dimethoxy-3-cyclobutene-
Example (46e) using 398 mg of 1,2-dione
The reaction was carried out in the same manner, and the title compound was converted into a yellow solid at 425
mg was obtained. NMR spectrum (CDCl_Three) δppm: 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-dioxy
So-cyclobut-1-enylamino) phenyl)-(4
-Methoxyphenyl) methyl] -2-phenyl Propio
Namide N-[(3- (2-methoxy-3,4-dioxocyclo
(But-1-enylamino) phenyl)-(4-methoxy
Phenyl) methyl] -2-phenylpropionamide 3
The reaction was carried out in the same manner as in 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-d₆) 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). Example 513-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione and its hydrochloride (Exemplary Compound No. 2-237) (51a) 3-amino-4- [3-((4-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-ci Clobute
N-1,2-dione Example 35 3-methoxy-4- [3-((4-methoxy
Cyphenyl)-(1- (3,4-difluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
294 mg of isomer (A) of butene-1,2-dione was added.
Dissolve in 8 ml of ethanol, 2N ammonia-ethanol
1.5 ml of the solution was added and reacted in the same manner as in Example (1d).
To give the isomer (A) of the title compound as a yellow solid
202 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) δppm: 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 The 3-methoxy-4- [3-((4-methoxy
Cyphenyl)-(1- (3,4-difluorophenyl)
Ethylamino) methyl) phenylamino] -3-cyclo
254 mg of isomer (B) of butene-1,2-dione was added.
Dissolve in 6 ml of ethanol, 2N ammonia-ethanol
The reaction was carried out in the same manner as in Example (1d).
Thus, isomer (B) of the title compound was converted into a yellow solid by 16
9 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) δppm: 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-methoxy
Enyl)-(1- (3,4-difluorophenyl) ethyl
Ruamino) methyl) phenylamino] -3-ci Clobute
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 add 1 ml of 4N hydrochloric acid / ethyl acetate solution to reduce
It was concentrated under reduced pressure. Solidification by adding methanol / ether to the residue
To give 158 mg of a white solid. NMR spectrum (DMSO-d₆) δppm: 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. Example 523-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 2.38 g of 3-nitro-4'-methoxybenzophenone
And 2- (t-butyl-dimethyl-silyloxy) -2-
4.64 g of phenylethylamine was added to anhydrous dichloromethane.
Dissolve in 40 ml and add 5.1 ml of triethylamine
Was. The reaction solution was cooled on ice, and anhydrous titanium tetrachloride (1.2 ml) was added.
After slowly dropping a 12 ml diluted solution of chloromethane,
Stirred at room temperature for 1 hour. Sodium bicarbonate aqueous solution
The solution and ethyl acetate are added, and the precipitated insoluble material is
It was removed by filtration. After separating the organic layer of the filtrate, the aqueous layer was treated with acetic acid.
Extracted with ethyl. Wash the combined organic layers with saturated saline
After drying over anhydrous sodium sulfate, the solvent is concentrated under reduced pressure.
This gave 6.88 g of the imine compound as a yellow oil.
The obtained oil was dissolved in 70 ml of ethanol and hydrogenated.
2.33 g of sodium cyanoborohydride and 0.8 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) using
4.95 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl_Three) δppm: −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-d
Trophenyl) methyl) amino] -1-phenylethano
Rule N- [2- (t-butyl-dimethylsilyloxy) -2-
Phenylethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl) methyl] amine in 4.95 g of 1M
Tetrabutylammonium fluoride-tetrahydrofuran solution
20 ml was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid
After diluting with ethyl acetate and washing with water and brine, anhydrous sulfuric acid
The extract was dried over magnesium and the solvent was concentrated under reduced pressure. Residue
Ricagel column chromatography (elution solvent: cyclo
Hexane / ethyl acetate = 3/1) to give the title compound
Was obtained as a pale yellow oil. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Cyphenyl) methyl) -amino] -1-phenylethano
Rule 2-[((4-methoxyphenyl)-(3-nitrophenyl
L) methyl) amino] -1-phenylethanol 3.2
6 g was dissolved in methanol 60 ml, and nickel chloride 6 water was added.
4.09 g of the hydrate and 1.3 g of sodium borohydride
And the reaction was carried out in the same manner as in Example (1b).
The product was obtained as a pale yellow oil (2.2 g). NMR spectrum (CDCl_Three) δppm: 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-phenyl)
Ruethyl) amino- (4-methoxyphenyl) methyl)
Enylamino] -4-methoxy-3-cyclobutene-
1,2-dione 2-[((3-aminophenyl)-(4-methoxyphenyl
Ru) methyl) amino] -1-phenylethanol 2.2
g in 40 ml of methanol.
-3-cyclobutene-1,2-dione (940 mg) was added.
The reaction was carried out in the same manner as in Example (1c) to give the title compound
Was obtained as a white foam. NMR spectrum (CDCl_Three) δppm: 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-methoxyphenyl)
Ru) methyl) phenylamino] -3-cyclobu Ten
1,2-dione 3- [3-((2-hydroxy-2-phenylethyla
Mino- (4-methoxyphenyl) methyl) phenylami
No))-4-Methoxy-3-cyclobutene-1,2-di
ON 1.35 g to 2N ammonia-ethanol solution 1
9 ml was added, and the reaction was carried out in the same manner as in Example (1d).
1.36 g of the title compound was obtained as a pale yellow solid. NMR spectrum (DMSO-d₆) Δppm: 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). Example 533-amino-4- [3-((2- (1H-indole-
3-yl) ethylamino)-(4-methoxyphenyl) meth
Tyl) phenylamino] -3-cyclobutene-1,2-
Dione (Exemplary Compound No. 2-1985) (53a) N- [2- (1H-indol-3-yl) d
Tyl] -N-[(4-methoxyphenyl)-(3-nitroph
Enyl) methyl] amine 1.5 g of 3-nitro-4'-methoxybenzophenone
1.86 g of tryptamine in 15 ml of anhydrous dichloromethane
, And 3.22 ml of triethylamine was added. Anti
The reaction solution was cooled on ice, and 0.77 ml of titanium tetrachloride in anhydrous dichloromethane was added.
After slowly dropping a diluted solution of 8 ml of dichloromethane, at room temperature
Stir for 2 hours. Sodium bicarbonate solution
Ethyl acetate was added, and the precipitated insoluble material was filtered through Celite.
Removed. After separating the organic layer of the filtrate, the aqueous layer was ethyl acetate.
Extracted. Wash the combined organic layers with saturated saline
After drying over sodium sulfate, the solvent is concentrated under reduced pressure.
2.63 g of the mine compound was obtained as a yellow oil. Obtained
The oily substance was dissolved in 30 ml of ethanol,
1.46 g of sodium borohydride and 0.5 ml of acetic acid
And the reaction was carried out in the same manner as in Example (1a).
The product was obtained as yellow oil (2.33 g). NMR spectrum (CDCl_Three) δppm: 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-indol-3-yl) ethyl
Ruamino]-(4-methoxyphenyl) methyl] phenyla
Min [2- (1H-indol-3-yl) ethyl]-[(4-
Methoxyphenyl)-(3-nitrophenyl) methyl] A
Dissolve 2.33 g of min in 50 ml of ethanol, and add
2.76 g of nickel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 878 mg of
Thus, 484 mg of the title compound was obtained as a pale yellow oil. NMR spectrum (CDCl_Three) δppm: 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-indole-3-i
L) ethylamino)-(4-methoxyphenyl) methyl) f
[Enylamino] -4-methoxy-3-cyclobutene-
1,2-dione 3-[(2- (1H-indol-3-yl) ethylamino)
-(4-methoxyphenyl) methyl] phenylamine 48
0 mg was dissolved in 5 ml of methanol to give 3,4-dimethoxy.
193 mg of c-3-cyclobutene-1,2-dione was added.
The reaction was carried out in the same manner as in Example (1c) to give the title compound
Was obtained as a pale yellow foam. NMR spectrum (CDCl_Three) δppm: 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-i
Ndol-3-yl) ethylamino)-(4-methoxyph
Enyl) methyl) phenylamino] -3-cyclobutene
-1,2-dione 3- [3-((2- (1H-indol-3-yl) ethyl
Ruamino)-(4-methoxyphenyl) methyl) phenyl
Amino] -4-methoxy-3-cyclobutene-1,2-
2N ammonia-ethanol solution in 340mg of dione
After adding 1.4 ml, the reaction was carried out in the same manner as in Example (1d).
This gave 257 mg of the title compound as a yellow solid. NMR spectrum (DMSO-d₆) Δppm: 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)3-amino-4- [3-((4-methoxyphenyl)-
(2-cyclohexylethylamino) methyl) phenyl
Amino] -3-cyclobutene-1,2-dione (exemplification
Compound number 2-437) (54a) N-[(4-methoxyphenyl)-(3-nitto
Rophenyl) methyl] -N- [2- (cyclohexene-1
-Yl) ethyl] amine 3-nitro-4'-methoxybenzophenone 2g and 2-
(Cyclohexen-1-yl) ethylamine 2.17 m
was dissolved in 20 ml of anhydrous dichloromethane, and triethyl
4.33 ml of amine were added. The reaction solution is cooled on ice and tetrachloride
Dilute 1.03 ml of titanium with 10 ml of anhydrous dichloromethane
After the solution was slowly added dropwise, the mixture was stirred at room temperature for 1 hour. Anti
An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to the reaction solution,
The precipitated insoluble matter was removed by filtration through Celite. Filtrate
After separating the organic layer, the aqueous layer was extracted with ethyl acetate. Matching
The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
After drying, the solvent is concentrated under reduced pressure to remove the imine compound from the brown oil.
2.70 g were obtained as a product. The resulting oil is ethanol
Dissolved in 60 ml of sodium borohydride
Example using 1.96 g and 0.67 ml of acetic acid
Reaction was carried out in the same manner as in (1a), and the title compound was converted into a yellow oily substance.
2.80 g was obtained. NMR spectrum (CDCl_Three) δppm: 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- (cy
Clohexen-1-yl) ethylamino) methyl] Fe
Nilamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- [2- (cyclohexen-1-yl)
Dissolve 2.80 g of [ethyl] amine in 60 ml of methanol
And 3.61 g of nickel chloride hexahydrate and borohydride
Same as Example (1b) using 1.15 g of sodium hydrogen
The reaction was performed. Reduction of the title compound and the cyclohexene ring
3-[(4-methoxy-phenyl)-(2-cyclo
Hexylethylamino) methyl] phenylamine
Was obtained as a yellow oil (2.15 g). NMR spectrum (CDCl_Three) 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-methoxy
-Phenyl)-(2- (cyclohexen-1-yl) e
Tylamino) methyl) phenylamino] -3- Cyclob
Ten-1,2-dione 3-[(4-methoxyphenyl)-(2- (cyclohexe
1-yl) ethylamino) methyl] phenylamine
And 3-[(4-methoxyphenyl)-(2-cyclohexyl
1. Mixture of [ethylamino) methyl] phenylamine
15 g was dissolved in 40 ml of methanol, and
953 mg of xy-3-cyclobutene-1,2-dione
In addition, a reaction was carried out in the same manner as in Example (1c). Crude product
Is subjected to reverse phase medium pressure chromatography (elution solvent: acetonitrile
Ril / acetate buffer aqueous solution (water: acetic acid: triethylamine =
1000: 2: 2) = 50/50)
This gave 815 mg of the product as a pale orange foam. NMR spectrum (CDCl_Three) δppm: 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-[(4-methoxy-phenyl)-(2-cyclo
Hexylethylamino) methyl] phenylamine
3-methoxy-4- [3-((4-methoxyphenyl)
)-(2-cyclohexylethylamino) methyl)
Enylamino] -3-cyclobutene-1,2-dione
632 mg were obtained as a white foam. NMR spectrum (CDCl_Three) δppm: 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-methoxy
Enyl)-(2-cyclohexylethylamino) methyl
Ru) phenylamino] -3-cyclobutene-1, 2-di
on The 3-methoxy-4- [3-((4-
Methoxyphenyl)-(2-cyclohexylethylamido
No) methyl) phenylamino] -3-cyclobutene-
630 mg of 1,2-dione, 2N ammonia-ethanol
Then, 2.8 ml of the reaction solution was added, and the reaction was performed in the same manner as in Example (1d).
The reaction yielded 536 mg of the title compound as a yellow solid.
Was. NMR spectrum (DMSO-d₆) 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. Example 553-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
Ruamino} -3-cyclobutene-1,2-di In 3- [phenyl-((R) -1-phenylethylamino) me
[Tyl] phenylamine isomer (A) 1.9 g, 4-t-
Butoxy-3-methoxy-3-cyclobutene-1,2-
Reaction was carried out in the same manner as in Example (1c) using 1.25 g of dione.
To give the isomer (A) of the title compound as a white solid
2.3 g were obtained. Isomer A NMR spectrum (CDCl3) 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 3- [phenyl-((R) -1-phenylethylamino) me
2.3 g of isomer of tyl] phenylamine (B), 4-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 Example (1c).
To give the isomer (B) of the title compound as a white solid.
2.53 g was obtained. Isomer B NMR spectrum (CDCl3) 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) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-t
-Butoxy-4- {3- [phenyl-((R) -1-F
Enylethylamino) methyl] phenylamino} -3-
1.0 g of isomer (A) of cyclobutene-1,2-dione
Is dissolved in 5 ml of dichloromethane and trifluoroacetic acid is dissolved.
1.5 ml was added, and the mixture was stirred at room temperature for 3 hours. Dilute the reaction solution
PH 4.5 using hydrochloric acid and aqueous sodium hydroxide solution.
, And extracted with methylene chloride. Organic layer with saline
After washing, drying over anhydrous magnesium sulfate, filtering and depressurizing
Concentrated. Suspend the solidified target in ethyl acetate
The crystals were collected by filtration to give the isomer (A) of the title compound as a gray solid.
69 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) δ ppm: 1.63 (3H, d, J
= 6.5Hz), 4.27 (1H, br), 4.97 (1H, br.s), 6.90 (1H, d,
J = 7.7Hz), 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 of -3-cyclobutene-1,2-dione (B)
Using 1.0 g and 1.5 ml of trifluoroacetic acid,
The reaction is carried out in the same manner as in the method, and the isomer (B) of the title compound is obtained.
Was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 563-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
Ruamino} -3-cyclobutene-1,2-di In 3- [phenyl-((S) -1-phenylethylamido
No.) 1.9 g of isomer (A) of methyl] phenylamine,
4-t-butoxy-3-methoxy-3-cyclobutene-
As in Example (1c), using 1.25 g of 1,2-dione
The isomer (A) of the title compound was converted to a white solid
2.3 g was obtained as a body. Also, 3- [phenyl-((S) -1-phenylethyl)
Amino) methyl] phenylamine isomer (B) 2.3
g, 4-t-butoxy-3-methoxy-3-cyclobute
Example (1c) using 1.54 g of n-1,2-dione
The reaction was carried out in the same manner as in
2.53 g were obtained as a colored solid.(56b) 3-hydroxy-4- {3- [phenyl-
((S) -1-phenylethylamino) methyl] phenyl
Ruamino} -3-cyclobutene-1,2-dione 3-t-butoxy-4- {3- [phenyl-((S)-
1-phenylethylamino) methyl] phenylamino}
Isomer of -3-cyclobutene-1,2-dione (A)
Example using 1.0 g and 1.5 ml of trifluoroacetic acid
The reaction was carried out in the same manner as in (55b), and the isomer of the title compound was obtained.
855 mg of (A) was obtained 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 of -3-cyclobutene-1,2-dione (B)
Example using 1.0 g and 1.5 ml of trifluoroacetic acid
The reaction was carried out in the same manner as in (55b), and the isomer of the title compound was obtained.
855 mg of (B) was obtained as a white solid. Isomer (B) Optical rotation [α]_D= -56.4 (c = 1.00, AcO
H). Example 574- {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-methoxy)
600 mg of (phenyl) ketone and 1- (3,4-diflu
809 mg of (hydrophenyl) ethylamine hydrochloride,
1.75 ml of ethylamine, 0.28 m of titanium tetrachloride
1, Sodium cyanoborohydride 583mg, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.18 ml.
This gave 830 mg of the title compound as a yellow foam. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(3-methoxyphenyl) methyl
Ru] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(2-methoxy-5-nitrophenyl)-(3-meth
Toxiphenyl) methyl] amine 810mg and secondary chloride
A solution of 1.43 g of tin in a 1: 1 mixture of concentrated hydrochloric acid and ethanol 20
Then, the mixture was dissolved in ml and heated under reflux for 2 hours. Remove the reaction solution from excess water
Adjust the pH to weak alkaline with sodium oxide, and add ethyl acetate
Extracted. The extract is washed with a saturated saline solution and magnesium sulfate is added.
After drying over water, 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]
・ Purification to give the isomer (A) of the title compound as a yellow oil
235 mg were obtained. Further, the isomer mixture is
Ram chromatography (elution solvent: cyclohexane /
(Ethyl acetate = 1/1) to give isomer (B) as a yellow oil
187 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-(3
-Methoxyphenyl) methyl] -4-methoxyphen Nil
Amino} -3-cyclobutene-1,2-dione 3-[(1- (3,4-difluorophenyl) ethyla
Mino)-(3-methoxyphenyl) methyl] -4-metho
220 mg of isomer (A) of xyloxyamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 203 mg of dione, the same procedure as in Example (1c) was carried out.
To give the isomer (A) of the title compound as a yellow foam.
305 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino)-(3-methoxyphenyl) methyl] -4-metho
180 mg of isomer (B) of xyloxyamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 166 mg of dione, in the same manner as in Example (1c),
To give the isomer (B) of the title compound as a yellow foam.
210 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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)
Enyl) ethylamino)-(3-methoxyphenyl) meth
Tyl] -4-methoxyphenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(3-methoxyphen)
Nyl) 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. Anti
After neutralizing the reaction solution with 3 ml of 1 N aqueous sodium hydroxide solution,
Diluted with water. The insolubles precipitated during dilution are collected by filtration, and the
The solid was washed with water, diethyl ether, and acetone sequentially, and then dried.
Dry to give isomer (A) of the title compound as a pale yellow solid
206 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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-diph
(Fluorophenyl) ethylamino)-(3-methoxyphen)
Nyl) 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. The reaction solution is 1N water
After neutralization with 2 ml of aqueous sodium oxide solution, the reaction solution was
Concentrated. Silica gel column chromatography of the residue
(Elution solvent: methylene chloride / methanol = 10/1)
Purify to give isomer (B) of the title compound as a pale yellow solid
88 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 584- {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)
-(4-methoxyphenyl) methyl] amine (2-methoxy-5-nitrophenyl)-(4-methoxy)
1.5 g of (phenyl) ketone and 1- (3,4-difluoro)
2.02 g of (phenyl) ethylamine hydrochloride, triet
4.37 ml of tylamine, 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 Example (1a) using 45 ml.
This gave 2.10 g of the title compound as a yellow oil. NMR spectrum (CDCl3) 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-difluoro
Phenyl) ethylamino)-(4-methoxyphenyl)
Methyl] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(2-methoxy-5-nitrophenyl)-(4-meth
Toxiphenyl) methyl] amine 2.0 g and stannic chloride
3.54 g, concentrated hydrochloric acid-ethanol 1: 1 mixed solution 40 m
The reaction was carried out in the same manner as in Example (57b) using
The isomer (A) of the title compound was converted into a yellow oil by 37
0 mg, 591 mg of isomer (B) as a yellow oil
Was. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -4-methoxy-f Eni
Ruamino} -3-cyclobutene-1,2-dione 3-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-metho
360 mg of isomer (A) of xyloxyamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 333 mg of dione, in the same manner as in Example (1c),
To give the isomer (A) of the title compound as a yellow foam.
260 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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). 3-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-metho
360 mg of isomer of xyphenylamine (B), 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 333 mg of dione, in the same manner as in Example (1c),
To give the isomer (B) of the title compound as a yellow foam.
To give 512 mg. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) -ethylamino)-(4-methoxyphenyl)
-Methyl] -4-methoxy-phenylamino ｝-3-hi
Droxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 250 m
The reaction and purification were carried out in the same manner as in Example (57d) using g.
To give 115% of the isomer (A) of the title compound as a pale yellow solid.
mg. Isomer (A) NMR spectrum (DMSO-d6) 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 =
2.3 Hz). Melting point: 252-255 ° C. 3-t-butoxy-4- {3-[(1- (3,4-diphf)
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 400 m
The reaction and purification were carried out in the same manner as in Example (57d) using g.
To give 230% of the isomer (B) of the title compound as a pale yellow solid.
mg. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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. Example 594- {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-nitrophen
Nyl)-(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 in the same manner as in Example (1a).
The reaction was performed to give 950 mg of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] -2,3-Dimethoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(3,4-dimethoxy-5-nitrophenyl)-
(4-methoxyphenyl) methyl] amine (950 mg)
985 mg of nickel chloride hexahydrate and sodium borohydride
In the same manner as in Example (1b),
Responded. The crude product obtained by post-treatment is
Column chromatography (ethyl acetate / toluene = 1
/ 10)) to give isomer (A) of the title compound.
215 mg as a yellow oil, isomer (B) as a yellow oil
370 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -2,3-dimethoxy Schiff
Phenylamino} -3-cyclobutene-1,2-dione 5-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -2,3-
360 mg of isomer (B) of dimethoxyphenylamine,
4-t-butoxy-3-methoxy-3-cyclobutene-
As in Example (1c), using 310 mg of 1,2-dione
The isomer (B) of the title compound is converted into a yellow foam
150 mg was obtained as a solid. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) -ethylamino)-(4-methoxyphenyl)
Methyl] -2,3-dimethoxy-phenylamido NO-3
-Hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {5-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -2,3-dimethoxyphenylamino}
Isomer (B) 1 of -3-cyclobutene-1,2-dione
Reaction and purification were carried out in the same manner as in Example (57d) using 47 mg.
To give the isomer (B) of the title compound as a yellow solid in 8
2 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 604- {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.
31ml, sodium borohydride sodium 660m
g, 0.20 ml of acetic acid as in Example (1a)
The reaction was carried out to give 990 mg of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] -2,3-Dimethoxyphenylamine N- [1- (3,5-difluorophenyl) ethyl] -N
-[(3,4-dimethoxy-5-nitrophenyl)-
870 mg of (4-methoxyphenyl) methyl] amine
1.04 g of nickel chloride hexahydrate and sodium borohydride
In the same manner as in Example (1b),
This gave 550 mg of the title compound as a colorless oil.
Was. NMR spectrum (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -2,3-dimethoxy Schiff
Phenylamino} -3-cyclobutene-1,2-dione 5-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -2,3-
Dimethoxyphenylamine 540 mg, 4-t-butoki
C-3-methoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using 348 mg.
This gave 260 mg of the title compound as a colorless foam. NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) -ethylamino)-(4-methoxyphenyl)
Methyl] -2,3-dimethoxy-phenylamido NO-3
-Hydroxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {5-[(1- (3,5-difu
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -2,3-dimethoxyphenylamino}
Using 247 mg of -3-cyclobutene-1,2-dione
The reaction and purification were carried out in the same manner as in Example (57d) to give the title.
137 mg of a mixture of isomers was obtained as a yellow solid. NMR spectrum (DMSO-d6) 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. Example 614- {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)
-(4-methoxyphenyl) methyl] amine (2-methoxy-5-nitrophenyl)-(4-methoxy)
1.29 g of (phenyl) ketone and 1- (3,5-diflu
1.74 g of (hydrophenyl) ethylamine hydrochloride,
3.76 ml of ethylamine, 0.59 m of titanium tetrachloride
1, sodium borohydride 1.25 g, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.39 ml.
This gave 1.78 g of the title compound as a yellow oil. NMR spectrum (CDCl3) δppm: 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] -4-methoxyphenylamine N- [1- (3,5-difluorophenyl) ethyl] -N
-[(2-methoxy-5-nitrophenyl)-(4-meth
Toxiphenyl) methyl] amine (1.75 g)
2.24 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (59b) using 651 mg.
And purified to give isomer (A) of the title compound as a yellow oil.
471 mg to give 650 mg of isomer (B) as an orange solid.
mg. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -4-methoxyphen Nil
Amino} -3-cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-metho
450 mg of isomer (A) of xyloxyamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
And using 416 mg of dione as in Example (1c).
To give the isomer (A) of the title compound as a yellow foam.
570 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-metho
630 mg of isomer (B) of xyloxyamine, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
Using 582 mg of dione, the same procedure as in Example (1c) was carried out.
To give the isomer (B) of the title compound as a yellow foam.
880 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] -4-methoxyphenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[(1- (3,5-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 200 m
The reaction and purification were carried out in the same manner as in Example (57d) using g.
To give the isomer (A) of the title compound as a pale green solid.
mg. Isomer (A) NMR spectrum (DMSO-d6) 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 to 263 ° C. 3-t-butoxy-4- {3-[(1- (3,5-diif
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 200 m
The reaction and purification were carried out in the same manner as in Example (57d) using g.
To give the isomer (B) of the title compound as a pale yellow solid in 122
mg. Isomer (B) NMR spectrum (DMSO-d6) δ ppm: 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. Example 624- {3-[((S) -1- (3,4-difluorophene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
Ten-1,2-dione (Exemplary Compound No. 2-42) (62a) 3-t-butoxy-4- {3-[((S)-
1- (3,4-difluorophenyl) ethylamino)-
(4-methoxyphenyl) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[((S) -1- (3,4-difluorophenyl)
[Ethylamino)-(4-methoxyphenyl) methyl] f
Isomer of phenylamine (B) 500 mg, 4-t-butene
Xy-3-methoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 500 mg of
Thus, the isomer (B) of the title compound was converted to a colorless foam by 6
05 mg was obtained. Isomer (B) NMR spectrum (CDCl3) 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-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((S) -1- (3,
4-difluorophenyl) ethylamino)-(4-metho
[Xyphenyl) methyl] phenylamino} -3-cyclo
Butene-1,2-dione isomer (B)
To 3 ml of ethyl acetate solution, add 3 ml of 4N HCl / acetic acid
The chill solution was added and stirred at room temperature for 1 hour. Reaction mixture
The solid precipitated after dilution with tyl ether is collected by filtration and dried.
To give the hydrochloride of the isomer (B) of the title compound as a pale yellow solid
472 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 634- {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] phenyla Mino
3-cyclobutene-1,2-dione 3-[((R) -1- (3,4-difluorophenyl)
[Ethylamino)-(4-methoxyphenyl) methyl] f
Isomer of phenylamine (B) 500 mg, 4-t-butene
Xy-3-methoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 410 mg of
The isomer (B) of the title compound was converted into a colorless foam by
50 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
4-difluorophenyl) ethylamino)-(4-metho
[Xyphenyl) methyl] phenylamino} -3-cyclo
Butene-1,2-dione isomer (B) 300 mg 5
2 ml trifluoroacetic acid in 2 ml anhydrous methylene chloride solution
Was added and stirred at room temperature for 1 hour. Solvent and excess trifluoro
After distilling off acetic acid under reduced pressure, 10 ml of ethyl acetate was added to the residue.
Redissolved in water. 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. reaction
The liquid was diluted with diethyl ether, and the precipitated solid was collected by filtration and dried.
By drying, the hydrochloride of the isomer (B) of the title compound is obtained.
260 mg were obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d6) 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: 192-196 ° C Optical rotation [α]_D= + 11.1 ° (c = 1.00, Ac
OH).(63c) 4- {3-[((R) -1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione 3-t-butoxy-4- {3-[((R) -1- (3,
4-difluorophenyl) ethylamino)-(4-metho
[Xyphenyl) methyl] phenylamino} -3-cyclo
Using 175 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (55b).
129 mg of the compound isomer (B) was obtained as a yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d6) 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: 193-200 ° C Optical rotation [α]_D= + 102.6 ° (c = 0.76, A
cOH). Example 644- {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-Nitrophenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ke
3.91 g of ton and (R) -1- (3,5-difluorofuran)
Enyl) ethylamine hydrochloride 4.42 g, triethyl
Amine 11.7ml, titanium tetrachloride 2.01ml, hydrogen
4.25 g of sodium cyanoborohydride, 1.31 of acetic acid
The reaction was carried out in the same manner as in Example (1a) using
Isomer (B) which elutes slower than the title compound
860 mg was obtained. Isomer (B) NMR spectrum (CDCl3) 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-difluoro
Phenyl) ethylamino)-(4-methoxyphenyl)
Methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl)
Tyl] -N-[(4-methoxyphenyl)-(3-nitro
820 mg of isomer (B) of phenyl) methyl] amine
1.13 g of nickel chloride hexahydrate and sodium borohydride
In the same manner as in Example (1b),
To give the isomer (B) of the title compound as a yellow oil.
480 mg was obtained. Isomer (B) NMR spectrum (CDCl3) 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) ethylamino)-
(4-methoxyphenyl) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
[Ethylamino)-(4-methoxyphenyl) methyl] f
Phenylamine isomer (B) 450 mg, 4-t-butene
Xy-3-methoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 450 mg of
Thus, isomer (B) of the title compound was converted into a yellow foam by 6
10 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) ethylamino)-(4-metho
[Xyphenyl) methyl] phenylamino} -3-cyclo
200 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
175 mg of the compound isomer (B) was obtained as a brown solid.
Was. Isomer (B) NMR spectrum (DMSO-d6) 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-diph
(Fluorophenyl) -ethylamino)-(4-methoxyphenyl)
Enyl) -methyl] -phenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) ethylamino)-(4-metho
[Xyphenyl) methyl] phenylamino} -3-cyclo
340 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (55b).
202 mg of the isomer (B) of the compound was obtained as a yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d6) 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 = 8.1Hz), 7.69 (1H, d, J = 0.5Hz). Melting point: 195-200 ° C Optical rotation [α]_D= + 117.3 ° (c = 1.03, A
cOH). Example 654- {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-nitro
Lophenyl) methyl] amine (4-ethoxyphenyl)-(3-nitrophenyl) ke
1.0 g of ton and 1- (3,5-difluorophenyl)
1.16 g of tylamine, 2.01 m of triethylamine
1, 0.49 ml of titanium tetrachloride, boron cyanide hydride
Performed using 975 mg of sodium and 0.32 ml of acetic acid
Reaction was carried out in the same manner as in Example (1a) to give the title compound as a yellow oil.
1.41 g was obtained as a product. NMR spectrum (CDCl3) 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
h t, 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-difluorophenyl)
Ru) ethylamino)-(4-ethoxyphenyl) methyl
Ru] phenylamine N- [1- (3,5-difluorophenyl) ethyl] -N
-[(4-ethoxyphenyl)-(3-nitrophenyl
1.39 g of methyl] amine and nickel chloride hexahydrate
1.84 g and 537 mg of sodium borohydride
The reaction was carried out in the same manner as in Example (59b), purified and
The isomer (A) of the title compound was converted into a yellow oily substance (316 m).
g, 531 mg of isomer (B) as a yellow oil. Isomer (A) NMR spectrum (CDCl3) 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 = 8.7Hz). Isomer (B) NMR spectrum (CDCl3) δppm: 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) ethylamino)-(4
-Ethoxyphenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-ethoxyphenyl) methyl] phenyla
Isomer of amine (A) 288 mg, 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 277
The reaction was carried out in the same manner as in Example (1c) using
393 mg of isomer (A) of the title compound as a yellow oil
Obtained. Isomer (A) NMR spectrum (CDCl3) 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). 3-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-ethoxyphenyl) methyl] phenyla
Miner isomer (B) 438 mg, 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 422
The reaction was carried out in the same manner as in Example (1c) using
494 mg of isomer (B) of the title compound as a yellow foam
Obtained. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-ethoxyphenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-diph
(Fluorophenyl) ethylamino)-(4-ethoxyfe
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 352 mg of 1,2-dione isomer (A)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
299 mg of isomer (A) was obtained as a light brown solid. Isomer (A) NMR spectrum (DMSO-d6) 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-Ziff
(Fluorophenyl) ethylamino)-(4-ethoxyfe
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 468 mg of isomer (B) of 1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
338 mg of isomer (B) was obtained as a yellow solid. Isomer (B) NMR spectrum (DMSO-d6) δ ppm: 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. Example 664- {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-prop
Ruoxyphenyl) methyl] amine (3-nitrophenyl)-(4-propyloxyphenyl)
790 mg of ketone and 1- (3,5-difluorophene)
Nyl) ethylamine 870 mg, triethylamine 1.
54 ml, titanium tetrachloride 0.37 ml, hydrogenated cyanation
Using 733 mg of sodium boron and 0.24 ml of acetic acid
And the reaction was carried out in the same manner as in Example (1a) to convert the title compound to yellow.
1.16 g were obtained as a colored oil. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-propyloxyphenyl)
Methyl] phenylamine N- [1- (3,5-difluorophenyl) ethyl]-
N-[(3-nitrophenyl)-(4-propyloxy
1.10 g of phenyl) methyl] amine and nickel chloride 6
Hydrate 1.41 g and sodium borohydride 411
Perform the same reaction as in Example (1b) using mg
915 mg of the compound were obtained as a yellow oil. NMR spectrum (CDCl3) 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
h q, J = 6.6 and 6.7Hz), 3.87 and 3.91 (total 2H, eac
h t, 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) ethylamino)-(4
-Propyloxyphenyl) methyl] phenylamido No
-3-cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-propyloxyphenyl) methyl] fe
Nylamine 860 mg, 4-t-butoxy-3-methoxy
Using 599 mg of C-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c). Post-processing
The obtained crude product is subjected to silica gel column chromatography.
-(Ethyl acetate / toluene = 1/10)
457m of the compound isomer (A) as a pale yellow foam
g, 206 mg of isomer (B) as a pale yellow foam
Was. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-propyloxyphenyl
Ru) methyl] phenylamino} -3-hydroxy C-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-diph
(Fluorophenyl) -ethylamino)-(4-propylthio)
[Xyphenyl) methyl] phenylamino} -3-cyclo
440 mg of isomer (A) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
381 mg of isomer (A) of the compound was obtained as a pale yellow solid.
Was. Isomer (A) NMR spectrum (DMSO-d6) 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-diph
(Fluorophenyl) ethylamino)-(4-propyloxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
Using 195 mg of isomer (B) of ten-1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title
170 mg of the compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 674- {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-isoprop
Loxyphenyl) methyl] amine (3-nitrophenyl)-(4-isopropoxyphenyl)
850 mg of ketone and 1- (3,5-difluorophene)
Nyl) ethylamine 936 mg, triethylamine 1.
66ml, titanium tetrachloride 0.39ml, hydrogenated cyanation
Using sodium boron 788mg, acetic acid 0.26ml
And the reaction was carried out in the same manner as in Example (1a) to convert the title compound to yellow.
1.20 g of a colored oil were obtained. NMR spectrum (CDCl3) δ ppm: 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-difluorophenyl)
Ru) ethylamino)-(4-isopropoxyphenyl)
Methyl] phenylamine N- [1- (3,5-difluorophenyl) ethyl] -N
-[(3-nitrophenyl)-(4-isopropoxyf
Phenyl) methyl] amine 1.17 g and nickel chloride 6 water
1.50 g of sum and 437 m of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using
1.0 g of the compound was obtained as a yellow oil. NMR spectrum (CDCl3) 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) ethylamino)-(4
-Isopropoxyphenyl) methyl] phenylamido No
-3-cyclobutene-1,2-dione 3-[(1- (3,5-difluorophenyl) ethyla
Mino)-(4-isopropoxyphenyl) methyl] fe
Nylamine 930 mg, 4-t-butoxy-3-methoxy
Using 648 mg of Ci-3-cyclobutene-1,2-dione
The reaction was carried out and purified in the same manner as in Example (66c).
463m of the isomer (A) of the title compound as a pale yellow foam
g, 407 mg of isomer (B) as a pale yellow foam
Was. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) δppm: 1.33-1.35 (9H,
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-difluorofuran)
Enyl) ethylamino)-(4-isopropoxyphenyl)
Ru) methyl] phenylamino} -3-hydroxy C-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,5-diph
(Fluorophenyl) ethylamino)-(4-isopropoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
Using 450 mg of the isomer (A) of ten-1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title
369 mg of the compound isomer (A) was obtained as a pale brown solid.
Was. Isomer (A) NMR spectrum (DMSO-d6) 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-diph
(Fluorophenyl) ethylamino)-(4-isopropoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
Using 386 mg of the isomer (B) of ten-1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title
302 mg of the compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 684- {3-[(1- (3,4-difluorophenyl) e
Tylamino)-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-39) (68a) 3-t-butoxy-4- {3-[(1-
(3,4-difluorophenyl) ethylamino)-(4
-Fluorophenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-fluorophenyl) methyl] phenyla
Mining isomer (B) 300 mg, 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 310
The reaction was carried out in the same manner as in Example (1c) using
267 mg of isomer (B) of the title compound as a colorless foam
Obtained. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-fluorophenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-fluorophene)
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 250 mg of 1,2-dione isomer (B)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
158 mg of isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 694- {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) ke
3.0 g of (R) -1- (3,5-difluorophene)
Nyl) ethylamine hydrochloride (3.55 g, triethyl alcohol)
9.38 ml of min, 1.61 ml of titanium tetrachloride, hydrogenated
Sodium cyanide 3.08g, acetic acid 1.05m
The reaction was carried out in the same manner as in Example (1a) using
The compound was obtained as a yellow oil (4.48 g). NMR spectrum (CDCl3) 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-difluoro
Phenyl) ethylamino)-(4-fluorophenyl)
Methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl)
Tyl] -N-[(4-fluorophenyl)-(3-nitro
4.40 g of phenyl) methyl] amine and nickel chloride 6
6.54 g of hydrate and 1.8 of sodium borohydride
The reaction was carried out and purified using 1 g in the same manner as in Example (59b).
To give the isomer (A) of the title compound as a yellow oil
1.24 g, 1.66 g of isomer (B) as a yellow oil.
g was obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-
(4-Fluorophenyl) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
[Ethylamino)-(4-fluorophenyl) methyl] f
500 mg of isomer of phenylamine (A), 4-t-butene
Xy-3-methoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 517 mg of
To give the isomer (A) of the title compound as a pale yellow foam
681 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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)
[Ethylamino)-(4-fluorophenyl) methyl] f
Isomer of phenylamine (B) 500 mg, 4-t-butene
Xy-3-methoxy-3-cyclobutene-1,2-di
The reaction was carried out in the same manner as in Example (1c) using 517 mg of
To give the isomer (B) of the title compound as a pale yellow foam
580 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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-diph
(Fluorophenyl) ethylamino)-(4-fluorophene)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) -ethylamino)-(4-f
Fluorophenyl) methyl] phenylamino} -3-cycl
627 mg of isomer (A) of lobutene-1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b).
542 mg of isomer (A) of the title compound was obtained as a white solid.
Was. Isomer (A) NMR spectrum (DMSO-d6) 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, 8.7Hz). 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-fur
Orophenyl) methyl] phenylamino} -3-cyclo
Using 551 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
501 mg of the isomer (B) of the compound was obtained as a yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d6) 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). Melting point: 187-190 ° C Optical rotation [α]_D= -12.8 ° (c = 1.00, AcO
H).(69e) 4- {3-[((R) -1- (3,5-diph
(Fluorophenyl) ethylamino)-(4-fluorophene)
Nyl) methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione 4- {3-[((R) -1- (3,5-difluorophene)
Nyl) ethylamino)-(4-fluorophenyl) methyl
L] phenylamino} -3-hydroxy-3-cyclobu
300 mg of isomer B of ten-1,2-dione hydrochloride
Dissolve in 5 ml of methanol, 1N-HCl and 1N-
After adjusting the pH to 4 with aqueous sodium hydroxide, dilute with water.
I shouted. After the precipitated solid was collected by filtration, water, diethyl ether
And dried to give the isomer (B) of the title compound as a white solid
164 mg was obtained. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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). Melting point: 188-192 ° C Optical rotation [α]_D= + 38.2 ° (c = 1.09, AcO
H). Example 704- {3-[(4-fluorophenyl)-((R) -1
-Phenylpropylamino) methyl] phenylamino}
-3-Hydroxy-3-cyclobutene-1,2-dione
Hydrochloride (Exemplary Compound No. 2-3111) (70a) N-[(4-fluorophenyl)-(3-nitro
Rophenyl) methyl] -N-((R) -1-phenylpro
Pill) amine (4-fluorophenyl)-(3-nitrophenyl) ke
2.0 g of ton and (R) -1-phenylpropylamine
2.11 g, 4.55 ml of triethylamine, titanium tetrachloride
1.08 ml of tan, sodium cyanoborohydride
Example (1a) using 2.16 g and 0.70 ml of acetic acid
To give the title compound as a yellow oil.
2.85 g were obtained. NMR spectrum (CDCl3) 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] phenylamido
In N-[(4-fluorophenyl)-(3-nitrophenyl
Ru) methyl] -N-((R) -1-phenylpropyl) a
2.70 g of min, 4.06 g of nickel chloride hexahydrate and
Example using 1.18 g of sodium borohydride
The reaction was performed and purified in the same manner as (59b), to give the title compound
778 mg of isomer (A) as a yellow oil, isomer
615 mg of (B) was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-fur
Orophenyl)-((R) -1-phenylpropylamido
No) Methyl] phenylamino} -3-cyclobu Ten
1,2-dione 3-[(4-fluorophenyl)-((R) -1-phenyl
Isomers of propylamino) methyl] phenylamine
(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 Example (1c) to give the title compound.
The compound (A) 710 mg was obtained as a colorless foam. Isomer (A) NMR spectrum (CDCl3) 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 Example (1c) to give the title compound.
760 mg of the sexual form (B) was obtained as a pale yellow foam. Isomer (B) NMR spectrum (CDCl3) 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-fluorophenyl)-
((R) -1-phenylpropylamino) methyl] fe
Nilamino} -3-hydroxy-3-cyclobute N-
1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl
)-((R) -1-phenylpropylamino) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
Example (63) using 500 mg of the on isomer (A)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
436 mg of (A) was obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d6) 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, 8.7Hz). Melting point: 190-194 ° C Optical rotation [α]_D= -131.5 (c = 1.13, AcO
H) 3-t-butoxy-4- {3-[(4-fluorophenyl
)-((R) -1-phenylpropylamino) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
Example (63) using 500 mg of the on isomer (B)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
427 mg of (B) was obtained as a light brown solid. Isomer (B) NMR spectrum (DMSO-d6) 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, 8.7Hz). Melting point: 180-185 ° C Optical rotation [α]_D= -38.5 (c = 0.50, AcO
H). Example 714- {3-[(4-chlorophenyl)-(1- (3,5
-Difluorophenyl) ethylamino) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobute -1
2-dione hydrochloride (Exemplary Compound No. 2-54) (71a) N-[(4-chlorophenyl)-(3-nitro
Phenyl) methyl] -N- (1- (3,5-difluorophenyl)
Enyl) ethyl) amine (4-chlorophenyl)-(3-nitrophenyl) keto
2.0 g of 1- (3,5-difluorophenyl) ethyl
2.40 g of triamine, 4.26 ml of triethylamine,
1.01 ml of titanium tetrachloride, borohydride cyanate
Example using 3.02 g of lithium and 0.66 ml of acetic acid
The title compound was reacted in the same manner as in (1a) to give a yellow oil.
2.92 g was obtained. NMR spectrum (CDCl3) 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
h s), 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
Ru] phenylamine N- [1- (3,5-difluorophenyl) ethyl] -N
-[(4-chlorophenyl)-(3-nitrophenyl)
2.79 g of [methyl] amine and nickel chloride hexahydrate
Using 79 g and 1.10 g of sodium borohydride
The reaction was carried out and purified in the same manner as in Example (59b).
808 mg of the compound isomer (A) as a colorless oil,
572 mg of isomer (B) was obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-chloro
Rophenyl)-(1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamino｝ -3 -Cyclo
Butene-1,2-dione 3-[(4-chlorophenyl)-(1- (3,5-diph
Fluorophenyl) ethylamino) methyl] phenylamido
Isomer (A) 562 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 555 m
g, and reacted in the same manner as in Example (1c).
731 mg of isomer (A) of the compound was obtained as a colorless foam.
Was. Isomer (A) NMR spectrum (CDCl3) 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-diph
Fluorophenyl) ethylamino) methyl] phenylamido
Isomer (B) 479 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 473m
g, and reacted in the same manner as in Example (1c).
644 mg of the isomer (B) of the compound was obtained as a colorless foam.
Was. Isomer (B) NMR spectrum (CDCl3) 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-chlorophenyl)-(1
-(3,5-difluorophenyl) ethylamino) methyl
Ru] phenylamino} -3-hydroxy-3- Cyclob
Ten-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-(1- (3,5-difluorophenyl) ethyla
Mino) methyl] phenylamino} -3-cyclobutene-
Performed using 300 mg of 1,2-dione isomer (A)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
245 mg of isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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: 182-185 ° C. 3-t-butoxy-4- {3-[(4-chlorophenyi)
)-(1- (3,5-difluorophenyl) ethyla
Mino) methyl] phenylamino} -3-cyclobutene-
Performed using 300 mg of 1,2-dione isomer (B)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
255 mg of isomer (B) was obtained as a brown solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 724- {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)
-(4-methoxyphenyl) methyl] amine (4-fluoro-3-nitrophenyl)-(4-methoxy
2.0 g of (phenyl) ketone and 1- (3,4-difluoro)
(Phenyl) ethylamine hydrochloride 2.81, triethyl
Luamine 6.08 ml, titanium tetrachloride 0.96 ml, water
2.03 g of sodium borohydride cyanide, 0.6 of acetic acid
The reaction was carried out in the same manner as in Example (1a) using
2.63 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] -2-fluorophenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(4-fluoro-3-nitrophenyl)-(4-
Methoxyphenyl) methyl] amine 2.5 g
3.29 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using 957 mg.
This gave 1.82 g of the title compound as a yellow oil. NMR spectrum (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -2-fluorophen Nil
Amino} -3-cyclobutene-1,2-dione 5-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -2-fur
Orophenylamine 500 mg, 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 477
The reaction was carried out and purified in the same manner as in Example (66c) using mg.
To give the isomer (A) of the title compound as a yellow oil
25 mg, 256 mg of isomer (B) as a yellow solid
Was. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] -2-fluorophenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {5-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -2-fluorophenylamino} -3-
Cyclobutene-1,2-dione isomer (A) 200 m
The reaction and purification were performed in the same manner as in Example (63b) using g.
To give 175 of the title compound as a pale gray solid.
mg. Isomer (A) NMR spectrum (DMSO-d6) 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-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -2-fluorophenylamino} -3-
225 m of isomer of cyclobutene-1,2-dione (B)
The reaction and purification were performed in the same manner as in Example (63b) using g.
Isomer of the title compound (B) as a white solid in 190 m
g was obtained. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 734- {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
Ru)-(4-methoxyphenyl) methyl] amine (2-Fluoro-5-nitrophenyl)-(4-methoxy)
828 mg of cyphenyl) ketone and 1- (3,4-diflu
Orophenyl) ethylamine hydrochloride 1.16 g, tri
2.52 ml of ethylamine, 0.40 m of titanium tetrachloride
1, 840 mg of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.62 ml.
Thus, 860 mg of the title compound was obtained as a yellow oil. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] -4-fluorophenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(2-fluoro-5-nitrophenyl)-(4-me
Toxiphenyl) methyl] amine 800mg
1.05 g of Kel hexahydrate and sodium borohydride
The reaction was carried out in the same manner as in Example (59b) using 306 mg.
And purified to give isomer (A) of the title compound as a yellow oil.
To give isomer (B) 35 mg as a yellow oil.
0 mg was obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino)-(4
-Methoxyphenyl) methyl] -4-fluorophene Nil
Amino} -3-cyclobutene-1,2-dione 3-[(1- (3,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-fur
268 mg of isomer (A) of 4-phenylphenylamine
t-butoxy-3-methoxy-3-cyclobutene-1,
As in Example (1c), using 255 mg of 2-dione
The reaction was carried out to give the isomer (A) of the title compound as a yellow oil.
348 mg was obtained. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino)-(4-methoxyphenyl) methyl] -4-fur
316 mg of isomer (B) of 4-phenylphenylamine
t-butoxy-3-methoxy-3-cyclobutene-1,
As in Example (1c), using 301 mg of 2-dione
The reaction was carried out to give the isomer (B) of the title compound as a yellow oil.
476 mg was obtained. Isomer (B) NMR spectrum (CDCl3) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.64 (9H, s), 3.67 (1H, q, J = 6.6Hz), 3.80 (3
H, s), 4.87 (1H, s), 6.86-7.27 (9H, m), 7.44 (1H, b
r).(73d) 4- {3-[(1- (3,4-difluorophenyl)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] -4-fluorophenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-fluorophenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 318 m
The reaction and purification were performed in the same manner as in Example (63b) using g.
258m of the isomer (A) of the title compound as a white solid
g was obtained. Isomer (A) NMR spectrum (DMSO-d6) 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.
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] -4-fluorophenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 444 m
The reaction and purification were performed in the same manner as in Example (63b) using g.
To give 325 of the title compound as a pale yellow solid.
mg. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 744- {3-[((S) -1-cyclohexylethylamido)
No)-(4-methoxyphenyl) methyl] phenylamido
NO-3-Hydroxy-3-cyclobutene-1,2-di
On hydrochloride (Exemplary Compound No. 2-2) (74a) 3-t-butoxy-4- {3-[((S)-
1-cyclohexylethylamino)-(4-methoxyphenyl)
Enyl) methyl] phenylamino} -3-cycl Lobuten
-1,2-dione 3-[((S) -1-cyclohexylethylamino)-
(4-methoxyphenyl) methyl] phenylamine1.
63 g, 4-t-butoxy-3-methoxy-3-cyclo
Example 1 (1.33 g of butene-1,2-dione) was used.
The reaction was carried out in the same manner as in c) to give the title compound as a pale yellow foam.
1.89 g was obtained. NMR spectrum (CDCl3) δppm: 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-cyclohexyl)
-Ethylamino)-(4-methoxyphenyl) methyl]
Phenylamino} -3-hydroxy-3-cycl Lobuten
-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((S) -1-cyclo
Hexylethylamino)-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-cyclobutene-1,2-
In the same manner as in Example (63b), using 482 mg of dione,
The title compound was converted to a white solid by 415m
g was obtained. NMR spectrum (DMSO-d6) δppm: 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. Example 754- {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-nitro
Lophenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ke
2.0 g of ton and 1- (2,4-difluorophenyl)
5.01 g of hydrochloride of tylamine, triethylamine
5 ml, titanium tetrachloride 1.03 ml, hydrogenated cyanide
Using 2.06 g of sodium iodide and 0.67 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted to yellow.
2.90 g were obtained as an oil. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru] phenylamine N- [1- (2,4-difluorophenyl) ethyl] -N
-[(4-methoxyphenyl)-(3-nitrophenyl
M) 2.80 g of methyl] amine and nickel chloride hexahydrate
3.34 g and 1.12 g of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) using the title compound
Was obtained as a yellow oil. NMR spectrum (CDCl3) 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 s), 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) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[(1- (2,4-difluorophenyl) ethyla
Mino)-(4-methoxyphenyl) methyl] phenyla
2.18 g of min, 4-t-butoxy-3-methoxy-3
Using 1.63 g of cyclobutene-1,2-dione,
The reaction was performed and purified in the same manner as in Example (66c).
812 mg of isomer (A) as yellow oil
754 mg of the body (B) was obtained as a pale yellow foam. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-difluorofuran)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (2,4-diph
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 395 mg of 1,2-dione isomer (A)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
336 mg of isomer (A) was obtained as a pink solid. Isomer (A) NMR spectrum (DMSO-d6) 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- Jiff
(Fluorophenyl) ethylamino)-(4-methoxy)
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 455 mg of isomer (B) of 1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
314 mg of isomer (B) was obtained as a light red solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 764- {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) ke
2.0 g of ton and 1- (3-chlorophenyl) ethylami
2.99 g of hydrochloride, 6.5 ml of triethylamine,
1.03 ml of titanium tetrachloride, borohydride cyanate
Example using 2.06 g of lithium and 0.67 ml of acetic acid
The title compound was reacted in the same manner as in (1a) to give a yellow oil.
2.69 g was obtained. NMR spectrum (CDCl3) 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-chlorophenyl) -ethyl
L-amino)-(4-methoxyphenyl) -methyl] -f
Phenylamine N- [1- (3-chlorophenyl) ethyl] -N-[(4
-Methoxyphenyl)-(3-nitrophenyl) methyl] amine (2.60 g)
3.11 g of nickel chloride hexahydrate and sodium borohydride
The same procedure as in Example (1b) was carried out using 1.04 g of thorium.
This gave 2.15 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl3) 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-methoxy
Phenyl) methyl] phenylamino} -3-ci Clobute
N-1,2-dione 3-[(1- (3-chlorophenyl) ethylamino)-
(4-methoxyphenyl) methyl] phenylamine2.
09 g, 4-t-butoxy-3-methoxy-3-cyclo
Using 1.57 g of butene-1,2-dione, Example (6)
The reaction was carried out and purified in the same manner as in 6c) to give the isomer of the title compound.
Compound (A) as a yellow oil (481 mg, isomer (B))
Was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-chlorophenyl)
[Ethylamino)-(4-methoxyphenyl) methyl] f
Phenylamino} -3-hydroxy-3-cyclo Butene
1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3-chlorofu
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 441 mg of the dione isomer (A)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
250 mg of (A) was obtained as a yellow foam. Isomer (A) NMR spectrum (DMSO-d6) 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-chlorofu
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 474 mg of the dione isomer (B)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
333 mg of (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d6) 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 = 8.7 Hz), 7.35-7.56 (10H, m). Melting point: 170-173 ° C. Example 773-hydroxy-4- {3-[(4-methoxyphenyi)
)-(1- (3-trifluoromethylphenyl) ethyl
Ruamino) methyl] phenylamino} -3-cyclobute
1,2-dione hydrochloride (Exemplary Compound No. 2-349)
4) (77a) N-[(4-methoxyphenyl)-(3-nitro
Rophenyl) methyl] -N- [1- (3-trifluoromethyl
Tylphenyl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ke
2.0 g ton and 1- (3-trifluoromethylphenyi)
F) 3.51 g of ethylamine hydrochloride, triethylamido
6.5 ml, titanium tetrachloride 1.03 ml, hydrogenated shear
2.06 g of sodium borohydride and 0.67 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) using the title compound
Was obtained as a yellow oil. NMR spectrum (CDCl3) 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-methoxyphenyl)-(1-
(3-trifluoromethylphenyl) ethylamino) me
Tyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
) Methyl] -N- [1- (3-trifluoromethyl
Nyl) ethyl] amine 2.85 g and nickel chloride hexahydrate
3.15 g and sodium borohydride 1.05 g
And reacted in the same manner as in Example (1b) to give the title compound.
The product was obtained as a yellow oil (2.60 g). NMR spectrum (CDCl3) 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-meth
Xyphenyl)-(1- (3-trifluoromethylphen)
Nyl) ethylamino) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-(1- (3-trif
Fluoromethylphenyl) ethylamino) methyl] phenyl
2-amine, 4-t-butoxy-3-methoxy
Using 1.49 g of -3-cyclobutene-1,2-dione
The reaction was carried out and purified in the same manner as in Example (66c).
The isomer (A) of the title compound was converted into a pale yellow foam by 620 m
g, 650 mg of isomer (B) as a pale yellow foam
Was. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-methoxy
Cyphenyl)-(1- (3-trifluoromethylphenyi)
Ru) ethylamino) methyl] phenylamino -3-
Clobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-(1- (3-trifluoromethylphenyl) ethyl
Ruamino) methyl] phenylamino} -3-cyclobute
Using 610 mg of the isomer (A) of 1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
522 mg of the desired isomer (A) was obtained as a brown solid. Isomer (A) NMR spectrum (DMSO-d6) 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) ethyl
Ruamino) methyl] phenylamino} -3-cyclobute
Using 630 mg of isomer (B) of 1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
457 mg of the desired isomer (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 784- {3-[(1- (3,4-dimethylphenyl) ethyl
Ruamino)-(4-methoxyphenyl) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobutene-1,
2-dione hydrochloride (Exemplary Compound No. 2-3349) (78a) N- [1- (3,4-dimethylphenyl) e
Tyl] -N-[(4-methoxyphenyl)-(3-nitro
Phenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) ke
1.0 g of ton and 1- (3,4-dimethylphenyl) ethyl
1.44 g of triamine hydrochloride, 3.2 of triethylamine
5 ml, titanium tetrachloride 0.51 ml, hydrogenated cyanide
Using 1.03g of sodium iodide and 0.33ml of acetic acid
The reaction was carried out in the same manner as in Example (1a), and the title compound was converted to yellow.
1.45 g were obtained as an oil. NMR spectrum (CDCl3) 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-dimethylphenyl)
[Ethylamino)-(4-methoxyphenyl) methyl] f
Phenylamine N- [1- (3,4-dimethylphenyl) ethyl] -N-
[(4-methoxyphenyl)-(3-nitrophenyl)
1.32 g of [methyl] amine and nickel chloride hexahydrate
Using 61 g and 539 mg of sodium borohydride
The reaction was carried out and purified in the same manner as in Example (1b).
The compound was obtained as a yellow oil (1.10 g). NMR spectrum (CDCl3) 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) -ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[(1- (3,4-dimethylphenyl) ethylamido
No)-(4-methoxyphenyl) methyl] phenylamido
1.06 g, 4-t-butoxy-3-methoxy-3-
Performed using 812 mg of cyclobutene-1,2-dione
The reaction was performed and purified in the same manner as in Example (66c) to give the title compound
456 mg of isomer (A) as yellow foam,
428 mg of (B) was obtained as a pale yellow foam. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-dimethylphene)
Nyl) ethylamino)-(4-methoxyphenyl) methyl
Ru] phenylamino} -3-hydroxy-3- Cyclob
Ten-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(1- (3,4-dimethyl
Tylphenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl] phenylamino} -3-cyclobutene-
Performed using 360 mg of 1,2-dione isomer (A)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
289 mg of isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-dimethyl)
Tylphenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl] phenylamino} -3-cyclobutene-
Performed with 350 mg of 1,2-dione isomer (B)
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound.
305 mg of isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 794- {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-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
L] phenylamino} -3-methoxy-3-cyclobute
1,2-dione isomer (B) 500 mg and 50 w
t% -hydroxyamine solution in 0.064 ml of meta
After stirring a 5 ml solution of ethanol for 1 hour at room temperature,
Was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
Raffy (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-d6) 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). Example 804- {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-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
L] phenylamino} -3-methoxy-3-cyclobute
300 mg of the isomer (B) of 1,2-dione and 50 w
Using 0.038 ml of t% -hydroxylamine aqueous solution
The reaction and purification were carried out in the same manner as in Example (79).
270 mg of sexual form (B) was obtained as a brown solid. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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). Example 81{2- [3-(((R) -1- (3,4-difluorophenyl)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl) phenylamino] -3,4-dioxo-1-cycl
Lobuten-1-yl-amino diacetic acid hydrochloride (exemplified compound
Object number 2-3513) (81a) {2- [3-(((R) -1- (3,4-di
Fluorophenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl) phenylamino] -3,4- Dioxo
-1-cyclobuten-1-yl-amino} -acetic acid t-
Butyl ester 4- {3-[[(R) -1- (3,4-
Difluorophenyl) ethylamino]-(4-methoxy
Phenyl) methyl] phenylamino} -3-methoxy-
Isomer (B) 30 of 3-cyclobutene-1,2-dione
0 mg and glycine t-butyl ester hydrochloride 116 m
g of t-butanol in 5 ml of suspension was added to triethylamine.
0.13 ml was added and reacted at room temperature for 3 hours. Reaction liquid
Was diluted with ethyl acetate and washed with saturated saline.
Dried with cesium and concentrated. Residue is silica gel column
Chromatography (elution solvent: cyclohexane / acetic acid
Purified with ethyl = 1/1) to give the isomer of the title compound (B)
Was obtained as a pale yellow foam. Isomer (B) NMR spectrum (CDCl3) 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-di
Fluorophenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl) phenylamino] -3,4- Dioxo
-1-cyclobuten-1-ylaminodiacetic acid hydrochloride {2- [3-(((R) -1- (3,4-difluorophenyl)
Enyl) ethylamino)-(4-methoxyphenyl) meth
Tyl) phenylamino] -3,4-dioxo-1-cycl
Lobuten-1-ylamino diacetic acid t-butyl ester
Example (63b) using 280 mg of isomer (B) of
Reaction and purification were conducted in the same manner to give the isomer (B) of the title compound in white.
250 mg were obtained as a solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 822- {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-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
L] phenylamino} -3-methoxy-3-cyclobute
300 mg of isomer (B) of 1,2-dione
Meta- of 0.26 ml of tylamine and 157 mg of taurine
The 5 ml solution was stirred at room temperature for 4 hours. 1N reaction solution
-After neutralization with hydrochloric acid, the mixture was diluted with water and ethyl acetate. Precipitation
The separated solid was collected by filtration and silica gel column chromatography.
-(Eluent: methylene chloride / methanol = 10/1)
Purified by isomerization to give the isomer (B) of the title compound as a white solid
205 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 834- {3-[(4-fluorophenyl)-(1- (thio
Phen-2-yl) ethylamino) methyl] phenyla
Mino} -3-hydroxy-3-cyclobutene-1,2-
Dione hydrochloride (Exemplary Compound No. 2-81) (83a) N-[(4-fluorophenyl)-(3-d
Trophenyl) methyl] -N- [1- (thiophene-2
-Yl) ethyl] amine 1.80 g of 4-fluoro-3'-nitrobenzophenone
And 1- (thiophen-2-yl) ethylamine hydrochloride
2.05 g, 6.1 ml of triethylamine and tetrachloride
Reaction in the same manner as in Example (1a) using 0.9 ml of titanium
Was carried out to obtain an imine compound. With the resulting imine compound
1.84 g of sodium cyanoborohydride and acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.6 ml.
Thus, 2.43 g of the title compound was obtained as a yellow oily substance. NMR spectrum (CDCl3) 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) methyl] fe
Nilamine N-[(4-fluorophenyl)-(3-nitrophenyl
M)]-N- [1- (thiophen-2-yl) d
Tyl] amine 2.41 g, nickel chloride hexahydrate 3.2
Using 2 g and 1.03 g of sodium borohydride
The reaction was carried out in the same manner as in Example (59b), and the product was separated and purified.
The compound isomer (A) was converted to a light yellow oily material by 687.
mg, isomer (B) of the title compound as a pale yellow oily substance.
552 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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.
1, 5.1Hz), 7.29 (2H, dd, J = 5.5, 8.6Hz). Isomer (B) NMR spectrum (CDCl3) 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-fur
Orophenyl)-(1- (thiophen-2-yl) ethyl
Ruamino) methyl] phenylamino} -3-ci Clobute
N-1,2-dione 3-[(4-fluorophenyl)-(1- (thiophene
-2-yl) ethylamino) methyl] phenylamine
Isomer (A) 320 mg and 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 431 m
g, and reacted in the same manner as in Example (1c).
431 mg of the compound isomer (A) as a white foamy solid
Obtained. Isomer (A) NMR spectrum (CDCl3) 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). 3-[(4-fluorophenyl)-(1- (thiophene
-2-yl) ethylamino) methyl] phenylamine
Isomer (B) 280 mg, 4-t-butoxy-3-methoate
190 mg of xy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c).
317 mg of the product isomer (B) as a white foamy solid
Was. Isomer (B) NMR spectrum (CDCl3) 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-fluorophenyl)-
(1- (thiophen-2-yl) ethylamino) methyl
Ru] phenylamino} -3-hydroxy-3-cycl Rob
Ten-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl
Ru)-(1- (thiophen-2-yl) ethylamino)
Methyl] phenylamino} -3-cyclobutene-1,2
-Isomer of dione (A) (351 mg), trifluoroacetic acid
Using 1.5 ml, the reaction was carried out in the same manner as in Example (63b).
Thus, the isomer (A) of the title compound was converted to a white solid by 28
2 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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
Ru)-(1- (thiophen-2-yl) ethylamino)
Methyl] phenylamino} -3-cyclobutene-1,2
285 mg of dione isomer (B), trifluoroacetic acid
Using 1.5 ml, the reaction was carried out in the same manner as in Example (63b).
Thus, the isomer (B) of the title compound was converted to a white solid by 22%.
5 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 844- {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 1.72 g of 4-fluoro-3'-nitrobenzophenone
And 1- (3,5-dimethoxyphenyl) ethylamine salt
2.73g, triethylamine 5.8ml and tetrachloride
Reaction in the same manner as in Example (1a) using 0.9 ml of titanium
Was carried out to obtain an imine compound. With the resulting imine compound
1.76 g of sodium cyanoborohydride, 0.1% of acetic acid.
The reaction was carried out in the same manner as in Example (1a) using
2.71 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl3) 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-dimethoxyphenyl)
Ru) ethylamino]-(4-fluorophenyl) methyl
Ru] phenylamine N- [1- (3,5-dimethoxyphenyl) ethyl] -N
-[(4-fluorophenyl)-(3-nitrophenyl
2.70 g of methyl] amine, nickel chloride hexahydrate
3.13 g and 1.00 g of sodium borohydride
The reaction was carried out in the same manner as in Example (59b) for separation and purification.
To give the isomer (A) of the title compound as a pale yellow oil
892 mg, isomer (B) of the title compound as a pale yellow oil
546 mg were obtained as quality. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(4
-Fluorophenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[[1- (3,5-dimethoxyphenyl) ethyla
Mino]-(4-fluorophenyl) methyl] phenyla
708 mg of the isomer of amine (A), 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 411
The reaction was carried out in the same manner as in Example (1c) using
The isomer (A) of the title compound was converted into a white foamy solid in 953 m
g was obtained. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[1- (3,5-dimethoxyphenyl) ethyla
Mino]-(4-fluorophenyl) methyl] phenyla
526 mg of the isomer of min (B), 4-t-butoxy-3
-Methoxy-3-cyclobutene-1,2-dione 306
The reaction was carried out in the same manner as in Example (1c) using
The isomer (B) of the title compound was converted to a white foamy solid by 673 m
g was obtained. Isomer (B) NMR spectrum (CDCl3) 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-dimethoxypropane)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dimension)
Toxiphenyl) ethylamino]-(4-fluorophene
Nyl) methyl] phenylamino} -3-cyclobutene-
426 mg of isomer (A) of 1,2-dione, trifluo
Using 2 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
The isomer (A) of the title compound was converted into a white solid to give 3
71 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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-dimension)
Toxiphenyl) ethylamino]-(4-fluorophene
Nyl) methyl] phenylamino} -3-cyclobutene-
338 mg of 1,2-dione isomer (B), trifluoro
In the same manner as in Example (63b),
To give the isomer (B) of the title compound as a white solid.
241 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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. Example 854- {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
Trifluorophenyl) ethyl] amine 2.14 g of 4-fluoro-3'-nitrobenzophenone
And 1- (3,4,5-trifluorophenyl) ethyla
3.33 g of min hydrochloride, 7.2 ml of triethylamine and
Same as Example (1a) using 1.1 ml of titanium tetrachloride
To give an imine compound. The resulting iminization
Compound and sodium borohydride 2.19 g, vinegar
The reaction was carried out in the same manner as in Example (1a) using 0.7 ml of the acid.
This gave 3.35 g of the title compound as a yellow oil. NMR spectrum (CDCl3) 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) -ethylamido
[No] -methyl] -phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl
M)]-N- [1- (3,4,5-trifluoro)
Phenyl) 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 Example (59b) using
To give the isomer (A) of the title compound as a pale yellow oily substance.
1.25 g, isomer (B) of the title compound as pale yellow oil
975 mg of material were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-fur
Orophenyl)-[1- (3,4,5-trifluorophenyl)
Enyl) ethylamino] methyl] phenylami NO-3
-Cyclobutene-1,2-dione 3-[(4-fluorophenyl)-[1- (3,4,5
-Trifluorophenyl) ethylamino] methyl] fe
Nylamine isomer (A) 450 mg, 4-t-butoki
C-3-methoxy-3-cyclobutene-1,2-dione
Using 266 mg, a reaction was conducted in the same manner as in Example (1c).
To give 9% of the isomer (A) of the title compound as a white foamy solid.
53 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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
-Trifluorophenyl) ethylamino] methyl] fe
928 mg of isomer (B) of nylamine, 4-t-butoxy
C-3-methoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using 548 mg.
To give the isomer (B) of the title compound as a white foamy solid
1.25 g were obtained. Isomer (B) NMR spectrum (CDCl3) 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-fluorophenyl)-
[1- (3,4,5-trifluorophenyl) ethyla
[Mino] methyl] phenylamino} -3-hydroxy C-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl
)-[1- (3,4,5-trifluorophenyl) e
[Tylamino] methyl] phenylamino} -3-cyclobu
473 mg of isomer (A) of ten-1,2-dione,
As in Example (63b), using 1 ml of fluoroacetic acid
Perform the reaction to convert the isomer (A) of the title compound to a white solid.
350 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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) e
[Tylamino] methyl] phenylamino} -3-cyclobu
509 mg of isomer (B) of ten-1,2-dione,
As in Example (63b), using 1 ml of fluoroacetic acid
The reaction was performed to convert the isomer (B) of the title compound into a white solid.
310 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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. Example 864- {3-[[1- (3,5-dichlorophenyl) -d
Tylamino]-(4-fluorophenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobute N-
1,2-dione hydrochloride (Exemplary Compound No. 2-350
5)(86a) N- [1- (3,5-dichlorophenyl) e
Tyl] -N-[(4-fluorophenyl)-(3-nitro
Lophenyl) methyl] amine 2.02 g of 4-fluoro-3'-nitrobenzophenone
And 1- (3,5-dichlorophenyl) ethylamine hydrochloride
3.00 g of salt, 6.8 ml of triethylamine and tetrasalt
In the same manner as in Example (1a),
The reaction was performed to obtain an imine compound. The resulting imine compound
With 2.07 g of sodium cyanoborohydride and vinegar
The reaction was carried out in the same manner as in Example (1a) using 0.7 ml of the acid.
This gave 3.40 g of the title compound as a yellow oil. NMR spectrum (CDCl3) 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-dichlorophenyl)
Ethylamino]-(4-fluorophenyl) methyl] f
Phenylamine N- [1- (3,5-dichlorophenyl) ethyl] -N
-[(4-fluorophenyl)-(3-nitrophenyl
3.39 g of methyl] amine, nickel chloride hexahydrate
3.86 g, using 1.23 g of sodium borohydride
The reaction was carried out in the same manner as in Example (59b) to separate and purify
The isomer (A) of the title compound was obtained as a pale yellow oily substance (97%).
0 mg, 5 mg of the isomer (B) of the title compound as a white solid.
67 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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} -3 −
Clobutene-1,2-dione 3-[[1- (3,5-dichlorophenyl) ethylamido
No]-(4-fluorophenyl) methyl] phenylami
Isomer (A) 491 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 279 m
g, and reacted in the same manner as in Example (1c).
400 mg of isomer (A) of the compound was obtained as a white solid.
Was. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[1- (3,5-dichlorophenyl) ethylamido
No]-(4-fluorophenyl) methyl] phenylami
Isomer (B) 535 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 304m
g, and reacted in the same manner as in Example (1c).
646 mg of the isomer (B) of the compound as a white foamy solid
Obtained. Isomer (B) NMR spectrum (CDCl3) δ ppm: 1.35 (3H, d, J =
6.7Hz), 1.64 (9H, s) .3.61 (1H, q, J = 6.7Hz), 4.59 (1H
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-dichlorophene)
Nyl) ethylamino]-(4-fluorophenyl) methyl
Ru] phenylamino} -3-hydroxy-3- Cyclob
Ten-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dic
Lorophenyl) ethylamino]-(4-fluorophenyl
Ru) methyl] phenylamino} -3-cyclobutene-
391 mg of 1,2-dione isomer (A), trifluoro
Using 1 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
The isomer (A) of the title compound was converted into a white solid to give 3
26 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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- Zig
Lorophenyl) ethylamino]-(4-fluorophenyl
Ru) methyl] phenylamino} -3-cyclobutene-
605 mg of 1,2-dione isomer (B), trifluoro
In the same manner as in Example (63b),
To give the isomer (B) of the title compound as a white solid.
498 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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. Example 874- {3-[[1- (3,4-difluorophenyl) p
Ropylamino]-(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 2.00 g of 4-methoxy-3'-nitrobenzophenone
And 1- (3,4-difluorophenyl) propylamine
2.75 g of hydrochloride, 6.5 ml of triethylamine and tetrasalt
In the same manner as in Example (1a),
The reaction was performed to obtain an imine compound. The resulting imine compound
And 1.97 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.7 ml.
Thus, 3.18 g of the title compound was obtained as a yellow oily substance. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) propylamino]-(4-methoxyphenyl) methyl
Ru] phenylamine N- [1- (3,4-difluorophenyl) propyl]
-N-[(4-methoxyphenyl)-(3-nitrophen
Nyl) methyl] amine 3.17 g, nickel chloride hexahydrate
3.66 g of product, 1.17 g of sodium borohydride
And the reaction was carried out in the same manner as in Example (1b).
2.76 g were obtained as a pale yellow oil. NMR spectrum (CDCl3) 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) propylamino]-
(4-methoxyphenyl) methyl] phenylamino} −
3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) propyl
Amino]-(4-methoxyphenyl) methyl] phenyl
Amine 2.70 g, 4-t-butoxy-3-methoxy
Using 1.56 g of -3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (66c),
To give the isomer (A) of the title compound as a white foam.
52 mg, isomer (B) of the title compound as a white foam
657 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) δ ppm: 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-difluorofuran)
Enyl) propylamino]-(4-methoxyphenyl)
Methyl] phenylamino} -3-hydroxy- 3-sik
Lobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) propylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
622 mg of isomer (A) of -1,2-dione, triflu
As in Example (63b), using 1.5 ml of oloacetic acid
Perform the reaction to convert the isomer (A) of the title compound to a white solid.
482 mg was obtained. Isomer (A) NMR spectrum (DMSO-d6) 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- Jiff
Fluorophenyl) propylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
626 mg of isomer (B) of -1,2-dione, triflu
As in Example (63b), using 1.5 ml of oloacetic acid
The reaction was performed to convert the isomer (B) of the title compound into a white solid.
498 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 884- {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 4-fluoro-2'-methoxy-5'-nitrobenzofu
3.11 g of enone and 1- (3,4-difluorophenyl)
R) 2.73 g of ethylamine hydrochloride, triethylamine
Example using 5.8 ml and 0.9 ml of titanium tetrachloride
The reaction was carried out in the same manner as in (1a) to obtain an imine compound. Profit
Imine compounds and sodium borohydride cyanide
Example 1. Using 1.76 g and 0.6 ml of acetic acid,
Perform the same reaction, and separate and purify the isomer of the title compound.
1.62 g of (A) as a white solid, isomer of the title compound
2.19 g of the compound (B) was obtained as a white solid. Isomer (A) NMR spectrum (CDCl3) 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 = 2.8Hz). Isomer (B) NMR spectrum (CDCl3) δppm: 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-difluorophenyl)
Ru) ethylamino]-(4-fluorophenyl) methyl
Ru] -4-methoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(4-fluorophenyl)-(2-methoxy-5-
Nitrophenyl) methyl] amine isomer (A) 700
mg, nickel chloride hexahydrate 800mg, borohydride
As in Example (1b) using 258 mg of sodium
The reaction was carried out, and the isomer (A) of the title compound was converted into a pale yellow oily substance.
532 mg were obtained as quality. Isomer (A) NMR spectrum (CDCl3) 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) 660
mg, 762 mg of nickel chloride hexahydrate, borohydride
As in Example (1b) using 243 mg of sodium
The reaction was carried out, and the isomer (B) of the title compound was converted into a pale yellow oily substance.
332 mg were obtained as quality. Isomer (B) NMR spectrum (CDCl3) 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) ethylamino]-(4
-Fluorophenyl) methyl] -4-methoxy Nil
Amino} -3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(4-fluorophenyl) methyl] -4-metho
526 mg of isomer (A) of 4-phenylphenylamine
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 351 mg of dione, in the same manner as in Example (1c),
To give the isomer (A) of the title compound as a white foamy solid.
588 mg was obtained. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino]-(4-fluorophenyl) methyl] -4-metho
Xiphenylamine (B) 324 mg, 4-t-butoki
C-3-methoxy-3-cyclobutene-1,2-dione
Using 232 mg, the reaction was carried out in the same manner as in Example (1c).
To give the isomer (B) of the title compound as a white foamy solid.
07 mg were obtained. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] -4-methoxyphenylamino} -3- Hydroxy
C-3-cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] -4-methoxyphenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 560 m
g, 1.5 ml of trifluoroacetic acid.
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-d6) 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-diph
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] -4-methoxyphenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 402m
g, 1 ml of trifluoroacetic acid, Example (55b)
The reaction was carried out in the same manner as in
153 mg were obtained as a colored solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 894- {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] a Min 4-fluoro-3 ', 4'-dimethoxy-5'-nitro
2.47 g of benzophenone and 1- (3,4-difluoro
2.83 g of phenyl) ethylamine hydrochloride, triethyl
Using 5.6 ml of amine and 1.0 ml of titanium tetrachloride,
The reaction was carried out in the same manner as in Example (1a) to obtain an imine compound.
Was. Obtained imine compounds and borohydride cyanide
Example (1) using 2.04 g of lithium and 0.7 ml of acetic acid
The reaction was carried out in the same manner as in a), and the title compound was converted to a yellow oily substance.
3.42 g was obtained. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino]-(4-fluorophenyl) methyl
Ru] -2,3-Dimethoxyphenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(4-fluorophenyl)-(3,4-dimethoxy
-5-nitrophenyl) methyl] amine 3.42 g, salt
3.65 g of nickel hydride hexahydrate, sodium borohydride
The reaction was carried out in the same manner as in Example (59b) using 1.17 g of
The product was separated and purified, and the isomer (A)
1.10 g as a color oil, isomer of the title compound
1.39 g of (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(4
-Fluorophenyl) methyl] -2,3-dimethoxy Schiff
Phenylamino} -3-cyclobutene-1,2-dione 5-[[1- (3,4-difluorophenyl) ethyla
Mino]-(4-fluorophenyl) methyl] -2,3-
637 mg of dimethoxyphenylamine isomer (A),
4-t-butoxy-3-methoxy-3-cyclobutene-
As in Example (1c), using 338 mg of 1,2-dione
In a similar manner to give the isomer (A) of the title compound in a white foam.
690 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino]-(4-fluorophenyl) methyl] -2,3-
660 mg of isomer (B) of dimethoxyphenylamine,
4-t-butoxy-3-methoxy-3-cyclobutene-
Same as Example (1c) using 350 mg of 1,2-dione
In a similar manner to give the isomer (B) of the title compound in a white foam.
602 mg were obtained as a solid. Isomer (B) NMR spectrum (CDCl3) 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)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] -2,3-dimethoxyphenylamino} -3-hi
Droxy-3-cyclobutene-1,2-dione 3-t-butoxy-4- {5-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] -2,3-dimethoxyphenylamino}
Isomer (A) 6 of -3-cyclobutene-1,2-dione
Example (5) using 88 mg and 1 ml of trifluoroacetic acid.
The reaction was carried out in the same manner as in 5b) to give the isomer of the title compound.
350 mg of (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-diph)
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] -2,3-dimethoxyphenylamino}
Isomer (B) 5 of -3-cyclobutene-1,2-dione
Example (5) was prepared using 95 mg and 1 ml of trifluoroacetic acid.
The reaction was carried out in the same manner as in 5b) to give the isomer of the title compound.
360 mg of (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 904- {3-[[1- (3,4-difluorophenyl) e
Tylamino]-(4-methoxyphenyl) methyl] ben
Ziramino {-3-hydroxy-3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-117) (90a) 3-t-butoxy-4- {3-[[1-
(3,4-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] benzylamino}- 3-
Cyclobutene-1,2-dione N-[(3-aminomethylphenyl)-(4-methoxy
Phenyl) methyl] -N- [1- (3,4-difluoro
Phenyl) ethyl] amine dihydrochloride 1.47 g, triet
4-t- in 0.8 ml of tylamine 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. Reaction liquid
Was neutralized with hydrochloric acid and concentrated under reduced pressure. Extract the residue with ethyl acetate
The organic layer was washed with water and saturated saline, and then washed with sodium sulfate.
It was dried over lithium and concentrated under reduced pressure. Silica gel residue
Matography (elution solvent: hexane / ethyl acetate = 2
/ 1) to give the title compound as a white foamy solid.
09 g were obtained. NMR spectrum (CDCl3) 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)
Enyl) ethylamino]-(4-methoxyphenyl) meth
Tyl] benzylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] benzylamino} -3-cyclobutene-
Using 1.08 g of 1,2-dione, Example (55b)
The same reaction was carried out, and the title compound was converted into a white solid in the form of 889.
mg. NMR spectrum (DMSO-d6) 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 br)
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. Example 914- {4-[[1- (3,4-difluorophenyl) e
Tylamino]-(4-methoxyphenyl) methyl] ben
Ziramino {-3-hydroxy-3-cyclobutene-
1,2-dione (Exemplary Compound No. 3-47) (91a) 3-t-butoxy-4- {4-[[1-
(3,4-difluorophenyl) ethylamino]-(4
-Methoxyphenyl) methyl] benzylamino}- 3-
Cyclobutene-1,2-dione N-[(4-aminomethylphenyl)-(4-methoxy
Phenyl) methyl] -N- [1- (3,4-difluoro
1.88 g of phenyl) ethyl] amine dihydrochloride,
3.3 ml of tylamine, 4-t-butoxy-3-methoxy
Using 883 mg of c-3-cyclobutene-1,2-dione
And the reaction was carried out in the same manner as in Example (90a).
To give the isomer (A) of the title compound as a white foam.
45 mg of isomer (B) of the title compound as a white foam
712 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-difluorofuran)
Enyl) ethylamino]-(4-methoxyphenyl) meth
Tyl] benzylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione 3-t-butoxy-4- {4-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] benzylamino} -3-cyclobutene-
Performed with 622 mg of 1,2-dione isomer (A)
The reaction was carried out in the same manner as in Example (55b), and the title compound was converted to white
168 mg were obtained as a solid. Isomer (A) NMR spectrum (DMSO-d6) 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 ° C (dec) 3-t-butoxy-4- {4-[[1- (3,4-diph.
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] benzylamino} -3-cyclobutene-
Using 705 mg of 1,2-dione isomer (B)
The reaction was carried out in the same manner as in Example (55b), and the title compound was converted to white
266 mg were obtained as a solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 924- {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) ethyla
Mino]-(4-methoxyphenyl) methyl] phenyla
Min 396 mg, 4-t-butoxy-3-methoxy-
Isomer (A) 23 of 3-cyclobutene-1,2-dione
Using 7 mg, the reaction was carried out in the same manner as in Example (1c).
The isomer (A) of the title compound was converted into a white foamy material in an amount of 525 m
g was obtained. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(4-methoxyphenyl) methyl] phenyla
Miner isomer (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 Example (1c) using
464 mg of isomer (B) of the compound as a white foam
Obtained. Isomer (B) NMR spectrum (CDCl3) 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)
Enyl) ethylamino]-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamino} -3-cyclobutene-
Using 511 mg of isomer (A) of 1,2-dione,
The reaction was carried out in the same manner as in Example (55b), and the
257 mg of sexual form (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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- Jiff
Fluorophenyl) -ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
774 mg of isomer (B) of -1,2-dione, triflu
Reaction was carried out in the same manner as in Example (55b) using 4 ml of oloacetic acid.
To give the isomer (B) of the title compound as a white solid
642 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) 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 = 7.4 Hz), 7.64 (1H, s). Melting point: 183 ° C (dec).(92c) 4- {3-[[1- (3,4-difluorophenyl)
Enyl) ethylamino]-(4-methoxyphenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamino} -3-cyclobutene-
462 mg of 1,2-dione isomer (B), ethyl acetate
Add 2 ml of 4N hydrochloric acid / ethyl acetate to 2 ml and add 1.5 hours
While stirring. The resulting solid is collected and ethyl acetate-diethyl
After washing with ether, the isomer (B) of the title compound was obtained as a white solid
120 mg was obtained as a body. Isomer (B) NMR spectrum (DMSO-d6) 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. Example 934- {3-[[1- (3,5-difluorophenyl) e
Tylamino]-(4-methoxyphenyl) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione (Exemplary Compound No. 2-56) (93a) 3-[[1- (3,5-difluorophenyl)
Ru) ethylamino]-(4-methoxyphenyl) methyl
Ru] phenylamine [1- (3,5-difluorophenyl) ethyl]-
[(4-methoxyphenyl)-(3-nitrophenyl)
8.59 g of [methyl] amine, nickel chloride hexahydrate
05 g and 2.89 g of sodium borohydride
The reaction was carried out in the same manner as in Example (59b), and the product was separated and purified.
1.18 of compound isomer (A) as pale yellow oil
g, isomer (B) of the title compound as a pale yellow oil
1.17 g were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(4
-Methoxyphenyl) methyl] phenylamino}- 3-
Cyclobutene-1,2-dione 3-[[1- (3,5-difluorophenyl) ethyla
Mino]-(4-methoxyphenyl) methyl] phenyla
552 mg of isomer of amine (A) 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 Example (1c).
Isomer (A) of the title compound as a white foam, 740
mg. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[1- (3,5-difluorophenyl) ethyla
Mino]-(4-methoxyphenyl) methyl] phenyla
570 mg of the isomer of amine (B) and 4-t-butoxy
-3-methoxy-3-cyclobutene-1,2-dione 3
Using 42 mg, the reaction was carried out in the same manner as in Example (1c).
Isomer (B) of the title compound as a white foam, 808
mg. Isomer (B) NMR spectrum (CDCl3) 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-difluorofuran)
Enyl) ethylamino]-(4-methoxyphenyl) meth
Tyl] phenylamino {3-hydroxy-3- Cyclob
Ten-1,2-dione 3-t-butoxy-4- {3-[[1- (3,5-diph
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamino} -3-cyclobutene-
Using 738 mg of 1,2-dione isomer (A)
The reaction was carried out in the same manner as in Example (55b) to give the isomer of the title compound.
489 mg of the compound (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-diff
Fluorophenyl) ethylamino]-(4-methoxy
Nyl) methyl] phenylamino} -3-cyclobutene-
Performed using 807 mg of 1,2-dione isomer (B)
The reaction was carried out in the same manner as in Example (55b) to give the isomer of the title compound.
510 mg of the compound (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 943-hydroxy-4- {3-[(4-methoxyphenyi)
)-((R) -1- (p-tolyl) ethylamino)
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione hydrochloride (Exemplary Compound No. 2-3491) (94a) N-[(4-methoxyphenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (p-to
Ryl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
10.79 g of tanone and (R) -1- (p-tolyl) ethyl
The same procedure as in Example (1a) was carried out using 5.67 g of
7.78 g of the title compound as a pale yellow oil.
Obtained. NMR spectrum (CDCl3) 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-methoxyphenyl)-((R)
-1- (p-tolyl) -ethylamino) methyl] phenyl
Luamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (p-tolyl) ethyl
[7] Dissolve 7.72 g of amine in 150 ml of ethanol
And 15.6 g of anhydrous tin (II) (II) chloride was added.
The mixture was heated under reflux for 3 hours. After cooling, the ethanol is distilled off
Dissolve the residue in ethyl acetate and add 1N aqueous sodium hydroxide
The organic layer was washed with the liquid and saturated saline. Organic layer is sulfuric anhydride
It was obtained by drying over magnesium and evaporating the solvent under reduced pressure.
The yellow oil was purified by silica gel column chromatography (solvent).
The solvent was purified using toluene / THF = 8/1),
Isomer (A) and isomer (B) of the title compound
1.43 g and 0.78 g were obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-meth
(Xyphenyl)-((R) -1- (p-tolyl) ethyl
Amino) methyl] phenylamino} -3-cycl Lobuten
-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (p
-Tolyl) ethylamino) methyl] phenylamine
1.41 g of the isomer (A) was dissolved in 25 ml of methanol,
3-t-butoxy-4-methoxy-3-cyclobutene-
Add 1.12 g of 1,2-dione and stir at room temperature for 1 hour
After that, the solvent was distilled off under reduced pressure. The obtained pale yellow foam
To silica gel column chromatography (elution solvent,
(Ruene / THF = 10/1) to give the title compound
780 mg of isomer (A) was obtained as a pale yellow foam. Isomer (A) NMR spectrum (CDCl3) 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
Sex form (B) 750 mg, 3-t-butoxy-4-methoxy
C-3-cyclobutene-1,2-dione 598 mg,
Isomer (A) of the title compound using 10 ml of ethanol
In the same manner as in the production of
990 mg of the compound (B) was obtained as a pale yellow oil. Isomer (B) NMR spectrum (CDCl3) 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-methoxy)
Cyphenyl)-((R) -1- (p-tolyl) ethyla
Mino) methyl] phenylamino} -3-cyclo Butene
1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-((R) -1- (p-tolyl) ethylamino)
Tyl] phenylamino} -3-cyclobutene-1,2-
Using 768 mg of the dione isomer (A),
The reaction was carried out in the same manner as in b), and the isomer (A)
584 mg were obtained as a pale yellow-white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-methoxyphenyi)
)-((R) -1- (p-tolyl) ethylamino)
Tyl] phenylamino} -3-cyclobutene-1,2-
Using 970 mg of the dione isomer (B),
The reaction was carried out in the same manner as in b), and the isomer (B)
652 mg were obtained as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 953-hydroxy-4- (3-{(4-methoxyphenyl)
)-[(R) -1- (4-methoxyphenyl) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
-1,2-dione hydrochloride (Exemplary Compound No. 2-74) (95a) N-[(R) -1- (4-methoxyphenyi)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
6.00 g of tanone and (R) -1- (4-methoxyphenyl)
(1) Using 5.32 g of ethylamine as in Example (1a)
Perform the same reaction to give the title compound as a pale yellow oil.
8.83 g were obtained. NMR spectrum (CDCl3) δ ppm:
 1.36 and 1.37 (total 3H, each d, J = 6.61 and 6.62H
z), 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 1H, each s), 6.77-6.93 (4H, m), 7.0
9-7.24 (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 7.94Hz), 8.01 and8.08 (total 1H, each d
d, J = 2.0, 7.9 and 2.0, 8.0Hz), 8.22 and 8.27 (total
1H, each d, J = 1.86 and 1.91Hz).(95b) 3-{(4-methoxyphenyl)-[(R)
-1- (4-methoxyphenyl) ethylamino] methyl
Ruphenylamine N-[(R) -1- (4-methoxyphenyl) ethyl]
-N-[(4-methoxyphenyl)-(3-nitrophen
Nil) methyl] amine 8.83 g, anhydrous tin chloride (I
I) (II) 17.6 g, using 50 ml of ethanol
And reacted in the same manner as in Example (94b) to give the title compound
Isomer (A) and isomer (B) of pale yellow oil, respectively
As a result, 1.02 g and 1.06 g were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-meth
Xyphenyl)-[(R) -1- (4-methoxyphenyl)
Ru) ethylamino] methyl @ phenylamino) -3-
Clobutene-1,2-dione 3-{(4-methoxyphenyl)-[(R) -1- (4
-Methoxyphenyl) ethylamino] methyl @ phenyl
Amine isomer (A) 990 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 65
Example (1c) using 5 mg and 25 ml of methanol
The reaction was carried out in the same manner as described above, and the isomer (A) of the title compound was converted to pale yellow
1.29 g of a colored foam were obtained. Isomer (A) NMR spectrum (CDCl3) 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)-[(R) -1- (4
-Methoxyphenyl) ethylamino] methyl @ phenyl
1.03 g of isomer (B) of amine, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 78
Example (1c) using 7 mg and 25 ml of methanol
In the same manner as described above, and the isomer (B) of the title compound was converted to pale yellow
1.17 g of a colored foam were obtained. Isomer (B) NMR spectrum (CDCl3) δ ppm: 1.34 (3H, d, J =
6.6Hz), 1.62 (9H, s), 3.61 (1H, q, J = 6.6Hz), 3.80 (3
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-methoxy)
Cyphenyl)-[(R) -1- (4-methoxyphenyl)
Ru) ethylamino] methyl @ phenylamino)- 3-sh
Clobutene-1,2-dione hydrochloride 3-t-butoxy-4- (3-{(4-methoxyphenyl)
)-[(R) -1- (4-methoxyphenyl) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
Using 1.25 g of isomer (A) of -1,2-dione,
The reaction was carried out in the same manner as in Example (63b), and the
831 mg of the compound (A) was obtained as a pale yellowish white solid. Isomer (A) NMR spectrum (DMSO-d6) 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) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
Using 1.11 g of isomer (B) of -1,2-dione,
The reaction was carried out in the same manner as in Example (63b), and the
911 mg of the compound (B) was obtained as a pale yellowish white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 963- {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
Number 2-39) (96a) N-[(R) -1- (3,4-difluorophenyl)
Enyl) ethyl] -N-[(4-fluorophenyl)-
(3-Nitrophenyl) methyl] amine (4-fluorophenyl)-(3-nitrophenyl) meth
12.91 g of tanone and (R) -1- (3,4-difluoro)
Using 10.19 g of (phenyl) ethylamine hydrochloride
The reaction was carried out in the same manner as in Example (1a), and the title compound was pale yellow.
18.47 g were obtained as a colored oil. NMR spectrum (CDCl3) 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-difluoro
Phenyl) ethylamino]-(4-fluorophenyl)
Methyl] phenylamine N-[(R) -1- (3,4-difluorophenyl)
Tyl] -N-[(4-fluorophenyl)-(3-nitro
18.44 g of rophenyl) methyl] amine, nickel chloride
7.69 g of sodium hexahydrate, sodium borohydride7.
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.
The isomer (A) and the isomer (B) were each converted into a pale yellow oil
Thus, 1.27 g and 2.79 g were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-
(4-Fluorophenyl) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[[(R) -1- (3,4-difluorophenyl)
Ethylamino]-(4-fluorophenyl) methyl] f
1.24 g of isomer (A) of phenylamine, 3-t-butene
Xy-4-methoxy-3-cyclobutene-1,2-di
Using 963 mg of methanol and 15 ml of methanol.
The reaction was carried out in the same manner as (94c), and the isomer of the title compound was obtained.
597 mg of (A) was obtained as a white foam. Isomer (A) NMR spectrum (CDCl3) 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)
Ethylamino]-(4-fluorophenyl) methyl] f
1.31 g of isomer (B) of phenylamine, 3-t-butene
Xy-4-methoxy-3-cyclobutene-1,2-di
Example 1 using 1.01 g of methanol and 16 ml of methanol.
Reaction was carried out in the same manner as in (1c), and the isomer of the title compound was obtained.
997 mg of (B) was obtained as a white foam. Isomer (B) NMR spectrum (CDCl3) 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-diph
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] phenylamino} -4-hydro Kishi-3
-Cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[(R) -1- (3,
4-difluorophenyl) ethylamino]-(4-fur
Orophenyl) methyl] phenylamino} -3-cyclo
Using 585 mg of isomer (A) of butene-1,2-dione
And reacted in the same manner as in Example (55b) to give the title compound
516 mg of isomer (A) was obtained as a pale yellow-white solid. Isomer (A) NMR spectrum (DMSO-d6) 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 = 1.7Hz) 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,
4-difluorophenyl) ethylamino]-(4-fur
Orophenyl) methyl] phenylamino} -3-cyclo
Using 979 mg of isomer (B) of butene-1,2-dione
The reaction was carried out in the same manner as in Example (55b) to give the title compound
868 mg of isomer (B) was obtained as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d6) 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 = 1.8Hz), 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-diph
Fluorophenyl) ethylamino]-(4-fluorophen
Nyl) methyl] phenylamino} -4-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3- {3-[[(R) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-fluorophenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
337 mg of the isomer (A) of ten-1,2-dione
And 4N hydrochloric acid-ethyl acetate solution 3
ml was added and dissolved. The solvent was distilled off under reduced pressure to obtain
The pale yellow foam was suspended in ether and collected by filtration.
337 mg of the product isomer (A) was obtained as a pale yellowish white solid.
Was. Isomer (A) NMR spectrum (DMSO-d6) 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 ° C (dec) Optical rotation [α]_D= -50.6 (c = 1.00, AcO
H) 3- {3-[[(R) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-fluorophenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
404 mg of the isomer (B) of ten-1,2-dione
Use 4 ml of ethanol, 3 ml of 4N hydrochloric acid-ethyl acetate solution
And the same as when producing the isomer (A) of the title compound
To give the isomer (B) of the title compound as a pale yellow-white solid
(B) NMR spectrum (DMSO-d6) δmg: 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, 8.7Hz). Melting point: 172-180 ° C (dec) Optical rotation [α]_D= -17.2 (c = 1.01, AcO
H). Example 973- {3-[[(R) -1- (3-fluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl] F
Enylamino} -4-hydroxy-3-cyclobu Ten
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) meth
11.16 g of tanone and (R) -1- (3-fluorophene)
Example using 7.62 g of nyl) ethylamine hydrochloride
The reaction was carried out in the same manner as in (1a), and the title compound was converted into a pale yellow oil.
15.11 g was obtained as a product. NMR spectrum (CDCl3) 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-fluorophenyl)
Ru) -ethylamino]-(4-methoxyphenyl) methyl
Ru] phenylamine N-[(R) -1- (3-fluorophenyl) ethyl]
-N-[(4-methoxyphenyl)-(3-nitrophen
Nyl) methyl] amine 15.08 g, nickel chloride 6 water
18.84 g of the sum, 6.0 g of sodium borohydride,
As in Example (59b) using 150 ml of methanol
To the isomer (A) of the title compound, isomer
(B) was obtained as a pale yellow oily material in an amount of 787 mg, 6
05 mg was obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(4-
Methoxyphenyl) methyl] phenylamino -3-
Clobutene-1,2-dione 3-[[(R) -1- (3-fluorophenyl) ethyl
Amino]-(4-methoxyphenyl) methyl] phenyl
Amine isomer (A) 765 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 60
Example (94) using 3 mg and 10 ml of methanol.
The reaction was carried out in the same manner as in c), and the isomer (A)
767 mg were obtained as a white foam. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[(R) -1- (3-fluorophenyl) ethyl
Amino]-(4-methoxyphenyl) methyl] phenyl
Amine isomer (B) 582 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 45
Example 9 (94c) using 9 mg and 8 ml of methanol
In the same manner as described above, and the isomer (B) of the title compound was converted to pale yellow
792 mg were obtained as a colored foam. Isomer (B) NMR spectrum (CDCl3) 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-fluoro
Phenyl) ethylamino]-(4-methoxyphenyl)
Methyl] phenylamino} -4-hydroxy- 3-sik
Lobutene-1,2-dione 3-t-butoxy-4- {3-[[(R) -1- (3-
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
772 mg of isomer (A) of -1,2-dione, triflu
Performed using 3 ml of oloacetic acid and 10 ml of dichloromethane.
The reaction was carried out in the same manner as in Example (55b), and the isomer of the title compound was obtained.
635 mg of (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) δppm: 1.29 (3H, d, J
= 6.6Hz), 3.57-3.62 (1H, br), 3.68 (3H, s), 4.35 (1H, b
r.s), 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
= 8.0Hz), 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-
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
Using 476 mg of isomer (B) of -1,2-dione,
Using 3 ml of trifluoroacetic acid and 10 ml of dichloromethane
The reaction was carried out in the same manner as in Example (55b) to give the title compound
232 mg of isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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).
14-117 ° C (dec) Optical rotation [α]_D= + 44.7 (c = 1.01, AcO
H).(97e) 3- {3-[[(R) -1- (3-fluoro
Phenyl) ethylamino]-(4-methoxyphenyl)
Methyl] phenylamino} -4-hydroxy- 3-sik
Lobutene-1,2-dione hydrochloride 3- {3-[[(R) -1- (3-fluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl] F
Phenylamino} -4-hydroxy-3-cyclobutene-
133 mg of 1,2-dione isomer (A)
Using 3 ml of 4 ml of 4N hydrochloric acid-ethyl acetate solution,
The reaction was carried out in the same manner as in Example (96e).
122 mg of the sex form (A) was obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d6) δ ppm: 1.67 (3H, d, J
= 6.8Hz), 3.74 (3H, s), 4.15-4.30 (1H, br), 5.03 (1H, b
r.s), 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- {3-[[(R) -1- (3,4-difluorophene)
Nyl) ethylamino]-(4-fluorophenyl) methyl
L] phenylamino} -4-hydroxy-3-cyclobu
404 mg of the isomer (B) of ten-1,2-dione
4 ml of ethanol, 2 ml of 4N hydrochloric acid-ethyl acetate solution
And reacting in the same manner as in Example (96e) to give the title compound
146 mg of isomer (B) was obtained as a pale yellow-white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 983- (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) meth
8.03 g of tanone, (R) -1- (3-fluorophenyl)
L) Example (1) using 5.75 g of ethylamine hydrochloride
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 as a pale yellow oil, respectively.
g, 1.67 g. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino] methyl
Ruphenylamine N-[(R) -1- (3-fluorophenyl) ethyl]
-N-[(4-fluorophenyl)-(3-nitrophen
Nil) methyl] amine isomer (A) (2.82 g), chloride
3.64 g of nickel hexahydrate, sodium borohydride
Example (1) using 1.16 g and 30 ml of methanol
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 colorless oil (2.52 g). Isomer (A) NMR spectrum (CDCl3) 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]
-N-[(4-fluorophenyl)-(3-nitrophen
Nyl) methyl] amine isomer (B) 1.63 g, chloride
Nickel hexahydrate 2.11 g, sodium borohydride
Example (1) was performed using 6.74 g and 20 ml of methanol.
The reaction was carried out in the same manner as in b) to give the isomer (B) of the title compound.
Was obtained as a colorless oil. Isomer (B) NMR spectrum (CDCl3) 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-full
Orophenyl)-[(R) -1- (3-fluorophenyl)
Ru) ethylamino] methyl @ phenylamino) -3-
Clobutene-1,2-dione 3-{(4-fluorophenyl)-[1- (3-fluoro
Lphenyl) ethylamino] methyldiphenylamine
Isomer (A) 2.48 g, 3-t-butoxy-4-methoate
2.02 g of xy-3-cyclobutene-1,2-dione,
As in Example (94c), using 35 ml of methanol
To give the isomer (A) of the title compound as a white foam.
3.49 g was obtained. Isomer (A) NMR spectrum (CDCl3) 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-{(4-fluorophenyl)-[(R) -1- (3
-Fluorophenyl) ethylamino] methyl @ phenyl
1.46 g of isomer (B) of amine, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione
Using Example 19 (94 g) and methanol 30 ml,
The reaction was carried out in the same manner as in c), and the isomer (B)
2.04 g was obtained as a white foam. Isomer (B) NMR spectrum (CDCl3) 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-fluorophenyl)-
[(R) -1- (3-fluorophenyl) ethylamido
No] methyl {phenylamino) -4-hydroxy- 3-
Cyclobutene-1,2-dione trifluoroacetate 3-t-butoxy-4- (3-{(4-fluorophenyl
)-[(R) -1- (3-fluorophenyl) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
1.29 g of isomer (A) of -1,2-dione
Dissolve in 13 ml of methane and add 1 ml of trifluoroacetic acid
Was. After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure.
Toluene was added and azeotroped twice. D.
The title compound was converted to a white solid by filtration.
1.34 g were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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) ethyl
Amino] methyl @ phenylamino) -3-cyclobutene
2.00 g of isomer (B) of -1,2-dione, triflu
Isomer using 4 ml of acetic acid and 8 ml of dichloromethane
The reaction is carried out in the same manner as in (A), and the isomer of the title compound is obtained.
1.68 g of (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d6) 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-fluorophenyl)-
[(R) -1- (3-fluorophenyl) ethylamido
No] methyl {phenylamino) -4-hydroxy- 3-
Cyclobutene-1,2-dione 3- (3-{(4-fluorophenyl)-[(R) -1
-(3-Fluorophenyl) ethylamino] methyl
Enylamino) -4-hydroxy-3-cyclobutene-
Isomer (B) 5 of 1,2-dione trifluoroacetate
13 mg is dissolved in 5 ml of methanol, and phthalate standard
80 ml of the liquid (pH 4.01) was added. The resulting white precipitate
Was collected by filtration and washed thoroughly with water to give the title compound as a white solid.
453 mg were obtained. NMR spectrum (CDCl3) 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-fluorophenyl)-
[(R) -1- (3-fluorophenyl) ethylamido
No] methyl {phenylamino) -4-hydroxy- 3-
Cyclobutene-1,2-dione hydrochloride 3- (3-{(4-fluorophenyl)-[(R) -1
-(3-Fluorophenyl) ethylamino] methyl
Enylamino) -4-hydroxy-3-cyclobutene-
Using 500 mg of 1,2-dione trifluoroacetate
The reaction was carried out in the same manner as in Example (63b) to give the title compound
410 mg was obtained as a yellow individual. NMR spectrum (CDCl3) 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, 8.5Hz). Melting point: 180 ° C (dec) Optical rotation [α]_D= -22.3 (c = 0.99, AcO
H). Example 993- (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
N-2-yl) methyl] amine (3-nitrophenyl)-(thiophen-2-yl) meth
3.03 g of tanone and 1- (3,4-difluorophenyl)
L) Example 2 (a) using 2.52 g of ethylamine
Perform the same reaction to give the title compound as a red-orange oil.
4.62 g were obtained. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino]-(thiophen-2-yl) methyl
Ruphenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(3-nitrophenyl)-(thiophen-2-i
4.60 g of methyl] amine, nickel chloride hexahydrate
5.84 g, sodium borohydride 1.86 g, meta
In the same manner as in Example (59b),
Then, the product is separated and purified, and the isomer (A)
Compound (B) was converted into a pale yellow oily substance in an amount of 1.025
g, 495 mg. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(H
Offen-2-yl) methyl {phenylamino)- 3-
Cyclobutene-1,2-dione 3-{[1- (3,4-difluorophenyl) ethyla
Mino]-(thiophen-2-yl) methyldiphenyla
1.03 g of min isomer (A), 3-t-butoxy-4
-Methoxy-3-cyclobutene-1,2-dione 809
Example (94c) using 15 mg of methanol and 15 ml of methanol.
The reaction was carried out in the same manner as described above, and the isomer (A) of the title compound was converted to white
932 mg were obtained as a foam. Isomer (A) NMR spectrum (CDCl3) 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) ethyla
Mino]-(thiophen-2-yl) methyldiphenyla
495 mg of the isomer of min (B), 3-t-butoxy-4
-Methoxy-3-cyclobutene-1,2-dione 391
Example (94c) using 10 mg of methanol and 10 ml of methanol.
And the isomer (B) of the title compound was converted to white.
709 mg were obtained as a foam. Isomer (B) NMR spectrum (CDCl3) 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)
Enyl) ethylamino]-(thiophen-2-yl) meth
Tyl @ phenylamino) -4-hydroxy-3 -Cyclo
Butene-1,2-dione trifluoroacetate 3-t-butoxy-4- (3-{[1- (3,4-diph
Fluorophenyl) ethylamino]-(thiophen-2-
Yl) methyl @ phenylamino) -3-cyclobutene-
906 mg of isomer (A) of 1,2-dione, trifluo
Example using 3 ml of acetic acid and 10 ml of dichloromethane
Reaction was carried out in the same manner as in (98d), and the isomer of the title compound was obtained.
851 mg of (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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).
Fluorophenyl) ethylamino]-(thiophen-2-
Yl) methyl @ phenylamino) -3-cyclobutene-
699 mg of 1,2-dione isomer (B), trifluoro
Example using 3 ml of acetic acid and 10 ml of dichloromethane
Reaction was carried out in the same manner as in (98d), and the isomer of the title compound was obtained.
666 mg of (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) δppm: 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). Example 1003- {5-[[(R) -1- (3,5-difluorophene)
Nyl) ethylamino]-(4-methoxyphenyl) methyl
2-fluorophenylamino} -4-hydroxy
-3-cyclobutene-1,2-dione trifluorovinegar
Acid salt (Exemplary compound number 2-3400) (100a) N-[(R) -1- (3,5-difluoro
Phenyl) ethyl] -N-[(4-fluoro-3-nitto
Rophenyl)-(4-methoxyphenyl) methyl] ami
In (4-fluoro-3-nitrophenyl)-(4-methoxy
(Phenyl) methanone 2.53 g, (R) -1- (3,
5-Difluorophenyl) ethylamine hydrochloride 1.78
The reaction was carried out in the same manner as in Example (1a) using g.
3.62 g of the compound was obtained as a yellow oil. NMR spectrum (CDCl3) 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-difluoro)
L-phenyl) ethylamino]-(4-methoxyphenyl)
Ru) methyl] -2-fluoro-phenylamine N-[(R) -1- (3,5-difluorophenyl)
Tyl] -N-[(4-fluoro-3-nitrophenyl)
-(4-methoxyphenyl) methyl] amine 3.60
g, nickel chloride hexahydrate 4.11 g, sodium borohydride
Implemented using 1.30 g of thorium and 50 ml of methanol
The reaction was carried out in the same manner as in Example (1b), and the title compound was converted into a yellow oil.
3.27 g was obtained as a product. NMR spectrum (CDCl3) 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) ethylamino]
-(4-methoxyphenyl) methyl] -2-f Ruorov
Phenylamino} -3-cyclobutene-1,2-dione 5-[[(R) -1- (3,5-difluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl]-
3.24 g of 2-fluoro-phenylamine, 3-t-butyl
Toxy-4-methoxy-3-cyclobutene-1,2-di
Example using 2.32 g of ON and 30 ml of methanol
Perform the same reaction as in (66c), separate and purify
Isomer (A) and isomer (B) in pale yellow foam
1.01 g and 817 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-di
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] -2-fluorophenylamido NO-4
-Hydroxy-3-cyclobutene-1,2-dione
Trifluoroacetic acid salt 3-t-butoxy-4- {5-[[(R) -1- (3,
5-difluorophenyl) ethylamino]-(4-metho
Xyphenyl) methyl] -2-fluorophenylamido
Isomer of no-3-cyclobutene-1,2-dione
(A) 539 mg, trifluoroacetic acid 3 ml, dichloro
Reaction similar to Example (98d) using 10 ml of methane
To give the isomer (A) of the title compound as a white solid in 3
58 mg were obtained. Isomer (A) NMR spectrum (DMSO-d6) 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-metho
Xyphenyl) methyl] -2-fluorophenylamido
Isomer of no-3-cyclobutene-1,2-dione
(B) 360 mg, trifluoroacetic acid 3 ml, dichloro
Reaction similar to Example (98d) using 10 ml of methane
To give the isomer (B) of the title compound as a white solid in 3
20 mg were obtained. Isomer (B) NMR spectrum (DMSO-d6) δ ppm: 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 = 8.7Hz), 7.85 (1H, dd, J = 2.0, 8.0Hz). Melting point: 180-182 ° C (dec) Optical rotation [α]_D= + 56.0 (c = 1.04, DM
SO). Example 1013- {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)
2.73 g of methanone, 1- (3,4-difluorophenyl)
(1) Example (1) using 1.94 g of ethylamine hydrochloride
The reaction was carried out in the same manner as in a), and the title compound was converted into a yellow oily substance.
3.77 g was obtained. NMR spectrum (CDCl3) 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-difluorophenyl)
Ru) ethylamino]-(4-methylthiophenyl) methyl
Ru] phenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(4-methylthiophenyl)-(3-nitrophenyl
3.74 g of methyl] amine, nickel chloride hexahydrate
4.29 g, 1.37 g of sodium borohydride and
As in Example (59b) using 80 ml of methanol
The reaction is carried out, separated and purified, and isomer (A) of the title compound,
The isomer (B) was converted into a colorless oil in the form of 796 m
g, 400 mg. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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) ethylamino]-(4
-Methylthiophenyl) methyl] phenylamino ｝ -3
-Cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(4-methylthiophenyl) methyl] phenyl
Amine isomer (A) 775 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 54
Example (94) using 9 mg and methanol (20 ml).
The reaction was carried out in the same manner as in c), and the isomer (A)
1.04 g was obtained as a white foam. Isomer (A) NMR spectrum (CDCl3) 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). 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(4-methylthiophenyl) methyl] phenyl
Amine isomer (B) 387 mg, 3-t-butoxy-
4-methoxy-3-cyclobutene-1,2-dione 27
Example 2 (94 mg) using 2 mg and 15 ml of methanol
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 (CDCl3) 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-difluoro
Phenyl) ethylamino]-(4-methylthiophenyl
Ru) methyl] phenylamino} -4-hydroxy -3-
Cyclobutene-1,2-dione trifluoroacetate 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(4-methylthiophene
Enyl) methyl] phenylamino} -3-cyclobutene
614 mg of isomer (A) of -1,2-dione, triflu
Performed using 3 ml of acetic acid and 15 ml of dichloromethane
The reaction was carried out in the same manner as in Example (98d), and the isomer of the title compound was obtained.
543 mg of (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-diph
Fluorophenyl) ethylamino]-(4-methylthiophene
Enyl) methyl] phenylamino} -3-cyclobutene
472 mg of isomer (B) of -1,2-dione, triflu
Performed using 3 ml of acetic acid and 12 ml of dichloromethane
The reaction was carried out in the same manner as in Example (98d), and the isomer of the title compound was obtained.
435 mg of (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d6) 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). Example 1023- {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)
-(3-nitrophenyl) methyl] amine (2,4-dimethoxyphenyl)-(3-nitrophenyl
3.32 g of methanone, 1- (3,4-difluorophenyl)
Example (1) using 2.24 g of (enyl) ethylamine
The reaction was carried out in the same manner as in a), followed by separation and purification.
Isomer (A) and isomer (B) as yellow oils, respectively.
940 mg and 740 mg were obtained. Isomer (A) NMR spectrum (CDCl3) 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 (CDCl3) 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-difluorophenyl)
Ru) ethylamino]-(2,4-dimethoxyphenyl)
Methyl] phenylamine N- [1- (3,4-difluorophenyl) ethyl] -N
-[(2,4-dimethoxyphenyl)-(3-nitroph
Enyl) methyl] amine isomer (A) 920 mg, salt
Nickel hydride hexahydrate 1.02 g, sodium borohydride
Example (1) using 325 mg of methanol and 50 ml of methanol.
The reaction was carried out in the same manner as in b), and the isomer (A)
543 mg were obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl3) 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] -N
-[(2,4-dimethoxyphenyl)-(3-nitroph
Phenyl) methyl] amine isomer (B) 720 mg, salt
Nickel hydride hexahydrate 799mg, sodium borohydride
Example (1) using 254 mg of methanol and 80 ml of methanol.
The reaction was carried out in the same manner as in b), and the isomer (B)
580 mg were obtained as a colorless oil. Isomer (B) NMR spectrum (CDCl3) 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) ethylamino]-
(2,4-dimethoxyphenyl) methyl] phenyla Mi
No｝ -3-cyclobutene-1,2-dione 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(2,4-dimethoxyphenyl) methyl] fe
Nylamine isomer (A) 522 mg, 3-t-butoki
Ci-4-methoxy-3-cyclobutene-1,2-dione
Example (9) using 362 mg and methanol (25 ml).
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 (CDCl3) 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). 3-[[1- (3,4-difluorophenyl) ethyla
Mino]-(2,4-dimethoxyphenyl) methyl] fe
Nylamine isomer (B) 549 mg, 3-t-butoki
Ci-4-methoxy-3-cyclobutene-1,2-dione
Using 380 mg and 25 ml of methanol, Example (9)
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 (CDCl3) 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-difluoro
Phenyl) ethylamino]-(2,4-dimethoxyfe
Nyl) methyl] phenylamino} -4-hydro Kishi-3
-Cyclobutene-1,2-dione 3-t-butoxy-4- {3-[[1- (3,4-diph
Fluorophenyl) ethylamino]-(2,4-dimethoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
707 mg of isomer (A) of ten-1,2-dione,
Using 4 ml of fluoroacetic acid and 12 ml of dichloromethane
The reaction was carried out in the same manner as in Example (55b).
543 mg of the isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d6) 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-diph)
Fluorophenyl) ethylamino]-(2,4-dimethoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
659 mg of isomer (B) of ten-1,2-dione,
Using 4 ml of fluoroacetic acid and 12 ml of dichloromethane
The reaction was carried out in the same manner as in Example (55b).
There was obtained 276 mg of the isomer (B) as a white solid. Isomer (B) NMR spectrum (DMSO-d6) δ ppm: 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). Example 1034- {3-[(4-chlorophenyl)-((R) -1-
(3-Fluorophenyl) ethylamino) methyl] fe
Nilamino} -3-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-19) (103a) N-[(4-chlorophenyl)-(3-d
Trophenyl) methyl] -N-[(R) -1- (3-f
Fluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) keto
880 mg of (R) -1- (3-fluorophenyl)
886 mg of ethylamine hydrochloride, triethylamine
2.58 ml, titanium tetrachloride 0.44 ml, hydrogen hydride
890 mg of sodium borohydride and 0.29 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) using the title compound
Was obtained as a yellow oil. NMR spectrum (CDCl_Three) 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) ethylamino) methyl
Ru] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3-fluorophene)
Nyl) ethyl] amine (1.23 g) and nickel chloride hexahydrate
1.52 g and sodium borohydride 509 mg
And reacted in the same manner as in Example (1b) to give the title compound.
The product was obtained as a pale yellow oil (1.12 g). NMR spectrum (CDCl_Three) Δppm: 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-k
Lorophenyl)-((R) -1- (3-fluorophenyl)
Ru) ethylamino) methyl] phenylamino -3-
Clobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3-
Fluorophenyl) ethylamino) methyl] phenyla
1.0 g of min, 4-t-butoxy-3-methoxy-3-
Performed using 779 mg of cyclobutene-1,2-dione
The reaction was performed and purified in the same manner as in Example (66c) to give the title compound
566 mg of isomer (A) as pale yellow foam
732 mg of the body (B) was obtained as a pale yellow foam. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-chlorophenyl)-
((R) -1- (3-fluorophenyl) ethylamido
No) methyl] phenylamino} -3-hydroxy- 3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-((R) -1- (3-fluorophenyl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
Using 410 mg of isomer (A) of 1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound
166 mg of isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
Using 470 mg of isomer (B) of -1,2-dione,
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound
362 mg of isomer (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1044- {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) keto
1.0 g of (R) -1- (3,5-difluorophenyl)
L) Ethylamine hydrochloride 1.11 g, triethylamido
2.93 ml, titanium tetrachloride 0.50 ml, hydrogenated silicon
1.01 g of sodium borohydride, 0.33 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) using
The product was obtained as yellow oil (1.45 g). NMR spectrum (CDCl_Three) 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-chlorophenyl)-((R)
-1- (3,5-difluorophenyl) ethylamino)
Methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3,5-difluoro)
Lphenyl) ethyl] amine 1.41g and nickel chloride
1.66 g of hexahydrate and sodium borohydride 55
The reaction was carried out in the same manner as in Example (1b) using 8 mg, and the
1.29 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl_Three) Δppm: 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-k
Lorophenyl)-((R) -1- (3,5-difluoro)
Phenyl) ethylamino) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3,
5-difluorophenyl) ethylamino) methyl] Fe
1.17 g of nylamine, 4-t-butoxy-3-methoxy
867 mg of Ci-3-cyclobutene-1,2-dione
The reaction was carried out and purified in the same manner as in Example (66c).
The isomer (A) of the title compound was obtained as a pale yellow oil in the form of 241 m
g, 365 mg of isomer (B) as a pale yellow oil
Was. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-chlorophenyl)-
((R) -1- (3,5-difluorophenyl) ethyl
Amino) methyl] phenylamino} -3-hydro Kiss
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-((R) -1- (3,5-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclo
230 mg of isomer (A) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
176 mg of the compound isomer (A) was obtained as a pale brown solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-cyclo
Using 351 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
262 mg of a compound isomer (B) was obtained as a pale yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1054- {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) keto
1.0 g of (R) -1- (3,4-difluorophenyl)
L) Ethylamine hydrochloride 1.11 g, triethylamido
2.93 ml, titanium tetrachloride 0.50 ml, hydrogenated silicon
1.01 g of sodium borohydride, 0.33 ml of acetic acid
The reaction was carried out in the same manner as in Example (1a) using
The product was obtained as a yellow oil (1.42 g). NMR spectrum (CDCl_Three) 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) ethylamino)
Methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3,4-difluoro)
1.30 g of rophenyl) ethyl] amine and nickel chloride
1.53 g of hexahydrate and sodium borohydride 51
The reaction was carried out in the same manner as in Example (1b) using
1.20 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl_Three) Δppm: 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-k
Lorophenyl)-((R) -1- (3,4-difluoro)
Phenyl) ethylamino) methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (3,
4-difluorophenyl) -ethylamino) methyl] f
1.15 g of phenylamine, 4-t-butoxy-3-methoxy
852 mg of xyl-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (66c) to give
308 mg of the compound isomer (A) as a pale yellow oil,
800 mg of isomer (B) was obtained as a pale yellow oil. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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-chlorophenyl)-
((R) -1- (3,4-difluorophenyl) ethyl
Amino) methyl] phenylamino} -3-hydro Kiss
3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-((R) -1- (3,4-difluorophenyl)
Ethylamino) methyl] phenylamino} -3-cyclo
Using 280 mg of isomer (A) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
229 mg of isomer (A) of the compound was obtained as a white solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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 = 8.6 Hz). Melting point: 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-cyclo
340 mg of isomer (B) of butene-1,2-dione
And reacted and purified in the same manner as in Example (63b).
258 mg of isomer (B) of the compound was obtained as a pale yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1064- {3-[[1- (3,5-dinitrophenyl) ethyl]
Ruamino]-(4-fluorophenyl) methyl] phenyl
Ruamino} -3-hydroxy-3-cyclobutene-1,
2-dione hydrochloride (Exemplary Compound No. 2-3506) (106a) N- {3-[[1- (3,5-dinitroph)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] phenyl} acetamide N- [3- (4-fluorofubenzoyl) phenyldia
Cetamide 830 mg, 1- (3,5-dinitrophenyl)
L) Ethylamine hydrochloride 1.19 g, triethylamine
Example using 2.7 ml and 0.4 ml of titanium tetrachloride
The reaction was carried out in the same manner as in (1a) to obtain an imine compound. Profit
Imine compounds and sodium borohydride cyanide
Example 1 (a) using 806 mg and acetic acid 0.3 ml
Perform the same reaction to give the title compound as a light brown foam.
1.16 g were obtained. NMR spectrum (CDCl_Three) 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-dinitrophenyl)
Ru) ethylamino]-(4-fluorophenyl) methyl
Ru] phenylamine N- {3-[[1- (3,5-dinitrophenyl) ethyl]
Ruamino]-(4-fluorophenyl) methyl] phenyl
Dissolve 1.15 g of ruacetamide in 16 ml of methanol
Then, 4 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 70 ° C. for 3 hours. Bored
Add aqueous sodium bicarbonate solution and concentrate under reduced pressure.
Extract with ethyl acetate, wash with water and saturated saline, sulfuric anhydride
Dried with sodium. After concentration under reduced pressure, the residue was silica gel
Column chromatography (elution solvent: hexane / acetic acid
Isolation and purification of ethyl compound (2/1)
(A) as red crystals 442 mg, isomer of the title compound
235 mg of body (B) was obtained as a yellow foam. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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) ethylamino]-(4-
Fluorophenyl) methyl] phenylamino}- 3-sh
Clobutene-1,2-dione 3-[[1- (3,5-dinitrophenyl) ethylamido
No]-(4-fluorophenyl) methyl] phenylami
Isomer (A) 414 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 221 m
g, and reacted in the same manner as in Example (1c).
394 mg of compound isomer (A) as yellow foam
Obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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). 3-[[1- (3,5-dinitrophenyl) ethylamido
No]-(4-fluorophenyl) methyl] phenylami
Isomer (B) 230 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 124m
g, and reacted in the same manner as in Example (1c).
284 mg of the compound isomer (B) as a yellow foamy solid
Obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-dinitroph)
Enyl) ethylamino]-(4-fluorophenyl) meth
Tyl] phenylamino} -3-hydroxy-3 -Cyclo
Butene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[1- (3,5-dini)
Trophenyl) ethylamino]-(4-fluorophenyl
Ru) methyl] phenylamino} -3-cyclobutene-
378 mg of 1,2-dione isomer (A), trifluoro
Using 2 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
To give the isomer (A) of the title compound as a pale yellow solid
338 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-zini
Trophenyl) ethylamino]-(4-fluorophenyl
Ru) methyl] phenylamino} -3-cyclobutene-
277 mg of isomer (B) of 1,2-dione, trifluo
Using 2 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
To give the isomer (B) of the title compound as a pale yellow solid
220 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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
Hz). Melting point: 190 ° C. (dec)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) ethyl
3.25 g of amine hydrochloride, 7.1 ml of triethylamine
And the same as in Example (1a) using 1.0 ml of titanium tetrachloride.
The reaction was carried out in the same manner to obtain an imine compound. The obtained imine
2.14 g of compound and sodium cyanoborohydride,
The reaction was carried out in the same manner as in Example (1a) using 0.7 ml of acetic acid.
This gave 3.35 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-[1-
(3,4,5-trifluorophenyl) ethylamino]
Methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- [1- (3,4,5-trifluoro)
Phenyl) ethyl] amine 3.34 g, nickel chloride 6
3.81 g of hydrate, 1.22 g of sodium borohydride
And the reaction was carried out in the same manner as in Example (1b).
The product was obtained as a pale yellow oil (2.83 g). NMR spectrum (CDCl_Three) Δppm: 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-me
Toxiphenyl)-[1- (3,4,5-trifluoro
Phenyl) ethylamino] methyl] phenyla Mino
3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-[1- (3,4,5
-Trifluorophenyl) ethylamino] methyl] fe
Nylamine 2.81 g, 4-t-butoxy-3-methoxy
1.61 g of C-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (66c),
To give 9% of the isomer (A) of the title compound as a white foamy solid.
13 mg, isomer (B) of the title compound as a white foamy solid
403 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 8.6Hz), 7.23-7.42 (3H, m). Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-methoxyphenyl)-
[1- (3,4,5-trifluorophenyl) ethyla
[Mino] methyl] phenylamino} -3-hydro Kishi-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-[1- (3,4,5-trifluorophenyl) e
[Tylamino] methyl] phenylamino} -3-cyclobu
828 mg of isomer (A) of ten-1,2-dione,
As in Example (63b), using 2 ml of fluoroacetic acid
Perform the reaction to convert the isomer (A) of the title compound to a white solid.
699 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-trifluorophenyl) e
[Tylamino] methyl] phenylamino} -3-cyclobu
392 mg of isomer (B) of ten-1,2-dione,
As in Example (63b), using 1.5 ml of fluoroacetic acid
The isomer (B) of the title compound was converted to a white solid
265 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1084- {3-[(4-chlorophenyl)-[1- (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
Trifluorophenyl) ethyl] amine 1.82 g of 4-chloro-3′-nitrobenzophenone,
1- (3,4,5-trifluorophenyl) ethylami
2.65 g of trihydrochloride, 5.7 ml of triethylamine and
As in Example (1a) using 0.9 ml of titanium chloride
The reaction was performed to obtain an imine compound. The resulting imine compound
And 1.74 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.7 ml.
This gave 2.74 g of the title compound as a yellow oil. NMR spectrum (CDCl_Three) 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-chlorophenyl)-[1-
(3,4,5-trifluorophenyl) ethylamino]
Methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N- [1- (3,4,5-trifluoro)
[Phenyl] ethyl] amine 2.71 g, nickel chloride 6
Hydrate 3.06 g, sodium borohydride 973 mg
The reaction was carried out in the same manner as in Example (59b) using
To give the isomer (A) of the title compound as a colorless oily substance.
To give 946 mg of isomer (B) of the title compound as a white solid
691 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-k
Lorophenyl)-[1- (3,4,5-trifluorophenyl)
Enyl) ethylamino] methyl] phenylami NO-3
-Cyclobutene-1,2-dione 3-[(4-chlorophenyl)-[1- (3,4,5-
Trifluorophenyl) ethylamino] methyl] phenyl
Luamine isomer (A) 923 mg, 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 Example (1c).
The isomer (A) of the title compound was converted to a white foamy solid by 834.
mg. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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-
Trifluorophenyl) ethylamino] methyl] phenyl
Lamine isomer (B) 595 mg, 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 Example (1c).
Isomer (B) of the title compound as a white foamy solid 583
mg. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-chlorophenyl)-
[1- (3,4,5-trifluorophenyl) ethyla
[Mino] methyl] phenylamino} -3-hydroxy C-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-[1- (3,4,5-trifluorophenyl) e
[Tylamino] methyl] phenylamino} -3-cyclobu
774 mg of isomer (A) of ten-1,2-dione,
As in Example (63b), using 1.5 ml of fluoroacetic acid
The isomer (A) of the title compound was converted to a white solid
637 mg were obtained as a body. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) e
[Tylamino] methyl] phenylamino} -3-cyclobu
510 mg of isomer (B) of ten-1,2-dione,
As in Example (63b), using 1.5 ml of fluoroacetic acid
The isomer (B) of the title compound was converted to a white solid
354 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1093-hydroxy-4- {3-[(4-methoxyphenyi)
)-(1-methyl-1-phenyl-ethylamino) methyl
Tyl] phenylamino} -3-cyclobutene-1,2-
Dione (Exemplary Compound No. 2-3136) (109a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N- (1-methyl-1-f
Enylethyl) amine (4-methoxyphenyl)-(3-nitrophenyl) meth
2.57 g of tanone, 1.35 g of cumylamine, triethyl
Dissolve 1.35 g of ruamine in 50 ml of dichloromethane
Then, under ice cooling, 1.65 ml of titanium tetrachloride
30 ml of the solution was added dropwise. Stir at room temperature for 2 hours
Then, the mixture was heated under reflux for 3 hours. After allowing to cool, the reaction mixture was
The mixture was diluted with 150 ml, and insoluble materials were removed by filtration. Filtrate with saturated charcoal
Wash with sodium bicarbonate solution and saturated saline
After drying using magnesium hydrosulfate, the solvent is decompressed.
Distilled off. The obtained brown oil was washed with ethanol 100m
1, sodium cyanoborohydride 2.51 g, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 2.58 ml.
And purified by separation to give the title compound as a yellow oil.
43 g were obtained. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-(1-
Methyl-1-phenylethylamino) methyl] phenyl
Amine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N- (1-methyl-1-phenylethyl
L) 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 Example (94b) using 00 ml.
1.21 g of the title compound was obtained as a yellow oil. NMR spectrum (CDCl_Three) 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, 8.1Hz), 7.41 (2H, d, J = 7.4Hz).(109c) 3-t-butoxy-4- {3-[(4-me
Toxiphenyl)-(1-methyl-1-phenylethyl)
Amino) methyl] phenylamino} -3-cycl Lobuten
-1,2-dione 3-[(4-methoxyphenyl)-(1-methyl-1-
Phenylethylamino) methyl] phenylamine 1.1
9 g, 3-t-butoxy-4-methoxy-3-cyclobut
886 mg of ten-1,2-dione, 40 ml of methanol
And reacted in the same manner as in (94c), using the title compound
Was obtained as a white foam. NMR spectrum (CDCl_Three) 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-meth
Xyphenyl)-(1-methyl-1-phenylethyla
Mino) methyl] phenylamino} -3-cyclo Butene
1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-(1-methyl-1-phenylethylamino) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
ON 1.40g, trifluoroacetic acid 10ml, dichloro
Reaction similar to Example (55b) using 35 ml of methane
Was carried out to obtain 1.24 g of the title compound as a white solid. NMR spectrum (DMSO-d₆) 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). Example 1103- (3-{(4-chlorophenyl)-[1- (2,
3,4-trifluorophenyl) -ethylamino] -me
Tyl {-phenylamino) -4-hydroxy-3-cycl
Lobutene-1,2-dione hydrochloride (Exemplary Compound No. 2
-3507) (110a) N-[(4-chlorophenyl)-(3-d
Trophenyl) methyl] -N- [1- (2,3,4-to
Trifluorophenyl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) meta
2.62 g of nonone and (1- (2,3,4-trifluorophenyl)
Enyl) ethylamine hydrochloride 2.12 g, triethyl alcohol
Using 6.97 ml of min and 1.6 ml of titanium tetrachloride
The reaction was carried out in the same manner as in Example (1a) to obtain an imine compound.
Was. Obtained imine compounds and borohydride cyanide
Example (1) using 2.51 g of lithium and 2.6 ml of acetic acid
The reaction was carried out in the same manner as in a), and the title compound was converted to a yellow oily substance.
As a result, 4.06 g was obtained. NMR spectrum (CDCl_Three) 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-chlorophenyl)-[1-
(2,3,4-trifluorophenyl) -ethylamido
[No] -methyl} -phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N- [1- (2,3,4-trifluoro)
Phenyl) ethyl] amine 3.96 g, 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 Example (59b) using
To give the isomer (A) of the title compound as a pale yellow oily substance.
1.05 g, isomer (B) of the title compound as a pale yellow oil
720 mg were obtained as material. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-k
Lorophenyl)-[1- (2,3,4-trifluorophenyl)
Enyl) ethylamino] methyldiphenylamido No) -3
-Cyclobutene-1,2-dione 3-{(4-chlorophenyl)-[1- (2,3,4-
Trifluorophenyl) ethylamino] methyldiphenyl
1.01 g of isomer of ruamine (A), 4-t-butoxy
-3-methoxy-3-cyclobutene-1,2-dione 6
The reaction was carried out in the same manner as in Example (1c) using 68 mg.
To give the isomer (A) of the title compound as a white foamy solid.
60 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) 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] methyldiphenyl
Lamine isomer (B) 700 mg, 4-t-butoxy
-3-methoxy-3-cyclobutene-1,2-dione 4
The reaction was carried out in the same manner as in Example (1c) using 62 mg.
To give the isomer (B) of the title compound as a white foamy solid.
00 mg was obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-chlorophenyl)-
[1- (2,3,4-trifluorophenyl) ethyla
Mino] methyl @ phenylamino) -4-hydroxy C-3
-Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- (3-{(4-chlorophenyi)
)-[1- (2,3,4-trifluorophenyl) e
Tylamino] methyl @ phenylamino) -3-cyclobut
520 mg of isomer (A) of ten-1,2-dione,
Using 6 ml of fluoroacetic acid, as in Example (63b)
Perform the reaction to convert the isomer (A) of the title compound to a white solid.
225 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-chlorophenyi)
)-[1- (2,3,4-trifluorophenyl) e
Tylamino] methyl @ phenylamino) -3-cyclobut
460 mg of isomer (B) of ten-1,2-dione,
As in Example (63b), using 5 ml of fluoroacetic acid
The reaction was performed to convert the isomer (B) of the title compound into a white solid.
337 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1113- {3-[[(R) -1- (4-fluorophenyl)
Ethylamino]-(4-methoxyphenyl) methyl] F
Phenylamino} -4-hydroxy-3-cyclobutene-
1,2-dione hydrochloride (Exemplary Compound No. 2-28) (111a) N-[(R) -1- (4-fluorophenyl)
Ru) ethyl] -N-[(4-methoxyphenyl)-(3
-Nitrophenyl) methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
5.14 g of tanone and (R) -1- (4-fluorophenyl)
R) 4.24 g of ethylamine hydrochloride, triethylamine
Example using 13.9 ml and 3.3 ml of titanium tetrachloride
The reaction was carried out in the same manner as in (1a) to obtain an imine compound. Profit
Imine compounds and sodium borohydride cyanide
Example (1a) using 5.03 g and 5.15 ml of acetic acid
And react the title compound as a yellow oil.
7.60 g were obtained. NMR spectrum (CDCl_Three) 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-fluorophene
Nyl) ethylamino]-(4-methoxyphenyl) methyl
Ru] phenylamine N-[(R) -1- (4-fluoro
Phenyl) ethyl] -N-[(4-methoxyphenyl)-(3-nitrophenyl) methyl] amine
7.60 g, 9.51 g of nickel chloride hexahydrate, hydrogenated
Example (59b) using 3.03 g of sodium boron
Reaction and separation and purification were performed in the same manner as in
1.52 g of (A) as a pale yellow oily substance,
1.39 g of isomer (B) was obtained as a pale yellow oily substance. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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) ethylamino]-(4
-Methoxyphenyl) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[[(R) -1- (4-fluorophenyl) -ethyl
Ruamino]-(4-methoxyphenyl) methyl] phenyl
1.50 g of isomer (A) of 4-amine, 4-t-butoxy
-3-methoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) using 1.10 g.
To give the isomer (A) of the title compound as a white foamy solid
1.95 g were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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) ethyl
Amino]-(4-methoxyphenyl) methyl] phenyl
1.35 g of amine isomer (B), 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 99
Using 3 mg, a reaction was carried out in the same manner as in Example (1c).
Isomer (B) of the title compound as a white foamy solid 2.1
4 g were obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-fluoro
L-phenyl) ethylamino]-(4-methoxyphenyl)
Ru) methyl] phenylamino} -4-hydroxy -3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[[(R) -1- (4-
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
1.92 g of isomer (A) of -1,2-dione, triflu
Reaction was carried out in the same manner as in Example (63b) using 8 ml of oloacetic acid.
To give the isomer (A) of the title compound as a white solid
1.85 g were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-
Fluorophenyl) ethylamino]-(4-methoxyphenyl
Enyl) methyl] phenylamino} -3-cyclobutene
2.12 g of isomer (B) of -1,2-dione, triflu
In the same manner as in Example (63b),
To give the isomer (B) of the title compound as a white solid.
1.81 g was obtained. Isomer (B) NMR spectrum (DMSO-d₆) 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). Example 1123- (3-{[(R) -1- (3,4-difluorophene)
Nylamino) ethylamino]-(p-tolyl) methyl
Phenylamino) -4-hydroxy-3-cyclobutene
-1,2-dione (Exemplary Compound No. 2-3386) (112a) N-[(R) -1- (3,4-difluoro
Phenyl) ethyl] -N-[(3-nitrophenyl)-
(P-Tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone4.
23 g and (R) -1- (3,4-difluorophenyl)
3.39 g of ethylamine hydrochloride, triethylamine 1
Example using 2.2 ml and 2.8 ml of titanium tetrachloride
The reaction was carried out in the same manner as in (1a) to obtain an imine compound. Profit
Imine compounds and sodium borohydride cyanide
Example (1a) using 4.41 g and 4.52 ml of acetic acid
And react the title compound as a yellow oil.
5.92 g were obtained. NMR spectrum (CDCl_Three) 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-difluoro)
Lphenyl) ethylamino]-(p-tolyl) methyl
Phenylamine N-[(R) -1- (3,4-difluorophenyl)
Tyl] -N-[(3-nitrophenyl)-(p-tri
5.88 g of methyl] amine, nickel chloride hexahydrate
Using 7.31 g and 2.33 g of sodium borohydride
The reaction was carried out in the same manner as in Example (59b) to separate and purify
The isomer (A) of the title compound was converted to a colorless oily substance by 0.9
1 g, isomer (B) of the title compound as a colorless oil
335 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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) ethylamino]
-(P-tolyl) methyl @ phenylamino)- 3-sik
Lobutene-1,2-dione 3-{[(R) -1- (3,4-difluorophenyl)
Ru) ethylamino]-(p-tolyl) methyldiphenyl
Amine isomer (A) 0.90 g, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 65
Using 8 mg, the reaction was carried out in the same manner as in Example (1c).
Isomer (A) of the title compound as a white foamy solid 230
mg. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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) methyldiphenylamido
Isomer (B) 305 mg, 4-t-butoxy-3-
Methoxy-3-cyclobutene-1,2-dione 224 m
g, and reacted in the same manner as in Example (1c).
460 mg of the compound isomer (B) as a white foamy solid
Obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-di
Fluorophenylamino) ethylamino]-(p-tri
M) methyl @ phenylamino) -4-hydroxy C-3-
Cyclobutene-1,2-dione 3-t-butoxy-4- (3-{[(R) -1- (3,
4-difluorophenyl) ethylamino]-(p-tri
Ru) methyl @ phenylamino) -3-cyclobutene-
220 mg of 1,2-dione isomer (A), trifluoro
Using 3 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
To give the isomer (A) of the title compound as a white solid
07 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-tri
Ru) methyl @ phenylamino) -3-cyclobutene-
509 mg of isomer (B) of 1,2-dione,
Using 3 ml of acetic acid, the reaction was carried out in the same manner as in Example (63b).
To give the isomer (B) of the title compound as a white solid
02 mg was obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1134- {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] amido In 4-methoxy-3'-nitrobenzophenone 1.73
g, (R) -1- (3,4,5-trifluorophenyl)
B) 2.28 g of ethylamine hydrochloride, triethylamine
Example using 5.6 ml and 0.8 ml of titanium tetrachloride
The reaction was carried out in the same manner as in (1a) to obtain an imine compound. Profit
Imine compounds and sodium borohydride cyanide
Example 1 (a) using 1.69 g and 0.6 ml of acetic acid
Perform the same reaction to give the title compound as a yellow oil.
2.63 g were obtained. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-
[(R) -1- (3,4,5-trifluorophenyl)
Ethylamino] methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3,4,5-tri
2.61 g of fluorophenyl) ethyl] amine,
3.06 g of nickel hexahydrate, sodium borohydride 9
The reaction was carried out in the same manner as in Example (1b) using 58 mg,
2.33 g of the title compound were obtained as a colorless oil. NMR spectrum (CDCl_Three) Δppm: 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-me
Toxiphenyl)-[(R) -1- (3,4,5-tri
Fluorophenyl) ethylamino] methyl] f Enilua
Mino} -3-cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-[(R) -1-
(3,4,5-trifluorophenyl) ethylamino]
Methyl] phenylamine 2.31 g, 4-t-butoxy
-3-methoxy-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (66c) using 1.32 g.
Separate and purify the isomer (A) of the title compound as a white foam.
950 mg as a solid, isomer (B) of the title compound as white
793 mg were obtained as a colored foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 8.7Hz), 7.23-7.40 (3H, m). Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-methoxyphenyl)-
[(R) -1- (3,4,5-trifluorophenyl)
Ethylamino] methyl] phenylamino｝ -3 -Hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 916 m
g, 2 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as described above, and the isomer (A)
628 mg were obtained as a color solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-methoxyphenyi)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 689 m
g, 2 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as in
616 mg were obtained as a color solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1144- {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 1.68 g of 4-chloro-3′-nitrobenzophenone,
(R) -1- (3,4,5-trifluorophenyl) d
2.21 g of tylamine hydrochloride, 5.3 of triethylamine
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. Obtained b
Mining compound and sodium cyanoborohydride 1.61
g and 0.5 ml of acetic acid in the same manner as in Example (1a).
And 2.44 g of the title compound as a yellow oily substance.
Obtained. NMR spectrum (CDCl_Three) 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-chlorophenyl)-[(R)
-1- (3,4,5-trifluorophenyl) ethyla
[Mino] methyl] phenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3,4,5-tri
Fluorophenyl) ethyl] amine 2.38 g,
2.69 g of nickel hexahydrate, sodium borohydride 8
The reaction was carried out in the same manner as in Example (59b) using 66 mg.
After separation and purification, the isomer (A) of the title compound is converted into a colorless oil.
942 mg of the title compound, isomer (B) of the title compound
663 mg were obtained as a colorless oil. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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, 8.5Hz), 7.12 (1H, t, J = 7.7Hz), 7.22 (4H, s). Isomer (B) NMR spectrum (CDCl_Three) 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-k
Lorophenyl)-[(R) -1- (3,4,5-trif
Fluorophenyl) ethylamino] methyl] Fe Nirami
No｝ -3-cyclobutene-1,2-dione 3-[(4-chlorophenyl)-[(R) -1- (3,
4,5-trifluorophenyl) ethylamino] methyl
Phenylamine isomer (A) 865 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 488 mg of dione, the same procedure as in Example (1c) was carried out.
To give the isomer (A) of the title compound as a white foamy solid.
947 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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,
4,5-trifluorophenyl) ethylamino] methyl
L] phenylamine isomer (B) 624 mg, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 353 mg of dione, in the same manner as in Example (1c),
To give the isomer (B) of the title compound as a white foamy solid.
797 mg were obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-chlorophenyl)-
[(R) -1- (3,4,5-trifluorophenyl)
[Ethylamino] methyl] phenylamino} -3- Hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-chlorophenyl
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 840 m
g, 2 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as described above, and the isomer (A)
744 mg were obtained as a colored solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-chlorophenyi)
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Cyclobutene-1,2-dione isomer (B) 757m
g, 2 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as in
662 mg were obtained as a color solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1154- {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] amido In 1.59 g of 4-fluoro-3'-nitrobenzophenone
And (R) -1- (3,4,5-trifluorophenyl)
2.20 g of ethylamine hydrochloride, 5.
Example (1) using 4 ml and 0.8 ml of titanium tetrachloride.
The reaction was carried out in the same manner as in a) to obtain an imine compound. Obtained
Imine compound and sodium cyanoborohydride
As in Example (1a) using 64 g and 0.6 ml of acetic acid
To give the title compound as a yellow oily substance in 2.5
0 g was obtained. NMR spectrum (CDCl_Three) 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-trifluorophenyl)
Ethylamino] methyl] phenylamine N-[(4-fluorophenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (3,4,5-tri
Fluorophenyl) ethyl] amine 2.46 g, dichloride
2.90 g of nickel hexahydrate, sodium borohydride 9
The reaction was carried out in the same manner as in Example (59b) using 27 mg.
Separate and purify the isomer (A) of the title compound as a colorless oil
760 mg as a substance, colorless isomer (B) of the title compound
716 mg were obtained as an oil. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 7.8Hz), 7.21-7.26 (2H, m). Isomer (B) NMR spectrum (CDCl_Three) 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-f
Fluorophenyl)-[(R) -1- (3,4,5-tri
Fluorophenyl) ethylamino] methyl] f Enilua
Mino} -3-cyclobutene-1,2-dione 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-
As in Example (1c), using 434 mg of 1,2-dione
In a similar manner to give the isomer (A) of the title compound in a white foam.
800 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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-
As in Example (1c), using 400 mg of 1,2-dione
In a similar manner to give the isomer (B) of the title compound in a white foam.
824 mg were obtained as a solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-fluorophenyl)-
[(R) -1- (3,4,5-trifluorophenyl)
Ethylamino] methyl] phenylamino｝ -3 -Hydro
Xy-3-cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl
)-[(R) -1- (3,4,5-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (A) 759 m
g, 3 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as described above, and the isomer (A)
635 mg were obtained as a colored solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-trifluorophene)
Nyl) ethylamino] methyl] phenylamino} -3-
Isomer of cyclobutene-1,2-dione (B) 740 m
g, 3 ml of trifluoroacetic acid, Example (63b)
The reaction was carried out in the same manner as in
590 mg were obtained as a colored solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1164- {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 1.69 g of 4-methyl-3'-nitrobenzophenone
(R) -1- (3,5-difluorophenyl) ethyla
2.19 g of min hydrochloride, 5.9 ml of triethylamine
Same as Example (1a) using 0.9 ml of titanium tetrachloride
To give an imine compound. The resulting iminization
Compound and 1.79 g of sodium borohydride cyanide, vinegar
The reaction was carried out in the same manner as in Example (1a) using 0.6 ml of the acid.
2.62 g of the title compound was obtained as a yellow oil. NMR spectrum (CDCl_Three) 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-difluoro)
Lophenyl) ethylamino]-(4-methylphenyl)
Methyl] phenylamine N-[(R) -1- (3,5-difluorophenyl)
Tyl] -N-[(4-methylphenyl)-(3-nitro
Phenyl) methyl] amine 2.59 g, nickel chloride 6
Hydrate 3.23 g, sodium borohydride 1.03 g
The reaction was carried out in the same manner as in Example (59b) using
To give the isomer (A) of the title compound as a colorless oil
1.02 g, isomer (B) of the title compound as a colorless oil
1.08 g was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 8.1Hz). Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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) ethylamino]-
(4-methylphenyl) methyl] phenylamido NO-3
-Cyclobutene-1,2-dione 3-[[(R) -1- (3,5-difluorophenyl)
Ethylamino]-(4-methylphenyl) methyl] fe
Nylamine isomer (A) 940 mg, 4-t-butoki
C-3-methoxy-3-cyclobutene-1,2-dione
Using 590 mg, the reaction was carried out in the same manner as in Example (1c).
To give the isomer (A) of the title compound as a white foamy solid
1.20 g were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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)
Ethylamino]-(4-methylphenyl) methyl] fe
Nylamine isomer (B) 990 mg, 4-t-butoki
C-3-methoxy-3-cyclobutene-1,2-dione
Using 618 mg, a reaction was carried out in the same manner as in Example (1c).
To give the isomer (B) of the title compound as a white foamy solid
1.09 g were obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-diph
Fluorophenyl) ethylamino]-(4-methylphenyl
Ru) methyl] phenylamino} -3-hydroxy C-3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(R) -1- (3,5
-Difluorophenyl) ethylamino]-(4-methyl
Phenyl) methyl] phenylamino} -3-cyclobute
1.10 g of isomer (A) of 1,2-dione
In the same manner as in Example (63b),
To give the isomer (A) of the title compound as a white solid.
712 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-methyl
Phenyl) methyl] phenylamino} -3-cyclobute
-1,2-dione isomer (B) 990 mg, trif
Using 3 ml of fluoroacetic acid, the reaction was performed in the same manner as in Example (63b).
To give the isomer (B) of the title compound as a white solid.
708 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1173- (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-
Tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone
02 g and 1- (3,4-difluorophenyl) ethyla
3.92 g of min, 13.9 ml of triethylamine and tetrasalt
In the same manner as in Example (1a),
The reaction was performed to obtain an imine compound. The resulting imine compound
And 6.27 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 6.5 ml.
This gave 7.79 g of the title compound as a yellow oil. NMR spectrum (CDCl_Three) 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-difluorophenyl)
Ru) ethylamino]-(p-tolyl) methyldiphenyl
Amine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(3-nitrophenyl)-(p-tolyl) methyl
[7] amine 7.76 g, nickel chloride hexahydrate 9.65
g, 3.07 g of sodium borohydride
The reaction was performed in the same manner as in (59b), and the mixture was separated and purified.
1.67 g of the product 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_Three) Δppm: 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_Three) Δppm: 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) ethylamino]-(p
-Tolyl) methyl @ phenylamino) -3-cycl Lobte
N-1,2-dione 3-{[1- (3,4-difluorophenyl) ethyla
Isomer of [mino]-(p-tolyl) methyldiphenylamine
Form (A) 1.64 g, 4-t-butoxy-3-methoxy
Using 1.29 g of -3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) to give the title compound
1.98 g of isomer (A) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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-{[1- (3,4-difluorophenyl) ethyla]
Isomer of [mino]-(p-tolyl) methyldiphenylamine
2.34 g of body (B), 4-t-butoxy-3-methoxy
Using 1.83 g of -3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) to give the title compound
1.98 g of isomer (B) of was obtained as a white foamy solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-difluoro)
Phenylamino) ethylamino]-(p-tolyl) methyl
(Ruphenylamino) -4-hydroxy-3- Cyclob
Ten-1,2-dione 3-t-butoxy-4- (3-{[1- (3,4-diph
Fluorophenyl) ethylamino]-(p-tolyl) methyl
(Ruphenylamino) -3-cyclobutene-1,2-di
Isomer (A) 1.95 g, trifluoroacetic acid 4 m
1 and the reaction was carried out in the same manner as in Example (55b).
1.50 g of isomer (A) of the title compound was obtained as a white solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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-diph
Fluorophenyl) ethylamino]-(p-tolyl) methyl
(Ruphenylamino) -3-cyclobutene-1,2-di
Isomer (B) 1.96 g, trifluoroacetic acid 4 m
1 and the reaction was carried out in the same manner as in Example (55b).
402 mg of the isomer (B) of the title compound was obtained as a white solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) 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) ethylamino)-(p
-Tolyl) methyl] phenylamino} -3-cyclo Bute
1,2-dione triethylammonium salt 3-hydroxy-4- {3-[(1- (3,4-difur
Orophenyl) ethylamino)-(p-tolyl) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
Suspension of 418 mg of isomer (B) in 5 ml of acetone
And added triethylamine to completely dissolve
Solvent and excess triethylamine are distilled off under reduced pressure.
did. The obtained white solid is suspended in diisopropyl ether.
After collecting the turbidity and drying, isomer (B) of the title compound is white
463 mg were obtained as a solid. NMR spectrum (DMSO-d₆) Δppm: 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) ethylamino)-(p
-Tolyl) methyl] phenylamino} -3-cyclo Bute
1,2-dione sodium salt 3-hydroxy-4- {3-[(1- (3,4-difur
Orophenyl) ethylamino)-(p-tolyl) methyl
Ru] phenylamino} -3-cyclobutene-1,2-di
Suspend 888 mg of the ON isomer (B) in 5 ml of acetone
And add 185 mg of sodium bicarbonate and 3 ml of distilled water.
I got it. The solution was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue.
In addition, it was dissolved, and the insoluble matter was removed by filtration. The filtrate is evaporated under reduced pressure,
The obtained white powder is dissolved in ethyl acetate, and the insoluble matter is removed by filtration.
Was. This was repeated three times, and the resulting white powder was n-hexane.
Suspended in sun and collected by filtration to obtain 652 mg of the title compound.
Was. NMR spectrum (DMSO-d₆) Δppm: 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). Example 1183-hydroxy-4- {3-[(4-methoxyphenyi)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
-1,2-dione (Exemplary Compound No. 2-13) (118a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (naph
Taren-1-yl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
5.32 g of tanone and (R) -1- (1-naphthyl) ethyl
3.55 g of triamine and 11.5 ml of triethylamine
As in Example (1a) using 3.4 ml of titanium tetrachloride
To give an imine compound. The resulting iminization
Compound and sodium borohydride 5.20 g, vinegar
The reaction was carried out in the same manner as in Example (1a) using 5.53 ml of the acid.
This gave 8.34 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-
((R) -1- (naphthalen-1-yl) ethylamido
No) Methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
Ru) methyl] -N-[(R) -1- (naphthalene-1-
8.32 g of yl) ethyl] amine, nickel chloride hexahydrate
9.51 g of product and 3.03 g of sodium borohydride
Then, the reaction was carried out in the same manner as in Example (59b), followed by separation and purification.
To give the isomer (A) of the title compound as a colorless oil
1.15 g, isomer (B) of the title compound as a colorless oil
462 mg was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 8.4Hz). Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-me
Toxiphenyl)-((R) -1- (naphthalene-1-
Yl) ethylamino) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (na
Phthalen-1-yl) ethylamino) methyl] phenyl
1.11 g of isomer (A) of amine, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 74
Using 8 mg, the reaction was carried out in the same manner as in Example (1c).
Isomer (A) of the title compound as a white foamy solid, 1.3
0 g was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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- (na
Phthalen-1-yl) ethylamino) methyl] phenyl
Amine isomer (B) 449 mg, 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 Example (1c).
Isomer (B) of the title compound as a white foamy solid 452
mg. NMR spectrum (CDCl_Three) Δppm: 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-meth
Xyphenyl)-((R) -1- (naphthalene-1-i
Ru) ethylamino) methyl] phenylamino -3-
Clobutene-1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
1.24 g of isomer (A) of -1,2-dione, triflu
Reaction was carried out in the same manner as in Example (55b) using 5 ml of acetic acid.
To give the isomer (A) of the title compound as a white solid
1.07 g was obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
434 mg of -1,2-dione isomer (B), triflu
Reaction was performed in the same manner as in Example (63b) using 3 ml of acetic acid.
To give the hydrochloride of the isomer (B) of the title compound as a white solid.
317 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1193-hydroxy-4- {3-[(4-methoxyphenyi)
)-((R) -1- (naphthalen-2-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
-1,2-dione (Exemplary Compound No. 2-14) (119a) N-[(4-methoxyphenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1- (naph
Taren-2-yl) ethyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
4.45 g of tanone and (R) -1- (2-naphthyl) ethyl
2.96 g of triamine and 9.6 ml of triethylamine
As in Example (1a) using 2.9 ml of titanium chloride
The reaction was performed to obtain an imine compound. The resulting imine compound
And 4.34 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 4.45 ml.
This gave 6.15 g of the title compound as a yellow oil. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-
((R) -1- (naphthalen-2-yl) ethylami
No) Methyl] phenylamine N-[(4-methoxyphenyl)-(3-nitrophenyl
M)]-N-[(R) -1- (naphthalene-2-
Il) ethyl] amine 6.13 g, nickel chloride hexahydrate
7.06g, 2.25g of sodium borohydride
And the reaction was carried out in the same manner as in Example (1b).
5.23 g were obtained as a pale yellow oil. NMR spectrum (CDCl_Three) 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, each d, J = 8.8Hz)
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-me
Toxiphenyl)-((R) -1- (naphthalene-2-
Yl) ethylamino) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[(4-methoxyphenyl)-((R) -1- (na
Phthalen-2-yl) ethylamino) methyl] phenyl
5.21 g of amine, 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 Example (66c), and the mixture was separated and purified.
The isomer (A) of the title compound was converted to a white foamy solid by 170
mg, isomer (B) of the title compound as a white foamy solid
176 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-meth
Xyphenyl)-((R) -1- (naphthalene-2-i)
Ru) ethylamino) methyl] phenylamino -3-
Clobutene-1,2-dione 3-t-butoxy-4- {3-[(4-methoxyphenyl)
)-((R) -1- (naphthalen-2-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
155 mg of isomer (A) of -1,2-dione, triflu
As in Example (55b), using 2.5 ml of oloacetic acid
Perform the reaction to convert the isomer (A) of the title compound to a white solid.
Thus, 113 mg was obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
170 mg of isomer (A) of -1,2-dione, triflu
As in Example (55b), using 2.5 ml of oloacetic acid
The reaction was performed to convert the isomer (B) of the title compound into a white solid.
141 mg were obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1203- (3-{[1- (3,4-difluorophenyl) e
Tylamino]-(pyridin-4-yl) methyldiphenyl
Ruamino) -4-hydroxy-3-cyclobutene-1,
2-dione dihydrochloride (Exemplary Compound No. 2-46) (120a) N- [1- (3,4-difluorophenyl)
Ru) ethyl] -N-[(3-nitrophenyl)-(pyri
Zin-4-yl) methyl] amine (3-nitrophenyl)-(pyridin-4-yl) meta
2.81 g of nonone and 1- (3,4-difluorophenyl)
1.94 g of ethylamine, 6.9 ml of triethylamine
And the same as Example (1a) using 2.0 ml of titanium tetrachloride.
The reaction was carried out in the same manner to obtain an imine compound. The obtained imine
3.19 g of the compound and sodium borohydride cyanide,
The reaction was carried out in the same manner as in Example (1a) using 3.2 ml of acetic acid.
This gave 2.10 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl_Three) 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), 8.52-8.62 (2H, m).(120b) 3-{[1- (3,4-difluorophenyl)
Ru) ethylamino]-(pyridin-4-yl) methyl}
Phenylamine N- [1- (3,4-difluorophenyl) ethyl]-
N-[(3-nitrophenyl)-(pyridine-4-i
Le) Methyl] amine 2.07 g, nickel chloride hexahydrate
2.66 g, using 848 mg of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) to separate and purify
684 mg of the title compound was obtained as a colorless oil. NMR spectrum (CDCl_Three) 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) ethylamino]-(pi
Lysin-4-yl) methyl {phenylamino)- 3-sh
Clobutene-1,2-dione 3-{[1- (3,4-difluorophenyl) ethyla
Mino]-(pyridin-4-yl) methyldiphenylamido
280 mg, 4-t-butoxy-3-methoxy-3-
Performed using 213 mg of cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) to give the title compound as a white foam.
292 mg were obtained as a solid. NMR spectrum (CDCl_Three) Δppm: 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-difluoro
Phenyl) ethylamino]-(pyridin-4-yl) meth
Tyl @ phenylamino) -4-hydroxy-3 -Cyclo
Butene-1,2-dione dihydrochloride 3-t-butoxy-4- (3-{[1- (3,4-diph
Fluorophenyl) ethylamino]-(pyridine-4-i
Ru) methyl @ phenylamino) -3-cyclobutene-
270 mg of 1,2-dione and 3 ml of trifluoroacetic acid
The reaction was carried out in the same manner as in Example (63b) to give the title
143 mg of the compound was obtained as a pale yellow solid. NMR spec
Torr (DMSO-d₆) Δppm: 1.65 (3H, m), 4.10-4.35 (1
H, 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 (total 2H, each s)
 d, J = 5.1 Hz). Melting point: 182 ° C. (dec). Example 1213- {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
Le) Methyl] amine (4-methoxyphenyl)-(3-nitrophenyl) meth
8.91 g of tanone and 3,4-difluorobenzylamine
The reaction was carried out in the same manner as in Example (1a) using 4.96 g.
12.72 g of the title compound was obtained as a pale yellow oil.
Was. NMR spectrum (CDCl_Three) Δppm: 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-difluorobenzylamido)
No)-(4-methoxyphenyl) methyl] phenylamido
In N- (3,4-difluorobenzyl) -N-[(4-
Toxiphenyl)-(3-nitrophenyl) methyl] a
12.68 g of min, 25.03 of anhydrous tin (II) chloride
g, 120 ml of ethanol, and Example (94b)
To give the title compound as a pale yellow oil.
13.32 g was obtained. NMR spectrum (CDCl_Three) Δppm: 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-methoxyphenyl)
Ru) methyl] phenylamino} -3-cyclobu Ten
1,2-dione 3-[(3,4-difluorobenzylamino)-(4-
Methoxyphenyl) methyl] phenylamine 1.32
g, 3-t-butoxy-4-methoxy-3-cyclobute
1.11 g of 1,2-dione and 30 ml of methanol
And the reaction was carried out in the same manner as in Example (1c).
This gave 1.11 g of the product as a pale yellow foam. NMR spectrum (CDCl_Three) 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-difluorobenzyl)
Ruamino)-(4-methoxyphenyl) methyl] phenyl
Ruamino} -4-hydroxy-3-cyclobute -1
2-dione trifluoroacetate 3-t-butoxy-4- {3-[(3,4-difluoro
Benzylamino)-(4-methoxyphenyl) methyl]
Phenylamino} -3-cyclobutene-1,2-dione
Dissolve 1.09 g in 30 ml of dichloromethane and add
2 ml of chloroacetic acid were added. Stir for 30 minutes at room temperature
Then, the solvent was distilled off under reduced pressure, toluene was added, and the mixture was azeotroped twice.
Was. The obtained white solid was suspended in ether and collected by filtration.
830 mg of the title compound was obtained as a white solid. NMR spectrum (DMSO-d₆) Δppm: 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. Example 1223-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) meth
9.91 g of tanone and (R) -1- (3-methoxyphenyl)
5.) ethylamine 5.83 g, triethylamine 21.
Example (1) using 5 ml and 6.15 ml of titanium tetrachloride.
The reaction was carried out in the same manner as in a) to obtain an imine compound. Obtained
8. Imine compound and sodium borohydride cyanide
As in Example (1a) using 68 g and 10 ml of acetic acid
The reaction was carried out to give the title compound as a yellow oil (9.07).
g was obtained. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-
[(R) -1- (3-methoxyphenyl) ethylamido
No] Methyldiphenylamine N-[(R) -1- (3-methoxyphenyl) ethyl]
-N-[(4-methoxyphenyl)-(3-nitrophen
Nyl) methyl] amine 9.04 g, anhydrous tin chloride (I
I) Using 17.5 g and 150 ml of ethanol
The reaction was carried out in the same manner as in Example (94b), separated and purified, and
1.48 of the compound isomer (A) as a pale yellow oil
g, isomer (B) of the title compound as a pale yellow oil
1.28 g were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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).(122c) 3-t-butoxy-4- {3-[((R)
-1- (3-methoxyphenyl) ethylamino)-(4
-Methoxyphenyl) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[((R) -1- (3-methoxyphenyl) ethyl
Amino)-(4-methoxyphenyl) methyl] phenyl
Amine isomer (B) 180 mg, 4-t-butoxy-
3-methoxy-3-cyclobutene-1,2-dione 18
Using 3 mg, a reaction was carried out in the same manner as in Example (1c).
185m of the title compound isomer (B) as a colorless foam
g was obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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) ethylamino)-(4-
Methoxyphenyl) methyl] phenylamino -3-
Clobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3-
Methoxyphenyl) ethylamino)-(4-methoxyphenyl)
Enyl) methyl] phenylamino} -3-cyclobutene
Using 180 mg of isomer (B) of -1,2-dione
The reaction and purification were carried out in the same manner as in Example (63b) to give the title compound
149 mg of isomer (B) was obtained as a pale brown solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1233- (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-d
Trophenyl) methyl] -N-[(R) -1-phenyl
Ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) meta
2.00 g of nonone and (R) -1-phenylethylamine
1.16 ml, triethylamine 4.24 ml and tetrachloride
The same procedure as in Example (1a) was carried out using 1.26 ml of titanium.
The reaction was performed to obtain an imine compound. The resulting imine compound
And 1.92 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.66 ml.
The isomer (A) of the title compound as a yellow oily substance
60 mg of the isomer (B) of the title compound as a yellow oil
720 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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] methyldiphenylamine N-[(4-chlorophenyl)-(3-nitrophenyl
L) methyl] -N-[(R) -1-phenylethyl]
Min isomer (A) 750mg, Nickel chloride hexahydrate
Using 972 mg and 309 mg of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) to separate and purify
The isomer (A) of the title compound was converted into a colorless oily substance (640 m).
g was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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 = 7.7Hz), 7.13-7.40 (9H, m). N-[(4-chlorophenyl)-(3-nitrophenyl
L) methyl] -N-[(R) -1-phenylethyl]
Min isomer (B) 710 mg, nickel chloride hexahydrate
Using 920 mg and 293 mg of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) to separate and purify
The isomer (B) of the title compound was converted into a colorless oily substance in an amount of 620 m
g was obtained. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-k
Lorophenyl)-[(R) -1-phenylethylamido
[No] methyl @ phenylamino) -3-cyclobute N-
1,2-dione 3-{(4-chlorophenyl)-[(R) -1-phenyi
Ruethylamino] methyl diphenylamine isomer
(A) 630 mg, 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 Example (1c) to give the title compound.
430 mg of an isomer (A) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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). 3-{(4-chloro-phenyl)-[(R) -1-fe
Nylethylamino] methyl diphenylamine isomer
(B) 610 mg, 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 Example (1c) to give the title compound.
794 mg of an isomer (B) was obtained as a white foamy solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-chlorophenyl)-
[(R) -1-phenylethylamino] methyldiphenyl
Ruamino) -4-hydroxy-3-cyclobutene -1,
2-dione 3-t-butoxy-4- (3-{(4-chlorophenyi)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamino) -3-cyclobutene-1,2-dione
Isomer (A) 430 mg and trifluoroacetic acid 2 ml
And reacted in the same manner as in Example (55b).
292 mg of the compound isomer (A) was obtained as a white solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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}
Phenylamino) -3-cyclobutene-1,2-dione
Of isomer (B) 324 mg and trifluoroacetic acid 2 ml
And reacted in the same manner as in Example (55b).
210 mg of the compound isomer (B) as a pale yellow solid
Was. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1243-hydroxy-4- (3-{(4-methoxyphenyl)
-)-[(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)
Ruethyl) amine (4-methoxyphenyl)-(3-nitrophenyl) meth
2.00 g of Tanone and (R) -1-phenylethylamine
1.18 ml, 4.31 ml of triethylamine and tetrachloride
The same procedure as in Example (1a) was performed using 1.28 ml of titanium.
The reaction was performed to obtain an imine compound. The resulting imine compound
And 1.95 g of sodium cyanoborohydride, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 0.67 ml.
2.08 g of the title compound was obtained as a yellow oily substance. NMR spectrum (CDCl_Three) 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-methoxyphenyl)-
[(R) -1-phenylethylamino] methyldiphenyl
Luamine N-[(4-methoxyphenyl)-(3-nitrophenyl
L) methyl] -N-[(R) -1-phenylethyl]
2.06 g of min, 2.70 g of nickel chloride hexahydrate, water
Example (59) using sodium borohydride (860 mg)
The reaction was carried out in the same manner as in b), followed by separation and purification.
Compound (A) as a yellow oily substance (510 mg, title compound)
672 mg of the product isomer (B) as a yellow oil
Was. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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-me
Toxiphenyl)-[(R) -1-phenylethylamido
No] methyl @ phenylamino) -3-cyclobut Ten
1,2-dione 3-{(4-methoxyphenyl)-[(R) -1-fe
Nylethylamino] methyl diphenylamine isomer
(A) 500 mg, 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 Example (1c) to give the title compound.
633 mg of an isomer (A) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 1.41 (3H, d, J =
6.3Hz), 1.62 (9H, s), 3.71 (4H, br), 4.60 (1H, s), 6.
77 (2H, d, J = 8.7 Hz), 7.05-7.56 (11H, m). 3-{(4-methoxyphenyl)-[(R) -1-fe
Nylethylamino] methyl diphenylamine isomer
(B) 660 mg, 4-t-butoxy-3-methoxy-
Using 731 mg of 3-cyclobutene-1,2-dione,
The reaction was carried out in the same manner as in Example (1c) to give the title compound.
389 mg of an isomer (B) was obtained as a white foamy solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-meth
Xyphenyl)-[(R) -1-phenylethylamido
[No] methyl @ phenylamino) -3-cyclobute N-
1,2-dione 3-t-butoxy-4- (3-{(4-methoxyphenyl)
-)-[(R) -1-phenylethylamino] methyl}
Phenylamino) -3-cyclobutene-1,2-dione
Isomer (A) of 620 mg and trifluoroacetic acid 3 ml
And reacted in the same manner as in Example (55b).
181 mg of the compound isomer (A) was obtained as a pale green solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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}
Phenylamino) -3-cyclobutene-1,2-dione
Of isomer (B) 324 mg and trifluoroacetic acid 2 ml
And reacted in the same manner as in Example (55b).
164 mg of the compound isomer (B) was obtained as a pale yellow solid.
Was. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 1.62 (3H, d, J
= 6.8Hz), 3.77 (3H, s), 4.13 (1H, q, J = 6.6Hz), 4.96 (1H
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). Example 1253- (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-
Tolyl) methyl] amine (3-nitrophenyl)-(p-tolyl) methanone3.
00g and (R) -1- (3-fluorophenyl) ethyl
2.62 g of amine hydrochloride, 8.6 ml of triethylamine
And 2.1 ml of titanium tetrachloride as in Example (1a).
The reaction was carried out in the same manner to obtain an imine compound. The obtained imine
3.13 g of the compound and sodium cyanoborohydride,
The reaction was carried out in the same manner as in Example (1a) using 1.1 ml of acetic acid.
This gave 3.59 g of the title compound as a brown oil.
Was. NMR spectrum (CDCl_Three) 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-fluorophene
Nyl) ethylamino]-(p-tolyl) methyldiphenyl
Luamine N-[(R) -1- (3-fluorophenyl) ethyl]
-N-[(3-nitrophenyl)-(p-tolyl) methyl
3.59 g of amine, nickel chloride hexahydrate 4.68
g, Example using 1.49 g of sodium borohydride
The reaction was performed in the same manner as in (59b), and the mixture was separated and purified.
Isomer (A) as a yellow oily substance (955 mg, standard)
649m of the isomer (B) of the title compound as a yellow oily substance
g was obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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) ethylamino]-(p
-Tolyl) methyl @ phenylamino) -3-cy Clobute
N-1,2-dione 3-{[(R) -1- (3-fluorophenyl) ethyl
Amino]-(p-tolyl) methyldiphenylamine
Sex form (A) 500 mg, 4-t-butoxy-3-methoxy
Using 554 mg of C-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) to give the title compound
633 mg of isomer (A) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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). 3-{[(R) -1- (3-fluorophenyl) ethyl
Amino]-(p-tolyl) methyldiphenylamine
Sex form (B) 660 mg, 4-t-butoxy-3-methoxy
Using 731 mg of C-3-cyclobutene-1,2-dione
The reaction was carried out in the same manner as in Example (1c) to give the title compound
389 mg of isomer (B) was obtained as a white foamy solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-fluoro
Lphenyl) ethylamino]-(p-tolyl) methyl
Phenylamino) -4-hydroxy-3-cycl Lobuten
-1,2-dione 3-t-butoxy-4- (3-{[(R) -1- (3-
Fluorophenyl) ethylamino]-(p-tolyl) meth
Tyl @ 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 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-d₆) Δppm: 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) meth
Tyl @ phenylamino) -3-cyclobutene-1,2-
324 mg of dione isomer (B), trifluoroacetic acid 2
The reaction was carried out in the same manner as in Example (55b) using
164m of the isomer (B) of the title compound as a pale yellow solid
g was obtained. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1264- {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
Le) ethyl] amine 1.0 g of (3-nitrophenyl) -phenyl ketone
Of (R) -1- (3-fluorophenyl) ethylamine
1.12 g of hydrochloride, 3.27 ml of triethylamine,
0.56 ml titanium chloride, sodium borohydride cyanide
Example 1 (1.13 g) and 0.37 ml of acetic acid.
The reaction was carried out in the same manner as in a) to give the title compound as a yellow oil.
1.45 g was obtained. NMR spectrum (CDCl_Three) 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-fluorophene
Nyl) ethylamino) -phenylmethyl] phenylami
In N-[(3-nitrophenyl) -phenylmethyl] -N-
[(R) -1- (3-fluorophenyl) ethyl] amido
1.37 g of nickel chloride, 2.14 g of nickel chloride hexahydrate and
Example (1) using 623 mg of sodium borohydride
The reaction was carried out in the same manner as in b) to give the title compound as a yellow oil.
1.16 g was obtained. NMR spectrum (CDCl_Three) 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) ethylamino) -fe
Nylmethyl] phenylamino} -3-cyclobu Ten
1,2-dione 3-[((R) -1- (3-fluorophenyl) ethyl
Amino) -phenylmethyl] phenylamine 1.14
g, 4-t-butoxy-3-methoxy-3-cyclobute
Using 983 mg of 1,2-dione, Example (66)
The reaction was carried out in the same manner as in c) to give the isomer (A) of the title compound.
As yellow foam, 591 mg of isomer (B) as yellow foam
660 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-fluoro
Lphenyl) ethylamino) -phenylmethyl] phenyl
Ruamino} -3-hydroxy-3-cyclobute -1
2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3-
Fluorophenyl) ethylamino) -phenylmethyl]
Phenylamino} -3-cyclobutene-1,2-dione
Example 63b using 360 mg of isomer (A)
In the same manner, the reaction and purification were performed to obtain the isomer (A) of the title compound.
301 mg was obtained as a light brown solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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]
Phenylamino} -3-cyclobutene-1,2-dione
Example 63b using 340 mg of isomer (B) of
In the same manner, the reaction and purification were performed to obtain the isomer (B) of the title compound.
301 mg was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1274- {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 1.0 g of (3-nitrophenyl) -phenyl ketone
(R) -1- (3,4-difluorophenyl) ethyla
1.24 g of min hydrochloride, 3.27 m of triethylamine
1, titanium tetrachloride 0.56 ml, boro cyanide hydride
Performed using 1.13 g of sodium and 0.37 ml of acetic acid
Reaction was carried out in the same manner as in Example (1a) to give the title compound as a yellow oil.
1.41 g was obtained as a product. NMR spectrum (CDCl_Three) 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-difluoro)
Lphenyl) ethylamino) -phenylmethyl] phenyl
Luamine N-[(3-nitrophenyl) -phenylmethyl] -N-
[(R) -1- (3,4-difluorophenyl) ethyl
[1] amine 1.36 g and nickel chloride hexahydrate 2.02
g and 588 mg of sodium borohydride
The title compound was reacted in the same manner as in Example (1b) to give an orange oil.
1.17 g was obtained as a product. NMR spectrum (CDCl_Three) Δppm: 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) ethylamino)
-Phenylmethyl] phenylamino} -3-cy Clobute
N-1,2-dione 3-[((R) -1- (3,4-difluorophenyl)
Ethylamino) -phenylmethyl] phenylamine
15 g, 4-t-butoxy-3-methoxy-3-cyclo
Using 939 mg of butene-1,2-dione, Example (6)
The reaction was carried out in the same manner as in 6c) to give the isomer of the title compound.
442 mg of (A) as pale yellow foam, isomer (B)
Was obtained as a yellow oil. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-di
Fluorophenyl) ethylamino) -phenylmethyl]
Phenylamino} -3-hydroxy-3-cycl Lobuten
-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
4-difluorophenyl) ethylamino) -phenylmeth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 300 mg of dione isomer (A)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
174 mg of (A) was obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) -phenylmeth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 195 mg of the dione isomer (B)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
152 mg of (B) was obtained as a pale yellow solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1284- {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
Enyl) ethyl] amine 1.0 g of (3-nitrophenyl) -phenyl ketone
(R) -1- (3,5-difluorophenyl) ethyla
1.24 g of min hydrochloride, 3.27 m of triethylamine
1, titanium tetrachloride 0.56 ml, boro cyanide hydride
Performed using 1.13 g of sodium and 0.37 ml of acetic acid
Reaction was carried out in the same manner as in Example (1a) to give the title compound as a yellow oil.
1.51 g was obtained as a product. NMR spectrum (CDCl_Three) 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-difluoro)
Lphenyl) ethylamino) -phenylmethyl] phenyl
Luamine N-[(3-nitrophenyl) -phenylmethyl] -N-
[(R) -1- (3,5-difluorophenyl) ethyl
[1] amine 1.36 g and nickel chloride hexahydrate 2.02
g and 588 mg of sodium borohydride
The reaction was carried out in the same manner as in Example (1b) to give the title compound as a colorless oil
1.25 g was obtained as a solid. NMR spectrum (CDCl_Three) 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) ethylamino)
-Phenylmethyl] phenylamino} -3-cy Clobute
N-1,2-dione 3-[((R) -1- (3,5-difluorophenyl)
Ethylamino) -phenylmethyl] phenylamine
25 g, 4-t-butoxy-3-methoxy-3-cyclo
Example (6) was prepared using 1.02 g of butene-1,2-dione.
The reaction was carried out in the same manner as in 6c) to give the isomer of the title compound.
733 mg of (A) as pale yellow foam, isomer (B)
To give 715 mg as a pale yellow foam. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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-di
Fluorophenyl) ethylamino) -phenylmethyl]
Phenylamino} -3-hydroxy-3-cycl Lobuten
-1,2-dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (3,
5-difluorophenyl) ethylamino) -phenylmeth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 325 mg of the dione isomer (A)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
251 mg of (A) was obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) -phenylmeth
Tyl] phenylamino} -3-cyclobutene-1,2-
Example (63) using 353 mg of the dione isomer (B)
Perform reaction and purification in the same manner as in b) to give the isomer of the title compound.
158 mg of (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1293- {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) meth
3.68 g of tanone and (R) -1- (1-naphthyl) ethyl
2.57 g of triamine and 8.36 ml of triethylamine
Same as Example (1a) using 2.47 ml of titanium tetrachloride
The reaction was carried out in the same manner to obtain an imine compound. The obtained imine
3.77 g of the compound and sodium cyanoborohydride,
Reaction was performed in the same manner as in Example (1a) using 3.86 ml of acetic acid.
To give 5.41 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl_Three) 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) ethylamido
No) Methyl] phenylamine N-[[(4-fluorophenyl)-(3-nitrophen
Nyl) -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 Example (1b) using
To give 4.46 g of the title compound as a pale yellow oil.
Was. NMR spectrum (CDCl_Three) Δppm: 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
h s), 7.83-7.95 (2H, m).(129c) 3-t-butoxy-4- {3-[(4-f
Fluorophenyl)-((R) -1- (naphthalene-1-
Yl) ethylamino) methyl] phenylamino ｝ -3-
Cyclobutene-1,2-dione 3-[(4-fluorophenyl)-((R) -1- (na
Phthalen-1-yl) ethylamino) methyl] phenyl
Amine 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 Example (66c) to give the title
0.62 g of the compound isomer (A) as a white foamy solid,
0.20 g of isomer (B) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-fluorophenyl)-
((R) -1- (naphthalen-1-yl) ethylamido
No) Methyl] phenylamino} -4-hydroxy -3-
Cyclobutene-1,2-dione hydrochloride 3-t-butoxy-4- {3-[(4-fluorophenyl
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
0.61 g of isomer (A) of -1,2-dione, triflu
Reaction was carried out in the same manner as in Example (63b) using 4 ml of oloacetic acid.
To give the isomer (A) of the title compound as a white solid in 28
5 mg were obtained. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
0.19 g of isomer (B) of -1,2-dione, triflu
Reaction was carried out in the same manner as in Example (63b) using 2 ml of acetic acid.
To give the hydrochloride of the isomer (B) of the title compound as a white solid.
147 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1303- {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
Taren-1-yl) ethyl] amine (4-chlorophenyl)-(3-nitrophenyl) meta
3.93 g of non- (R) -1- (1-naphthyl) ethyl
2.57 g of amine, 8.36 ml of triethylamine and
Same as Example (1a) using 2.47 ml of titanium chloride
To give an imine compound. The resulting iminization
Compound and sodium borohydride 3.77 g, vinegar
The reaction was performed in the same manner as in Example (1a) using 3.86 ml of the acid.
This gave 5.42 g of the title compound as a yellow oil.
Was. NMR spectrum (CDCl_Three) 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-chlorophenyl)-((R)
-1- (Naphthalen-1-yl) ethylamino) methyl
Ru] phenylamine N-[[(4-chlorophenyl)-(3-nitrophenyl
Ru) methyl] -N-[(R) -1- (naphthalene-1-
Yl) ethyl] amine 5.38 g, nickel chloride hexahydrate
6.15 g of product and 1.98 g of sodium borohydride
Then, the reaction was carried out in the same manner as in Example (1b), followed by separation and purification.
This gave 4.30 g of the title compound as a pale yellow oil. NMR spectrum (CDCl_Three) Δppm: 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-k
Lorophenyl)-((R) -1- (naphthalene-1-i)
Ru) ethylamino) methyl] phenylamino -3-
Clobutene-1,2-dione 3-[(4-chlorophenyl)-((R) -1- (naph
Taren-1-yl) ethylamino) methyl] phenyla
4.29 g of min, 4-t-butoxy-3-methoxy-3
Using 2.45 g of cyclobutene-1,2-dione,
The reaction was performed and purified in the same manner as in Example (66c).
1.49 g of the isomer (A) as a white foamy solid
1.81 g of the product (B) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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)_Three) Δppm: 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-chlorophenyi
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
0.80 g of isomer (A) of -1,2-dione, triflu
Reaction was performed in the same manner as in Example (63b) using 5 ml of acetic acid.
To give the isomer (A) of the title compound as a white solid in 47
0 mg was obtained. Isomer (A) NMR spectrum (DMSO-d₆) 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-chlorophenyi)
)-((R) -1- (naphthalen-1-yl) ethyl
Amino) methyl] phenylamino} -3-cyclobutene
0.68 g of isomer (B) of -1,2-dione, triflu
Reaction was performed in the same manner as in Example (63b) using 5 ml of acetic acid
To give the hydrochloride of the isomer (B) of the title compound as a white solid.
477 mg were obtained as a body. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1313- (3-{(4-fluorophenyl)-[(R) -1
-Phenylethylamino] methyl @ phenylamino)-
4-hydroxy-3-cyclobutene-1,2-dione
(Exemplary Compound No. 2-5) (131a) N-[(4-fluorophenyl)-(3-
Nitrophenyl) methyl] -N-[(R) -1-phenyl
Ruethyl] amine (4-fluorophenyl)-(3-nitrophenyl) meth
3.00 g of tanone and (R) -1-phenylethylamine
1.85 ml, triethylamine 6.78 ml and tetrachloride
The same procedure as in Example (1a) was carried out using 2.02 ml of titanium.
The reaction was performed to obtain an imine compound. The resulting imine compound
And sodium cyanoborohydride 3.08 g, acetic acid
The reaction was carried out in the same manner as in Example (1a) using 1.05 ml.
This gave 3.93 g of the title compound as a yellow oil. NMR spectrum (CDCl_Three) 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] methyldiphenyl
Luamine N-[(4-fluorophenyl)-(3-nitrophenyl
L) methyl] -N-[(R) -1-phenylethyl]
3.90 g of min, 5.29 g of nickel chloride hexahydrate, water
Example (59) using 1.68 g of sodium borohydride
The reaction was carried out in the same manner as in b), followed by separation and purification.
Compound (A) as a colorless oily substance (1.24 g, title compound)
848 mg of the product isomer (B) was obtained as a colorless oily substance.
Was. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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-f
Fluorophenyl)-[(R) -1-phenylethylamido
No] methyl @ phenylamino) -3-cyclobut Ten
1,2-dione 3-{(4-fluorophenyl)-[(R) -1-fe
Nyl-ethylamino] methyl diphenylamine isomer
(A) 1.24 g, 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 Example (1c) to give the title compound.
1.22 g of an isomer (A) was obtained as a white foamy solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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-fe
Nylethylamino] methyl diphenylamine 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 Example (1c) to give the title compound.
There was obtained 1.03 g of an isomer (B) as a white foamy solid. Isomer (B) NMR spectrum (CDCl_Three) Δppm: 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-fluorophenyl)-
[(R) -1-phenylethylamino] methyldiphenyl
Ruamino) -4-hydroxy-3-cyclobute -1
2-dione 3-t-butoxy-4- (3-{(4-fluorophenyl
-)-[(R) -1-phenylethylamino] methyl}
Phenylamino) -3-cyclobutene-1,2-dione
Isomer (A) 830 mg and trifluoroacetic acid 4 ml
The reaction was carried out in the same manner as in Example (63b) to give the title
610 mg of the compound isomer (A) was obtained as a pale green solid.
Was. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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}
Phenylamino) -3-cyclobutene-1,2-dione
Isomer (B) 618 mg and trifluoroacetic acid 3 ml
And reacted in the same manner as in Example (62b).
484 mg of the compound isomer (B) was obtained as a white solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 1.60 (3H, d, J
= 5.9Hz), 4.14 (1H, br), 5.09 (1H, s), 6.95 (1H, d, J =
7.8Hz), 7.23-7.63 (11H, m), 7.70 (1H, s). Melting point: 209 ° C (dec) Optical rotation [α] D = -20.5 (c = 1.00, DM
SO). Example 1323- (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) methanone4.
23 g and (R) -1- (3,4-difluorophenyl)
As in Example 117 using 3.39 g of ethylamine
The product was reacted and purified to give 20% of the 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). Example 1333-hydroxy-4- {3-[((R) -1- (1-na
Phthyl) ethylamino) -phenylmethyl] phenyla
Mino} -3-cyclobutene-1,2-dione (exemplified compound
(Article number 2-3161) (133a) N-[(R) -1- (1-naphthyl) ethyl
] -N-[(3-nitrophenyl) -phenylmethyl]
Amine (Exemplary Compound No. 2-) 1.0 g of (3-nitrophenyl) -phenyl ketone
(R) -1- (1-naphthyl) ethylamine 1.09
g, triethylamine 2.68 ml, titanium tetrachloride 0.
56 ml, sodium cyanoborohydride 1.13
g, acetic acid 0.37 ml, as in Example (1a)
The reaction was carried out to give 1.63 g of the title compound as a yellow oil.
Obtained. NMR spectrum (CDCl_Three) 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- (1-naphthyl) d
Tylamino) -phenylmethyl] phenylamine N-[(R) -1- (1-naphthyl) ethyl] -N-
[(3-Nitrophenyl) -phenylmethyl] amine
56 g, nickel chloride hexahydrate 2.23 g and hydrogenation
Example (1b) using 650 mg of sodium boron
The reaction was carried out in the same manner to give the title compound as a yellow oil.
35 g were obtained. NMR spectrum (CDCl_Three) Δppm: 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- (1-naphthyl) ethylamino) -phenylmethyl
Ru] phenylamino} -3-cyclobutene-1 , 2-di
on 3-[((R) -1- (1-naphthyl) ethylamino)
-Phenylmethyl] phenylamine 1.28 g, 4-t
-Butoxy-3-methoxy-3-cyclobutene-1,2
-Using 1.0 g of dione, the reaction was carried out in the same manner as in Example (66c).
After purification, the isomer (A) of the title compound was converted to a yellow foam.
680 mg as isomer, isomer (B) as pale yellow foam
670 mg were obtained. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) Δppm: 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- (1-naphthyl) ethylamino) -phenylmethyl
Ru] phenylamino} -3-cyclobutene-1, 2-di
On hydrochloride 3-t-butoxy-4- {3-[((R) -1- (1-
Naphthyl) -ethylamino) -phenyl-methyl] -fu
Enylamino} -3-cyclobutene-1,2-dione
Same as Example (63b) using 400 mg of isomer (A)
Reaction and purification were carried out in the same manner to give the isomer (A) of the title compound.
315 mg were obtained as a yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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- (1-
Naphthyl) ethylamino) -phenylmethyl] phenyl
Isomers of amino｝ -3-cyclobutene-1,2-dione
(B) Similar to Example (63b), using 240 mg
And purified to give the isomer (B) of the title compound as a white solid.
195 mg was obtained. Isomer (B) NMR spectrum (DMSO-d₆) 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). Example 1343-hydroxy-4- {3-[((R) -1- (1-na
Phenyl) ethylamino)-(p-tolyl) methyl]
Nilamino} -3-cyclobutene-1,2-dione (eg
Compound No. 2-3164) (134a) N-[(R) -1- (1-naphthyl) ethyl
] -N-[(3-nitrophenyl)-(p-tolyl) meth
[Tyl] 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
0.55 ml, sodium cyanoborohydride 1.1
Same as Example (1a) using 0 g and 0.36 ml of acetic acid
To give 1.60 of the title compound as a yellow oil.
g was obtained. NMR spectrum (CDCl_Three) 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- (1-naphthyl) d
Tylamino)-(p-tolyl) methyl] phenylamine N-[(R) -1- (1-naphthyl) ethyl] -N-
[(3-nitrophenyl)-(p-tolyl) methyl] amido
1.51 g of nickel chloride, 2.08 g of nickel chloride hexahydrate and
Example (1) using 607 mg of sodium borohydride
The reaction was carried out in the same manner as in b) to give the title compound as a yellow oil.
1.40 g was obtained. NMR spectrum (CDCl_Three) Δppm: 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- (1-naphthyl) ethylamino)-(p-tri
Ru) methyl] phenylamino} -3-cyclobutene-
1,2-dione 3-[((R) -1- (1-naphthyl) ethylamino)
-(P-tolyl) methyl] phenylamine 1.40 g,
4-t-butoxy-3-methoxy-3-cyclobutene-
Using 1.06 g of 1,2-dione, Example (66c)
The reaction is carried out and purified in the same manner to give the isomer (A) of the title compound.
As a yellow foam, 780 mg, isomer (B) as yellow foam
790 mg were obtained as a solid. Isomer (A) NMR spectrum (CDCl_Three) Δppm: 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_Three) 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- (1-naphthyl) ethylamino)-(p-tolyl)
Methyl] phenylamino} -3-cyclobutene-1,2
-Dione hydrochloride 3-t-butoxy-4- {3-[((R) -1- (1-
Naphthyl) ethylamino)-(p-tolyl) methyl]-
Phenylamino} -3-cyclobutene-1,2-dione
Example (63b) using 400 mg of isomer (A) of
In the same manner, the reaction and purification were performed to obtain the isomer (A) of the title compound.
343 mg were obtained as a pale yellow solid. Isomer (A) NMR spectrum (DMSO-d₆) Δppm: 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- (1-
Naphthyl) ethylamino)-(p-tolyl) methyl]
Enylamino} -3-cyclobutene-1,2-dione
Same as Example (63b) using 300 mg of isomer (B)
Reaction and purification in the same manner to convert the isomer (B) of the title compound to yellow
218 mg were obtained as a color solid. Isomer (B) NMR spectrum (DMSO-d₆) Δppm: 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). Example 1353-hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino) phenylmethyl
Ru] phenylamino} -3-cyclobutene-1,2-di
ON (Exemplified Compound No. 2-3508) 3-nitrobenzophenone and (R) -1- (2,3-di
Example 55 using (fluorophenyl) ethylamine
When the reaction and purification are performed in the same manner, the title compound is obtained. Example 1363-hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(p-tri
Ru) methyl] phenylamino} -3-cyclobutene-
1,2-dione (Exemplary compound number 2-351) (3-nitrophenyl)-(p-tolyl) methanone
(R) -1- (2,3-difluorophenyl) ethyla
When the reaction and purification were carried out in the same manner as in Example 55 using
The title compound is obtained. Example 1373-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) meth
Tanone and (R) -1- (2,3-difluorophenyl)
The reaction and purification were performed in the same manner as in Example 55 using ethylamine.
This gives the title compound. Example 1383-hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(4-chloro
Phenyl) methyl] phenylamino} -3-cyclobute
N-1,2-dione (Exemplified Compound No. 2-3510) (3-nitrophenyl)-(4-chlorophenyl) meta
Non and (R) -1- (2,3-difluorophenyl)
Reaction and purification were carried out in the same manner as in Example 55 using tylamine.
The title compound is obtained. Example 1393-hydroxy-4- {3-[((R) -1- (2,3
-Difluorophenyl) ethylamino)-(4-methoxy)
[Ciphenyl) methyl] phenylamino} -3-cyclobu
Ten-1,2-dione (Exemplary Compound No. 2-3512) (3-nitrophenyl)-(4-methoxyphenyl) meth
Tanone and (R) -1- (2,3-difluorophenyl)
The reaction and purification were performed in the same manner as in Example 55 using ethylamine.
This gives the title compound. Test Example 1 Bile using cells expressing human ileal bile acid transporter
Measurement of sap acid transporter inhibitory activity 1) Human ileal bile acid transporter cDNA of animal cells
Human ileal bile acid transport introduced into expression vector
(Hereinafter referred to as hIBAT) cDNA (GenBank accession
 number U10417) from a human kidney-derived cDNA library (commercial
Product name: Marathon-Ready^TMFrom Clontech) as a mold and PC
Amplified using the R method. Sense oligonucleotide for PCR
5'-aacgttgcttaactcaaccagc-3 '(hI
Corresponds to 512-533 sequence of BAT cDNA: SEQ ID NO:
1) as an antisense oligonucleotide primer
5'-ctcgtctgttttgtccacttga-3 '(1649-1 of hIBAT cDNA)
Corresponding to 670 sequences: SEQ ID NO: 2) in the sequence listing was used. PCR
After agarose gel electrophoresis of the reaction product, it corresponds to 1159 bases
Collect the desired cDNA from a single band and use it for animal cell expression.
(Eukaryotic TA cloning)
kit, manufactured by Invitrogen). 2) Construction of human ileal-type bile acid transporter-expressing cells The hIBAT expression vector obtained in 1) was derived from human colon cancer
Cell line: Caco-2 cells (ATCC # HTB-37)
Product name: Lipofectamine Plus, manufactured by Gibco BRL)
And transfected with the antibiotic G418 (trade name:
Geneticin, GibcoBRL) and treat the cells with G418 resistance
A stable expression cell of the target vector having the following was obtained. 3) Measurement of bile acid transporter inhibitory activity Collagen-coated 96-well culture plate (trade name: BI
4 × 10 in each well of
^Four / Ml of hIBAT-expressing Caco-2 cells
After culturing, the medium was appropriately changed for 7 days and cultured. For main culture system
After adding the sample (the compound of Example 2), 1.0 μCi
Radioactive taurocholic acid ([^ThreeH] -taurocholic acid:
NEN) and add 5% CO_Two At 37 ° C in the presence of
Incubate for an hour, then radiate the radioactive taurocholate
Cells were taken up by bile acid transporters.
After incubation, the cells were ice-cold 0.2% bovine serum
Albumin (bovine serum albumin), 1 mM non-radiated
PBS containing phosphate taurocholic acid (phosphate buffered s
aline) 5 times, then leave overnight to dry the plate
I let it. 250 μl per well of a 96-well plate
Liquid scintillation cocktail (Product name: Microscint2
0, manufactured by Packard Co., Ltd.)
Topcount (Packard Inc.)
) Was measured for radioactivity. Without test compound
Radioactivity of control and test compound at constant concentration
Calculated inhibition rate (%) from radioactivity when using
To inhibit type bile acid transporter activity by 50%
The concentration of the compound was determined. Table 7 shows the results. Following results
Therefore, the compound of the present invention is an excellent ileal bile acid transporter.
Exhibited a protein inhibitory activity.

[Table 7] Example Compound No.IC ₅₀ (μg / ml) 2 (isomer B) 5.5 . Test Example 2 Measurement of Bile Acid Transporter Inhibitory Activity Male Syrian golden hamster was used for the experiment.
Animals were housed in metal cages with free access to food and water. The test drug was orally administered (100 mg / 10 ml / kg) as a suspension in 0.5% carboxymethylcellulose. Administration 1.5
After hours, [ ³ H] -taurocholic acid (1 μC
i) was administered orally. ^[3 H] - oral administration 24 of taurocholate
After an hour, the hamster is dissected, gallbladder bile is collected,
Radioactivity in gallbladder bile was determined. The inhibition rate (%) was determined from the radioactivity of the control, which was obtained without using the test compound, and the radioactivity when the test compound was used at a certain concentration. Inhibition rate (%) = 100− (radioactivity when test compound was used) / radioactivity of control × 100 The results are shown in Table 8. From the following results, the compound of the present invention showed excellent ileal bile acid transporter inhibitory activity.

[Table 8] Example compound number Inhibition rate (%) 2 (Isomer B) 61.87 64e 80.0 . Formulation Example 1 Tablet Compound of Example 2 10 mg Lactose 68.5 Crystalline cellulose 20 Carboxymethyl starch Sodium 5 Light silicic anhydride 0.5 Magnesium stearate 1 105 mg

The compound having the general formula (I) of the present invention is useful as an ileal bile acid transporter inhibitor.

[Sequence List] SEQUENCE LISTING <110> Sankyo Co., Ltd. <120> Cyclobutene Derivatives <130> 2000071SC <140> <141> <150> JP HEI11-207169 <151> 1999-07-22 <160> 2 < 170> PatentIn Ver. 2.0 <210> 1 <211> 22 <212> DNA <213> Homo Sapiens <400> 1 aacgttgctt aactcaacca gc 22 <210> 2 <211> 22 <212> DNA <213> Homo Sapiens <400 > 2 ctcgtctgtt ttgtccactt ga 22

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/167 A61K 31/167 31/197 31/197 31/255 31/255 31/341 31/341 31 / 381 31/381 31/4045 31/4045 31/4402 31/4402 31/4406 31/4406 31/4409 31/4409 A61P 1/16 A61P 1/16 3/06 3/06 9/10 9/10 101 101 43/00 111 43/00 111 C07C 233/22 C07C 233/22 233/80 233/80 251/48 251/48 309/14 309/14 C07D 209/14 C07D 209/14 213/30 213/30 213 / 32 213/32 213/38 213/38 307/52 307/52 333/20 333/20 333/36 333/36 333/58 333/58 (72) Inventor Keita Kono 1-chome Hiromachi, Shinagawa-ku, Tokyo No. 2-58 Sankyo Co., Ltd. (72) Inventor Ken Kitayama 2-58 Hiromachi, Shinagawa-ku, Tokyo 2-58 Sankyo Co., Ltd.

Claims (41)

[Claims] 1. A compound of 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] Represents an aryl group substituted with 1 to 5 substituents, or a heterocyclic group substituted 1 to 5 with a group selected from substituent groups a and b, wherein R ² is a cycloalkyl group, an aryl group, 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 each represents a hydrogen atom or a substituent group; a represents a group selected from a, and A represents the following 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. ), A dashed line indicates a double bond, D indicates a carbon atom, E indicates a group having ＮN—O—, and a dashed line indicates a single bond. E represents an oxygen atom, a sulfur atom, a group having -NH- or-
A group having CO— is shown. ], A pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, 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 <substituent group b> a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group, Di-lower alkylcarbamoyl group, nitro group, cycloalkyl group, aryl group, aryloxy group, aralkyloxy group, arylthio group, and substituent group a
A cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio group substituted by 1 to 3 groups selected from 2. The method according to claim 1, wherein the general formula (I) is represented by the general formula (Ia) or (Ib): Or a pharmacologically acceptable salt thereof, an ester or other derivative thereof. 3. The compound according to claim 1, wherein the compound of the formula (I) is the formula (Ia), a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 4. The compound according to claim 1, wherein Z is a single bond or a C ₁ -C ₂ alkylene group.
Pharmacologically acceptable salts thereof, esters or other derivatives thereof. 5. The compound according to claim 1, wherein Z is a single bond or a methylene group, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 6. The compound according to claim 1, wherein Z is a single bond, a pharmacologically acceptable salt thereof,
Esters or other derivatives thereof. 7. The compound according to claim 1, wherein R ⁵ is a hydrogen atom or a lower alkyl group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 8. The compound according to claim 1, wherein R ⁵ is a hydrogen atom or a methyl group, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 9. The compound according to claim 1, wherein R ⁵ is a hydrogen atom, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 10. The compound according to claim 1, wherein R ⁶ is a hydroxy group or an amine residue, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 11. The compound according to claim 1, wherein R ⁶ is a hydroxy group, a hydroxyamino group or an amino group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 12. The compound according to claim 1, wherein R ⁶ is a hydroxy group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 13. The compound according to claim 1, wherein X and Y are oxygen atoms, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 14. The compound according to claim 1, wherein D is a group having CH or a nitrogen atom, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 15. The compound according to any one of claims 1 to 13, wherein D is a group having CH, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 16. The compound according to any one of claims 1 to 15, wherein E is a group having an oxygen atom, a sulfur atom or —NH—, a pharmaceutically acceptable salt thereof, an ester thereof or Other derivatives. 17. The compound according to any one of claims 1 to 15, wherein E is a group having —NH—, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 18. The compound 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. Salts, esters or other derivatives thereof. 19. 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 (the substituent is a hydroxy group, An oxo group, an aryl group or an aryl group substituted by 1 to 3 groups selected from the substituent group a)), a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 20. The compound according to any one of claims 1 to 17, wherein G is a C ₁ -C ₆ alkylene group, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 21. The compound according to any one of claims 1 to 17, wherein G is a C ₁ -C ₄ alkylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 22. The compound according to any one of claims 1 to 17, wherein G is a methylene, methylmethylene or ethylmethylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 23. The compound according to any one of claims 1 to 17, wherein G is a methylmethylene group, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 24. The method according to claim 1, wherein R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, or a group selected from a substituent group a and b. A compound which is an aryl group substituted by one or a heterocyclic group substituted by 1 to 3 groups selected from substituent groups a and b, a pharmacologically acceptable salt thereof, an ester thereof and other derivatives. 25. The method according to any one of claims 1 to 23, wherein R ¹ is an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, a substituent group a and an aryl group substituted by 1 to 3 groups with a group selected from b, or a 5- to 6-membered aryl group which may be condensed with a benzene ring and substituted by 1 to 3 groups with a group selected from substituent groups a and b Compounds that are aromatic heterocyclic groups, pharmacologically acceptable salts thereof, esters or other derivatives thereof. 26. The compound according to any one of claims 1 to 23, wherein R ¹ is an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or 1-3. A 5- or 6-membered aromatic heterocyclic group which may be condensed with a substituted aryl group or a benzene ring (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 and a group selected from substituent group a). And pharmacologically acceptable salts thereof, esters and other derivatives thereof. 27. The method according to claim 1, wherein R ¹ is an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, 5 or 6 which may be condensed with an individually substituted aryl group or a benzene ring
Membered aromatic heterocyclic 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, a nitro group, a cycloalkyl group, an aryl group, an aryloxy group and an arylthio group Or a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 28. The method according to claim 1, wherein R ¹ is a C ₆ -C ₁₀ aryl group, thienyl group, furyl group, pyrrolyl group, thiazolyl group, oxazolyl group, imidazolyl group, Pyridyl group, condensed with benzene ring, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,
An imidazolyl or pyridyl group, or a 1 to 3 substituted C ₆ -C ₁₀ aryl group (the substituent comprises a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group) Or a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 29. The method according to any one of claims 1 to 23, wherein R ¹ is phenyl, 1-naphthyl, 2-naphthyl,
Fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-hydroxyphenyl, 4-hydroxy Phenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
Compounds which are 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4,5-trifluorophenyl, thienyl or pyridyl groups, pharmacologically acceptable salts thereof, esters or other derivatives thereof. 30. The method according to claim 1, wherein R ¹ is phenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, , 4-Dichlorophenyl, 3,5-
Compounds which are dichlorophenyl, 2-thienyl or 4-pyridyl group, pharmacologically acceptable salts thereof, esters or other derivatives thereof. 31. The method according to any one of claims 1 to 30, wherein R ² is substituted by 1 to 3 R ² with a group selected from a cycloalkyl group, an aryl group, a heterocyclic group and a substituent group a. 1 to 3 of the substituted aryl group or a group selected from the substituent group a.
A compound which is a monosubstituted heterocyclic group, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 32. The method according to any one of claims 1 to 30, wherein R ² is an aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or 1-3. 5 or 6 which may be condensed with an individually substituted aryl group or a benzene ring
A compound which is a membered aromatic heterocyclic group (the substituent is a group selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group); Salts, esters or other derivatives thereof. 33. The method according to any one of claims 1 to 30, wherein R ² is an aryl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group,
A thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or pyridyl group condensed with a pyridyl group or a benzene ring, or a substituted aryl group (the substituent may be a halogen atom, a hydroxy group, a lower alkyl group, a halogeno group, A lower alkyl group or a lower alkoxy group), a pharmaceutically acceptable salt thereof,
Esters or other derivatives thereof. 34. The method according to any one of claims 1 to 30, wherein R ² is a C ₆ -C ₁₀ aryl group, a 2-thienyl group,
A compound which is a pyridyl group or a single-substituted C ₆ -C ₁₀ 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); Pharmacologically acceptable salts,
Esters or other derivatives thereof. 35. The method according to any one of claims 1 to 30, wherein R ² is a phenyl group or a single-substituted phenyl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group). A lower alkyl group or a lower alkoxy group), a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 36. The compound according to any one of claims 1 to 30, wherein R ² is a phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 4-methoxyphenyl group, Pharmacologically acceptable salts, esters or other derivatives thereof. 37. The method according to any one of claims 1 to 36, wherein R ³ and R ⁴ are the same or different and each is hydrogen, hydroxy, halogen, lower alkoxy, amino or di-. Compounds that are lower alkylamino groups, pharmacologically acceptable salts thereof, esters or other derivatives thereof. 38. The compound according to any one of claims 1 to 36, wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, a hydroxy group or a lower alkoxy group, or a pharmaceutically acceptable compound thereof. Salts, esters or other derivatives thereof. 39. The compound according to any one of claims 1 to 36, wherein R ³ and R ⁴ are a hydrogen atom, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 40. The compound according to claim 1, wherein the compound is one selected from the following, a pharmacologically acceptable salt thereof, an ester thereof, and other derivatives. 3- (3-{(4-fluorophenyl)-[1-phenylethylamino] methyl} phenylamino) -4-hydroxy-3-cyclobutene-1,2-dione, 3- (3-{(4-chlorophenyl) )-[1-Phenylethylamino] -methyl {phenylamino) -4-hydroxy-3-cyclobutene-1,2-dione, 3-hydroxy-4- (3-{(4-methoxyphenyl)-[1- Phenylethylamino] methyl {phenylamino) -3-cyclobutene-1,2-dione, 3-hydroxy-4- {3-[(4-methoxyphenyl)-(1- (naphthalen-1-yl) ethylamino)
Methyl] phenylamino} -3-cyclobutene-1,2
-Dione, 4- {3-[(1- (3-fluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, 3- (3-{( 4-fluorophenyl)-[1- (3-
Fluorophenyl) -ethylamino] methyl @ phenylamino) -4-hydroxy-3-cyclobutene-1,2
-Dione, 4- {3-[(4-chlorophenyl)-(1- (3-fluorophenyl) ethylamino) methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione, 3- { 3-[[1- (3-fluorophenyl) ethylamino]-(4-methoxyphenyl) methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2-
Dione, 4- {3-[(1- (3,4-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3
-Hydroxy-3-cyclobutene-1,2-dione, 3- {3-[[1- (3,4-difluorophenyl) ethylamino]-(4-fluorophenyl) methyl] phenylamino} -4-hydroxy- 3-cyclobutene-
1,2-dione, 4- {3-[(4-chlorophenyl)-(1- (3,4
-Difluorophenyl) ethylamino) 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, 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-
1,2-dione, 4- {3-[(4-chlorophenyl)-(1- (3,5
-Difluorophenyl) ethylamino) methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,
2-dione, 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-
1,2-dione, 4- {3-[(1- (3,5-difluorophenyl) ethylamino) -phenylmethyl] phenylamino} -3
-Hydroxy-3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, 3-amino-4- [3-((4-fluorophenyl)-
(1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1-phenylethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3- (4-pyridyl- (1-phenylethylamino) methyl) phenylamino]- 3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3-fluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-fluorophenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, 3-amino-4- [3- (4-methoxyphenyl- (1
-(3,4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3- (4-pyridyl- (1- (3,
4-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3- (phenyl- (1- (3,5-
Difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-fluorophenyl)-
(1- (3,5-difluorophenyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-
Dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,5-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1- (4-pyridyl) ethylamino) methyl) phenylamino] -3-cyclobutene-1,2-dione, 3-amino-4- [3-((4-methoxyphenyl)-
(1- (3,4-difluorophenyl) ethylamino)
Methyl) phenylamino] -3-cyclobutene-1,2
-Dione, 3- {3-[(4-chlorophenyl)-(1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -4-hydroxy-3-cyclobutene-1,2-dione, 3- Hydroxy-4- {3-[(1- (1-naphthyl)
Ethylamino) -phenylmethyl] phenylamino}-
3-cyclobutene-1,2-dione, 3- {3-[(4-fluorophenyl)-(1- (naphthalen-1-yl) ethylamino) methyl] phenylamino} -4-hydroxy-3-cyclobutene- 1,2-
Dione, 3-hydroxy-4- {3-[(1- (1-naphthyl)
Ethylamino)-(p-tolyl) methyl] phenylamino} -3-cyclobutene-1,2-dione, 3- (3-{[1- (3-fluorophenyl) ethylamino]-(p-tolyl) methyl {Phenylamino) -4
-Hydroxy-3-cyclobutene-1,2-dione, 3- (3-{[1- (3,4-difluorophenylamino) ethylamino]-(p-tolyl) methyl} phenylamino) -4-hydroxy- 3-cyclobutene-1,2
-Dione, and 4- {3- [1- (3,5-difluorophenyl) ethylamino]-(4-methylphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene-1,2-dione. 41. A pharmaceutical composition comprising the compound according to any one of claims 1 to 40, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof as an active ingredient.